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Supplements Revealed
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SUPPLEMENTS REVEALED
SUPPLEMENTS BUYER GUIDE
PART ONE: THE EXPERTS

TABLE OF CONTENTS
Ann Shippy 1
Anna Cabala 2
Ben Cote 3
Ben Greenfield 4
Bryan Haycock 5
Buck Rizvi 6
Cameron George 7
Carli Stein 8
Chandler George 9
Chris Shade 10
Edward Group 11
Eric & Sabrina Zielinski 12
Evan DeMarco 13
Grace Liu 14
Greg Horn 15
Harris B. Williams Jr. 16
James Lavalle 17
Jane Barlow-Christensen 18
Jason Sonners 19
Jayson Calton 20
John Hewlett 21
Jonathan Hunsacker 22
Jonathan Lizotte 23
Kellyann Petrucci 24
Kiran Krishnan 25
Loren Israelsen 26
SUPPLEMENTS REVEALED
SUPPLEMENTS BUYER GUIDE
Michelle Norris 27
Mira Calton 28
TABLE OF CONTENTS
Patrick Sullivan Jr. 29
Robert Craven 30
Steven Gundry 31
Terry Wahls 32
Tim Skwiat 33
Tina Anderson 34
Tom Aarts 35
Trevor Cates 36
Trina Felber 37
Tyler Lebaron 38
Warren Phillips 39
Will Stowe 40
PART TWO: THE RESEARCH

Research Guide 41
Table of Contents 42
Research Compilation 66-446
Links to companies and supplements mentioned in this

guide are available in your online member's portal, and
on the Supplements Revealed blog.
2019-2020 REVEALED FILMS, INC. ALL RIGHTS RESERVED

1
Dr. Ann Shippy

Meet Ann:
Ann is a Functional Medicine Physician in Texas. She was originally a Chemical Engineer and worked for
IBM for 10 years.
Things changed when she got sick, and the 8-9 doctors she went to seeking answers could not help her.
She started researching her condition on the internet and seeking help from practitioners like
nutritionists, naturopaths, and acupuncturists. Through diet and supplements, she finally figured out
how to get herself well.
Functional Medicine helps her to offer her patients what she wishes had been available to her. She can
offer them the most holistic way possible to get better.
She feels that her MD gives her credibility and a strong foundation, and that allopathic medicine has an
important role in healthcare. After getting her MD, she practiced in allopathic medicine for several
years, and ended up getting sick again with auto-immune disorders.
At that point she went back and got her Functional Medicine degree. She says it “gets up back to the
biochemistry and physiology and looks at the person as a whole - you know, what’s going on in your gut
can affect your brain, your skin, you know the whole rest of your body. So we look at the system as a
whole.”
Ann’s Recommendations:
Supplements she uses include modified citrus pectin, clay, charcoal, magnesium glycinate, liposomal
glutathione, glycine.
For brain she recommends phosphatidylcholine which helps to build healthy cell membranes and
receptors.
There is a form of CoQ10 that she recommends for mitochondrial health called MitoQ.
She likes nicotinamide diribacide for brain health.
She shares that NAD and milk thistle also help detoxify.
Ann’s Recommended Supplement Brands:
Thorne, Xymogen, Designs for Health, Premier Research, Research Nutritionals, Quicksilver. B. complex.
Metalloclear is a supplement that supports phase one of
detoxification.
2
Dr. Anna Cabeca
Meet Anna:
Anna Cabeca is an MD, OB-GYN. She is also trained in integrative and regenerative medicine. She
specializes in transitional hormonal stages such as menopause. “Menopause is mandatory, but suffering
is optional.”
As to HRT, “It takes more than hormones to fix our hormones.” Prescriptions only patch the problems
without addressing the symptoms.
Most women experience a hormonal transition phase between 35-45 with irregular cycles, mood issues,
bloating, PMS, anxiety, and other symptoms. It is a phase of hormonal and neurological vulnerability.
This is due to a decline of progesterone.
Allopathic doctors tend to put women on birth control pills and antidepressants, and often perform
endometrial ablation and hysterectomy at this time. These women are still experiencing irritability, brain
fog, loss of libido, and memory issues. She now treats this with more natural options and went from 2-3
surgeries a week to 2-3 a year. Nutrition and lifestyle play a role as well as supplements.
Nutrition and lifestyle play a role as well as supplements. She likes to start patients on a modified
elimination diet with no whites, no bread, no sweets, and no red meat. She recommends intermittent
fasting and restricting carbs.
Women in the transition stage benefit greatly from the keto diet and being in a state of ketosis. The
hormonal drop of progesterone and estrogen inhibits women’s ability to fuel their brains with glucose,
so ketosis greatly improves this. This improves energy and decreases symptoms. In just 10 days, they see
a 50% reduction in symptoms.
Sleep is also key - “Anti-aging at its finest.”
She promotes good quality omega 3 and essential fatty acids like DHA and EPA. Our diets tend to be very
deficient in these. It is important to get a good brand, because in the past some have had heavy metal
and mercury content.
Anna’s Recommendations:
She promotes magnesium and D3 paired with K2. Melatonin for sleep. Vitex and chasteberry for gyn
complaints. Vitamin C, methylated B vitamins, milk thistle. Transdermal bioidentical progesterone. Men
should up magnesium, arganine, and zinc.
Ann’s Recommended Supplement Brands:
MegaMaca is her proprietary supplement for sexual health, hormone support, adrenal adaptogens,
menopausal support, magnesium, anti-inflammatory, and general nutritional supplementation.
3
Ben Cote
Meet Ben:
Ben is the director of Brand & Connectivity at Neurohacker Collective. He was drawn to the organization
for their integrity and the brilliance of their science.
“Healthy, happy people make better decisions.” We have a lot of problems, and we need people
operating at their best to solve those problems.
Pharmaceuticals just target one symptom, or one specific part of one system. This leads to the
unwanted side effects that these are known for. “Our approach is to look at how the entire system
functions, understand that it’s regulated well before you were sick or before you were unhealthy. We
want to get you back to that state, and not just to that state of regulating well, but to a state where
you’re regulating better at a higher capacity, upregulate your system so that you are working at a higher
resilience.”
Qualia was one of his first nootropic products at Neurohacker. It works the first time you take it -
“You’re feeling the focus, energy and drive immediately… it wipes out that feeling of overwhelm when
you have too much stuff to do and you don’t know how or where to get started on anything.” It gets
better the longer you use it. The emotional resilience piece kicks in at about the 3-month point. “The
longer you take it, the better it gets, and the longer you take it, the less you need of it.”
“Nootropics are just ingredients that can upgrade or improve cognitive performance.” They support and
improve higher processes of brain.
Their products are blends, and their labels list all components and amounts. “We want you to know
exactly what you’re putting in your body and exactly how much.” They looked at all the research behind
ingredients before including them. They whittled down a lot of ingredients to settle on 42. They also
looked at how well the ingredients worked together and chose them for synergy.
Most nootropics have fewer ingredients, but that limits what aspect of cognition they address. The long
list of ingredients in their products is to address the whole brain and the whole person, not just aspects.
“There’s no point in having a ton of energy if you don’t have the focus to drive it.”
Ben’s Recommendations:
Ben’s focus is on Nootropics. Eternis targets cellular function and mitochondrial health.
Recommended brands:
Neurohacker produces Eternis (for better aging) Qualia (for mental performance), Qualia Nootropic
Energy (energy + mental performance), and Qualia Focus (support for mental focus).
4
Ben Greenfield
Meet Ben:
Ben is a Fitness and Nutrition expert. He takes a lot of supplements, makes supplements, and helps
companies design supplements. He has been immersed in the supplement culture for a long time.
He studied exercise physiology and biomechanics at the University of Idaho, and was also interested in
nutrition and biochemistry. Much of his work centers around making customized supplement
recommendations based upon his knowledge.
He is also a competitive athlete. Athletes and physically athletic people can benefit greatly from
supplements.
But what about the average person who is not as physically active? Their need for nutrients is not as
great as an athlete’s is. He says that there are still some important considerations that need to be in
place to take care of the body. For example, many people are deficient in magnesium and potassium
because our soil is so depleted. Organic food can help with this, but it is a gap many people need to fill.
We also have pollutants, toxins, and heavy metals in our environment that require a detoxification
supplement. “So maybe in addition to the blueberries and our salad, consuming a whole-spectrum
antioxidant on the days… things that support an antioxidant response would be smart for someone.”
Supplements are as old as society itself, and people used to always make them. “Nowadays we can go to
Amazon… similar to how our ancestors would have done going out and plant foraging.”
“People who aren’t eating organic, well-composted, mineral rich produce from really good soil, those
are people who might benefit from multivitamins and minerals. People who are up against a sickness or
an illness, your kids came home from school and there’s a flu going around, those are people who might
benefit from supplementation with immune support. And then people who are simply living a post
industrial lifestyle, right, you’re not living on a pristine Himalayan mountaintop, and your body has a lot
of inflammation and oxidation that occurs.”
Ben’s Recommendations:
Creatine - not just for athletes, it also serves as a good nootropic. A quality multi-vitamin and mineral
complex. Fish oil, fatty oil, or para-essential oil supplementation. A bitter such as bitter melon to
enhance digestion and enhance insulin response. Vitamin D and magnesium for people testing low on
these. CBD or hemp for sleep.
Recommended Brands:
Kion, Thorne, and TianChi.

5
Bryan Haycock
Meet Bryan:
Bryan is an Exercise Physiologist. His interest in supplements goes back to his college days. He read a lot
of studies, and created substantiation portfolios for supplement manufacturers. He says that for every
claim a manufacturer makes, they need to find 2 double-blind placebo-controlled studies to
substantiate. There are low barriers to entry into the supplement market. Anyone willing to
bankroll a supplement can put one on the market.
“One of the biggest misconceptions about the dietary supplement industry is that it is not regulated…
that’s the groupthink, that’s the public notion.” It is not regulated by the FDA as pharmaceuticals are,
but falls under FTC and other regulators.
Country of origin is important to consider. China used to be automatically suspect but has improved. It
has felt the impact of its bad reputation and is working to overcome this. Manufacturers and consumers
are pressuring them to step up. India has also improved for similar reasons. These two countries are the
largest suppliers for ingredients in supplements.
“That is because of economies of scale, right, they can produce tremendous amounts of these materials
for pennies on the dollar compared to Europe or the United States.”
There are prescription fish oils that are no different than over-the-counter and are even from the same
supply sources. “The prescription will legally say ‘lowers your triglycerides’ and the dietary supplement
says ‘supports heart health.’” But the pharmaceutical companies try to dissuade people from buying the
supplement version.
A current trend is the microbiome, referring to all the DNA that you carry and host that is not your own.
“We’ve realized that the microbiome is a fundamental component of human health.” Our microbiomes
are getting more damaged over time. Food sensitivities are evidence of this. “The microbiome has lost
its ability to regulate inflammatory reactions and sensitivities in our gut that normally not be bothered
by gluten of any kind. It’s not that gluten has become bad for people, it’s that peoples’ microbiome has
become dysbiotic.”
Published science can also become very political. “There’s a lot of bias in medical publishing, and it’s not
perfect.” Sometimes a study is a hit job and fueled by an agenda. The media also does not dig deep into
the research, and only gets the tagline that the researcher wants associated with the study.
“At the simplest level, buy products that you can trust.”
Bryan’s Recommendations/Recommended brands:

No specific recommendations - he just encourages consumers to look at research behind products, sourcing, third-
party quality standards, and finding a company that they can trust.
6
Buck Rizvi
Meet Buck:
Buck is the founder and CEO of RealDose Nutrition. He has 21 years of marketing and sales experience in
the high-tech industry. He became fascinated with dietary supplements and nutrition, especially in the
area of anti-aging and life extension.
The first product he developed was for digestive health, and capitalized on recent focus on gut health.
There are unethical players in this market, and consumers should look for signs of quality and purity of
products.
Leaky gut and high permeability of the gut can lead to inflammation and autoimmune problems.
“Disease really starts in the gut, in the digestive tract… So, I decided that this was something we wanted
to focus on, help people understand that this is a problem.” Thus, they focus on the supplement and
lifestyle education.
Many probiotics on the market do not survive the acid that is in the stomach. Good probiotics can
provide digestive comfort, healing of the lining of the digestive tract, and help with weight loss. These
products must be enteric coated and contain enough of the probiotics to have the desired effect.
RealDose Nutrition’s tagline is “the right ingredients at the real dose.” Buck says, “The mission really is
to address the shenanigans that I mentioned that have been going on in the dietary supplement space
where people are making health claims that have not been substantiated.”
While some online marketing is bad, there is a good side. “There is, for companies like a RealDose
Nutrition, an opportunity to educate, to tell a story, not be so much focused on sexy packaging, but to
help the consumer make a wise decision.” Other brands are doing the same, and he sees that as a
“bright spot.”
He recommends that we read supplement ingredients like we read nutrition labels on food and look for
branded ingredients.
Buck’s Recommendations:
High-quality buffered vitamin C to avoid digestive discomfort. Omega 3s, Vitamin D. RightBiotics Rx
probiotic. Rhodiola, an adaptogen. Svetol Green Coffee extract.
Brand Recommendations:
RealDose Nutrition
7
Cameron George
Meet Cameron:
The cofounder of Kavaplex, Cemeron considers Dr. Dan Pompa his mentor. After being very athletic and
active, in his late teens he developed chronic fatigue, depression, anxiety, and nervous system
disturbances. He was under a lot of stress and wasn’t really taking care of his health.
He was put on Adderall and other psychotropics. He says it was a disaster and accelerated his
deterioration. He ended up in full blown psychosis and all his problems were worse. He also developed
autoimmune problems.
At this point he’d been labeled with many different autoimmune diseases - Crohn’s, lupus, MS
etc. Anticonvulsant drugs like xanax and klonopin are narcotics, and he was on very high doses just to
keep convulsions at bay. His goal was to get off the drugs, and Dr. Pompa helped him to gradually
stabilize.
“So I was looking for plant compounds that weren’t addictive and weren’t toxic, that could actually give
a similar crutch-like effect, but without all the side effects and toxicity.”
He came across kava as a substitute for benzodiazepines. It grows in the South Pacific in places like Fiji,
Tonga, Vanuatu, etc. The root of the plant is used. It is deemed very sacred and is a social pillar of many
island cultures.
He was familiar with supplement versions of kava that were underwhelming and weak. Experts told him
that the supplement is just a weak extract, and that the real deal is the kava root drink as prepared in
South Pacific cultures.
He started experimenting with different strains of actual kava and noticed a substantial difference. It
elicits a reverse tolerance and has cumulative effects as it builds up. After a couple of weeks, he had a
substantial reduction of symptoms, and after a couple of months he was getting better results than he
had gotten with medications and began to taper off of them.
In 2 years, he was a new person. In 3 years, he was truly able to fully function again - at the 4 year point
he is now working with the doctors who helped him through his problems.
Cameron’s Recommendations:
His focus is kava for adaptogenic wellness. Not all kava is created equal, so you need to make sure it’s as
close to the natural complex as possible.
Kavaplex is Cameron’s proprietary blend.

8
Carli Stein
Meet Carli:
Founder & CEO of Beekeeper’s Naturals, Carli has an autoimmune condition that does not allow her to
take antibiotics. Any illness has always been an ordeal, and she started searching in the natural health
world for a viable alternative.
In college, she was in Italy and got strep throat. A pharmacist gave her propolis, and this was her first
introduction to bee products. It worked, so she began beekeeping for her own needs and further
researching benefits.
The medicinal use of bee propolis goes back to at least 300 BC. “We’ve been using propolis long before
the advent of modern medicine. If you look at how propolis works in the body, it’s antiviral,
antimicrobial, antifungal, and antibacterial. So, it is a really great alternative to more chemical based
solutions that we use to heal.”
“Propolis is - you can think of it as the immune system of the hive.” Bees line the hive and cell walls with
it and give it to newborn baby bees. If a predator gets in the hive, they sting and kill it, then mummify it
in propolis because they can’t carry the body out. It is powerful enough to keep them safe from the
decay of a dead predator.
Bees do so much more than honey. Honey is their energy source - it’s their carbs. It’s very high in
antioxidants, is antiviral, and is high in live enzymes.
“Royal jelly is the food of the queen bee… for humans, it’s been used anecdotally across cultures for so
many things, from anti-aging benefits to hormonal balance, but in terms of concrete studies we’ve seen
a big focus on the effects of royal jelly on the brain.” It’s high in acetylcholine and improves brain-body
messaging. It has fatty acids that act as catalysts for neurogenesis.
Her first steps in this business were learning to bee keep and work with the products that come from
the hive. Her company wishes to hold itself to the highest standards and validate the medical claims that
they make. They work with a third party chem team to help build the best products and submit to third
party pesticide testing.
Carli’s Recommendations:
Bee products such as propolis for antimicrobial, royal jelly "brain shots", bee pollen for anti-
inflammatory, energy, endurance, vitamins and protein.
Recommended Brands:
Beekeeper's Naturals
9
Chandler George
Meet Chandler:
Chandler is a Chiropractor and owner of Ageless Energy Health. He used to do anti-aging health spas,
but “Better than looking good is being healthy on the inside.”
His focus is MCT and mushrooms. These mushrooms originate in China, and he used to go to Chinatown
to buy them. He always associated it with acupuncture. While still grown and sourced in China, they are
processed and packaged in the US.
“People are looking for hacks in their life, and I think the mushroom was the next evolution.” Medicinal
mushrooms have been trending up in interest “because it’s affordable… it’s in abundant supply.” People
need to be more educated about it, just like they needed to better understand chiropractic. He believes
that mushrooms will go mainstream in 2-3 years.
There are about 10 different types of medicinal mushrooms - he features 6 in his product. “Medicinal
mushrooms… are geared more towards energy, or heart function, or cognition. They have certain
properties that do certain things that we know of from the research primarily by the Chinese.” Chinese
medical doctors still use mushrooms for many purposes.
Mushrooms tend to regulate hormones, especially at midlife, and balances out mood swings. “I think
that’s life changing right there in and of itself.”
More testing is needed to prove all the data points, “but I think we’re getting to that point.” The
changes and benefits are subtle and build up in the system. People often notice a strong difference after
21 days.
He has an MCT oil powder popular among people who like to work out, and keto and paleo dieters. “The
reason I’m excited about the medium chain triglycerides is because it gives brain food. I’m after baby
boomers and our brains to do better.” It replaces the sugars you get from carbs without the belly fat. It
gives you something stronger to run your brain on.
The results of MCT powder? “Fullness, less hunger. You’re not necessarily sharper, but your brain
doesn’t fatigue as fast.”
Chandler’s Recommendations:
Medicinal Mushrooms for energy, heart function, and cognition. MCT oil, and MCT powder.
Ageless Energy Health

10
Chris Shade
Meet Chris:
Chris Shade is the founder of Quicksilver Scientific. He was an environmental scientist and lost his
respect for science’s ability to help people. “I realized that a lot of environmental science was just
pretending to clean up pollution.” He wanted to do something more impactful and went into organic
and regenerative farming.
He also studied environmental toxicology, especially involving mercury. He shifted to developing

supplements for metals detoxification without using synthetic chelators.
He himself had mercury toxicity. This, in part, led him to develop a glutathione system as opposed to
chemical chelators that are harsher. “I needed to get glutathione into the body so that I could mop up all
this mercury with glutathione.”
Toxicity is a problem opposite of deficiency, and most consumers think of supplements in terms of
deficiency. Excesses, “distort your natural vitality. They’re holding down energy generation in the
thyroid, and the adrenals, and the mitochondria. Or they’re distorting your neurotransmitters, distorting
your hormones. They’re keeping you away from your optimal.”
Glutathione as a pill is not bioavailable because the stomach breaks it down. This led to the use of
liposomes and nanoparticles. The supplement is dissolved in small liposome capsules. Absorption of the
supplement begins in the mouth and is mostly done in the upper GI. They pass through the mucosa and
to the bloodstream before the stomach can destroy them.
These kinds of products need to be tested and proven for stability, and any consumer wishing to take
glutathione should look into what kind of testing their supplement is subjected to.
A big focus is detoxification. But “because we got so good at the deliveries, we’re expanding into all
these other areas of wellness where the delivery is a really crucial part of really getting the dream out of
the supplement.”
With this in mind, CBD will be one of the next products that Quicksilver launches with enhanced
bioavailability. Other herbs and compounds will be blended with it to enhance the entourage effect.
Chris’s Recommendations:
Liposomal glutathione as detox for heavy metal and other toxins. He is also a fan of CBD for balancing
hormones, neurotransmitters, immune response, and neuroinflammation. He recommends CBD in a
nanoemulsion, not an oil.
Quicksilver Scientific products.

11
Dr. Edward Group

Meet Edward:
Edward has a traditional medical background, and was always taught that natural medicine was
‘witchcraft’ and bunk, and that pharmaceuticals were the way to go. A lot of his early career was spent
dealing with patients’ cancer.
He met a researcher who was looking into treatments that would help cancer patients, and he joined
the research team. They also wanted to determine the root cause of the disease. The answer was “poor
lifestyle, poor environment, toxic food air and water, the accumulation of chemicals and toxins in the
system, with the accumulation of stress, unhappiness, anger, fear… not only did we find the root cause
of cancer, but we found the root cause of all negative health problems.”
When you know the root cause of disease, you can work backwards. The most successful natural doctors
are detoxifying and cleansing patients first.
Most chemicals and toxins enter the body via the gut, although there are other means. The steps are
cleansing and healing the gut, then the liver, then cleanse out fungus, yeast, parasites, etc. then detox
heavy metals and chemicals. Then comes the supplementation.
“Education is a big part of the healing process.” The patient must be educated about this protocol as it is
undertaken. They “let people know the power of cleansing their body and the power of healing that
they have within. Because everybody has a self-healing mechanism, it’s just suppressed.”
“That’s really what supplementation is all about - allowing you to become in charge of your own body
and allowing the body to heal itself.”
Talk to supplement companies and ask about how they farm and harvest. Look for the most pure, toxin-
free, and safely processed products available.
Edward’s Recommendations:
Dr. Group prioritizes liver and GI cleanse and detox, heavy metals detox, and antimicrobial detox. In
general, he recommends that consumers choose supplements that are non-GMO, organic, sustainable,
even quantum farmed. Probably the best multivitamin is juicing organic produce.
Global Healing Center proprietary supplements.

12
Dr. Eric and Sabrina Zielinski
Meet Eric and Sabrina:
A husband and wife team, Eric and Sabrina are co-authors of The Essential Oils Diet.
Sabrina started using orange and peppermint oils to help her children’s fevers come down. They have
often been able to lessen the duration and severity of illness by using oils. She also gave each kid an oil
massage to help with sleep.
Eric resisted oils at first as too “perfumy” and not manly. He was a medical writer, and someone
commissioned him to write some articles about oils, and that is when he dug in deeper. He realized that
the use of oils was evidence based.
Eric says, “Medicine, chemists, just don't invent chemical structures out into the air to come up with
drugs. They get this, the plant structures, from essential oils.” Essential oils are well metabolized by the
body. Tests have shown that oils are taken in, distributed throughout the body, then completely
metabolized relatively quickly.
They talked about weight loss and their book. “Research has shown inhaling grapefruit and inhaling lime
triggers the brain to produce what's known as lipolysis, just to burn fat cells.” Essential oils also tighten
and tone and help eliminate cellulite. “So when it comes to anti-aging, throw away the Botox. Let's get
out the essential oils.”
Personally, Dr. Z has also used oils for depression, anxiety, and panic attacks. "Nothing can stop a panic
attack like essential oils.” The best are citrus related: bergamot, neruli. “I would challenge anyone
watching right now to go into their kitchen, get an orange, a lime, a grapefruit, whatever you have and
just cut it and just smell it. That's the healing power of essential oils.”
Oils can be diffused, taken in capsules, and rubbed on with a carrier oil.
Eric and Sabrina’s Recommendations:
“Flu shot”: vitamin C, coconut oil, Himalayan salt, and clove, eucalyptus, lemon, orange, and rosemary.
Anti-inflammatory oils: citrus, chamomile, lavender, and peppermint.
For allergies: peppermint, lavender, lemon, tea tree.
For pain: clary sage
For weight loss: grapefruit and inhaling lime weight loss
For anxiety and depression: citrus related: bergamot, neruli
Eric and Sabrina’s Website: www.naturallivingfamily.com

13
Evan DeMarco
Meet Evan:
Evan is a nutrition expert and the director of market development at KD Pharma Group, the largest
manufacturer of prescription grade omega three products in the world.
His career had varied from writer to investment banker, prior to this line of work. His next step was
sports nutrition, because he had always been athletic and loved baseball and other sports. He went back
to college to study chemistry to better prepare him for product development. The combination of
studying and working in this field gave him a passion for quality product development.
“I got to understand the potential of dietary supplements if they’re done right. I also got to see all the
harm that comes from not doing it right.”
Most big brands of fish oil are 1812 oil that has not been further refined to remove the undesirable
elements. While this is not bad in and of itself, our diets already tend to have too many of the
undesirable fats. These unrefined fish oils may actually be exacerbating inflammatory conditions.
“The hard challenge for us to educate the consumer that if you see 1000mg of fish oil, it might only have
300mg of Omega 3s.” Consumers should look for info on the label and read and choose carefully.
His company sends the 1812 oil to a manufacturer in Germany that has 5 different extraction
technologies. No harsh chemicals are used. A clean, pure omega 3 is what’s left.
His company is involved heavily in CBD as well. “Hemp is one of the oldest medicinal compounds on the
planet.” It used to be grown on every farm, but was displaced by the cotton industry. Extraction of CBD
oil is much the same as the process for fish oil.
Evan’s Recommendations:
Omega 3s, fish oil, EPA, DHA. CBD is also good for anxiety, sleep, and weight.
KD Pharma Group. He also recommends that consumers shop for supplements on iHerb.com, an online
retailer that vets all the companies that sell on their platform.
14
Grace Liu
Meet Grace:
Grace holds a PHARMD and AFMCP. Founder of the Gut Institute, she is a Functional Medicine
Practitioner, with a history as a pharmacist. She reacted badly to a dental implant, a vaccine, an IUD, and
antibiotics. What helped her the most was focusing on gut health and getting her microbiome better.
In her quest to get herself better again, she converted over to functional medicine.
There are trillions of cells in the gut, as many as there are in the body. “They’re our other half… Just feed
them, and they give us everything that we need: serotonin and all our good neurotransmitters for
happiness, as well as longevity chemicals, anticancer chemicals… that keep us happy, healthy, and
whole.”
This is the first generation in which kids are not expected to live as long as their parents or
grandparents. “A lot of it… is linked to antibiotics.”
First, we are killing off the microbiome of the animals we eat. Kids even test positive for veterinary
antibiotics. “Studies show now the use of antibiotics will lead to obesity later.” Antibiotics make animals
fat for slaughter, and we are getting fat too.
The microbiome affects hormones in males. More and more men under 40 are not experiencing normal
sexual function. They are tired, achy, unhappy, depressed, agitated, and anxious. Treating the gut and
eliminating endotoxins often yields dramatic and speedy results. In men who had low testosterone, free
testosterone will triple and full testosterone will double.
She makes a good probiotic to increase microbiome diversity, and there are other good ones on the
market. There are practical tips people can keep in mind when selecting a probiotic.
“It’s always great to look at third-party testing - that there’s as much potency in the bottle as what’s
stated.” Also, it is good to talk to an integrated and functional health practitioner about choices. “We
kinda know which ones work.” They’ve seen them work on very complex cases and know what will give
good results for the average person.
“If it’s a good probiotic, then it will engraft. Engraftment means that it is actually sticking in the system
and producing.” If people are feeling better, it is probably engrafting.
Grace’s Recommendations:
Probiotics with a high fiber diet to create the optimal prebiotic environment. She suggests that
consumers cycle different brands of probiotics. She likes bee propolis spray to lower bad oral pathogens.
Her brand is Bifimaximus, but she also recommends Equilibrium, Megaspore, and TerraFlora.
15
Greg Horn
Meet Greg:
Greg develops supplements and has worked in the wellness industry for many years. He is the CEO of
Specialty Nutrition Consulting.
He credits the book Sugar Blues that he read when he was 15 for sparking his interest in health and
nutrition. His career started with GNC and was there for 11 years. He did research, development and
marketing, and eventually was the CEO.
Next, he went to Garden of Life, a natural and organic supplement and nutrition company. At this time,
he developed a medical condition called chemical sensitivity that transformed his view of natural health
and forced him to adopt a much more natural lifestyle.
His passion is to bridge the gap between what is proven in the lab in terms of health benefits to a
product that the consumer can purchase. “We sift through a lot of garbage to get to the rubies.”
When buying supplements, “the lower the price you’re paying, the more they’ve optimized for cost on
that product.” Treating or trying to avoid deficiencies and looking at RDA is a valid approach. They are
not therapeutic or proactive doses, but they do help you avoid a deficiency.
Gut health is an experiential problem that people want to get corrected right away. He believes in a
whole gut approach that includes prebiotics.
Fermentation of vitamins and supplements put them is a more absorbable form. The body may perceive
them to be more like food.
Heart health - mitochondria are the energy generators in the cells, and they require CoQ10. A new long-
term study was just published that showed a dramatic reduction (40%) in cardiac events when taking
CoQ10 and selenium.
“I’m deeply passionate about this intersection between nutrition and health and outcomes for people…
you can’t do that without putting it into a brand that they’re going to be attracted to and buy and try.”
Greg’s Recommendations:
Take prebiotics to encourage a healthy gut microbiome. Fermented supplements are more absorbed by
the body. CoQ10 with selenium are recommended for heart and mitochondrial health.
Specialty Nutrition Consulting brand.

16
Harris B. Williams Jr.
Meet Harris:
Harris is the co-founder of Univera. He’s been involved in fitness and natural products for nearly 40
years.
He was looking for a company with plant based and science-based products “where you could take the
best of science and nature to humankind.”
He found a company that worked with aloe vera and genomics. “Genomics is really looking at anything
at the DNA level.” They looked for supplements to repair damage and upregulate the body’s repair
mechanisms - to address aging. They test plants at the DNA level to see if they are going to be boosting
repair. “That’s what we’re looking for - plants that will upregulate repair in the DNA, and push down on
the damage.”
The impact is substantive enough to make a difference. “You see it in the thousands of people now who
have been using the products for 20 years.”
Aloe vera has one of the biggest impacts on DNA repair. It has been used for thousands of years and
even goes back to Alexander the Great, and was taken into battle for wound treatment. His company
has done the most aloe vera research on the planet. 80% of our immune system is in our stomach. Most
reflux and bowel problems are because we have destroyed the immune system in our stomach.
Aloe vera helps with collagen production, healing effects, immune boost, and is good for the gut.
They are also working on products to address inflammation naturally. Aloe vera is a large molecule and
has to be processed correctly. They grow and process to allow it to get through the gut and be absorbed
and used by the body. Their delivery system enhances absorption 300%. Most commercial aloe products
are watered down.
New research includes bamboo, “Which really helps increasing circulation.”
He is a cancer survivor, and his doctors are amazed at his health. He is still athletic and active well into
middle age. “65% or aging is lifestyle choices, 35% is genetic.”
Drink it so that you heal from within. Absorbable aloe shows up as results for skin, joints, nails and hair,
gut, and pulls out glyphosates.
Harris’s Recommendations:
Aloe vera products for gut health, immune benefits, healing, collagen production, and as an anti-
inflammatory.
Univera
17
James Lavalle
Meet James:
James Lavalle (RPh, CCN) is an integrative medicine expert. The foundation of the pharmacy school he
went to was rooted in natural therapies and botanical extractions.
He wrote 4 databases about natural therapies, herb-drug interactions, drug induced nutrient depletions,
as well education for physicians and healthcare professionals about supplements and natural therapies.
The nutritional supplement world faces two challenges - the idea that it makes expensive urine, and the
overblown “it can fix everything” claims. “And the truth is somewhere in between.”
He is now directing a clinic at the NFL Hall of Fame village for retired athletes. The goal is to not just help
people recover, but to feel their best. “The harder an athlete trains, the more stress they put on their
body… that means that they need to eat right, but the reality you may not be able to get all the
nutrients that you need from your diet… you can do that with the use of dietary supplements.”
Most average people want to feel better, but the first problem that needs to be addressed is diet, then
exercise and sleep. “We got to get some lifestyle guidance into an individual to help them make better
choices so it gives their body the ability to heal, and the ability to maximize their performance.”
“Everybody needs to take a multivitamin, probiotic, fish oil, and vitamin D. And by the time you get to
that, you start to get weary on how many things you’re going to take...it’s really important to pick things
that are going to change someone’s life. They need to feel better, and you can get that with natural
therapies.”
The way you breathe is important. He teaches a simple box breathing technique: inhale of a 4 count,
hold on a 4 count, exhale on a 4 count, hold another 4 count. “Do that 3 to 4 minutes a couple times a
day and it can have an unbelievable effect on your nervous system.”
Most people are deficient in magnesium. There are lots of magnesium supplements to consider, and you
have to think of absorption. Magnesium glycinate is one of the most absorbable. Magnesium taurate is
an amino acid combo that has added cardiovascular benefits. Magnesium malate is really good for the
muscles. Magnesium citrate can give diarrhea and is recommended to avoid. A good magnesium will
make people feel better.
James’s Recommendations:
AlphaGPC for neuroprotective, athletic response time, and dementia. He also says you should take
curcumin, a multivitamin, a probiotic, fish oil, and vitamin D.
He is a proponent of adaptogens such as ashwagandha, relora, ginseng, rhodiola, theanine, holy basil.
Magnesium glycinate or taurate are important. A good multivitamin and mineral with amino acid
chelated minerals is a good idea.
18
Jane Barlow-Christenson
Meet Jane:
Jane is a Master Herbalist and owner of Barlow Herbal. Her dad was a botanist, and she grew up around
all things plants.
She and Patrick toured her plant curing room where lomatium wild harvest is drying. Everything is done
by hand, even the harvest, in order to protect the environment…plants are collected from where they
grow naturally, which is called “wildcrafting.”
Lomatium has thick roots (sometimes called black carrots) that have to be chopped up within 24 hours
and then put on drying trays. The shrink to ⅓ of their size when dried. It consolidates and oxidizes. If you
cure it in alcohol, it doesn’t work as well and loses potency.
They can only collect it in the fall. After drying (about 3 weeks), it is then bagged an sent to the
manufacturer. When drying, they can not be touching. They grind it in a hammermill. The manufacturer
tests it for purity and contaminants. Then a tincture is made from cane alcohol, 190 proof.
She is particularly known for lomatium, but that worries her, because there is not enough wild lomatium
for everyone who wants it. But she also works with other herbs, formulations, tinctures, and
formulations.
“The number one thing that is special about this is that everything is done with love...and then the fact
that it actually helps people heal.” Lomatium is anti-microbial: antifungal, viral, yeast, antibiotic. She has
seen success with some tough things like HPV and shingles.
A lot of people use lomatium as a preventative during cold and flu season, “because your body doesn’t
appear to build an immunity to it.” Jane also takes it when she travels. It can work for acute or chronic
infections, or prevention.
This is probably the most powerful herb they make. The herb was used heavily by two local Indian
tribes. This is a mainstay of their business, but they also have anti-candida, parasite cleanse, etc.
Jane’s Recommendations:
Lomatium for anti-microbial: antifungal, viral, yeast, antibiotic. They also have anti-candida, parasite
cleanse, etc.
Brand Recommendation:
Barlow herbal
19
Jason Sonners
Meet Jason:
Jason is a Chiropractor at Core Therapies who makes use of supplementation. He had a

herniated disc and was looking for non-invasive therapies. Even when the worst of symptoms
had responded to chiropractic treatment, he was left with drop foot and lingering pain.
He has also studied kinesiology and nutrition. For his lingering symptoms, he was taking Omega
3s and Omega 6s for inflammation and tissue support, turmeric and resveratrol for
inflammation, and other supplements to feed and support the nervous system.
At a conference in Las Vegas, he has the opportunity to try hyperbaric oxygen and spent a half
an hour in a chamber. His foot felt different right away. The vendor explained that the chamber
was increasing blood flow to the troubled area, so he went in it again a few more times over
the weekend. This gave him about 50% recovery.
“I look at oxygen now as that missing nutrient.”
An insufficient amount of oxygen results in hypoxia. Because of his injury, the area around his
food had become hypoxic, and hyperbaric restored that needed oxygen. Hyperbaric basically
megadoses the nutrient oxygen in acute situations.
It was never his goal to own a vitamin store in his practice, but he found himself frequently
recommending supplements to patients and started stocking his favorites. He carries
supplements from 8 or 9 different companies, picking the best that each has to offer.
The manufacturing process is very important, because this is when a supplement could be
damaged or contaminated. What fillers and lubricants are being used?
The individual’s reaction must also be monitored, because different people will react
differently. A practitioner should monitor it. He also tests to identify deficiencies and helps
patients find foods to supply the nutrient.
Jason’s Recommendations:
He is a big proponent of hyperbaric oxygen therapy and considers oxygen the "missing nutrient". He also
recommends doing bloodwork to test your levels and supplement according to the results.
20
Jayson Calton
Meet Jayson:
Jayson has a PhD in Biomedical Science and Human Nutrition. His main focus earlier in his career was
weight loss, and he worked with a keto style diet back in the 90s. There were studies supporting a high
fat diet for weight loss at that time.
He even tried it himself, and lost weight very quickly, but felt fatigued as a result. He read up on Atkins,
and was determined to find a way to allow people to do keto and feel good. He started towards a plan
that allowed 20% protein.
Clients he put on the diet were experiencing benefits beyond weight loss, “All the clients that would
come to me to lose a few pounds were also coming back and saying, ‘Wow, I’m sleeping better, my
attention is great, I feel so much more energy.’ So I thought, well, this is a big piece of the puzzle.”
The fact that people are using carbs as their fuel source all the time is a major contributor to diabetes,
obesity, and other diseases. “I think there’s some benefit to using fat as the primary fuel source at least
for part of the time.”
The next key that he found was micronutrients. “It only stands to reason that if we are deficient in them,
our bodies would be showing some kind of a disease state or health condition.”
“It’s really about understanding about how to prepare the foods, and that’s one of the things that again
we have learned as we traveled and lived with these indiginous tribes.” Proper preparation will reduce
the rate of micronutrient significantly.
What about green juicing? He suggests cooking them, keeping them in the fridge, and then using them
for juicing. “Also try to use foods that just don’t have high tannin levels.”
He recommends what he calls the nutrivore diet. Most diets out now have scientific evidence showing
that they have actual benefits. What makes any individual feel good is valid for them. “But one thing
that is a universal truth in all nutrition and medicine, and that there is no dispute over, is that you need
to be sufficient in your essential micronutrients, or you will get a health condition or disease.”
Many vitamins and minerals are competitors, and should not be paired in supplements. Separating
competitors increases their benefits. This applies to many health conditions.
Jayson’s Recommendations:
He recommends “nutravore dieting” with a focus on micronutrients. He educates consumers on picking

the best supplements for their needs.
21
John Hewlett
Meet John:
The founder and formulator of Cardio Miracle, John used to work in the financial industry. He had an
appendectomy about 12 years ago and had numerous complications with it, almost costing his life.
He heard about nitric oxide at this time and Nobel Prize winning research that had come from it in 1998.
When he was told he needed a quadruple bypass, he refused because of all the problems he’d had post
appendectomy.
He looked into nitric oxide at the time, met with researchers, and started taking a direct marketing
brand that was available at the time. Within 6 weeks, his health had turned around, and he felt like he’d
found the answer to the genetic heart disease tendency that ran in his family. He left the financial
industry and became an advocate for nitric oxide.
“I met with a practicing endocrinologist... and he had been giving it to his patients, and it had dramatic
impact on their diabetes and their complications of their diabetes, because nitric oxide is the body's
strongest and most effective antioxidant, and even anti inflammatory.”
There are safe and non-pharmaceutical ways to increase your nitric oxide. They are arginine, beet, kale,
citrulline (a watermelon extract). They stimulate the body to produce the nitric oxide. He believes that
every surgery and blood transfusion should include a nitric oxide supplement.
In his opinion, D3 and nitric oxide are two foundational supplements everyone should take.
Their formula has over 40 synergistic ingredients including hawthorn berry, ginseng, astragalus,
selenium, grape seed extract, B vitamins, Vitamins C and E, and a number of antioxidants. Nitric oxide
helps to deliver the efficacy of each of these.
Nitric oxide is related to NAD because both are amino acids. Nitric acid is the body’s regulator. It
improves the conditions of those suffering from chronically degenerative arteries, neuropathy,
osteoporosis, periodontal disease or Alzheimer's, and other chronic illnesses.
John’s Recommendations:
Nitric oxide, turmeric, astaxanthin, arginine, beet, kale, and citrulline.
Cardio Miracles
22
Jonathan Hunsacker
Meet Jonathan:
Jonathan is the founder of Organixx. His early career was internet marketing and working on a project
called The Truth about Cancer. At the time, his personal health was poor. He was overweight, smoking,
and drinking. Facing fatherhood for the first time was his wake-up call.
He started to investigate the role of supplements in his quest to get healthier, and his company decided
to create their own brand.
The cheapest and lowest quality supplement are synthetics, like cheap one a day vitamins. “They're all
made from synthetic ingredients, and so your body does not recognize them. It's not very bioavailable. A
lot of times it passes right through you.”
He explains that dark yellow urine is a sign that supplements are not being absorbed. Whole food
supplements are a better option because they are real foods. Even better is organic whole foods.
The next best supplements would be sprouted or fermented. They are easier for the body to ingest.
Labels can be a little deceptive, because what is listed is often not what your body is able to use. Look
for an organic certifying company like NOFA organic on the label, because this designation is regulated.
Avoid ones that just say “natural” because any supplement can say that.
Tablets are not absorbed as well, even if they do say USDA organic. He recommends capsules or liquid.
He believes that everyone should take a high quality multivitamin. Even people with great diets may not
be getting enough nutrients due to over farming and soil depletion.
He also recommends turmeric and its active ingredient curcumin. This fights inflammation and stress-
related fallout. He recommends fermented turmeric for the bioavailability. Turmeric with piperine is
more bioavailable, but inflames the gut. He says fermented is easier on the gut and the better choice.
He is also a big fan of a clean source of collagen. We make less collagen as we age, and joints start
hurting and skin starts sagging. You also need adequate vitamin G for the collagen to be properly
absorbed.
He also suggests that we face the biggest thing that is holding us back. For him, it was smoking. He
advocate for making the biggest change first. Once he conquered smoking, everything was easier.
Jonathan’s Recommendations:
7M mushroom whole food supplement. Fermented turmeric for optimal absorption. Whole food
multivitamins.
Organixx and Primal Life Organics products.

23
Jonathan Lizotte
Meet Jonathan:
Jonathan is the founder of Designs for Health Inc. He has a background in weight loss and detox using
natural supplements. While he used to be involved in natural health services, he made the switch to
purely nutritional products.
He had a business background, and his wife at the time was a registered dietician, and her passion for
natural health helped to get him started. They were surrounded by a number of like-minded healthcare
practitioners.
Most of their products are marketed and geared towards healthcare practitioners to carry and sell to
patients. Much of this had to do with their connections. He also appreciates that he can get deeper into
the science of the products with this group. They have over 300 products.
With B vitamins, there is no choice but to use some synthetics, but most vitamins have natural choice
options. Folate is often used as the synthetic folic acid. While it does help avoid deficiencies, it could
promote some cancers. The synthetic is much less expensive than the natural form. ($15 per kilo vs.
$10,000 per kilo).
He is currently fascinated by a form of vitamin E, the ‘delta fraction’ (delta tocotrienol), one of the 8
isomers of vitamin E. There has been extensive research this in Denmark, showing a doubling of life
expectancy of stage 4 ovarian cancer patients. No other supplement has shown this kind of therapeutic
potential. Delta tocotrienol is potentially effective for all kinds of cancers. It also helps to stabilize blood
sugar and stimulate weight loss.
His company also offers a quality magnesium and zinc, minerals that are relatively hard to get in the
diet. Both are important to supplement.
He recommends that people work with practitioners who can help them identify and address specific
problems. It is very individualized.
Jonathan’s Recommendations:
Delta tocotrienol, Vitamin E, Zinc, Vitamin D, probiotics, magnesium, and fish oil. Their company has
over 300 products such as blends for joint health, gut health, etc.
Designs for Health, Inc. They have over 300 products such as blends for joint health, gut health, etc.
24
Dr. Kellyann Petrucci
Meet Kellyann:
Kellyann (MS, ND) is the creator of the Bone Broth Diet. She has always gravitated towards health and
wellness, even when she was a teenager. At 15, she started working for Princeton University student
health services. She ended up going to chiropractic school and naturopathic school, and eventually the
Paracelsus Clinic in Switzerland.
Listening and empathy are her keys to really helping patients. “What it really comes down to so much is
the six inches between our ears. That’s what I learned. And I learned that that affects our cellular
matrix… our cells literally communicate and talk to one another. And it’s really important that you get
your cells talking to one another in a really positive manner because your cells can work for you or
against you.”
Everything in life, every action, causes her to think, “How’s this going to affect my cells?” Foods are part
of this - how does each food affect the cellular matrix?
She felt extremely tired at 40 and worked to get to the cause. She started using bone broth, and then
used it on others when she saw the benefit. She noticed it helped people feel better, their skin looked
better, and they lost some weight.
Bone broth is beneficial because people tend to be very demineralized, and bone broth supplements
that as well as protein. “The big wow is the fact that it’s got collagen in there, and collagen is cooked
gelatin.” Gelatin heals the gut.
She is the author of The Bone Broth Diet, and it became a NYT bestseller. It is still holding strong, and
interest in bone broth as a supplement is strong. It is high in nutrition and low in calories.
Bone broth is not canned soups. “You want to look for bone broth that gels.” You also want to make
sure it is organic. “The health of the animal transfers over to you, we know that as an indisputable fact.
So, you want to get really clean food in general. Particularly, your meat products should be clean.”
It is important to make sure that your bone broth has the right kind of salt, “salt can kill you or make you
well.” Look for mineralized salts on the label. Light gray or pink salts are the best, plus no caking agents.
This healthy foundation gives you timeless beauty.
Kellyann’s Recommendations:
Bone broth, organic and free-range. Mineralized salts are best.
The Bone Broth Diet, DKA Lifestyle, and her proprietary Bone Broth products.
25
Kiran Krishnan
Meet Kiran:
Kiran is a research microbiologist. “I was born a supernerd - My superpower is I’m a supernerd who can
talk to humans.” He likes to break down complex ideas to make them understandable, and deconstruct
them to make them practical.
Studies show much more allergies and asthma in children when homes are sterilized. “Their exposure to
microbes actually builds strength in their immune system, built a certain type of knowledge within their
immune system. We kill, kill, kill the bacteria, not understanding that basically 90% of what we are is
bacteria.”
“We really are a collection of organisms. There’s a word for it, it’s called holobiome… The holobiome
means a super-organism. So what we really are is a walking talking rain forest. We are a collection of
mini-ecologies all over our body.”
How did our ancestors get their probiotics - how did it happen in nature? A lot of it comes from the birth
canal at birth. Breastfeeding provides 600-800 species of bacteria. In the first couple of years of life,
closeness to other family members and caregivers continues to pass along seeding bacteria. For the rest
of your life, the bacteria come from the environment. There has got to be bacteria in the environment
that acts as a probiotic.
Kiran works at Microbiome Labs. They started creating products about 5 years ago. They started doing
studies on bacteria and which survived the best when given as supplements. The spore producing
bacteria were the heartiest. “If nature gave them the capabilities of surviving through this really harsh
gauntlet, it means that they’re probably designed and supposed to be doing that.”
Leaky gut sets off a big immune response because of the toxicity in the blood - going up as much as six
times previous levels measured before eating. Proper gut balance is vital to good health.
Kiran’s Recommendations:
Don’t over-sterilize your environment. Fasting is a good idea. Don’t expect probiotics that aren’t spore-
based to make it to your gut.
Megaspore Biotic brand of Probiotic

26
Loren Israelsen
Meet Loren:
Loren is the President of the United Natural Products Alliance. He got involved in the nutrition industry
40 years ago as he was finishing law school. He was offered a job as general council at Nature’s Way. He
believes that he may have been the first general council in the supplement industry in 1981.
“Many people become, we call them medical refugees. They’re looking for answers. They’ll go through
the process very often of, I would say a conventional Western medical experiment.” Western medicine
is very good at dealing with emergencies, but less good at chronic and management issues.
The public has risen up in a huge show of support for the supplement industry. They demanded the right
to be able to choose the supplements that they wanted to use. There were raids, seizures, and
prosecutions going on at the time that threatened the industry.
The FDA was not going to change their opinion, so the industry turned to Congress. They turned to a
congressional caucus, and this became one of the biggest health issues of the 1990s. “It became a
revolution.” Congress was caught by surprise by public involvement and communication pouring in.
The language they chose focused on supplements was “dietary supplement” because it is open ended,
and not claiming to be a medication. They tried to envision 5, 10, 20 years down the road to include
unforeseen changes and trends.
Lawful speech and social media censorship are also an issue. Misleading and defrauding speech is clearly
not allowed - the FTC regulates this, so does the FDA need to be involved? The internet complicated
where these boundaries fall for natural health.
Self-policing is fundamental. Companies must have discipline to give consumers what they are saying
they are getting. He sees it as his duty to get companies that don’t engage in self-policing as much up to
standards. Consumers have a right to know what is really in a product - how do we communicate it in a
quick, easy, understandable way?
Well-regarded certifications include: United States Pharmacopeia (USP), TGA (an Australian Government
Standard), NSF, Organic USDA.
Looking to the future of the industry, he sees CBD as a big issue, and any regulatory changes that may
come about. Synthetic technologies are bringing big changes: AI, Robotics, and Synthetic Biology.
People do have a voice in this country, and it has historically been a powerful thing. Consumers can have
a voice in how these issues play out.
Loren’s Recommendations:
He did not recommend specific supplements, but is a proponent of consumer education, personalized
supplementation based on labs, and the understanding of supplement regulation.
27
Michelle Norris
Meet Michelle:
Michelle is the CEO and Co-Founder of Paleo FX. She used to be a chef and specialized in Italian foods,
especially breads. She was also very sick and experienced fatigue, fibromyalgia and IBS. She was also
diagnosed with early onset rheumatoid arthritis. Her husband encouraged her to look into celiac
disease, and she disregarded it.
Her celiac test came back negative, and the doc wanted to do a biopsy because her symptoms sounded
like celiac to him. She decided to try a paleo diet instead to see if that would help. After a few weeks all
her symptoms were gone. She also started to lose weight and look healthier, and people were really
noticing. Then she realized that she could really help people with her information. One of her first steps
was to start her own blog.
She helped guide people gradually into the diet, removing sugar and gluten first, because it can be a
difficult transition to do all at once.
“I would say paleo is not a diet. Paleo is definitely a lifestyle... And Paleo f(x) is not a diet conference, it's
not diet and nutrition. It's there. There's a piece of it there, but it is a lifestyle conference.
“What we believe is that there are six pillars of health. There's physical health, mental health, emotional
health, relational health, financial health, and spiritual health. And if you don't have all of those, you
can't truly be healthy.” Lifestyle changes need to occur that affect all of these pillars. The paleo diet is a
template for other aspects of the lifestyle.
The paleo diet is based on the way our ancestors ate. Although we can’t mimic it exactly, it takes the
best from that diet and uses some of the technology we have today. The basis is whole foods. We have
too many hyper-palatable engineered and processed Franken-foods. It is junk and does not meet
nutrition needs.
She explains that we are not adapted or evolved to eat the modern diet. She encourages people to quit
looking for quick fixes and magic pills and consider dietary change. A pill is not a fix because it is just
more toxins coming into your body.
While some may at first think paleo is restrictive, she finds it freeing. You know that what you are eating
is nourishing and healthful fuel for the body. It tastes good and makes you feel better.
Michelle’s Recommendations:
The Paleo Diet lifestyle. Eat what our ancestors ate. Avoid processed foods, pay attention to all 6 areas
of health: physical health, mental health, emotional health, relational health, financial health, and
spiritual health.
Paleo FX
28
Mira Calton
Meet Mira:
Mira is the co-owner of Calton Nutrition. She was at one time an over-stressed, under-nourished, fast-
paced workaholic publicist in New York City. She started developing back aches, and blamed it on her
heels, workouts, etc. She ended up doing most of her job while laying on her couch with her laptop.
She was diagnosed with osteoporosis at age 30. She was given a very grim prognosis of being bedridden
for the rest of her life. In addition to medication, calcium was recommended to her, which is what got
her started in supplements. She sold her company, moved in with her sister in Florida, and began to
research. At this point she met Dr. Calton.
After 2 years of treatment by Dr. Calton, her osteoporosis and osteopenia were gone. She has been
losing muscle as well as bone, and muscle was rebuilding. Her pain and disability were gone.
She describes the ABCs of what consumers should know when choosing supplements: “A is absorption.
Certain things hinder absorption such as binders, fillers, excipients. Liquids are more absorbable. Tablets
need to be disintegrate within 20 minutes. B stands for beneficial quantities and forms. There is a
different form for each micronutrient… find a company that’s giving you bioactive forms, macellated
forms, things that are going to make it easier for you to absorb the micronutrients. C is the
micronutrient competition… micronutrients compete for absorption, receptor site, they compete for
formulation space, they degrade each other, and that really, really key. It happens all the time.“
The biggest surprise for her in her current position is how much it still affects her, especially emotionally
as she works with people in tough situations who really are able to get better. Her purpose is “hoping
someone else gets it before they get so sick. Hoping that they get the information.”
She encourages people to do their homework, and wants to support them in their healing journey. You
have to make a personal investment in this - no one can give it to you. “Know that you’re the first
person that has to come to your defense… it is work.”
Mira’s Recommendations:
She is a proponent of bioactive forms of micronutrients. Be aware of the ABC’s she mentions above. Do
your homework, don’t hesitate to call a supplement company and ask where they source their products
etc.
Calton Nutrition.
29
Patrick Sullivan Jr.

Meet Patrick:
Patrick is the Chief Edutainment Officer and Co-founder of Jigsaw Health. He and his father began Jigsaw
Health in 2005. His father had numerous chronic health challenges - GI, low energy, trouble sleeping. He
identified magnesium deficiency as one of his primary problems, and tried various supplements. He
identified a need for a slow-release magnesium in a very absorbable form.
The name Jigsaw health refers to finding the pieces to your own health puzzle. Their top seller is a
timed/sustained release magnesium called MagSRT. It uses cofactors and fibers to slow down the
magnesium in the GI tract. “And that enables the absorption to be so much better, so much more
tolerable on the gut.”
“One of the number one syptoms of magnesium deficiency is tension, leg cramps, back pain, that muscle
tension in the shoulders. Those kinds of things are kind of a dead giveaway for magnesium deficiency.
Also, frequent headaches, low energy, trouble sleeping, those kinds of things are indicative of
magnesium deficiency.”
At least 68% of the population is not getting enough magnesium as defined by RDI. Other doctors
estimate that the number is closer to 80-85%. Many argue that the RDI is way too low anyway.
His dad also discovered that he is a poor methylator. “Poor methylators - they’re bad at turning inactive
B vitamins like cyanocobalamin, which is the inactive form of B12, they’re bad at turning that into
methylcobalamin.” They created a sustained released B vitamin to address this.
“B vitamins are so good for energy. They’re incredibly good for detoxification. And for us, being the
magnesium people, one of our favorite things about B vitamins is how they help to make the
magnesium react.”
Their tagline is “It’s fun to feel good.” That is the passion that drives them. They do this through
Edutainment. One way they do this is a video series they call #FunnyFriday. It is a 2-year long video
series. They may be the only supplement manufacturers in the industry that has a costume budget.
Patrick’s Recommendations:
Most people are deficient in magnesium. Detox is important. Take a methylated form of vitamin B.
magnesium L-Threonate for brain health.
Jigsaw Health
30
Robert U. Craven
Meet Robert:
Robert is the former CEO of MEGA Food. He started in the supplement industry with a small company in
Florida that eventually became Garden of Life. He fell in love with the industry. The industry appealed to
his left and right brain - strategy and packaging as well as “everybody’s a hugger.”
He looks for several things when buying a supplement. One is recommendation. People in a health food
store are more trained about the products than a retailer. Health food stores can help you go deeper in
understanding.
When asked if the rule “you get what you pay for” holds true, he answers, “I think it has to do with the
person, right? So if you can’t afford $25 a month, certainly take a supplement. There’s tons and tons of
science out there that says take a multi, take your omega, take your probiotic, right? But if you find that
if you take a multi at that level and it’s tough on your system, and it hurts your compliance… Everyone
has a different taste level. I think the folks who are looking for premium will pay premium.”
Transparency in the supplement world needs to be driven by the consumer. “If you’re a smart
consumer, you’ll demand transparency.” They actually put live webcams throughout their facility for this
reason.
Mega Foods bought organic produce from partner farmers and process them in their own facility for
inclusion in 130 different products. “Those ingredients would be a combination of just food, or food and
supplements, or a yeast-based mineral. So, the yeast would predigest the minerals and make it easier to
absorb... so we manufactured our own ingredients from the food, then we manufactured our own
supplements from the ingredients.”
What about companies getting ingredients from China? “It has everything to do with the supplier. I met
with our Chinese supplier this morning… we’ve visited China, we audit them, we go deep with them.”
Consumers should look for companies that go out of their way to show the steps they take for quality
and transparency. But there is regulation, and even co-manufacturers are inspected and held to regs.
DSHEA tells them what they can and can’t say about the products.
Iron is a supplement that is greatly needed, especially among women. The problem with it is compliance
because it is hard on the stomach. A food based iron is better tolerated. Vitamin C is another concern.
“We’re not getting our veggies. If you’re not getting your veggies, you’re likely to be Vitamin C
deficient.” Vitamin D is a common deficiency in the US. Omegas are important for brain development,
especially for kids.
Robert’s Recommendations:
He recommends Iron for women. Also, vitamins C and D for all. Get recommendations from health food
stores. Look for food-based supplements.
Mega Food - a line of organic whole food-based supplements.

31
Steven Gundry
Meet Steven:
Steven is a former cardiologist, professor, and author. He describes a patient he calls “Big Ed’ who had
inoperable coronary artery disease. All the arteries were blocked, and he was not a candidate for stents
and bypasses. He traveled the country trying to find a surgeon who would take him, and everyone
turned him down.
Ed had lost some weight and started taking supplements, but Dr. Gundry didn’t think it would make a
difference, he believed the supplements were a waste of time. They did another angiogram, and 50% of
the blockages were cleaned out. Putting the previous angiogram beside it, it looked like two different
patients.
He started looking into the supplements. Some were natural versions of medications cardiologists use
intravenously, and this got him very interested in supplements. He eventually realized that he should be
teaching people how to avoid the heart surgeon, and resigned his position. He has written 4 NYT
bestsellers on heart health, diet, and supplements, including The Plant Paradox and The Longevity
Paradox. After 17 years, he had become successful with his writing and has his own supplement line.
Vitamin D is the first supplement he gets his patients on and is shocked at how many people are low.
About 70% of his practice is now autoimmune disease, and they all have very low vitamin D levels.
Research has also shown that almost all people with cancer have low D, and that D is suppressive of
cancer growth. D also is essential for certain stem cells that grow and divide in the gut.
He also believes that leaky gut is the origin of most of the disease states that he sees.
He discussed MTHFR gene mutation that affects methylation. If you have this gene, you don’t make the
proper methyl folate and methyl B12 because of enzyme deficiencies. A sublingual methyl B12 is good
for most anyone, especially this group. Methyl folate is inexpensive and easy to take.
He believes more research needs to be done on the longevity promoting properties of mushrooms.
They’ve launched a mushroom product called MVitality. Research shows, “humans who eat about 2
cups of mushrooms a week - cooked or raw, and that’s not much - have about a 90% reduction in
Alzheimer’s compared to people who don’t”
94% of our fate is determined by what we eat and the microbiome within us, and that’s actually very
liberating!... we are in control of our fate through our mouth.
Steven’s Recommendations:
He is a proponent vitamin D paired with K2, Omega 3s -primarily DHA, methyl B12 sublingual, plant
polyphenols like resveritrol, mushrooms, and organic fermented green tea.
GundryMD proprietary products.

32
Terry Wahls
Meet Terry:
Terry worked for years as a physician in a university setting in Iowa, and in veteran’s affairs. She was a
typical internal medicine doctor and very skeptical of supplements and complementary medicine. Then
he was diagnosed with MS.
She began with daily injections to blunt the immune response that was causing symptoms. She got
weaker and within 3 years was in a wheelchair.
She went through stages of grief with her illness. She came to acceptance, but still made it a goal to slow
her decline if possible. She went on a paleo diet and began to take supplements. At one point, she got
frustrated and quit all her supplements, but then couldn’t get out of bed the next day and felt worse.
When she resumed them, she felt better immediately. This bolstered her confidence.
She looked into electrostimulation (e-stim) of muscles. It helps maintain muscle mass and improves
quality of life, although wheelchair bound patients cannot walk again. She had it done, and it was very
painful, but helped just a little.
She was still weak, experiencing pain, and wheelchair bound. She was getting regular pain injections.
She was trying to come to terms with the possibility of becoming bedridden, having dementia, and
having constant pain.
Her supplement regimen focuses on B vitamins, CoQ10, rhibos, carnitine, lipoic acid, a variety of
minerals, a variety of fats, sulfur amino acids.
Diet was the one single thing she changed in her life that truly helped her. “I love the paleo diet, but I
have to be clear. The paleo diet did not recover me. Supplements did not recover me. E-stim certainly
helped my mood, and I’m sure accelerated my recovery. There’s some magic about my reimagining my
paleo diet in a very particular way… so the speed of that year was just breathtaking.”
She went from being wheelchair-bound to walking again, and her neurologist had her taper off the MS
medication she was on. Her success was so great that she went on to do studies on her specific diet, and
has helped may with MS return to health.
“Diet and lifestyle are why we become ill. Diet and lifestyle are how we become well.”
Terry’s Recommendations:
For mitochondrial health: B vitamins, CoQ10, folic acid, carnetine, sulpher amino acids, Fish oil/Omega
3s, zinc.
She created a nutritional protocol called Wahl's protocol for healing that focuses on diet.
33
Tim Skwiat
Meet Tim:
Tim is an MEd, Pn2, CSCS, and is the Director of Scientific Affairs at Biotrust. He was always very active in
sports and started lifting weights in High Schools. In college he studied health sciences and exercise
physiology. He started learning about the power of nutrition and supplements and became a
“supplement junkie.”
Over time, he started to mistrust supplements, not knowing where to go with them, and not
recommending them. He finally found a group that had his same philosophy about supplements, i.e.,
that they should just make them so that they knew that the best standards were being met, so he joined
their team. They formed Biotrust nutrition.
Biotrust was very successful very quickly. They put a lot of time and effort into building a company that
really disrupted the industry. They created strong relationships within the health and fitness community,
and created an affiliate network to help market the products. They are dedicated to quality.
He talked about the background work and research needed to create a supplement, choosing the right
ingredients, sourcing, and testing. “You don’t want paint thinner, for example, in your supplement. You
don’t want pesticides, you don’t want heavy metals… here you are thinking you’re putting something
truly beneficial into your body, yet it’s a vehicle for these other potentially toxic things.”
They currently have 17 products. There are two kinds of supplements, supplements that provide
essential nutrients like vitamins, minerals, essential fatty acids, and amino acids. Then there are
supplements with non-essential nutrients, like herbal supplements.
He encourages people to search for functional medicine and naturopathic doctors. They don’t all
practice the same, so don’t be afraid to shop around - look at reviews and consider them.
If you are interested in a product, find their website and research more. Look for third party testing.
Look at whether it is produced in an FDA registered facility. Sometimes they will also have a certificate
of analysis.
Tim’s Recommendations:
He considers some staples to be a protein supplement, a probiotic, digestive enzymes, magnesium,

oregano oil as needed for antimicrobial. For pregnant women: a prenatal, Omega 3s, and probiotic. If
detox is needed: glutathione, PQQ, Restore
He formulates for Biotrust which carries 17 products. Companies he recommends include Thorne,
Jarrow, Now Foods, Quicksilver scientific.
34
Tina Anderson
Meet Tina:
Tina is the CEO and co-founder of Just Thrive Probiotic. She and her husband were originally in the
pharmaceutical industry, and she witnessed firsthand the abuse and push for overprescribing
pharmaceuticals. They developed an interest in preventative health and health maintenance.
“We didn’t want our kids to be on antibiotics all the time… we just knew that there was something we
could focus on that was more in line with natural healing.”
They started studying the importance and impact of gut health. She referred to the microbiome project
and her study of it as key to understanding “the microbiome was really dictating your health, or lack of
health.”
She cautions that lactobacillus and bifidobacter strains do not survive the gut, and that this is what most
store brands are made of. They don’t make it past the acidic gastric barrier and into the intestines
alive. With that in mind, they licensed specific bacillus endospores. “These strains are able to naturally
survive the gastric system… they naturally are organisms that have this shell around themselves, an
endospore shell… that allows it to stay dormant until it gets to the intestines.”
The bacillus endospores they use are a few different strains that are found together in nature and work
synergistically. “So we’re going back to nature. That’s our approach, is to go back to nature. As a result,
we see how effective it is.”
Our ancestors consumed these strains on a daily basis, so a certain amount of probiotic is meant to be a
daily thing. “The world today is wreaking havoc on our guts. We know from the antibiotics, just a single
course of antibiotics, will cause disruption at least a year in our gut flora. Antibiotics in our foods,
glyphosates, GMOs, round up, all that stuff is just wreaking havoc on our guts on a daily basis.” Stress
also harms the gut microbiome.
People taking their product feel better in a couple of weeks, less brain fog, clearer skin, more energy,
and improved mood. Serotonin is produced in a healthy gut. Sleep improves and digestion gets more
regular.
They want to bring products to the market that they feel are missing and needed, including their new
Vitamin K2-7, important for heart health and bone health. It also has magnesium and zinc.
Tina’s Recommendations:
Probiotics made with bacteria that form spores, Vitamin K2-7, prebiotics.
Just Thrive Probiotic. They also have a Vitamin K27 product with magnesium and zinc.
35
Tom Aaarts
Meet Tom:
Tom’s interest in nutrition began with athletics and sports nutrition. He decided to mix his passion for
athletics, business skills, and his interest in nutrition. He is the owner of Nutrition Capital Network.
He started with a newsletter called Nutrition Business Journal. “We became sort of instant experts on
tracking the entire nutrition industry.” They came up with research that industry leaders started to
read. Later he sold the publication and most on to an advisory capacity with industry leaders. He
eventually partnered with some associates to form the Nutrition Capital Network to help companies find
sources of capital in order to grow their businesses.
“The case for supplements is, in my experience, pretty simple. We are not eating the same foods that
we ate years and years ago because the soil is not as good. And if the soil is not as good, the food
nutrients are not as good. So, almost everyone recognizes that the food supply has less nutrients in it”
What companies does he think are really good? He advises to avoid products that are too inexpensive,
as they are probably not effective. He recommends studying labels. Whole food supplements absorb
better. Avoid excipients, binders and fillers. He particularly likes practitioner companies that sell through
health care professionals. Examples of practitioner products are Designs for Health, Metagenics, and
OrthoMolecular. They have higher standards because practitioners give them more scrutiny and know
that the products reflect their reputation. Often, the product companies were started by practitioners.
His thoughts on CBD: He was surprised at how fast is got big. “CBD is an ingredient that is taking off like
a rocket. And this year the growth rate is 5 times the growth rate of the industry.” There needs to be
more science about diagnosis that CBD treats and correct dosages. He expects most of the science for
CBD to focus on pain and sleep. Then products must be tested for purity and efficacy and the right
claims be made for it.
He is very interested in personalized nutrition. “The future supplement company may be a technology
company that uses diagnostics to tell us what we need to take.” This will change the industry.
Tom’s Recommendations:
Magnesium, zinc, detox, vitamin D, Fish Oil, basic vitamins and minerals as "insurance." Also: maca for
energy and adaptogen benefit, ashwagandha for adaptogenic benefit, probiotic, CoQ10, niagin, a good
whole foods vitamin.
Tom owns Nutrition Capital Network. He favors the practitioner companies that sell through doctors,
chiropractors, etc. Practitioner companies he likes: Designs for Health, MetaGenics, OrthoMolecular.
36
Trevor Cates
Meet Trevor:
Trevor is a ND and has been practicing for about 20 years. She is founder of The Spa Dr. She had a lot of
health struggles as a child, and a holistic physician was the only one who turned her health around - this
inspired her to this field. She had allergies, recurring strep, colitis, hives, and eczema. She always
reacted to meds. She didn’t feel like a normal kid, and she ended up feeling like an outcast.
She loves how naturopathy supports the body’s innate ability to heal by finding the root cause. She was
the first female naturopath licensed in California. She was even appointed to the state’s naturopathic
advisory council by the Governor.
Diet and lifestyle changes are a primary tool, but she can prescribe meds when necessary. They make
use of supplements, and are very aware of possible interactions.
“I focus on skin, because I see skin as our magic mirror. It gives us great clues about overall health. A lot
of times the root causes behind health issues show up first on the skin.” It is a focus of her book Clean
Skin from Within and as her practice as The Spa Doctor.
Nutritional deficiencies are one of the big root causes of health issues that show up on the skin. “If we
can address those root causes, nutritional deficiencies, oxidative damage, hormonal imbalances,
inflammation, microbiome imbalances, blood sugar issues. If we address those, we’re going to help the
skin, and we’re going to help so many other aspects of our health.”
It is best to take nutrients in their proper balance and pairings, and not take them in isolation. “We want
to mimic nature and how we find nutrients in nature. I think there’s so much power in that, and most of
the time we want to be taking the supplements in that balance of what we find in nature.”
If someone can’t afford a high-quality multivitamin, she’d rather that they not get one at all over getting
a cheaper one. Quality is a huge issue and some brands make matters worse rather than better.
An important aspect of supplements is compliance. “If you’re going to be taking supplements, you want
to be actually taking the supplements rather than just sit in your refrigerator or your cabinet. You want
to actually be taking them.”
Trevor’s Recommendations:
She recommends a high quality multivitamin and mineral, fish oil, probiotic She also generally
recommends B vitamins, CBD, antioxidants and collagen peptides for anti-aging. Vitamin C, bone broth.
For acne: zinc, chromium, fatty acids.
Trevor’s company is The Spa Doctor. She likes the brands Designs for Health, Pure Encapsulations, and
Thorne. Favorite fish oil brands are Nordic Naturals and Omax
37
Trina Felber
Meet Trina:
Trina is a registered nurse and CEO of Primal Life Organics. She spent a lot of time nursing in a burn unit
and helping people recover from severe skin damage. She went back to school to learn anesthesia and
became a nurse anesthetist. She committed to becoming healthier after a miscarriage. She noticed that
her skin care products had a lot of toxins in them.
Your skin is your largest organ. “Your skin basically eats whatever you put on it.” She was concerned that
the toxins in her skincare could cross to her unborn baby. She ditched her products and used olive oil to
moisturize, then started formulating her own products.
She studied a lot about metabolism in her anesthetist training. The liver is a protective mechanism.
“You have to stop and think about what you’re supplementing your skin with. Because everybody wants
to look younger, everybody wants to look better and healthier, but if you’re putting toxins on your skin
and they’re absorbing directly into your bloodstream, they could be traveling to your brain, your heart,
your lungs, everywhere except to your liver to be detoxified. So you could be getting more harm than
good.”
Her husband has entrepreneurial skills, and helped her get her business running under the name Olive’s
Organic Botanicals. She connected with the people at PaleoHacks, and rebranded to appeal to that
market since her stuff was already paleo anyway. They called it Blue Ocean.
When her daughter was 2, they found a deep natural cavity that had developed in utero, probably with
Trina had been sick while pregnant. She started researching how to heal and remineralize teeth and
cavities. She found a way to realkalize the mouth and rebuild the oral microbiome. This remineralized
the tooth, and her daughter never had to have it pulled.
Good bacteria from the mouth is supposed to be swallowed and repopulate the gut. Regular toothpaste
is killing too much good bacteria. “It’s like taking a potent antibiotic every time you brush your teeth and
then hoping to regrow your good microbiome within those 12 hours, and it doesn’t happen.”
A healthy mouth microbiome will be able to kill off bad bacteria. If you don’t do that, then you are
swallowing bad bacteria.. Irritated gums are the sign of impending or existing leaky gut.
In addition to the oral hygiene products, Trina also created non-toxic face and body care products.
Trina’s Recommendations:
Non-toxic skincare, aluminum free deodorant, and organic/toxin free oral care. Oral care includes
components such as clays to detox, clean up biome, and heal teeth. Gum serum formula with CBD and
essential oils. Her deodorant has magnesium, hemp, coconut. She recommends probiotics.
Primal Life Organics brand.

38
Tyler Lebaron
Meet Tyler:
Tyler is the founder of Molecular Hydrogen Institute. He has a background in biochemistry and
physiology, and he researches hydrogen gas. He became interested when he read a journal article about
the therapeutic effects of hydrogen. He did some of his own research, and even ended up pursuing it
further in Japan where the original research was done. His group now is a science based non-profit.
Even at high levels, there are no toxic effects of hydrogen. “Now we’re showing that hydrogen gas can
actually have some therapeutic effects. Well then, this is really something that we need to get out, and
people can actually use on a daily basis.”
The research is still very new. There are about 12,000 to 13,000 publications showing therapeutic effects
of hydrogen gas. The preliminary results are very promising, and he does more research is called for.
In order for therapeutic benefits to occur, hydrogen needs to be ingested and get into the bloodstream.
Being the smallest molecule, it can easily penetrate the gastric barrier. A lot of nutrients are ionically
charged, and must use a transporter to get into the body. This is not true for hydrogen. H2 is extremely
bioavailable.
They have done studies on hydrogen’s effect on Parkinson’s, arthritis, metabolic syndrome,
hyperlipidemia, and even stroke. “Hydrogen gas is this panacea, it has this ubiquitous effect… the reason
is because hydrogen gas helps with some of the most fundamental causes of some of these diseases.”
Fasting triggers the release of ghrelin, which has a number of beneficial effects, including growth
hormone release and anti-inflammatory effects. Hydrogen gas also induces ghrelin secretion.
There are also hydrogen producing tablets that can be dropped in water. This is also a source of
magnesium.
Research about hydrogen has really ramped up in the last 10 years, and the market tends to be about 10
years behind the science. It is starting to hit the market now, and influencers are starting to talk about it.
In 10 years, he thinks it may be ubiquitous. “I think you’re going to start seeing this in some of the big
stores.”
Tyler’s Recommendations:
Hydrogen gas as a supplement.
Molecular Hydrogen Institute

39
Warren Phillips
Meet Warren:
Warren is the co-founder of Cytodetox. He studied environmental science and wanted to work to clean
up the environment. He ended up getting very sick from doing clean up work at abandoned mines. His
symptoms got so bad that he was nearly suicidal. A friend advised him that he was not running from
something, but going towards something new.
Doctors tried to give him Effexor and encouraged him to exercise. But his scientific side wondered about
the heavy metals he had been exposed to. He also asked about the science behind the drugs he was
being given, and was given vague answers. The medication only made him feel worse.
He started searching on the internet, such as it was, for answers in 2005. He finally met Dr. Dan Pompa,
who was doing pioneering work in detox, “And I hooked up with him and he started giving me
supplements and doing some things, and I'm like, these are the first things that actually... these
alternative methods... were the first things that start making me feel better.”
He read up on heavy metal toxicity and found that the symptoms were abnormal shyness, sound
sensitivity, fibromyalgia, weight-gain and sometimes it can turn into weight loss. He had gained a lot of
weight and was up to 220 pounds. “Once I became open to supplements, alternative health, I gently
start moving down that road. Not all in, but cautiously, testing some of these supplements and things
that actually start making me feel better for the first time.”
He started trying chelation therapy and detoxification. Dietary changes helped to ease the toxic load on
his body. Weight started to come off, inflammation went down, and healing on a hormonal level started
to take place. “One of the magic bullets is diet in your life because that's something everybody can do to
decrease your toxic load immediately. Within a few weeks your body can start feeling a lot better.”
He started to explore ways to lower the toxic burden. He learned about liver and kidney support and
detoxification pathways. He used glutathione to help pull toxins out.
It is important to support organs so that they can handle detox. They worked on finding binders to pull
out the toxins effectively and safely. He also suggests rotating high quality probiotics. They help support
the gut through detox and rebuild it.
Warren’s Recommendations:
He focuses on things that bind with toxins and remove them. Carbon/charcoal binds to organic toxins.
Xylites for non-organic toxins. He recommends rotating good probiotics.
Cytodotox company - heavy metal and toxin detox.

40
Will Stow
Meet Will:
Will is the Chief Scientific Officer at MitoQ Limited. He is a pharmacologist by training.
Will discusses the difference between CoQ10 and Ubiquinol, two very popular supplements taken for
their antioxidant and cell energizing properties. “CoQ10 is a naturally occurring substance in the body.
It's used by the body as an antioxidant and also in the energy production process.” Ubiquinol and CoQ10
are both different versions of the same molecule.
“Ubiquinol is the active version of the molecule, and when that attacks a free radical, it gets oxidized
down to the CoQ10 variant. Then what happens is the CoQ10 is reduced back to the active Ubiquinol
variant, so they're two versions of the same thing, and they cycle in between each other. Ubiquinol is
seen as the active form, as I mentioned, possibly a little bit better absorbed than regular CoQ10.”
CoQ10 is often used for heart health. “The heart uses a lot of energy. It produces a lot of energy. So
therefore if you take something that supports energy, then systemically, then the heart's going to be
one of the major benefactors of a supplement like that.” It is actually somewhat hard for the body to
absorb, so consumers should look for a brand that has technologies and techniques to try to improve
absorption.
This supplement is not just for people with heart health concerns, but can be thought of as a lifestyle
supplement. It is especially recommended for people who take statins, since those directly lower natural
CoQ10 levels. While CoQ10 does not alleviate statin effects for everyone, it’s the best option available.
His product MitoQ is designed to be absorbable and bioavailable. They were able to reduce the size of
the molecule, making it smaller and therefore more absorbable and better able to enter the
mitochondria.
In terms of other health benefits of MitoQ, “It's been shown to have great benefits in arterial health.
That's the ability of our blood vessels to relax and dilate. Free radical damage makes our arteries stiff…
reducing that free radical damage in the arteries can make them much more supple and you have much
more control over your blood pressure.” In some cases, people can get off of the blood pressure meds.
Will’s Recommendations:
Ubiquinol form of CoQ10 for energy, heart health, and antioxidant.
MitoQ Limited
43
Research Compilation
Research on Supplements, Herbs and
Nutrient-rich Foods
From A to Z
… …
44
Table of Contents
Adaptogens ............................................................................................................................................................................. 23
Novel molecular mechanisms for the adaptogenic effects of herbal extracts on isolated brain cells
using systems biology. ............................................................................................................................ 23
Immunopotentiating significance of conventionally used plant adaptogens as modulators in
biochemical and molecular signalling pathways in cell mediated processes. ........................................ 25
Evaluation of Rhodiola rosea supplementation on skeletal muscle damage and inflammation in
runners following a competitive marathon. ........................................................................................... 25
Plants and the central nervous system. .................................................................................................. 26
Astragali radix: could it be an adjuvant for oxaliplatin-induced neuropathy? ....................................... 27
Antihistaminic activity of aqueous extract of stem bark of Ailanthus excelsa Roxb. ............................. 27
Adaptogenic Herbs: List, Effectiveness, and Health Benefits ................................................................. 28
Ginseng ................................................................................................................................................... 29
Changes in stomach motor-secretory function during immobilization and pain stress and their
correction with bioactive food supplement Lymphosan. ....................................................................... 30
Aloe ............................................................................................................................................................................................. 30
Aloe Genus Plants: From Farm to Food Applications and Phytopharmacotherapy ............................... 31
The Genus Aloe: Phytochemistry and Therapeutic Uses Including Treatments for Gastrointestinal
Conditions and Chronic Inflammation. ................................................................................................... 31
Biomedical applications of Aloe vera. ..................................................................................................... 32
Antiglycation Activity and HT-29 Cellular Uptake of Aloe-Emodin, Aloin, and Aloe arborescens Leaf
Extracts.................................................................................................................................................... 33
Ultrasound mediated accelerated Anti-influenza activity of Aloe vera.................................................. 33
In vitro Fermentation of Polysaccharides from Aloe vera and the Evaluation of Antioxidant Activity and
Production of Short Chain Fatty Acids. ................................................................................................... 34
Dose-Dependent Effects of Aloin on the Intestinal Bacterial Community Structure, Short Chain Fatty
Acids Metabolism and Intestinal Epithelial Cell Permeability. ............................................................... 35
Alpha Lipoic Acid ................................................................................................................................................................ 36
Insights on the Use of α-Lipoic Acid for Therapeutic Purposes. ............................................................. 36
Alpha Lipoic Acid Reduces Symptoms and Inflammation Biomarkers in Patients with Chronic
Hemorrhoidal Illness. .............................................................................................................................. 36
Prevention of Bortezomib-Related Peripheral Neuropathy With Docosahexaenoic Acid and α-Lipoic
Acid in Patients With Multiple Myeloma: Preliminary Data. .................................................................. 37
45
A Case for Alpha-Lipoic Acid as an Alternative Treatment for Diabetic Polyneuropathy....................... 38

Non-pharmacologic treatments for symptoms of diabetic peripheral neuropathy: a systematic review.
................................................................................................................................................................ 39
Systemic administration of α-lipoic acid suppresses excitability of nociceptive wide-dynamic range
neurons in rat spinal trigeminal nucleus caudalis................................................................................... 40
Effect of α-lipoic acid on symptoms and quality of life in patients with painful diabetic neuropathy. . 41
Comparative evaluation of the electrophysiological, functional and ultrastructural effects of alpha
lipoic acid and cyanocobalamin administration in a rat model of sciatic nerve injury. ......................... 41
Combination Analgesic Development for Enhanced Clinical Efficacy (CADENCE Trial): Study Protocol
for a Double-Blind, Randomized, Placebo-Controlled Crossover Trial of an Alpha-Lipoic Acid -
Pregabalin Combination for the Treatment of Fibromyalgia Pain. ......................................................... 42
Pain Improvement With Novel Combination Analgesic Regimens (PAIN-CARE): Randomized Controlled
Trial Protocol. .......................................................................................................................................... 44
Observational multicentric study on chronic sciatic pain: clinical data from 44 Italian centers. ........... 45
Innovations in the Management of Musculoskeletal Pain With Alpha-Lipoic Acid (IMPALA Trial): Study
protocol for a Double-Blind, Randomized, Placebo-Controlled Crossover Trial of Alpha-Lipoic Acid for
the Treatment of Fibromyalgia Pain. ...................................................................................................... 46
Alpha-lipoic Acid After Median Nerve Decompression at the Carpal Tunnel: A Randomized Controlled
Trial. ........................................................................................................................................................ 47
Arnica ........................................................................................................................................................................................ 48
Lychnophora pinaster ethanolic extract and its chemical constituents ameliorate hyperuricemia and
related inflammation. ............................................................................................................................. 48
An integrated approach with homeopathic medicine and electro-acupuncture in anaesthesiology
during breast cancer surgery: Case reports. ........................................................................................... 49
Arnica compositum, Hekla lava and Acidum Nitricum Together are Superior to Arnica compositum
Alone in the Local Treatment of Symptomatic Calcific Periarthritis of the Shoulder: A Pilot Study. ..... 50
Phytomedicine in Joint Disorders. .......................................................................................................... 51
Feasibility, acceptability, and tolerability of RGN107 in the palliative wound care management of
chronic wound symptoms....................................................................................................................... 52
The influence of seasonality on the content of goyazensolide and on anti-inflammatory and anti-
hyperuricemic effects of the ethanolic extract of Lychnophora passerina (Brazilian arnica). ............... 53
Mexican Arnica (Heterotheca inuloides Cass. Asteraceae: Astereae): Ethnomedical uses, chemical
constituents and biological properties. .................................................................................................. 54
Physiotherapy and a Homeopathic Complex for Chronic Low-back Pain Due to Osteoarthritis: A
Randomized, Controlled Pilot Study. ...................................................................................................... 55
46
Herbal Medicine for Low Back Pain: A Cochrane Review. ...................................................................... 56

Cumulative therapeutic effects of phytochemicals in Arnica montana flower extract alleviated
collagen-induced arthritis: inhibition of both pro-inflammatory mediators and oxidative stress. ........ 57
A Clinical Trial with Brazilian Arnica (Solidago chilensis Meyen) Glycolic Extract in the Treatment of
Tendonitis of Flexor and Extensor Tendons of Wrist and Hand. ............................................................ 58
Ashwagandha (Withania somnifera) ....................................................................................................................... 59
Antihyperalgesic effects of ashwagandha (Withania somnifera root extract) in rat models of
postoperative and neuropathic pain. ..................................................................................................... 59
Efficacy & safety evaluation of Ayurvedic treatment (Ashwagandha powder & Sidh Makardhwaj) in
rheumatoid arthritis patients: a pilot prospective study. ....................................................................... 60
Ayurvedic management in cervical spondylotic myelopathy. ................................................................ 61
ASHWAGANDHA ..................................................................................................................................... 61
12 Proven Health Benefits of Ashwagandha .......................................................................................... 62
Hypoglycemic, diuretic and hypocholesterolemic effect of winter cherry (Withania somnifera, Dunal)
root.......................................................................................................................................................... 62
Natural products with hypoglycemic, hypotensive, hypocholesterolemic, antiatherosclerotic and
antithrombotic activities. ........................................................................................................................ 63
Evaluation of anti-inflammatory effect of Withania somnifera root on collagen-induced arthritis in
rats. ......................................................................................................................................................... 63
Protective effects of Withania somnifera root on inflammatory markers and insulin resistance in
fructose-fed rats. .................................................................................................................................... 64
Exploratory study to evaluate tolerability, safety, and activity of Ashwagandha (Withania somnifera) in
healthy volunteers. ................................................................................................................................. 65
A randomized, double blind placebo controlled study of efficacy and tolerability of Withaina
somnifera extracts in knee joint pain. .................................................................................................... 66
Bee Propolis, Pollen, and Honey................................................................................................................................. 67
Antioxidant Potential of Propolis, Bee Pollen, and Royal Jelly: Possible Medical Application. .............. 67
Biological Properties and Therapeutic Applications of Propolis. ............................................................ 68
Honey, Propolis, and Royal Jelly: A Comprehensive Review of Their Biological Actions and Health
Benefits. .................................................................................................................................................. 68
Tumor-suppressing potential of stingless bee propolis in in vitro and in vivo models of differentiated-
type gastric adenocarcinoma. ................................................................................................................. 69
Antioxidant activity of honey supplemented with bee products. .......................................................... 70
The phytochemistry of the honeybee..................................................................................................... 70
Biological and therapeutic properties of bee pollen: a review............................................................... 71
47
In vivo activity assessment of a "honey-bee pollen mix" formulation. .................................................. 72

From the hive: Honey, a novel weapon against cancer. ......................................................................... 73
Antiproliferative effects of honey and of its polyphenols: a review. ..................................................... 73
Activities of different types of Thai honey on pathogenic bacteria causing skin diseases, tyrosinase
enzyme and generating free radicals. ..................................................................................................... 74
Bone Broth .............................................................................................................................................................................. 75
What is Bone Broth, and What Are The Benefits?.................................................................................. 75
L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent. ......................... 75
L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent. ......................... 76
Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre,
randomised, double-blind, non-inferiority trial versus celecoxib. ......................................................... 77
Glucosamine therapy for treating osteoarthritis. ................................................................................... 78
Oral ingestion of a hydrolyzed gelatin meal in subjects with normal weight and in obese patients:
Postprandial effect on circulating gut peptides, glucose and insulin. .................................................... 81
Boswellia ................................................................................................................................................................................. 81
Phytomedicine in Joint Disorders. .......................................................................................................... 81
A randomized, double blind, placebo controlled, cross over study to evaluate the analgesic activity of
Boswellia serrata in healthy volunteers using mechanical pain model. ................................................. 82
Dietary supplements for treating osteoarthritis: a systematic review and meta-analysis..................... 83
Five Herbs Plus Thiamine Reduce Pain and Improve Functional Mobility in Patients With Pain: A Pilot
Study. ...................................................................................................................................................... 84
Management of muscular dystrophy during osteoarthritis disorder: A topical phytotherapeutic
treatment protocol. ................................................................................................................................ 85
A pilot, randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of a novel
Boswellia serrata extract in the management of osteoarthritis of the knee. ........................................ 86
Natural Products for Promoting Joint Health and Managing Osteoarthritis. ......................................... 87
A Placebo-Controlled Double-Blind Study Demonstrates the Clinical Efficacy of a Novel Herbal
Formulation for Relieving Joint Discomfort in Human Subjects with Osteoarthritis of Knee. ............... 88
Efficacy of curcumin and Boswellia for knee osteoarthritis: Systematic review and meta-analysis. ..... 88
Efficacy and safety of curcumin and its combination with boswellic acid in osteoarthritis: a
comparative, randomized, double-blind, placebo-controlled study. ..................................................... 89
A novel boswellic acids delivery form (Casperome®) in the management of musculoskeletal disorders:
a review. .................................................................................................................................................. 90
48
A commercialized dietary supplement alleviates joint pain in community adults: a double-blind,

placebo-controlled community trial. ................................................................................................... 91
Oral herbal medicines marketed in Brazil for the treatment of osteoarthritis: A systematic review and
meta-analysis. ......................................................................................................................................... 92
Methylsulfonylmethane and boswellic acids versus glucosamine sulfate in the treatment of knee
arthritis: Randomized trial. ..................................................................................................................... 93
Evaluation of the effect of Elaeagnus angustifolia alone and combined with Boswellia thurifera
compared with ibuprofen in patients with knee osteoarthritis: a randomized double-blind controlled
clinical trial. ............................................................................................................................................. 94
Broad Spectrum Enzymes .............................................................................................................................................. 95
Impaired Intestinal Permeability Contributes to Ongoing Bowel Symptoms in Patients With
Inflammatory Bowel Disease and Mucosal Healing................................................................................ 95
Early-life enteric infections: relation between chronic systemic inflammation and poor cognition in
children. .................................................................................................................................................. 96
Roles of the gut in the metabolic syndrome: an overview. .................................................................... 96
Risk factors associated with intestinal permeability in an adult population: A systematic review........ 97
Interactions between gut bacteria and bile in health and disease......................................................... 98
Gut microbiota functions: metabolism of nutrients and other food components................................. 99
Digestive Enzyme Supplementation in Gastrointestinal Diseases .......................................................... 99
The role of enzyme supplementation in digestive disorders................................................................ 100
Digestive and nutritional considerations in celiac disease: could supplementation help? .................. 100
Camphor................................................................................................................................................................................ 101
The pharmacology of topical analgesics. .............................................................................................. 101
Topical therapies for knee osteoarthritis.............................................................................................. 102
Camphor--a fumigant during the Black Death and a coveted fragrant wood in ancient Egypt and
Babylon--a review. ................................................................................................................................ 103
A randomized, double blind, placebo controlled trial of a topical cream containing glucosamine
sulfate, chondroitin sulfate, and camphor for osteoarthritis of the knee. ........................................... 103
CAMPHOR ............................................................................................................................................. 104
Clinical efficacy of polyherbal formulation Eezpain spray for muscular pain relief. ............................ 105
[Study on antiinflammatory effect of different chemotype of Cinnamomum camphora on rat arthritis
model induced by Freund's adjuvant].[Article in Chinese] ................................................................... 105
How to Use Camphor Safely: Benefits and Precautions ....................................................................... 106
Capsasin ................................................................................................................................................................................ 107
49

Topical therapies for knee osteoarthritis.............................................................................................. 108
Topical therapies in the management of chronic pain. ........................................................................ 109
Topical therapy for osteoarthritis: clinical and pharmacologic perspectives. ...................................... 110
Conditional Recommendations for Specific Dietary Ingredients as an Approach to Chronic
Musculoskeletal Pain: Evidence-Based Decision Aid for Health Care Providers, Participants, and
Policy Makers. ...................................................................................................................................... 111
Capsaicin, Nociception and Pain. .......................................................................................................... 112
Capsaicin: Current Understanding of Its Mechanisms and Therapy of Pain and Other Pre-Clinical and
Clinical Uses. ......................................................................................................................................... 112
Topical capsaicin (high concentration) for chronic neuropathic pain in adults.................................... 113
Topical therapies in the management of chronic pain. ........................................................................ 115
Uses of Capsaicin Cream ....................................................................................................................... 116
Capsaicin Cream .................................................................................................................................... 116
Chamomile ........................................................................................................................................................................... 117
Medicinal plants and their isolated phytochemicals for the management of chemotherapy-induced
neuropathy: therapeutic targets and clinical perspective. ................................................................... 117
The natural plant flavonoid apigenin is a strong antioxidant that effectively delays peripheral
neurodegenerative processes............................................................................................................... 118
Plant-derived medicines for neuropathies: a comprehensive review of clinical evidence. ................. 119
Evaluation of the effect of topical chamomile (Matricaria chamomilla L.) oleogel as pain relief in
migraine without aura: a randomized, double-blind, placebo-controlled, crossover study. ............... 120
Gel of chamomile vs. urea cream to prevent acute radiation dermatitis in patients with head and neck
cancer: a randomized controlled trial................................................................................................... 120
GABA-modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence.
.............................................................................................................................................................. 121
5 Ways Chamomile Tea Benefits Your Health ...................................................................................... 122
What Is Chamomile? ............................................................................................................................. 123
Chondroitin Sulfate......................................................................................................................................................... 123
Natural Products for Promoting Joint Health and Managing Osteoarthritis. ....................................... 123
Nutrition, osteoarthritis and cartilage metabolism. ............................................................................. 125
50
What is the current status of chondroitin sulfate and glucosamine for the treatment of knee
osteoarthritis?....................................................................................................................................... 126
Chondroitin Sulfate and Glucosamine as Disease Modifying Anti- Osteoarthritis Dru gs (DMOADs). . 126
Predictive modeling of therapeutic response to chondroitin sulfate/glucosamine hydrochloride in
knee osteoarthritis. ............................................................................................................................... 127
Avocado/Soybean Unsaponifiables, Glucosamine and Chondroitin Sulfate Combination Inhibits
Proinflammatory COX-2 Expression and Prostaglandin E2 Production in Tendon-Derived Cells......... 128
How to treat osteoarthritis in obese patients? .................................................................................... 128
Comparison of Glucosamine-Chondroitin Sulfate with and without Methylsulfonylmethane in Grade I-
II Knee Osteoarthritis: A Double Blind Randomized Controlled Trial. .................................................. 129
Effectiveness of Non-Animal Chondroitin Sulfate Supplementation in the Treatment of Moderate Knee
Osteoarthritis in a Group of Overweight Subjects: A Randomized, Double-Blind, Placebo-Controlled
Pilot Study. ............................................................................................................................................ 130
CoQ10 ..................................................................................................................................................................................... 131
Coenzyme Q10 in Cardiovascular and Metabolic Diseases: Current State of the Problem ................. 131
Coenzyme Q10 and Heart Failure: A State-of-the-Art Review. ............................................................ 132
Recent Developments in the Role of Coenzyme Q10 for Coronary Heart Disease: a Systematic Review.
.............................................................................................................................................................. 133
CoQ10 increases mitochondrial mass and polarization, ATP and Oct4 potency levels, and bovine
oocyte MII during IVM while decreasing AMPK activity and oocyte death.......................................... 134
Cellular factories for coenzyme Q10 production .................................................................................. 135
Coenzyme Q10 ...................................................................................................................................... 136
CoQ10 supplementation rescues nephrotic syndrome through normalization of H2S oxidation
pathway ................................................................................................................................................ 136
A high-throughput screen of real-time ATP levels in individual cells reveals mechanisms of energy
failure .................................................................................................................................................... 137
High plasma coenzyme Q10 concentration is correlated with good left ventricular performance after
primary angioplasty in patients with acute myocardial infarction ....................................................... 138
Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of
poor maternal nutrition and accelerated postnatal growth1 .............................................................. 139
Creatine ................................................................................................................................................................................. 140
Creatine Supplementation and Upper Limb Strength Performance: A Systematic Review and Meta-
Analysis. ................................................................................................................................................ 140
Creatine, Creatine Kinase, and Aging. ................................................................................................... 141
51
Creatine and its potential therapeutic value for targeting cellular energy impairment in
neurodegenerative diseases. ................................................................................................................ 142
Creatine supplementation in the aging population: effects on skeletal muscle, bone and brain........ 143
Creatine supplementation: can it improve quality of life in the elderly without associated resistance
training? ................................................................................................................................................ 143
Cerebral energetic effects of creatine supplementation in humans. ................................................... 144
Effect of Ten Weeks of Creatine Monohydrate Plus HMB Supplementation on Athletic Performance
Tests in Elite Male Endurance Athletes. ............................................................................................... 145
Delta Tocotrienol (Delta Fraction Vitamin E) .................................................................................................. 146
The use of delta-tocotrienol and lovastatin for anti-osteoporotic therapy. ........................................ 146
Effects of Delta-tocotrienol Supplementation on Liver Enzymes, Inflammation, Oxidative stress and
Hepatic Steatosis in Patients with Nonalcoholic Fatty Liver Disease. .................................................. 147
Omega 3-DHA and Delta-Tocotrienol Modulate Lipid Droplet Biogenesis and Lipophagy in Breast
Cancer Cells: the Impact in Cancer Aggressiveness. ............................................................................. 148
Beneficial effects of δ-tocotrienol against oxidative stress in osteoblastic cells: studies on the
mechanisms of action. .......................................................................................................................... 149
Vitamin E and Alzheimer's disease: the mediating role of cellular aging. ............................................ 150
High plasma levels of vitamin E forms and reduced Alzheimer's disease risk in advanced age........... 152
Annatto (Bixa orellana) δ-TCT supplementation protected against embryonic DNA damages through
alterations in PI3K/ Akt-Cyclin D1 pathway. ......................................................................................... 152
Natural forms of vitamin E and metabolites-regulation of cancer cell death and underlying
mechanisms. ......................................................................................................................................... 153
Devil’s Claw ......................................................................................................................................................................... 154
Review of Anti-Inflammatory Herbal Medicines................................................................................... 154
Devil's claw (Harpagophytum procumbens) and chronic inflammatory diseases: A concise overview on
preclinical and clinical data. .................................................................................................................. 155
Kynurenic acid content in anti-rheumatic herbs. ................................................................................. 155
Natural products and their (semi-)synthetic forms in treatment of migraine: History and current
status..................................................................................................................................................... 156
Bioactive Compounds and Extracts from Traditional Herbs and Their Potential Anti-Inflammatory
Health Effects. ....................................................................................................................................... 157
Natural or Plant Products for the Treatment of Neurological Disorders: Current Knowledge. ........... 158
Anti-Osteoporotic Activity of Harpagoside by Upregulation of the BMP2 and Wnt Signaling Pathways
in Osteoblasts and Suppression of Differentiation in Osteoclasts........................................................ 159
Harpagoside Content in Devil's Claw Extracts. ..................................................................................... 159
52
Herbal Medicine for Low Back Pain: A Cochrane Review. .................................................................... 160
DMSO (Dimethyl Sulphoxide) ................................................................................................................................... 161
Thermal Sensitivity and Dimethyl Sulfoxide (DMSO)............................................................................ 161
A Novel Compound Analgesic Cream (Ketamine, Pentoxifylline, Clonidine, DMSO) for Complex
Regional Pain Syndrome Patients. ........................................................................................................ 162
Dimethyl sulfoxide (DMSO) as intravesical therapy for interstitial cystitis/bladder pain syndrome: A
review.................................................................................................................................................... 163
Dimethylsulfoxide ................................................................................................................................. 164
What Is DMSO? ..................................................................................................................................... 165
DMSO .................................................................................................................................................... 165
Systematic review of the nutritional supplements dimethyl sulfoxide (DMSO) and
methylsulfonylmethane (MSM) in the treatment of osteoarthritis. .................................................... 166
Dimethyl Sulfoxide (DMSO) and Methylsulfonylmethane (MSM) for Osteoarthritis ........................... 167
Feverfew ............................................................................................................................................................................... 168
Widespread pain reliever profile of a flower extract of Tanacetum parthenium. ............................... 168
Nutraceuticals in Migraine: A Summary of Existing Guidelines for Use. .............................................. 169
Migraine Headache Prophylaxis. .......................................................................................................... 169
St. John's Wort seed and feverfew flower extracts relieve painful diabetic neuropathy in a rat model
of diabetes. ........................................................................................................................................... 170
A double-blind placebo-controlled pilot study of sublingual feverfew and ginger (LipiGesic™ M) in the
treatment of migraine. ......................................................................................................................... 171
Fish Oil ................................................................................................................................................................................... 172
Fish Oil and Osteoarthritis: Current Evidence....................................................................................... 172
Acute antinociceptive effect of fish oil or its major compounds, eicosapentaenoic and
docosahexaenoic acids on diabetic neuropathic pain depends on opioid system activation. ............. 173
Anti-pain and anti-inflammation like effects of Neptune krill oil and fish oil against carrageenan
induced inflammation in mice models: Current statues and pilot study. ............................................ 174
Supplementation of eicosapentaenoic acid-rich fish oil attenuates muscle stiffness after eccentric
contractions of human elbow flexors. .................................................................................................. 174
Dynamic changes to lipid mediators support transitions among macrophage subtypes during muscle
regeneration. ........................................................................................................................................ 175
FISH OIL ................................................................................................................................................. 176
Phytalgic, a food supplement, vs placebo in patients with osteoarthritis of the knee or hip: a
randomised double-blind placebo-controlled clinical trial.............................................................. 176
53
13 Benefits of Taking Fish Oil ................................................................................................................ 177

Marine Oil Supplements for Arthritis Pain: A Systematic Review and Meta-Analysis of Randomized
Trials. ..................................................................................................................................................... 178
Fish Oil Increases Specialized Pro-resolving Lipid Mediators in PAD (The OMEGA-PAD II Trial). ......... 179
Ginger ..................................................................................................................................................................................... 180
A double-blind placebo-controlled pilot study of sublingual feverfew and ginger (LipiGesic™ M) in the
treatment of migraine. ......................................................................................................................... 180
Gingerols and shogaols: Important nutraceutical principles from ginger. ........................................... 181
Ginger (Zingiber officinale) as an Analgesic and Ergogenic Aid in Sport: A Systemic Review. ............. 182
Double-blind placebo-controlled randomized clinical trial of ginger (Zingiber officinale Rosc.) in the
prophylactic treatment of migraine...................................................................................................... 182
Ginger for health care: An overview of systematic reviews. ................................................................ 183
Does diet play a role in reducing nociception related to inflammation and chronic pain? ................. 184
Ginger for Arthritis: Does It Work? ....................................................................................................... 185
placebo-controlled community trial. ................................................................................................. 185
GINGER .................................................................................................................................................. 186
Musculoskeletal Pain: Evidence-Based Decision Aid for Health Care Providers, Participants, and Policy
Makers. ................................................................................................................................................. 187
Glucosamine ....................................................................................................................................................................... 188
Efficacy and safety of glucosamine sulfate in the management of osteoarthritis: Evidence from real-
life setting trials and surveys. ............................................................................................................... 188
A retrospective observational study of glucosamine sulfate in addition to conventional therapy in
hand osteoarthritis patients compared to conventional treatment alone. ......................................... 189
How to treat osteoarthritis in obese patients? .................................................................................... 190
Natural Products for Promoting Joint Health and Managing Osteoarthritis. ....................................... 191
Policy Makers. ...................................................................................................................................... 191
Avocado/Soybean Unsaponifiables, Glucosamine and Chondroitin Sulfate Combination Inhibits
Proinflammatory COX-2 Expression and Prostaglandin E2 Production in Tendon-Derived Cells.
.............................................................................................................................................................. 192
Predictive modeling of therapeutic response to chondroitin sulfate/glucosamine hydrochloride in
knee osteoarthritis. ............................................................................................................................... 193
54
What is the current status of chondroitin sulfate and glucosamine for the treatment of knee
osteoarthritis?....................................................................................................................................... 195
Chondroitin Sulfate and Glucosamine as Disease Modifying Anti- Osteoarthritis Drugs (DMOADs).
.............................................................................................................................................................. 196
arthritis: Randomized trial. ................................................................................................................... 196
Nutrition, osteoarthritis and cartilage metabolism. ............................................................................. 199
Glutathione .......................................................................................................................................................................... 201
Glutathione and glutathione analogues; therapeutic potentials. ........................................................ 201
Wu JH, Batist G. Biochim Biophys Acta. 2013 May;1830(5):3350-3. doi:
10.1016/j.bbagen.2012.11.016. Epub 2012 Nov 28. ............................................................... 201
Glutathione and infection. .................................................................................................................... 202
Glutathione and adaptive immune responses against Mycobacterium tuberculosis infection in healthy
and HIV infected individuals. ................................................................................................................ 203
Liposomal Glutathione Supplementation Restores TH1 Cytokine Response to Mycobacterium
tuberculosis Infection in HIV-Infected Individuals. ............................................................................... 204
Demonstration of the Antioxidant Capabilities of a Product Formulated With Antioxidants Stabilized in
Their Reduced Form .............................................................................................................................. 204
Glutathione Benefits ............................................................................................................................. 205
What are the benefits of glutathione? ................................................................................................. 205
What Is Glutathione? A Detailed Guide to the Antioxidant and Supplement ...................................... 206
Hemp Extract with CBD ................................................................................................................................................ 207
Plant-derived medicines for neuropathies: a comprehensive review of clinical evidence. .......... 207
Natural or Plant Products for the Treatment of Neurological Disorders: Current Knowledge..... 207
Clinicians' Guide to Cannabidiol and Hemp Oils. .................................................................................. 208
A selective review of medical cannabis in cancer pain management. ................................................. 209
Topical Medical Cannabis: A New Treatment for Wound Pain-Three Cases of Pyoderma Gangrenosum.
.............................................................................................................................................................. 210
55
Cannabidiol: promise and pitfalls. ........................................................................................................ 211

Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin
type-1 and melastatin type-8................................................................................................................ 211
The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein
hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells. .............................. 212
7 Benefits and Uses of CBD Oil (Plus Side Effects) ................................................................................ 212
Endocannabinoid system: An overview of its potential in current medical practice. .......................... 213
Pharmacotherapeutic considerations for use of cannabinoids to relieve pain in patients with
malignant diseases ................................................................................................................................ 214
An Update of Current Cannabis-Based Pharmaceuticals in Pain Medicine .......................................... 215
Endocannabinoid System: A Multi-Facet Therapeutic Target. ............................................................. 215
Cannabis and cannabinoids: pharmacology and rationale for clinical use. .......................................... 216
Cannabinoids......................................................................................................................................... 217
Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis.......... 218
Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex)
in the treatment of pain caused by rheumatoid arthritis. .................................................................... 219
Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice. . 220
Holy Basil/Tulsi (Ocimum tenuiflorum)............................................................................................................. 220
Medicinal herbs in the treatment of neuropathic pain: a review. ....................................................... 221
HOLY BASIL ............................................................................................................................................ 221
Tulsi - Ocimum sanctum: A herb for all reasons ................................................................................... 222
Ocimum sanctum Linn. A reservoir plant for therapeutic applications: An overview.......................... 223
Anti-Inflammatory, gastrointestinal and hepatoprotective effects of Ocimum sanctum Linn: an ancient
remedy with new application. .............................................................................................................. 223
Validation of traditional claim of Tulsi, Ocimum sanctum Linn. as a medicinal plant. ......................... 224
Therapeutic uses of Ocimum sanctum Linn (Tulsi) with a note on eugenol and its pharmacological
actions: a short review. ......................................................................................................................... 224
The Health Benefits of Holy Basil .......................................................................................................... 225
Ameliorative potential of Ocimum sanctum in chronic constriction injury-induced neuropathic pain in
rats. ....................................................................................................................................................... 225
Horsetail ............................................................................................................................................................................... 226
Horsetail ................................................................................................................................................ 226
Horsetail – Benefits and Side Effects .................................................................................................... 227
56
Equisetum arvense L. Extract Induces Antibacterial Activity and Modulates Oxidative Stress,
Inflammation, and Apoptosis in Endothelial Vascular Cells Exposed to Hyperosmotic Stress............. 227
Equisetum arvense (common horsetail) modulates the function of inflammatory immunocompetent
cells. ...................................................................................................................................................... 228
Equisetum arvense hydromethanolic extracts in bone tissue regeneration: in vitro osteoblastic
modulation and antibacterial activity. .................................................................................................. 229
Anabolic therapy with Equisetum arvense along with bone mineralising nutrients in ovariectomized
rat model of osteoporosis. .................................................................................................................... 230
Does Horsetail Help You Pee?............................................................................................................... 230
Phytomedicine in Joint Disorders. ........................................................................................................ 231
Osteoporosis Alternative Treatments................................................................................................... 231
Study. .................................................................................................................................................... 232
Kava ......................................................................................................................................................................................... 234
Kava for Generalized Anxiety Disorder: A Review of Current Evidence. .............................................. 234
Activity and mechanism of flavokawain A in inhibiting P-glycoprotein expression in paclitaxel
resistance of lung cancer. ..................................................................................................................... 235
Kava for generalised anxiety disorder: A 16-week double-blind, randomised, placebo-controlled study.
.............................................................................................................................................................. 236
Kava and its Kavalactones Inhibit Norepinephrine-induced Intracellular Calcium Influx in Lung Cancer
Cells. ...................................................................................................................................................... 237
Cyclization of flavokawain B reduces its activity against human colon cancer cells. ........................... 238
Identification of a Kavain Analog with Efficient Anti-inflammatory Effects. ........................................ 239
Reduction of Articular and Systemic Inflammation by Kava-241 in a Porphyromonas gingivalis-Induced
Arthritis Murine Model. ........................................................................................................................ 239
Lomatium ............................................................................................................................................................................. 240
Antibacterial activity of components from Lomatium californicum..................................................... 240
Phytotoxic and antifungal compounds from two Apiaceae species, Lomatium californicum and
Ligusticum hultenii, rich sources of Z-ligustilide and apiol, respectively. ............................................. 241
Antiviral screening of British Columbian medicinal plants. .................................................................. 241
Suksdorfin: an anti-HIV principle from Lomatium suksdorfii, its structure-activity correlation with
related coumarins, and synergistic effects with anti-AIDS nucleosides. .............................................. 242
Native American food and medicinal plants, 8. Water-soluble constituents of Lomatium dissectum.242
57
Maca ........................................................................................................................................................................................ 243

Medicinal effects of Peruvian maca (Lepidium meyenii): a review................................................. 243
Effect of Lepidium meyenii (Maca), a root with aphrodisiac and fertility-enhancing properties, on
serum reproductive hormone levels in adult healthy men. ............................................................. 243
Physicochemical and functional properties of a protein isolate from maca (Lepidium meyenii)
and the secondary structure and immunomodulatory activity of its major protein component. 244
Lepidium meyenii (Maca) in male reproduction. ............................................................................. 244
Chemical composition and health effects of maca (Lepidium meyenii). ........................................ 245
A double-blind placebo-controlled trial of maca root as treatment for antidepressant-induced
sexual dysfunction in women. ............................................................................................................ 246
Magnesium .......................................................................................................................................................................... 247
Migraine Headache Prophylaxis. .......................................................................................................... 247
10 Evidence-Based Health Benefits of Magnesium .............................................................................. 247
MAGNESIUM ......................................................................................................................................... 248
Magnesium supplementation improves indicators of low magnesium status and inflammatory stress
in adults older than 51 years with poor quality sleep. ......................................................................... 248
Magnesium supplementation, metabolic and inflammatory markers, and global genomic and
proteomic profiling: a randomized, double-blind, controlled, crossover trial in overweight individuals.
.............................................................................................................................................................. 249
Effects of magnesium depletion on inflammation in chronic disease. ................................................. 250
Magnesium, inflammation, and obesity in chronic disease. ................................................................ 251
Burning magnesium, a sparkle in acute inflammation: gleams from experimental models. ............... 252
Exacerbated immune stress response during experimental magnesium deficiency results from
abnormal cell calcium homeostasis. ..................................................................................................... 252
Inflammatory response following acute magnesium deficiency in the rat. ......................................... 252
Magnesium sulfate inhibits inflammation through P2X7 receptors in human umbilical vein endothelial
cells. ...................................................................................................................................................... 253
Menthol (Mint, Mentha) ............................................................................................................................................... 254
8 Health Benefits of Mint ...................................................................................................................... 254
WILD MINT ............................................................................................................................................ 254
TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain...... 255
The role and mechanism of action of menthol in topical analgesic products. ..................................... 256
Menthol: a refreshing look at this ancient compound. ........................................................................ 257
58
Comparison of the Effect of Topical Application of Rosemary and Menthol for Musculoskeletal Pain in
Hemodialysis Patients. .......................................................................................................................... 258
Efficacy and safety profile of a topical methyl salicylate and menthol patch in adult patients with mild
to moderate muscle strain: a randomized, double-blind, parallel-group, placebo-controlled,
multicenter study. ................................................................................................................................. 259
Comparison of diclofenac gel, ibuprofen gel, and ibuprofen gel with levomenthol for the topical
treatment of pain associated with musculoskeletal injuries. ............................................................... 260
Delayed Onset Muscle Soreness and Topical Analgesic Alter Corticospinal Excitability of the Biceps
Brachii. .................................................................................................................................................. 260
Milk Thistle ......................................................................................................................................................................... 261
Silybum marianum (milk thistle) and its main constituent, silymarin, as a potential therapeutic plant in
metabolic syndrome: A review. ............................................................................................................ 261
Effects of silymarin on metabolic syndrome: a review. ........................................................................ 262
The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a
randomized, double-blind, placebo-controlled, clinical trial. ............................................................... 263
Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and
nutraceutical uses in liver diseases. ...................................................................................................... 264
Flavonolignans: One Step Further in the Broad-Spectrum Approach of Cancer. ................................. 264
The effect of milk thistle (Silybum marianum) and its main flavonolignans on CYP2C8 enzyme activity
in human liver microsomes. .................................................................................................................. 266
Molecular Hydrogen....................................................................................................................................................... 267
Molecular Hydrogen as a Neuroprotective Agent. ............................................................................... 267
Molecular hydrogen as a novel antioxidant: overview of the advantages of hydrogen for medical
applications. .......................................................................................................................................... 267
Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and
potential of hydrogen medicine. .......................................................................................................... 268
Effects of Molecular Hydrogen Assessed by an Animal Model and a Randomized Clinical Study on Mild
Cognitive Impairment. .......................................................................................................................... 269
Hydrogen ameliorates chronic intermittent hypoxia-induced neurocognitive impairment via inhibiting
oxidative stress. .................................................................................................................................... 270
Hydrogen protects against chronic intermittent hypoxia induced renal dysfunction by promoting
autophagy and alleviating apoptosis. ................................................................................................... 271
The preventive and therapeutic effects of molecular hydrogen in ocular diseases and injuries where
oxidative stress is involved. .................................................................................................................. 272
MSM ......................................................................................................................................................................................... 273
59
Methylsulfonylmethane: Applications and Safety of a Novel Dietary Supplement. ............................ 273

A randomized controlled trial evaluating methylsulfonylmethane versus placebo to prevent knee pain
in military initial entry trainees. ............................................................................................................ 274
Dimethyl Sulfoxide (DMSO) and Methylsulfonylmethane (MSM) for Osteoarthritis .................... 275
8 Science-Backed Benefits of MSM Supplements ................................................................................ 275
Assessment of safety and efficacy of methylsulfonylmethane on bone and knee joints in osteoarthritis
animal model. ....................................................................................................................................... 276
Efficacy of methylsulfonylmethane supplementation on osteoarthritis of the knee: a randomized
controlled study. ................................................................................................................................... 276
arthritis: Randomized trial. ................................................................................................................... 278
Systematic review of the nutritional supplements dimethyl sulfoxide (DMSO) and
methylsulfonylmethane (MSM) in the treatment of osteoarthritis. .................................................... 279
Evaluation of the Effect of Mega MSM on Improving Joint Function in Populations Experiencing Joint
Degeneration ........................................................................................................................................ 280
placebo-controlled community trial. .................................................................................................... 281
Open-label, randomized, controlled pilot study of the effects of a glucosamine complex on Low back
pain ....................................................................................................................................................... 282
Mushrooms.......................................................................................................................................................................... 283
The effects of dietary supplementation with Agaricales mushrooms and other medicinal fungi on
breast cancer: Evidence-based medicine ............................................................................................. 284
Impact of Agaricus bisporus Mushroom Consumption on Gut Health Markers in Healthy Adults ...... 284
Antioxidant Versus Pro-Apoptotic Effects of Mushroom-Enriched Diets on Mitochondria in Liver
Disease .................................................................................................................................................. 285
Traditional knowledge and use of wild mushrooms by Mixtecs or Ñuu savi, the people of the rain,
from Southeastern Mexico ................................................................................................................... 286
An Inulin-Specific Lectin with Anti-HIV-1 Reverse Transcriptase, Antiproliferative, and Mitogenic
Activities from the Edible Mushroom Agaricus bitorquis ..................................................................... 288
Mushroom Lectins as Promising Anticancer Substances. ..................................................................... 288
Medicinal mushroom modulators of molecular targets as cancer therapeutics. ................................ 289
Nettle (Urtica) .................................................................................................................................................................... 289
60
Study. .................................................................................................................................................... 289
Antinociceptive and anti-inflammatory properties of the hydroalcoholic extract of stems from
Equisetum arvense L. in mice. .............................................................................................................. 291
6 Evidence-Based Benefits of Stinging Nettle ....................................................................................... 292
Randomized controlled trial of nettle sting for treatment of base-of-thumb pain. ............................. 292
Nettle sting of Urtica dioica for joint pain--an exploratory study of this complementary therapy. .... 293
Nettle sting for chronic knee pain: a randomised controlled pilot study. ............................................ 293
Phytalgic, a food supplement, vs placebo in patients with osteoarthritis of the knee or hip: a
randomised double-blind placebo-controlled clinical trial. .................................................................. 294
Evaluation of Antioxidant, Antidiabetic and Antiobesity Potential of Selected Traditional Medicinal
Plants..................................................................................................................................................... 295
Nootropics............................................................................................................................................................................ 296
Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors. ...................................... 296
Pharmacokinetic and pharmacodynamic of the cognitive enhancer modafinil: Relevant clinical and
forensic aspects. ................................................................................................................................... 296
Brain Ageing, Cognition and Diet: A Review of the Emerging Roles of Food-Based Nootropics in
Mitigating Age-related Memory Decline. ............................................................................................. 297
Neuroprotection with Natural Antioxidants and Nutraceuticals in the Context of Brain Cell
Degeneration: The Epigenetic Connection. .......................................................................................... 298
Nootropics are the Brain Boosters Everyone Will Be Taking in 2018 ................................................... 299
What are nootropics (smart drugs)?..................................................................................................... 299
Oat Straw (Avena Sativa) ............................................................................................................................................. 300
Avena sativa (Oat), a potential neutraceutical and therapeutic agent: an overview. .......................... 300
Oats ....................................................................................................................................................... 301
Whole grain oats, more than just a fiber: Role of unique phytochemicals. ......................................... 301
An extract from wild green oat improves rat behaviour. ..................................................................... 302
Avenanthramide C from germinated oats exhibits anti-allergic inflammatory effects in mast cells. .. 302
Avenanthramides, polyphenols from oats, exhibit anti-inflammatory and anti-itch activity. ............. 303
Potential health benefits of avenanthramides of oats. ........................................................................ 303
Avenanthramides are bioavailable and have antioxidant activity in humans after acute consumption of
an enriched mixture from oats. ............................................................................................................ 304
Can Oat Straw Extract Improve Your Health? ....................................................................................... 304
61
Oregano Oil (Carvacrol) ............................................................................................................................................... 305

Bactericidal Property of Oregano Oil Against Multidrug-Resistant Clinical Isolates. ........................... 305
Oregano ................................................................................................................................................ 305
In vitro activities of non-traditional antimicrobials alone or in combination against multidrug-resistant
strains of Pseudomonas aeruginosa and Acinetobacter baumannii isolated from intensive care units.
.............................................................................................................................................................. 306
Oregano. ............................................................................................................................................... 307
Biological and pharmacological activities of carvacrol and carvacrol bearing essential oils. ............... 308
Acaricidal activity of oregano oil and its major component, carvacrol, thymol and p-cymene against
Psoroptes cuniculi in vitro and in vivo. ................................................................................................. 308
Biological Activities of Asteraceae (Achillea millefolium and Calendula officinalis) and Lamiaceae
(Melissa officinalis and Origanum majorana) Plant Extracts. ............................................................... 309
6 Science-Based Health Benefits of Oregano........................................................................................ 309
Anti-inflammatory and anti-ulcer activities of carvacrol, a monoterpene present in the essential oil of
oregano. ................................................................................................................................................ 310
Anti-inflammatory effects of carvacrol: evidence for a key role of interleukin-10. ............................. 310
What are the health benefits of oregano? ........................................................................................... 311
Probiotics ............................................................................................................................................................................. 312
Using probiotics in clinical practice: Where are we now? A review of existing meta-analyses ........... 312
Probiotics for the prevention of pediatric antibiotic-associated diarrhea. .......................................... 313
The Clinical and Economic Impact of Probiotics Consumption on Respiratory Tract Infections:
Projections for Canada .......................................................................................................................... 315
Efficacy of Using Probiotics with Antagonistic Activity against Pathogens of Wound Infections: An
Integrative Review of Literature ........................................................................................................... 321
Stress matters: Randomized controlled trial on the effect of probiotics on neurocognition .............. 322
Probiotics in Disease Prevention and Treatment ................................................................................. 323
Cutting Edge: Probiotics and Fecal Microbiota Transplantation in Immunomodulation ..................... 328
Implications of Probiotics on the Maternal-Neonatal Interface: Gut Microbiota, Immunomodulation,
and Autoimmunity ................................................................................................................................ 332
Systematic review: probiotics in the management of lower gastrointestinal symptoms – an updated
evidence-based international consensus.............................................................................................. 334
Salvia/Sage .......................................................................................................................................................................... 335
Natural products and their (semi-)synthetic forms in treatment of migraine: History and current
status..................................................................................................................................................... 335
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Medicinal herbs in the treatment of neuropathic pain: a review. ....................................................... 336

12 Health Benefits and Uses of Sage .................................................................................................... 337
Polyphenolics of Salvia--a review.......................................................................................................... 337
In vitro antioxidant and antiproliferative activities of nine Salvia species. .......................................... 337
Sage tea drinking improves lipid profile and antioxidant defences in humans. ................................... 338
Metformin-like effect of Salvia officinalis (common sage): is it useful in diabetes prevention? ......... 338
Salvia officinalis, Rosmarinic and Caffeic Acids Attenuate Neuropathic Pain and Improve Function
Recovery after Sciatic Nerve Chronic Constriction in Mice. ................................................................. 339
Comparison of benzydamine hydrochloride and Salvia officinalis as an adjuvant local treatment to
systemic nonsteroidal anti-inflammatory drug in controlling pain after tonsillectomy, adenoidectomy,
or both: an open-label, single-blind, randomized clinical trial. ............................................................ 340
Salvia divinorum: from recreational hallucinogenic use to analgesic and anti-inflammatory action. . 341
Salvia mellifera-How Does It Alleviate Chronic Pain? ........................................................................... 342
SAM-e (Ademetionine).................................................................................................................................................. 342
Sam-E .................................................................................................................................................... 342
Ademetionine ....................................................................................................................................... 342
Evidence-Based Evaluation of Complementary Health Approaches for Pain Management in the United
States. ................................................................................................................................................... 343
Chondroprotection and the prevention of osteoarthritis progression of the knee: a systematic review
of treatment agents. ............................................................................................................................. 344
Therapeutic benefits of the methyl donor S-adenosylmethionine on nerve injury-induced mechanical
hypersensitivity and cognitive impairment in mice. ............................................................................. 345
A pilot study of S-adenosylmethionine in treatment of functional abdominal pain in children. ......... 346
[S-adenosyl L-methionine in CNS diseases]. ......................................................................................... 347
One-Carbon Metabolism Supports S-Adenosylmethionine and Histone Methylation to Drive
Inflammatory Macrophages. ................................................................................................................ 348
Skullcap (Scutellaria) .................................................................................................................................................... 348
Cartilage Protection and Analgesic Activity of a Botanical Composition Comprised of Morus alba,
Scutellaria baicalensis, and Acacia catechu. ......................................................................................... 348
A combination of Scutellaria baicalensis and Acacia catechu extracts for short-term symptomatic relief
of joint discomfort associated with osteoarthritis of the knee. ........................................................... 349
UP446, analgesic and anti-inflammatory botanical composition. ........................................................ 349
Analgesic effects of a standardized bioflavonoid composition from Scutellaria baicalensis and Acacia
catechu.................................................................................................................................................. 351
63
Elucidation of the Anti-Inflammatory Mechanisms of Bupleuri and Scutellariae Radix Using System
Pharmacological Analyses. .................................................................................................................... 351
GABA-modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence.
.............................................................................................................................................................. 352
Skullcap (Scutellaria Baicalensis) Hexane Fraction Inhibits the Permeation of Ovalbumin and Regulates
Th1/2 Immune Responses. ................................................................................................................... 353
Baicalin Attenuates Joint Pain and Muscle Dysfunction by Inhibiting Muscular Oxidative Stress in an
Experimental Osteoarthritis Rat Model. ............................................................................................... 353
Oxidative stress, aging, and diseases .................................................................................................... 354
Skullcap: Benefits, Side Effects, and Dosage......................................................................................... 355
Turmeric (Curcuma) ...................................................................................................................................................... 355
Plant-derived medicines for neuropathies: a comprehensive review of clinical evidence. ......... 355
Review of Anti-Inflammatory Herbal Medicines................................................................................... 356
Does diet play a role in reducing nociception related to inflammation and chronic pain? ................. 357
Policy Makers. ...................................................................................................................................... 358
Medicinal herbs in the treatment of neuropathic pain: a review. ................................................... 359
Study. .................................................................................................................................................... 361
10 Proven Health Benefits of Turmeric and Curcumin ......................................................................... 362
Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of
preclinical and clinical research. ........................................................................................................... 362
Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative,
cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. ................................... 363
Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern
targets. .................................................................................................................................................. 363
Role of curcumin in health and disease. ............................................................................................... 364
Curcumin as "Curecumin": from kitchen to clinic. ................................................................................ 364
Curcumin: the Indian solid gold. ........................................................................................................... 365
The targets of curcumin. ....................................................................................................................... 366
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Curcumin in inflammatory diseases...................................................................................................... 366

Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-kappaB activation,
inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation.
.............................................................................................................................................................. 367
Antioxidant and anti-inflammatory properties of curcumin. ............................................................... 368
Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). ........ 368
Turmeric with Black Pepper ..................................................................................................................................... 369
Why Turmeric and Black Pepper Is a Powerful Combination ............................................................... 369
Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials ................................................. 370
Curcumin: A Review of Its’ Effects on Human Health ........................................................................... 371
Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. ........ 371
Studies on the in vitro absorption of spice principles--curcumin, capsaicin and piperine in rat
intestines............................................................................................................................................... 372
Ubiquinol .............................................................................................................................................................................. 373
Ubiquinol is superior to ubiquinone to enhance Coenzyme Q10 status in older men......................... 373
Effect of ubiquinol supplementation on biochemical and oxidative stress indexes after intense
exercise in young athletes. ................................................................................................................... 374
A sensitive mass spectrometric assay for mitochondrial CoQ pool redox state in vivo. ...................... 375
Ubiquinol Improves Endothelial Function in Patients with Heart Failure with Reduced Ejection
Fraction: A Single-Center, Randomized Double-Blind Placebo-Controlled Crossover Pilot Study. ...... 375
Ubiquinol (reduced Coenzyme Q10) in patients with severe sepsis or septic shock: a randomized,
double-blind, placebo-controlled, pilot trial. ........................................................................................ 377
Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson's
disease. ................................................................................................................................................. 378
Myocardial energetics and ubiquinol in diastolic heart failure. ........................................................... 379
Combining Ubiquinol With a Statin May Benefit Hypercholesterolaemic Patients With Chronic Heart
Failure. .................................................................................................................................................. 379
Vitamin D3 ........................................................................................................................................................................... 380
Dietary vitamin D3 deficiency alters intestinal mucosal defense and increases susceptibility to
Citrobacter rodentium-induced colitis.................................................................................................. 380
Investigating Transdermal Delivery of Vitamin D3 ............................................................................... 382
UVB Exposure of Farm Animals: Study on a Food-Based Strategy to Bridge the Gap between Current
Vitamin D Intakes and Dietary Targets ................................................................................................. 383
65
Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Progression-Free Survival

Among Patients With Advanced or Metastatic Colorectal Cancer ....................................................... 384
The SUNSHINE Randomized Clinical Trial ............................................................................................. 384
Effect of calcium phosphate and vitamin D3 supplementation on bone remodelling and metabolism of
calcium, phosphorus, magnesium and iron .......................................................................................... 386
Cholecalciferol (Vitamin D3) Improves Myelination and Recovery after Nerve Injury ........................ 387
Efficacy of vitamin D3 supplementation in reducing incidence of pulmonary tuberculosis and mortality
among HIV-infected Tanzanian adults initiating antiretroviral therapy: study protocol for a
randomized controlled trial .................................................................................................................. 388
Vitamin K2 ........................................................................................................................................................................... 389
Effect of vitamin K2 on type 2 diabetes mellitus: A review. ................................................................. 389
Regulation of bone remodeling by vitamin K2. .................................................................................... 390
Vitamin K2 in bone metabolism and osteoporosis. .............................................................................. 390
Vitamin K2 Status and Arterial Stiffness Among Untreated Migraine Patients: A Case-Control Study.
.............................................................................................................................................................. 391
Therapeutic effects of systemic vitamin k2 and vitamin d3 on gingival inflammation and alveolar bone
in rats with experimentally induced periodontitis................................................................................ 392
Treatment with vitamin D3 and/or vitamin K2 for postmenopausal osteoporosis. ............................ 393
White Willow Bark .......................................................................................................................................................... 394
Herbal Medicine for Low Back Pain: A Cochrane Review. ............................................................... 395
Willow Bark: Nature’s Aspirin ............................................................................................................... 398
Bioaccessibility in vitro of nutraceuticals from bark of selected Salix species. .................................... 399
Efficacy and Safety of White Willow Bark (Salix alba) Extracts............................................................. 399
A systematic review on the effectiveness of willow bark for musculoskeletal pain. ........................... 400
Willow bark extract: the contribution of polyphenols to the overall effect......................................... 400
In vitro anti-proliferative effects of the willow bark extract STW 33-I. ................................................ 401
Anti-inflammatory effects of the willow bark extract STW 33-I (Proaktiv(®)) in LPS-activated human
monocytes and differentiated macrophages........................................................................................ 402
Salicin-7-sulfate: A new salicinoid from willow and implications for herbal medicine. ....................... 403
66
Adaptogens
Novel molecular mechanisms for the adaptogenic effects of herbal extracts on
isolated brain cells using systems biology.
Panossian, Seo, Efferth T. Phytomedicine. 2018 Nov 15;50:257-284. doi:
10.1016/j.phymed.2018.09.204. Epub 2018 Sep 20.
https://www.ncbi.nlm.nih.gov/pubmed/30466987
Abstract
INTRODUCTION:
Adaptogens are natural compounds or plant extracts that increase adaptability and survival of organisms
under stress. Adaptogens stimulate cellular and organismal defense systems by activating intracellular
and extracellular signaling pathways and expression of stress-activated proteins and neuropeptides. The
effects adaptogens on mediators of adaptive stress response and longevity signaling pathways have
been reported, but their stress-protective mechanisms are still not fully understood.
AIM OF THE STUDY:
The aim of this study was to identify key molecular mechanisms of adaptogenic plants traditionally used
to treat stress and aging-related disorders, i.e., Rhodiola rosea, Eleutherococcus senticosus, Withania
somnifera, Rhaponticum carthamoides, and Bryonia alba.
MATERIALS AND METHODS:
To investigate the underlying molecular mechanisms of adaptogens, we conducted RNA sequencing to

profile gene expression alterations in T98G neuroglia cells upon treatment of adaptogens and analyzed
the relevance of deregulated genes to adaptive stress-response signaling pathways using in silico
pathway analysis software.
RESULTS AND DISCUSSION:

67
At least 88 of the 3516 genes regulated by adaptogens were closely associated with adaptive stress
response and adaptive stress-response signaling pathways (ASRSPs), including neuronal signaling related
to corticotropin-releasing hormone, cAMP-mediated, protein kinase A, and CREB; pathways related to
signaling involving CXCR4, melatonin, nitric oxide synthase, GP6, Gαs, MAPK, neuroinflammation,
neuropathic pain, opioids, renin-angiotensin, AMPK, calcium, and synapses; and pathways associated
with dendritic cell maturation and G-coupled protein receptor-mediated nutrient sensing in
enteroendocrine cells. All samples tested showed significant effects on the expression of genes encoding
neurohormones CRH, GNRH, UCN, G-protein-coupled and other transmembrane receptors TLR9, PRLR,
CHRNE, GP1BA, PLXNA4, a ligand-dependent nuclear receptor RORA, transmembrane channels,
transcription regulators FOS, FOXO6, SCX, STAT5A, ZFPM2, ZNF396, ZNF467, protein kinases MAPK10,
MAPK13, MERTK, FLT1, PRKCH, ROS1, TTN), phosphatases PTPRD, PTPRR, peptidases, metabolic
enzymes, a chaperone (HSPA6), and other proteins, all of which modulate numerous life processes,
playing key roles in several canonical pathways involved in defense response and regulation of
homeostasis in organisms. It is for the first time we report that the molecular mechanism of actions of
melatonin and plant adaptogens are alike, all adaptogens tested activated the melatonin signaling
pathway by acting through two G-protein-coupled membrane receptors MT1 and MT2 and upregulation
of the ligand-specific nuclear receptor RORA, which plays a role in intellectual disability, neurological
disorders, retinopathy, hypertension, dyslipidemia, and cancer, which are common in aging.
Furthermore, melatonin activated adaptive signaling pathways and upregulated expression of UCN,
GNRH1, TLR9, GP1BA, PLXNA4, CHRM4, GPR19, VIPR2, RORA, STAT5A, ZFPM2, ZNF396, FLT1, MAPK10,
MERTK, PRKCH, and TTN, which were commonly regulated by all adaptogens tested. We conclude that
melatonin is an adaptation hormone playing an important role in regulation of homeostasis. Adaptogens
presumably worked as eustressors ("stress-vaccines") to activate the cellular adaptive system by
inducing the expression of ASRSPs, which then reciprocally protected cells from damage caused by
distress. Functional investigation by interactive pathways analysis demonstrated that adaptogens
activated ASRSPs associated with stress-induced and aging-related disorders such as chronic
inflammation, cardiovascular health, neurodegenerative cognitive impairment, metabolic disorders, and
cancer.
CONCLUSION:
This study has elucidated the genome-wide effects of several adaptogenic herbal extracts in brain cells
culture. These data highlight the consistent activation of ASRSPs by adaptogens in T98G neuroglia cells.
The extracts affected many genes playing key roles in modulation of adaptive homeostasis, indicating
their ability to modify gene expression to prevent stress-induced and aging-related disorders. Overall,
this study provides a comprehensive look at the molecular mechanisms by which adaptogens exerts
stress-protective effects.
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Immunopotentiating significance of conventionally used plant adaptogens as

modulators in biochemical and molecular signalling pathways in cell
mediated processes.
Kaur P, et al. Biomed Pharmacother. 2017 Nov;95:1815-1829. doi:
10.1016/j.biopha.2017.09.081. Epub 2017 Oct 6.
Abstract
Natural products are of great surge in the identification of chemopreventive agents and biologically
active molecules for the development of new promising therapeutic agents. These agents influence the
cascade of biochemical and molecular signalling pathways involved in numerous physiological and
pathological processes. The natural agents combat the dogma associated with the most dreaded,
unconquered health concern and a multigenic disease- cancer. A category of plants known as
adaptogens maintain perturbed homoeostasis, augment adaptations to noxious stimuli (exposure to
cold, heat, pain, general stress, infectious organisms) and offer endurance to attenuate several disorders
in human beings. The well known adaptogens and immunomodulators such as Rhodiola rosea, Withania
somnifera, Tinospora cordifolia, Bacopa monnieri, Emblica officinalis, Glycyrrhiza glabra, Asparagus
racemosus, Ocimum sanctum and Panax notoginseng claimed to have significant antioxidant and
anticarcinogenic properties due to the presence of various biologically active chemical compounds.
Their immunopotentiating activity is mediated through the modulation of T-cell immunity biochemical
factors, transcription factors, some genes and factors associated with tumor development and
progression. The combinatory formulation of active immunostimulating constituents from these plants
may provide better homeostasis. These immunostimulant factors suggest their potential therapeutic
significance in adjuvant or supportive therapy in cancer treatment.
Evaluation of Rhodiola rosea supplementation on skeletal muscle damage and

inflammation in runners following a competitive marathon.
Shanely RA, et al. Brain Behav Immun. 2014 Jul;39:204-10. doi:
10.1016/j.bbi.2013.09.005. Epub 2013 Sep 18.
Abstract
Adaptogens modulate intracellular signaling and increase expression of heat shock protein 72 (HSP72).
Rhodiola rosea (RR) is a medicinal plant with demonstrated adaptogenic properties. The purpose of this
study was to measure the influence of RR supplementation on exercise-induced muscle damage,
delayed onset of muscle soreness (DOMS), plasma cytokines, and extracellular HSP72 (eHSP72) in
69
experienced runners completing a marathon. Experienced marathon runners were randomized to RR

(n=24, 6 female, 18 male) or placebo (n=24, 7 female, 17 male) groups and under double-blinded
conditions ingested 600mg/day RR extract or placebo for 30days prior to, the day of, and seven days
post-marathon. Blood samples were collected, and vertical jump and DOMS assessed the day before,
15min post- and 1.5h post-marathon. DOMS was also assessed for seven days post-marathon. Marathon
race performance did not differ between RR and placebo groups (3.87±0.12h and 3.93±0.12h,
respectively, p=0.722). Vertical jump decreased post-marathon (time effect, p<0.001) with no difference
between groups (interaction effect, p=0.673). Post-marathon DOMS increased significantly (p<0.001)
but the pattern of change did not differ between groups (p=0.700). Myoglobin (Mb), creatine
phosphokinase (CPK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin (IL)-
6, IL-8, IL-10, monocyte chemotactic protein-1 (MCP-1), granulocyte-colony-stimulating factor (G-CSF),
C-reactive protein (CRP), and eHSP72 all increased post-marathon (all p<0.001), with no group
differences over time (all p>0.300). In conclusion, RR supplementation (600mg/day) for 30days before
running a marathon did not attenuate the post-marathon decrease in muscle function, or increases in
muscle damage, DOMS, eHSP72, or plasma cytokines in experienced runners.
Plants and the central nervous system.

Carlini EA. Pharmacol Biochem Behav. 2003 Jun;75(3):501-12.
Abstract
This review article draws the attention to the many species of plants possessing activity on the central
nervous system (CNS). In fact, they cover the whole spectrum of central activity such as psychoanaleptic,
psycholeptic and psychodysleptic effects, and several of these plants are currently used in therapeutics
to treat human ailments. Among the psychoanaleptic (stimulant) plants, those utilized by human beings
to reduce body weight [Ephedra spp. (Ma Huang), Paullinia spp. (guaraná), Catha edulis Forssk. (khat)]
and plants used to improve general health conditions (plant adaptogens) were scrutinized. Many species
of hallucinogenic (psychodysleptic) plants are used by humans throughout the world to achieve states of
mind distortions; among those, a few have been used for therapeutic purposes, such as Cannabis sativa
L., Tabernanthe iboga Baill. and the mixture of Psychotria viridis Ruiz and Pav. and Banisteriopsis caapi
(Spruce ex Griseb.) C.V. Morton. Plants showing central psycholeptic activities, such as analgesic or
anxiolytic actions (Passiflora incarnata L., Valeriana spp. and Piper methysticum G. Forst.), were also
analysed.Finally, the use of crude or semipurified extracts of such plants instead of the active substances
seemingly responsible for their therapeutic effect is discussed.
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Astragali radix: could it be an adjuvant for oxaliplatin-induced neuropathy?

Di Cesare Mannelli L,et al. Sci Rep. 2017 Feb 10;7:42021. doi: 10.1038/srep42021.
Abstract
Neurotoxicity is a major side effect of platinum derivatives both during and after treatment. In the
absence of effective pharmacological compounds, the opportunity to identify safe adjuvant treatments
among medicinal plants seems appropriate. Astragali radix is an adaptogenic herbal product recently
analyzed in platinum-treated cancer patients. With the aim of evaluating the anti-neuropathic profile of
Astragali radix, a previously characterized aqueous (Aqu) and two hydroalcoholic (20%HA and 50%HA)
extracts were tested in a rat model of oxaliplatin-induced neuropathy. Repeated administrations
significantly reduced oxaliplatin-dependent hypersensitivity with 50%HA, the most effective, fully
preventing mechanical and thermal hypersensitivity. Ex vivo, 50%HA reduced morphometric and
molecular alterations induced by oxaliplatin in peripheral nerve and dorsal-root-ganglia. In the spinal
cord and in brain areas, 50%HA significantly decreased activation of microglia and astrocytes.
Furthermore, 50%HA prevented the nephro- and hepato-toxicity induced by the anticancer drug. The
protective effect of 50%HA did not alter oxaliplatin-induced apoptosis in colon tumors of Pirc rats, an
Apc-driven model of colon carcinogenesis. The hydroalcoholic extract (50%HA) of Astragali radix relieves
pain and promotes the rescue mechanisms that protect nervous tissue from the damages triggering
chronic pain. A safe profile strongly suggests the usefulness of this natural product in oxaliplatin-induced
neuropathy.
Antihistaminic activity of aqueous extract of stem bark of Ailanthus excelsa

Roxb.
Kumar D, Bhat ZA, Singh P, Bhujbal SS, Deoda RS. Pharmacognosy Res. 2011
Jul;3(3):220-4. doi: 10.4103/0974-8490.85014.
Abstract
BACKGROUND:
Biologically active compounds from natural sources are of interest as possible new drugs for different
diseases. Over many centuries humans have been mining the bounties of nature for discovering natural
products that have been used for the treatment of all human diseases. Ailanthus excelsa Roxb.
(Simaroubaceae) is widely used in the Indian system of medicine as an antiasthmatic, antispasmodic,
bronchodilator, anticolic pain, anticancer, antidiabetic etc. The plant was also reported for its
antiasthmatic, bronchodilatory, antiallegic and many more such activities.
OBJECTIVE:
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To evaluate the antihistaminic activity of aqueous extract of stem bark of Ailanthus excelsa Roxb.
We have studied the effect of aqueous extract of stem barks of A. excelsa Roxb. at a doses 100 μg/mL in
the isolated goat tracheal chain preparation in vitro and 100, 200, 400 mg/kg doses orally in passive paw
anaphylaxis in rat, clonidine-induced catalepsy in mice models in vivo for its antihistaminic activity.
RESULTS:
Aqueous extract of stem barks of A. excelsa Roxb. significantly (***P<0.001) inhibits the percentage
contraction at concentration of 100 μg/mL in goat tracheal chain preparation. A. excelsa Roxb. extract
(100, 200, and 400 mg/kg oral) and dexamethasone (0.5 mg/kg, i.p.) also significantly reduced
(**P<0.01) the paw volume at fourth hour and the percentage inhibition was found to be 13.98%,
28.49%, 42.47% and 46.77% respectively. The aqueous extract of stem barks of A. excelsa Roxb. (100,
200, 400 mg/kg, p.o.) and chlorpheniramine maleate (10 mg/kg, i.p.) significantly inhibited (*P<0.05,
**P< 0.01) clonidine-induced catalepsy in mice at 150 min after the administration of clonidine.
CONCLUSION:
The aqueous extract of stem bark of A. excelsa Roxb. possess significant antihistaminic activity (H1-
antagonist) and can be attributed to bronchodilating, anti-inflammatory, adaptogenic activity etc. Hence
detailed study needs to be conducted to evaluate the phytoconstituent responsible for the above
mentioned results and their clinical efficacy in the treatment of related diseases.
KEYWORDS:
Ailanthus excelsa Roxb; antihistaminic activity; passive paw anaphylaxis
Adaptogenic Herbs: List, Effectiveness, and Health Benefits

Medically reviewed by Debra Rose Wilson, PhD, MSN, RN, IBCLC, AHN-BC, CHT on
June 28, 2017 — Written by Chaunie Brusie, RN, BSN
https://www.healthline.com/health/adaptogenic-herbs
Overview
Adaptogens are herbal pharmaceuticals. They work to counteract the effects of stress in the body. Stress
causes very real physical changes in the body, including harming the neurological, endocrine, and
immune systems. Adaptogens have stimulant properties that help counteract those harmful effects.
Adaptogens were first developed and studied during World War II. Scientists were looking for a way to
help healthy pilots work at even greater levels. Basically, they were looking for a “superhero” pill that’d
72
let the pilots fly better, faster, and for longer periods of time. And they thought they found it in the form
of adaptogens.
The Soviet Union published military studies about a stimulant called Schisandra chinensis that was used.
It was found that berries and seeds eaten by Nanai hunters reduced their thirst, hunger, and exhaustion.
It even improved their ability to see at night.
How do adaptogens work?
Adaptogens work at a molecular level by regulating a stable balance in the hypothalamic, pituitary, and
adrenal glands. These are involved in the stress response. They work by “hacking” the stress response in
the body. Typically, when our bodies are stressed, we go through three stages of stress:
• alarm phase
• phase of resistance
• phase of exhaustion
As we encounter a stressor — say we start lifting weights — our body responds by kicking out hormones
like adrenaline that improve muscle performance and increase our ability to concentrate and pay
attention to the task at hand in the phase of resistance. Our body is literally resisting the stressor, so we
feel energized and clearer, thanks to our body giving us a boost to fight the stressor.
And then, as we fatigue, we enter in the exhaustion phase. Adaptogens basically stretch out that “sweet
spot” in the middle — the phase of resistance — allowing us to hang out in the powerful part longer.
Adaptogens have been studied in both animals and isolated neuronal cells. Researchers have found they
have several effects on the body:
• neuroprotective elements
• anti-fatigue properties
• antidepressive effects
• stimulant for central nervous system
Ginseng
Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National
Library of Medicine (US); 2006-.
Excerpt
The roots of American ginseng (Panax quinquefolius), Asian ginseng (Panax ginseng), and several other
species contain steroidal saponins called ginsenosides that are purported to be adaptogens (i.e., to
increase endurance and improve memory). Ginseng has no specific uses during breastfeeding. Ginseng is
73
generally well tolerated in adults and is "generally recognized as safe" (GRAS) by the U.S. Food and Drug
Administration. The most common side effects include headache, hypertension, diarrhea, sleeplessness,
skin rash, and vaginal bleeding. Ginseng decreases the blood levels of some drugs, such as warfarin, and
enhances the effect of sedating drugs. With long-term use, nervousness, diarrhea, confusion, depression
or depersonalization may occur. Gynecomastia and breast pain have been reported.[1][2] No data exist
on the safety and efficacy of ginseng in nursing mothers or infants. Because of its possible estrogenic
activity and lack of information during breastfeeding, many sources recommend that ginseng not be
used during lactation. Dietary supplements do not require extensive pre-marketing approval from the
U.S. Food and Drug Administration. Manufacturers are responsible to ensure the safety, but do not need
to prove the safety and effectiveness of dietary supplements before they are marketed. Dietary
supplements may contain multiple ingredients, and differences are often found between labeled and
actual ingredients or their amounts. A manufacturer may contract with an independent organization to
verify the quality of a product or its ingredients, but that does not certify the safety or effectiveness of a
product. Because of the above issues, clinical testing results on one product may not be applicable to
other products. More detailed information about dietary supplements is available elsewhere on the
LactMed Web site.
Changes in stomach motor-secretory function during immobilization and pain

stress and their correction with bioactive food supplement Lymphosan.
Sotnikova ED. Bull Exp Biol Med. 2008 Jun;145(6):669-72.
Abstract
We studied the effects of immobilization and pain stress on motor and secretory function of the
stomach in dogs and correction of these changes with bioactive supplement Lymphosan. The stress
factors induced pronounced changes in physiological parameters: immobilization stress induced
hypersecretion, while pain stress inhibited the glandular apparatus. In animals treated with Lymphosan,
both stress factors produced less pronounced changes and motor and secretory functions of the
stomach were near to the control level. Thus, when used as a corrector of stress reactions, Lymphosan
produced adaptogenic effects on the stomach and normalized the stress-induced disturbances.
Aloe
74
Aloe Genus Plants: From Farm to Food Applications and

Phytopharmacotherapy
Bahare Salehi, et al. Int J Mol Sci. 2018 Sep; 19(9): 2843. Published online 2018
Sep 19. doi: 10.3390/ijms19092843
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163315/
Abstract
Aloe genus plants, distributed in Old World, are widely known and have been used for centuries as
topical and oral therapeutic agents due to their health, beauty, medicinal, and skin care properties.
Among the well-investigated Aloe species are A. arborescens, A. barbadensis, A. ferox, and A. vera.
Today, they account among the most economically important medicinal plants and are commonly used
in primary health treatment, where they play a pivotal role in the treatment of various types of diseases
via the modulation of biochemical and molecular pathways, besides being a rich source of valuable
phytochemicals. In the present review, we summarized the recent advances in botany, phytochemical
composition, ethnobotanical uses, food preservation, and the preclinical and clinical efficacy of Aloe
plants. These data will be helpful to provide future directions for the industrial and medicinal use of Aloe
plants.
Keywords: Aloe species, aloin, plicataloside, isovitexin, aloe emodin, aloesin, aloinoside
The Genus Aloe: Phytochemistry and Therapeutic Uses Including Treatments

for Gastrointestinal Conditions and Chronic Inflammation.
Cock IE. Prog Drug Res. 2015;70:179-235.
Abstract
Plants of the genus Aloe have perhaps the longest recorded history of medicinal usage and are amongst
the most widely used plants for traditional medicinal purposes worldwide. Aloe vera, Aloe ferox, Aloe
arborescens and Aloe perryi are the best known and most widely used, but many other species are also
used for their therapeutic properties. The Aloes have been used since ancient times, particularly for the
treatment of microbial infections, gastrointestinal disorders and inflammatory conditions. In addition to
their myriad uses in traditional therapeutics, the Aloes have also been used as components of cosmetic
formulations, and in the food and beverage industries. Despite their wide acceptance, studies from
different laboratories often report wide variations in the therapeutic bioactivities from within the same
Aloe species, even when the same extraction procedures are used. Furthermore, leaves from individual
Aloe plants within the same species may have widely varying levels of the bioactive phytochemicals.
75
Phytochemical analyses have shown that many Aloe species contain various carbohydrate polymers
(notably glucomannans) and a range of other low molecular weight phenolic compounds including
alkaloids, anthraquinones, anthrones, benzene and furan derivatives, chromones, coumarins, flavonoids,
phytosterols, pyrans and pyrones. There has been a wealth of information published about the
phytochemistry and therapeutic potential of the Aloes (especially Aloe vera). Much of this has been
contradictory. Intra- and interspecies differences in the redox state of the individual Aloe components
and in the ratios of these components may occur between individual plants. These factors may all affect
the physiological properties of Aloe extracts. Due to the structure and chemical nature of many of the
Aloe phytochemicals, it is likely that many of the reported medicinal properties are due to antioxidant or
prooxidant effects. The antioxidant/prooxidant activities of many Aloe phytochemicals depend not only
on their individual levels, but also on the ratios between the various components and their individual
redox states. Therefore, discrepancies between bioactivity studies are likely when using different crude
mixtures. This report aims to summarise the phytochemistry of the Aloes and (a) examine how their
constituents may be responsible for their medicinal properties and (b) some possible reasons for the
wide variations reported for their medicinal properties and (c) their therapeutic mechanisms. Some
future areas of research into the medicinal activities of this important genus are also highlighted.
Biomedical applications of Aloe vera.

Gao Y, Kuok KI, Jin Y, Wang R. Crit Rev Food Sci Nutr. 2019;59(sup1):S244-S256.
doi: 10.1080/10408398.2018.1496320. Epub 2018 Sep 13.
Abstract
Over the last centuries, Aloe vera, a plant species belonging to the genus Aloe, have been extensively
studied for various therapeutic activities, including anti-bacterial, anti-viral, anti-cancer activity, as well
as immunoregulative and hepatoprotective properties, although some of these claimed efficacies are
controversial as demonstrated by some of the recent studies. In spite of the intensive historic and recent
use of this herb and its extracts in various areas, a well-balanced, systematic review seems crucial in
order to gain in-depth comprehensive knowledge about this plant and to reflect and revive the use of
Aloe vera in biomedical sciences. This review will focus on summarization of the pharmacological
activities and clinical studies of Aloe and various extracts, as well as its extensive application in food
chemistry, and will also discuss the future prospects of biomedical applications of this herb.
KEYWORDS:
; bioactivities; clinical applications; food; natural products; toxicology

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Antiglycation Activity and HT-29 Cellular Uptake of Aloe-Emodin, Aloin, and

Aloe arborescens Leaf Extracts.
Froldi G, Baronchelli F, Marin E, Grison M. Molecules. 2019 Jun 5;24(11). pii:
E2128. doi: 10.3390/molecules24112128.
Abstract
Aloe arborescens is a relevant species largely used in traditional medicine of several countries. In
particular, the decoction of leaves is prepared for various medicinal purposes including antidiabetic care.
The aim of this research was the study of the antiglycation activity of two A. arborescens leaf extracts
and isolated compounds: aloin and aloe-emodin. These phytoconstituents were quantitatively assessed
in methanolic and hydroalcoholic extracts using high performance liquid chromatography (HPLC)
analysis. In addition, the total phenolic and flavonoid contents were detected. In order to study their
potential use in diabetic conditions, the antiglycation and antiradical properties of the two extracts and
aloin and aloe-emodin were investigated by means of bovine serum albumin (BSA) and 1,1-diphenyl-2-
picryl-hydrazil (DPPH) assays; further, their cytotoxicity in HT-29 human colon adenocarcinoma cells was
evaluated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. Furthermore,
the ability of aloin and aloe-emodin to permeate the cellular membranes of HT-29 cells was determined
in order to estimate their potential in vivo absorption. This assessment indicated that aloe-emodin can
substantially pass through cell membranes (~20%), whereas aloin did not permeate into HT-29 cells.
Overall, the data show that both the methanolic and the hydroalcoholic A. arborescens extracts
determine significant inhibition of glycation and free-radical persistence, without any cytotoxic activity.
The data also show that the antiglycation and the antiradical activities of aloin and aloe-emodin are
lower than those of the two extracts. In relation to the permeability study, only aloe-emodin is able to
cross HT-29 cellular membranes, showing the attitude to pass through the intestinal layer. Overall, the
present data surely support the traditional use of A. arborescens leaf extracts against hyperglycemic
conditions, while aloin and aloe-emodin as potential drugs need further study.
KEYWORDS:
BSA assay; DPPH assay; MTT assay; antiglycation activity; cellular uptake; plant extracts
Ultrasound mediated accelerated Anti-influenza activity of Aloe vera.

Gansukh E, et al. Sci Rep. 2018 Dec 12;8(1):17782. doi: 10.1038/s41598-018-
35935-x.
Abstract
77
Aloe vera (AV) is popular and has been commercialized as a beauty product, laxative, herbal medicine,
the antimicrobial activity of AV is proven. The antiviral activity of AV however, has not been well
documented except for a handful reports. Till date extraction of AV compounds is popularized using
organic solvents, since the active components are effectively extracted in methanol. In the current work,
we have employed a 5 min ultrasound based extraction for the effective extraction of aloin and aloe-
emodin compounds from AV in water. This rapid, one-pot extraction process resulted in enhanced
extraction of flavonoids and phenolics and enrichment of the aloin and aloe-emodin moieties in the
ulrasonicated water extracts. The extracts were tested for their anti-influenza activity and, the results
showed that the ultrasound extraction enabled the water extracts to show excellent anti influenza
activity comparable to that seen in the methanolic extracts. Compared to the methanolic extracts which
showed high cytotoxicity, the water extracts showed zero cytotoxicity. Spectrophotometric scans of the
extracts confirmed the enrichment of the aloin and aloe emodin peaks in the ultrasonicated extracts of
AV, suggesting their handiwork behind the anti-influenza activity. The demonstrated technique if
appropriately implicated, would lead to promising solutions in the pharmaceutical pursuit against
influenza virus.
In vitro Fermentation of Polysaccharides from Aloe vera and the Evaluation of

Antioxidant Activity and Production of Short Chain Fatty Acids.
Tornero-Martínez A, et al. Molecules. 2019 Oct 7;24(19). pii: E3605. doi:
10.3390/molecules24193605.
Abstract
Soluble or fermentable fibre has prebiotic effects that can be used in the food industry to modify the
composition of microbiota species to benefit human health. Prebiotics mostly target Bifidobacterium
and Lactobacillus strains, among others, which can fight against chronic diseases since colonic
fermentation produces short chain fatty acids (SCFAs). The present work studied the changes produced
in the fibre and polyphenolic compounds during in vitro digestion of gel (AV) and a polysaccharide
extract (AP) from Aloe vera, after which, these fractions were subjected to in vitro colonic fermentation
to evaluate the changes in antioxidant capacity and SCFAs production during the fermentation. The
results showed that the phenolic compounds increased during digestion, but were reduced in
fermentation, as a consequence, the antioxidant activity increased significantly in AV and AP after the
digestion. On the other hand, during in vitro colon fermentation, the unfermented fibre of AV and AP
responded as lactulose and the total volume of gas produced, which indicates the possible use of Aloe
vera and polysaccharide extract as prebiotics.
KEYWORDS:
78
Aloe vera; Aloe vera polysaccharides; SCFAs; antioxidant capacity; in vitro fermentation
Dose-Dependent Effects of Aloin on the Intestinal Bacterial Community

Structure, Short Chain Fatty Acids Metabolism and Intestinal Epithelial Cell
Permeability.
Gokulan K, Kolluru P, Cerniglia CE, Khare S. Front Microbiol. 2019 Mar 26;10:474.
doi: 10.3389/fmicb.2019.00474. eCollection 2019.
Abstract
Aloe leaf or purified aloin products possess numerous therapeutic and pharmaceutical properties. It is
widely used as ingredients in a variety of food, cosmetic and pharmaceutical products. Animal studies
have shown that consumption of aloe or purified aloin cause intestinal goblet cell hyperplasia, and
malignancy. Here, we tested antibacterial effects of aloin, against intestinal commensal microbiota.
Minimum inhibitory concentration of aloin for several human commensal bacterial species (Gram-
positive and Gram-negative) ranged from 1 to 4 mg/ml. Metabolism studies indicated that Enterococcus
faecium was capable of degrading aloin into aloe-emodin at a slower-rate compared to Eubacterium
spp. As a proof of concept, we incubated 3% rat fecal-slurry (an in vitro model to simulate human colon
content) with 0.5, 1, and 2 mg/ml of aloin to test antimicrobial properties. Low aloin concentrations
showed minor perturbations to intestinal bacteria, whereas high concentration increased Lactobacillus
sp. counts. Aloin also decreased butyrate-production in fecal microbiota in a dose-dependent manner
after 24 h exposure. The 16S rRNA sequence-data revealed that aloin decreases the abundance of
butyrate-producing bacterial species. Transepithelial resistant result revealed that aloin alters the
intestinal barrier-function at higher concentrations (500 μM). In conclusion, aloin exhibits antibacterial
property for certain commensal bacteria and decreases butyrate-production in a dose -dependent
manner. HIGHLIGHTS -Aloin exhibits antibacterial properties for certain intestinal commensal bacteria.
-In rat fecal slurry (an in vitro model to simulate human colon content), longer aloin exposure (24 h)
decreases the butyrate production in dose dependent manner. -The 16s rRNA sequencing data show
that aloin decreased the abundance of butyrate producing bacterial species. -Rat intestinal
commensal bacteria metabolized aloin into aloe-emodin. -Aloin altered the intestinal epithelial cells
barrier integrity, however, the metabolic product of aloin - Aloe-emodin did not alter epithelial cells
permeability.
KEYWORDS:
aloin; antimicrobial activity; commensal bacterial community; epithelial cell barrier function; short chain
fatty acids
79
Alpha Lipoic Acid

Insights on the Use of α-Lipoic Acid for Therapeutic Purposes.
Salehi B, et al. Biomolecules. 2019 Aug 9;9(8). pii: E356. doi:
10.3390/biom9080356.
Abstract
α-lipoic acid (ALA, thioctic acid) is an organosulfur component produced from plants, animals, and
humans. It has various properties, among them great antioxidant potential and is widely used as a
racemic drug for diabetic polyneuropathy-associated pain and paresthesia. Naturally, ALA is located in
mitochondria, where it is used as a cofactor for pyruvate dehydrogenase (PDH) and α-ketoglutarate
dehydrogenase complexes. Despite its various potentials, ALA therapeutic efficacy is relatively low due
to its pharmacokinetic profile. Data suggests that ALA has a short half-life and bioavailability (about
30%) triggered by its hepatic degradation, reduced solubility as well as instability in the stomach.
However, the use of various innovative formulations has greatly improved ALA bioavailability. The R
enantiomer of ALA shows better pharmacokinetic parameters, including increased bioavailability as
compared to its S enantiomer. Indeed, the use of amphiphilic matrices has capability to improve ALA
bioavailability and intestinal absorption. Also, ALA's liquid formulations are associated with greater
plasma concentration and bioavailability as compared to its solidified dosage form. Thus, improved
formulations can increase both ALA absorption and bioavailability, leading to a raise in therapeutic
efficacy. Interestingly, ALA bioavailability will be dependent on age, while no difference has been found
for gender. The present review aims to provide an updated on studies from preclinical to clinical trials
assessing ALA's usages in diabetic patients with neuropathy, obesity, central nervous system-related
diseases and abnormalities in pregnancy.
Alpha Lipoic Acid Reduces Symptoms and Inflammation Biomarkers in

Patients with Chronic Hemorrhoidal Illness.
Šabanović M, et al. Int J Vitam Nutr Res. 2018 Dec;88(5-6):281-290. doi:
10.1024/0300-9831/a000251. Epub 2019 May 29.
80
Abstract
Background: Oral dietary supplementation is becoming increasingly popular as an addition to classical

approaches for the prevention and treatment of hemorrhoidal disease. Aim: To examine the effect of
orally administrated alpha lipoic acid (ALA), known for its antioxidant and anti-inflammatory properties,
in the treatment of patients with permanent symptoms of hemorrhoidal disease. Methods: Patients
with second- and third-degree hemorrhoids (n = 100) were enrolled into a randomized, open label,
single-center trial. The study group (n = 50) was treated with 200 mg of orally administered ALA once a
day during the 12-week period, the control group (n = 50) did not receive any treatment. Results: There
were no significant differences in demographics, diagnosis, or exposure to major risk factors between
the study and placebo group at baseline. ALA significantly improved subjective efficacy variables, such as
pain and discomfort (p < 0.01) as well as objective signs of the disease, such as bleeding (p < 0.01), in
comparison to the control group. Furthermore, the 3-month treatment significantly reduced the number
of patients with positive C-reactive protein (CRP) value (serum CRP > 5 mg/L) from 18% before to only
2% after the treatment (χ2 = 4.65; p < 0.01). Average leukocyte count has also been significantly reduced
in the treatment group (p < 0.01) from 7.29 × 109/L before to 6.18 × 109/L after treatment. Conclusions:
The obtained results indicate that ALA is effective in the treatment of second- and third-degree
hemorrhoids. Larger, double-blind controlled trials are needed to confirm the results and to investigate
optimal treatment regimens.
KEYWORDS:
Alpha lipoic acid; anti-inflammatory effect; clinical study; hemorrhoids
Prevention of Bortezomib-Related Peripheral Neuropathy With

Docosahexaenoic Acid and α-Lipoic Acid in Patients With Multiple Myeloma:
Preliminary Data.
Maschio M, et al. Integr Cancer Ther. 2018 Dec;17(4):1115-1124. doi:
10.1177/1534735418803758. Epub 2018 Oct 8.
Abstract
BACKGROUND AND AIMS:
Peripheral neuropathy is a common complication of chemotherapy that can induce marked disability
that negatively affects the quality of life in patients with multiple myeloma (MM). The aim of this study
was to prevent the onset or the worsening of peripheral neuropathy in MM patients treated with
bortezomib (BTZ), using a new nutritional neuroprotective compound. We report preliminary results of
18 out of 33 patients who completed the study.
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METHODS:
We administered a tablet of Neuronorm to patients, containing docosahexaenoic acid 400 mg, α-lipoic
acid 600 mg, vitamin C 60 mg, and vitamin E 10 mg bid for the whole follow-up period. Neurological visit
assessment, electroneurography, and evaluation scales were performed at baseline and after 6 months.
RESULTS:
At 6 months, 8 patients had no chemotherapy-induced peripheral neuropathy, while 10 patients

experienced chemotherapy-induced peripheral neuropathy of grade 1 according to the Common
Terminology Criteria for Adverse Events, one of them with pain. Seventeen patients did not report
painful symptoms; no limitation of functional autonomy and stability in quality of life domains explored
was observed.
CONCLUSIONS:
Our results seem to indicate that early introduction of a neuroprotective agent in our patients with MM
treated with BTZ could prevent the onset or the worsening of neuropathic pain, avoiding the
interruption of the therapy with BTZ, and maintaining a good functional autonomy to allow normal daily
activities. Despite the limitations due to the fact that this is a preliminary study, in a small population,
with short follow-up, our data seem to indicate that the nutraceutical may have some potential to be
considered for a future trial.
KEYWORDS:
ALA; DHA; bortezomib; docosahexaenoic acid; multiple myeloma; peripheral neuropathy; peripheral
neuropathy assessment; α-lipoic acid
A Case for Alpha-Lipoic Acid as an Alternative Treatment for Diabetic

Polyneuropathy.
Nguyen N, Takemoto JK. J Pharm Pharm Sci. 2018;21(1s):177s-191s. doi:
10.18433/jpps30100.
Abstract
PURPOSE:
The aim of this systematic review is to evaluate current evidence of alpha-lipoic acid (ALA) regarding
efficacy, safety, and cost to accurately compare it with other diabetic polyneuropathy (DPN) treatments.
The intention is to provide recommendations on future research and to promote utilization of ALA in the
United States (US).
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METHODS:
A literature search was conducted on three databases: Scopus, PubMed, and Web of Science. The
following criteria were used to select studies: (1) randomized controlled trials (RCTs) and open-label
trials on ALA, (2) review articles and meta-analyses of RCTs on ALA, (3) study population consisting of
patients with diabetes mellitus, peripheral neuropathic pain, and/or metabolic syndrome.
RESULTS:
Twenty-five publications were selected including five RCTs and three open-label studies. Most clinical
trials were conducted outside of the US. Current data provides evidence for the benefits of ALA in DPN
treatment at a dose of 600 mg per day, either intravenously (IV) or orally, for a duration of at least 3
weeks with minimal side effects.
CONCLUSIONS:
ALA demonstrates effectiveness in treating DPN through multiple mechanisms to modulate

pathophysiology and control symptoms. In addition, ALA exhibits activity in weight management and
insulin sensitivity. The use of ALA for DPN in the US is worth considering because commonly prescribed
medications have unclear mechanisms, more pronounced adverse effects, and are more expensive than
ALA. Further research needs to be conducted to assess long-term efficacy of ALA in US patients.
Non-pharmacologic treatments for symptoms of diabetic peripheral

neuropathy: a systematic review.
Amato Nesbit S, et al. Curr Med Res Opin. 2018 Aug 17:1-11. doi:
10.1080/03007995.2018.1497958. [Epub ahead of print]
Abstract
OBJECTIVE:
To systematically assess benefits and harm of non-pharmacologic interventions for diabetic peripheral
neuropathy (DPN) symptoms.
METHODS:
MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from 1966 to
May 24, 2016 for randomized controlled trials. Two reviewers evaluated studies for eligibility, serially
abstracted data, evaluated risk of bias, and graded strength of evidence (SOE) for critical outcomes (pain
and quality-of-life).
RESULTS:
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Twenty-three trials were included. For pain, alpha-lipoic acid was more effective than placebo
(moderate SOE) and frequency-modulated electromagnetic stimulation was more effective than sham
(low SOE) in the short-term but not the long-term. Electrical stimulation (including transcutaneous) was
not effective for pain (low SOE). Spinal cord stimulation was more effective than usual care for pain (low
SOE), but had serious complications, and studies had no sham arm. Evidence for cognitive behavioral
therapy and acupuncture was insufficient; no exercise or physical therapy trials met inclusion criteria.
No interventions reported sufficient evidence on quality-of-life. Most studies were short-term with
unclear risk of bias.
CONCLUSIONS:
Alpha-lipoic acid and spinal cord stimulation were effective for pain; studies were short-term with
quality deficits. Spinal cord stimulation had serious adverse events. Further research should address
long-term outcomes and other non-pharmacologic treatments.
KEYWORDS:
Diabetes; Diabetic peripheral neuropathy; Pain
Systemic administration of α-lipoic acid suppresses excitability of nociceptive

wide-dynamic range neurons in rat spinal trigeminal nucleus caudalis.
Hidaka S, et al. Neurosci Res. 2019 Jul;144:14-20. doi:
10.1016/j.neures.2018.06.003. Epub 2018 Jun 6.
Abstract
Although a modulatory role has been reported for α-lipoic acid (LA) on T-type Ca2+ channels in the
nervous system, the acute effects of LA in vivo, particularly on nociceptive transmission in the trigeminal
system, remain to be determined. The aim of the present study was to investigate whether acute
intravenous LA administration to rats attenuates the excitability of wide dynamic range (WDR) spinal
trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical
stimulation in vivo. Extracellular single unit recordings were made from seventeen SpVc neurons in
response to orofacial mechanical stimulation of pentobarbital-anesthetized rats. Responses to both non-
noxious and noxious mechanical stimuli were analyzed in the present study. The mean firing frequency
of SpVc WDR neurons in response to both non-noxious and noxious mechanical stimuli was significantly
and dose-dependently inhibited by LA (1-100 mM, i.v.) and maximum inhibition of the discharge
frequency of both non-noxious and noxious mechanical stimuli was seen within 5 min. These inhibitory
effects lasted for approximately 10 min. These results suggest that acute intravenous LA administration
suppresses trigeminal sensory transmission, including nociception, via possibly blocking T-type Ca2+
channels. LA may be used as a therapeutic agent for the treatment of trigeminal nociceptive pain.
84
Effect of α-lipoic acid on symptoms and quality of life in patients with painful
diabetic neuropathy.
Agathos E, et al. J Int Med Res. 2018 May;46(5):1779-1790. doi:
10.1177/0300060518756540. Epub 2018 Mar 8.
Abstract
Objective To examine the effect of α-lipoic acid on neuropathic symptoms in patients with diabetic
neuropathy (DN). Methods Patients with painful DN were treated with 600 mg/day α-lipoic acid, orally,
for 40 days. Neuropathy Symptom Score (NSS), Subjective Peripheral Neuropathy Screen Questionnaire
(SPNSQ) and douleur neuropathique (DN)4 questionnaire scores were assessed at baseline and day 40.
Quality-of-life treatment effects were assessed by Brief Pain Inventory (BPI), Neuropathic Pain Symptom
Inventory (NPSI) and Sheehan Disability Scale (SDS). Changes in body weight, arterial blood pressure,
fasting serum glucose and lipids were also assessed. Results Out of 72 patients included, significant
reductions in neuropathic symptoms were shown by reduced NSS, SPNSQ and DN4 scores at day 40
versus baseline. BPI, NPSI, and SDS in terms of work disability, social life disability, and family life
disability scores were also significantly reduced. Moreover, 50% of patients rated their health condition
as 'very much better' or 'much better' following α-lipoic acid administration. Fasting triglyceride levels
were reduced, but no difference was found in body weight, blood pressure, fasting glucose, or other
lipids at day 40 versus baseline. Conclusions A-lipoic acid administration was associated with reduced
neuropathic symptoms and triglycerides, and improved quality of life.
Comparative evaluation of the electrophysiological, functional and

ultrastructural effects of alpha lipoic acid and cyanocobalamin administration
in a rat model of sciatic nerve injury.
Horasanli B, et al. J Back Musculoskelet Rehabil. 2017 Sep 22;30(5):967-974. doi:
10.3233/BMR-150386.
Abstract
BACKGROUND:
Vitamin B12 and alpha lipoic acid (ALA) are known to promote functional and morphological recovery
after peripheral nerve injury.
OBJECTIVE:
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To compare the regenerative and neuroprotective effects of vitamin B12 and ALA treatment after sciatic
nerve injury.
METHODS:
A total of 40 rats were randomly assigned to control (sciatic nerve exposure without injury or
anastomosis), sham (sciatic nerve injury and epineural anastomosis were performed but no treatment
was administered), PS (isotonic saline was administered for 12 weeks after surgery), ALA (2 mg/kg ALA
was administered for 12 weeks after surgery), and vitamin B12 groups (2 mg/kg cyanocobalamin was
administered for 12 weeks after surgery). Functional recovery was determined by footprint analysis, in
vivo neurophysiology, and ex vivo histopathological examination.
RESULTS:
ALA treatment produced significant improvements in sciatic functional index values and non-significant
improvements on electroneuromyography compared to vitamin B12 treatment. Upon histopathological
examination, the regenerative effects of ALA were relevant to axonal structural recovery whereas
vitamin B12 produced greater improvements in edema and myelination.
CONCLUSIONS:
While both vitamin B12 and ALA produced improvements after sciatic nerve injury, ALA was more
functionally effective. The unique ultrastructural effects of vitamin B12 and ALA treatment should be
considered in future studies.
KEYWORDS:
Alpha lipoic acid; cyanocobalamin; electroneuromyography; nerve regeneration; neuroprotection;

sciatic nerve injury
Combination Analgesic Development for Enhanced Clinical Efficacy (CADENCE

Trial): Study Protocol for a Double-Blind, Randomized, Placebo-Controlled
Crossover Trial of an Alpha-Lipoic Acid - Pregabalin Combination for the
Treatment of Fibromyalgia Pain.
Gilron I, Tu D, Holden R, Towheed T, Vandenkerkhof E, Milev R. JMIR Res Protoc.
2017 Aug 4;6(8):e154. doi: 10.2196/resprot.8001.
Abstract
BACKGROUND:
86
Fibromyalgia is a clinical disorder commonly presenting with chronic widespread pain as well as sleep
disturbance, fatigue, depression, and cognitive dysfunction. There is an urgent need for treatment
strategies that provide better pain relief and fewer adverse effects (AEs). Efforts to develop rational
combinations of specific fibromyalgia treatments have demonstrated potential for measurable
improvements in pain relief, quality of life, and health care utilization. More than half of fibromyalgia
patients receive 2 or more analgesics but current combination use is based on limited evidence. As an
early proof-of-concept project from the Canadian Institutes of Health Research-Strategy on Patient-
Oriented Research Chronic Pain Network, this trial protocol is expected to advance the field by
rigorously evaluating a new treatment combination for fibromyalgia.
OBJECTIVE:
We will test the hypothesis that analgesic combinations containing at least one nonsedating agent
would be as safe but more effective than either monotherapy because of additive pain relief without
increasing overall AEs. Pregabalin (PGB), a sedating anticonvulsant, is proven effective for fibromyalgia,
and the antioxidant, alpha-lipoic acid (ALA), one of the only nonsedating systemic agents proven
effective for neuropathic pain, is currently being evaluated in fibromyalgia. Thus, we will conduct a
clinical trial to compare a PGB+ALA combination to each monotherapy for fibromyalgia.
METHODS:
Using a double-blind, double-dummy, crossover design, 54 adults with fibromyalgia will be randomly
allocated to 1 of 6 sequences of treatment with PGB, ALA, and PGB+ALA combination. During each of 3
different treatment periods, participants will take 2 sets of capsules containing (1) ALA (or placebo) and
(2) PGB (or placebo) for 31 days, followed by an 11-day taper/washout period. The primary outcome will
be mean daily pain intensity (0 to 10 scale) at maximal tolerated doses (MTDs) during each period.
Secondary outcomes, assessed at MTD, will include global improvement, adverse events, mood, and
quality of life.
RESULTS:
This trial attained ethics approval March 6, 2017 (Queen's University Health Sciences and Affiliated
Teaching Hospitals Research Ethics Board protocol number ANAE-313-17), and recruitment is set to start
in August 2017.
CONCLUSIONS:
This trial will provide rigorous evidence comparing the efficacy of a PGB-ALA combination to PGB alone
and ALA alone in the treatment of fibromyalgia.
TRIAL REGISTRATION:
International Standard Randomized Controlled Trial Number ISRCTN14939460; https://www.isrctn.com/

ISRCTN1493946 (Archived by WebCite at http://www.webcitation.org/6sFqAjxkt).
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Pain Improvement With Novel Combination Analgesic Regimens (PAIN-CARE):

Randomized Controlled Trial Protocol.
Gilron I, et al. JMIR Res Protoc. 2017 Jun 8;6(6):e111. doi: 10.2196/resprot.7493.
Abstract
BACKGROUND:
Neuropathic pain (NP) (including painful diabetic neuropathy, postherpetic neuralgia, etc) affects
approximately 7% to 8% of the population and is associated with a devastating symptom burden as well
as a profound economic impact for patients, their families, and the health care system. Current
therapies have limited efficacy and dose-limiting adverse effects (AEs). Rational combination therapy
with carefully selected NP drugs has shown potential for measurable improvements in pain relief,
quality of life, and health care use. Today, over half of NP patients concurrently receive 2 or more
analgesics but combination use is based on little evidence. Research is urgently needed to identify safer,
more effective combinations.
OBJECTIVE:
We hypothesize that analgesic combinations containing at least 1 nonsedating agent would be as safe
but more effective than either monotherapy without increasing overall AEs because of additive pain
relief. Pregabalin (PGB), a sedating anticonvulsant, is proven effective for NP; the antioxidant alpha-
lipoic acid (ALA) is one of the only nonsedating systemic agents proven effective for NP. Thus, we will
conduct a clinical trial to compare a PGB+ALA combination to each monotherapy for NP.
METHODS:
Using a double-blind, double-dummy, crossover design, 54 adults with NP will be randomly allocated to
1 of 6 sequences of treatment with PGB, ALA and PGB+ALA combination. During each of 3 different
treatment periods, participants will take 2 sets of capsules containing (1) ALA or placebo and (2) PGB or
placebo for 31 days, followed by an 11-day taper/washout period. The primary outcome will be mean
daily pain intensity (0-10) at maximally tolerated dose (MTD) during each period. Secondary outcomes,
assessed at MTD, will include global improvement, adverse events, mood, and quality of life.
RESULTS:
Participant recruitment is expected to begin September 1, 2017. The proposed trial was awarded
external peer-reviewed funding by the Canadian Institutes of Health Research (Canada) on July 15, 2016.
CONCLUSIONS:
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This trial will provide rigorous evidence comparing the efficacy of a PGB+ALA combination to PGB alone
and ALA alone in the treatment of NP.
KEYWORDS:
alpha-lipoic acid; anticonvulsant; antioxidant; neuropathic pain; pregabalin
Observational multicentric study on chronic sciatic pain: clinical data from 44

Italian centers.
Checchia GA, et al. Eur Rev Med Pharmacol Sci. 2017 Apr;21(7):1653-1664.
Abstract
OBJECTIVE:
To provide information on the clinical presentation of sciatic neuropathy and its management in a real-
world setting, and to analyze the effects of a multimodal approach based on the association of physical
and pharmacological therapy.
PATIENTS AND METHODS:
A multicentric observational prospective study was conducted in 44 Italian tertiary centers specialized in
Physical Medicine and Rehabilitation, Orthopedics, Neurology, Neurosurgery, and Rheumatology. To
develop a shared management of LPB with sciatica, a dedicated clinical record was proposed to collect
data about diagnosis, treatment, and outcomes. Pain, disability, and quality of life were recorded trough
validated questionnaires at baseline and after a two-month follow-up.
RESULTS:
394 patients (age, mean ± SD 55.7 ± 14.1 years, 57.1% females) with chronic LBP and sciatica were
enrolled in the study. The characteristics of the selected group showed a certain variability in the clinical
presentation. At baseline, patients received several different therapeutic options among physical,
pharmacological and neurotrophic treatments. A subgroup of 312 patients was treated with a
combination of neurotrophic agents containing alpha-lipoic acid (ALA). After a two-month follow-up, a
general improvement in both perceived pain and functional disabilities was observed. A significant
improvement (p < 0.001) in the Pain Numeric Rating Scale (NRS), Roland e Morris Disability
Questionnaire (RMDQ) and Brief Pain Inventory (BPI) Italian short version was observed.
CONCLUSIONS:
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Sciatic neuropathy is a multifaceted condition managed by means of a wide spectrum of therapeutic

options. The results of this study suggest that a multimodal approach based on the association of ALA
with physical and pharmacological therapies can be beneficial in the treatment of LBP with sciatica.
Innovations in the Management of Musculoskeletal Pain With Alpha-Lipoic

Acid (IMPALA Trial): Study protocol for a Double-Blind, Randomized, Placebo-
Controlled Crossover Trial of Alpha-Lipoic Acid for the Treatment of
Fibromyalgia Pain.
Gilron I, et al. JMIR Res Protoc. 2017 Mar 28;6(3):e41. doi: 10.2196/resprot.7198.
Abstract
BACKGROUND:
Fibromyalgia is a common disorder characterized by chronic widespread pain, sleep disturbance,

fatigue, depression, and cognitive dysfunction, resulting in substantial disability. As current analgesics
provide incomplete relief and disabling side effects that aggravate fatigue and cognitive dysfunction,
there is a need for new pain treatments with better efficacy and tolerability. Alpha-lipoic acid (ALA) is an
antioxidant proven effective in painful diabetic neuropathy with minimal side effects.
OBJECTIVE:
We hypothesize that this agent will provide benefits in fibromyalgia because of several similarities with
neuropathic pain and also because it does not cause sedation, fatigue, or mental-slowing. To test this,
we have designed a clinical trial that will assess pain, side effects, and other outcomes in participants
with fibromyalgia.
METHODS:
Using a crossover design, 24 adults with fibromyalgia will be randomly allocated to 1 of the 2 sequences
of ALA and placebo. Participants will take capsules containing ALA or placebo for 4 weeks followed by a
1-week washout followed by a second 4-week treatment and 1-week washout period. ALA (or matching
placebo) capsules will be titrated to 1800 mg/day over each 4-week period. The primary outcome will be
mean daily pain intensity (0-10) during week 4 of each period. Secondary outcomes, assessed during
week 4 of each period, will include global improvement, adverse events, mood, and quality of life.
RESULTS:
This trial was registered in the International Standard Randomized Controlled Trial registry March 15,
2016 (Number ISRCTN58259979), and it attained ethics approval on December 3, 2016 (Queen's
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University Health Sciences & Affiliated Teaching Hospitals Research Ethics Board protocol number ANAE-
287-15). The recruitment started in February 2017.
CONCLUSIONS:
This trial will provide evidence for the efficacy of ALA in fibromyalgia.
KEYWORDS:
alpha-lipoic acid; antioxidants; fibromyalgia; pain
Alpha-lipoic Acid After Median Nerve Decompression at the Carpal Tunnel: A

Randomized Controlled Trial.
Boriani F, et al. J Hand Surg Am. 2017 Apr;42(4):236-242. doi:
10.1016/j.jhsa.2017.01.011. Epub 2017 Feb 28.
Abstract
PURPOSE:
The postoperative course of median nerve decompression in carpal tunnel syndrome may be associated
with complications. The aim of this study was to explore the possible effects of alpha-lipoic acid (ALA) in
the postoperative period after surgical decompression of the median nerve at the wrist.
METHODS:
We conducted a double-blind prospective, randomized, controlled trial. A total of 64 patients with

proven carpal tunnel syndrome were enrolled and randomly assigned into 1 of 2 groups: group A (n =
32) patients had surgical decompression of the median nerve followed by ALA for 40 days, and group P
(n = 32) patients had surgical decompression followed by placebo. The primary end point of the study
was a comprehensive indicator of sensory and motor nerve conduction velocity (electrophysiology
score) at 3 months after surgery, Other end points were static 2-point discrimination, Boston Carpal
Tunnel score, presence or absence of pillar pain, and use of analgesics beyond the second postoperative
day.
RESULTS:
Alpha-lipoic acid did not improve nerve conduction velocity or Boston Carpal Tunnel score significantly.
However, a statistically significant reduction in the postoperative incidence of pillar pain was noted in
the ALA group. In addition, static 2-point discrimination improved in both groups.
CONCLUSIONS:
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Postoperative administration of ALA for 40 days after median nerve decompression may result in a
lower incidence of pillar pain. This treatment is relatively well tolerated, which may support its value as
standard postoperative supplementation after carpal tunnel decompression if further studies on larger
samples confirm these preliminary findings.
TYPE OF STUDY/LEVEL OF EVIDENCE:
Therapeutic I.
KEYWORDS:
Carpal tunnel syndrome; alpha-lipoic acid; median nerve decompression; pillar pain
Arnica
Lychnophora pinaster ethanolic extract and its chemical constituents
ameliorate hyperuricemia and related inflammation.
Martins de Sá Müller C, Coelho GB, Carolina de Paula Michel Araújo M, Saúde-
Guimarães DA. J Ethnopharmacol. 2019 Oct 5;242:112040. doi:
10.1016/j.jep.2019.112040. Epub 2019 Jun 25.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE:
Lychnophora pinaster, known as "Brazilian arnica" is used in folk medicine as alcoholic extract to treat
inflammation, pain, rheumatism and bruises.
AIM OF THE STUDY:
Evaluate the effects of the Lychnophora pinaster's ethanolic extract and its chemical constituents on
inflammation and hyperuricemia.
Ethanolic and hexanic extracts were obtained from the aerial parts of L. pinaster. Sesquiterpene E-
lychnophoric acid was isolated from hexanic extract and identified by RMN, GC/MS and IR. In vivo anti-
hyperuricemic and anti-inflammatory effects of the ethanolic extracts from L. pinaster (40, 125,
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375 mg/kg), E-lychnophoric acid and other constituents previous isolated from L. pinaster and identified
in the ethanolic extract by HPLC/UV/DAD (rutin, quercetin and vitexina flavonoids, caffeic, cinnamic and
chlorogenic acids, lupeol and stigmasterol, at dose of 15 mg/kg) were assayed by experimental model of
oxonate-induced hyperuricemia in Swiss mice, liver xanthine oxidase (XOD) inhibition and by MSU-
induced paw edema in mice.
RESULTS:
Ethanolic extract and all its components presented anti-hyperuricemic activity by inhibiting the hepatic
xanthine oxidase activity. Ethanolic extract and its chemical constituents, except quercetin and vitexin,
were able to reduce paw edema size induced by urate crystals. Hypouricemic and anti-inflammatory
results obtained for the ethanolic extract (40, 125, 375 mg/kg) and E-lychnophoric acid (15 mg/kg) were
similar those obtained for standard drugs, allopurinol (10 mg/kg) and indomethacin (3 mg/kg).
CONCLUSION:
Ethanolic extract and E-lychnophoric, chlorogenic, cinnamic and caffeic acids, rutin, lupeol and
stigmasterol presented anti-inflammatory and anti-hyperuricemic actvities. These compounds are
responsible for the activities presented by the ethanolic extract of L. pinaster. Ethanolic extract and its
chemical constituents can be considered promising agents in the therapeutic of inflammation,
hyperuricemia and gout.
KEYWORDS:
Brazilian arnica; E-lychnophoric acid; Gout; Hyperuricemia; Inflammation; Xanthine oxidase
An integrated approach with homeopathic medicine and electro-acupuncture

in anaesthesiology during breast cancer surgery: Case reports.
Bosco F, et al. J Pharmacopuncture. 2018 Jun;21(2):126-131. doi:
10.3831/KPI.2018.21.016. Epub 2018 Jun 30.
https://www.ncbi.nlm.nih.gov/pubmed/?term=An+integrated+approach+with+homeopathic+medicine+
and+electro-acupuncture+in+anaesthesiology+during+breast+cancer+surgery%3A+Case+reports.
Abstract
This study investigates the effect of a combination of homeopathic medicine and electro-acupuncture in
two patients with breast cancer and severe liver disease who could not receive standard anaesthesia
therapy due to liver problems. Specifically, measurable and quantifiable parameters were used to
evaluate whether an integrated approach-consisting of electro-acupuncture and a homeopathic
medicine diluted above Avogadro's limit (that is, above a potency of 12CH) during the pre-surgical,
surgical and post-surgical phases--can improve general well-being of a patient undergoing breast cancer
surgery. In breast cancer surgery, we employed an integrated approach consisting of induction with
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hypnotics and muscle relaxants, followed by maintenance with anaesthetic gas, combined with a
homeopathic treatment (Arnica montana 15CH and Apis mellifica 15CH) before and after surgery and an
electro-acupuncture treatment performed in the pre- and post-surgical phases without any
analgesic/pain relieving medications. Both of the patients treated with the integrated approach
improved their overall condition without need for other common pain relieving medicines. Additionally,
thanks to their rapid awakening, the patients were not relocated to a protected area and the
hospitalization was shorter. A multidisciplinary approach incorporating homeopathic medicine and
electro-acupuncture can be a solution for patients who need or ask about a different and/or safer
alternative to the standard treatment. This approach can offer a safe, much less expensive, non-invasive
and viable alternative for such cases. Moreover it can be useful for an opioids free anesthesia.
KEYWORDS:
Anaesthesiology; Breast cancer; Electro-acupuncture; Homeopathy; Multidisciplinary approach
Arnica compositum, Hekla lava and Acidum Nitricum Together are Superior to
Arnica compositum Alone in the Local Treatment of Symptomatic Calcific
Periarthritis of the Shoulder: A Pilot Study.
Zanella S, et al. Rev Recent Clin Trials. 2018;13(2):150-155. doi:
10.2174/1574887113666180319165700.
Abstract
BACKGROUND:
To evaluate the usefulness of Arnica compositum (AC) + Acidum nitricum (AN) + Hekla lava (HL)
ointment in Emergency Medicine Department (EMD) as alternative nonpharmacological local treatment
of patients with symptomatic calcific periarthritis of the shoulder (CPS) and to compare the
effectiveness of this mixture against AC ointment alone.
METHODS:
A series of 41 consecutive patients (20 women, 19 men, median age 49 years, range 25-80 years) with
non-traumatic painful unilateral CPS were randomly assigned to receive local treatment with AC+AN+HL
ointment mixture (Group A, cases, N=21) or AC ointment alone (Group B, controls, N=20). The
radiological Gartner classification of the CPS, and the quantification of pre- and post-treatment pain
intensity using a Visual Analogue Scale (VAS) were obtained. The orthopedic evaluation of Shoulder
Motion (SM) was also performed. The use of painkillers was reported as a number of doses needed.
RESULTS:
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Age, gender distribution, Gartner type, main calcification size, baseline VAS (VAS-0) and degree of SM
did not differ (p=NS) between Groups. After 3-day therapy, the reduction of pain in Group A (4.5±2.5)
was superior to that observed in Group B (2.7±2.6) (p =0.03). The same result was observed in the
improvement of SM in Group A (69.4±24.9) than in Group B (51.1±21.1) (p =0.015). No local or general
adverse effects were noted. The number of doses of paracetamol was similar, but Group A patients used
less ibuprofen (p =0.007).
CONCLUSION:
Local administration of the AC+AN+HL ointment mixture, which in our pilot study was superior to AC
alone, could be safely suggested as an alternative uneventful treatment of patients with CPS.
KEYWORDS:
Acidum nitricum; anti-inflammatory activity; arnica compositum; calcific periarthritis of the shoulder;
hekla lava.
Phytomedicine in Joint Disorders.

Dragos D, et al. Nutrients. 2017 Jan 16;9(1). pii: E70. doi: 10.3390/nu9010070.
Abstract
Chronic joint inflammatory disorders such as osteoarthritis and rheumatoid arthritis have in common an
upsurge of inflammation, and oxidative stress, resulting in progressive histological alterations and
disabling symptoms. Currently used conventional medication (ranging from pain-killers to biological
agents) is potent, but frequently associated with serious, even life-threatening side effects. Used for
millennia in traditional herbalism, medicinal plants are a promising alternative, with lower rate of
adverse events and efficiency frequently comparable with that of conventional drugs. Nevertheless,
their mechanism of action is in many cases elusive and/or uncertain. Even though many of them have
been proven effective in studies done in vitro or on animal models, there is a scarcity of human clinical
evidence. The purpose of this review is to summarize the available scientific information on the
following joint-friendly medicinal plants, which have been tested in human studies: Arnica montana,
Boswellia spp., Curcuma spp., Equisetum arvense, Harpagophytum procumbens, Salix spp., Sesamum
indicum, Symphytum officinalis, Zingiber officinalis, Panax notoginseng, and Whitania somnifera.
KEYWORDS:
herbs; medicinal plants; osteoarthritis; rheumatoid arthritis

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Feasibility, acceptability, and tolerability of RGN107 in the palliative wound

care management of chronic wound symptoms.
Madisetti M, Kelechi TJ, Mueller M, Amella EJ, Prentice MA. J Wound Care. 2017
Jan 2;26(Sup1):S25-S34. doi: 10.12968/jowc.2017.26.Sup1.S25.
Abstract
OBJECTIVE:
To assess the feasibility, acceptability and tolerability of RGN107 use, a natural powder blend of Arnica
Montana, Calendula Officinalis, Mentha Arvensis and Santalum Album, among hospice patients and
their wound caregivers in the palliative wound care management of chronic wound symptoms at end-of-
life.
METHOD:
Data were collected between May 2013 and November 2015. A pilot trial conducted among 50 hospice
patients with symptomatic (pain, odour, or exudate) chronic wounds. Caregivers received initial RGN107
protocol training, actively applied the powder to patient wounds for 4-weeks, and completed an 8-week
retrospective survey. Feasibility was assessed by measuring process outcomes, including the number
and proportion of participants referred, screened eligible, enrolled, withdrawn and successfully
completed. Acceptability measures included: a protocol training evaluation, caregiver pre and post self-
efficacy ratings, retrospective usability, symptom control management and comparative technique
caregiver ratings, and recorded open-ended comments. Tolerability was assessed through a 12-week
cumulative review of the study adverse event profile.
RESULTS:
Feasibility, tolerability and acceptability of use of the RGN107 powder for chronic wounds were
established. Recruitment goals were achieved and 92 % of the patients successfully completed the
study. 95 % of wound caregivers would recommend the powder for use in this population.
CONCLUSION:
This study supports the feasibility, acceptability and tolerability of a wound care powder that espouses a
multi-symptom palliative comfort care approach for hospice patients with chronic wounds at end-of-life.
Further research is needed to establish the efficacy of the powder.
KEYWORDS:
chronic wounds; hospices; palliative wound care; wound exudate; wound odour; wound pain
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The influence of seasonality on the content of goyazensolide and on anti-

inflammatory and anti-hyperuricemic effects of the ethanolic extract of
Lychnophora passerina (Brazilian arnica).
de Albuquerque Ugoline BC, et al. J Ethnopharmacol. 2017 Feb 23;198:444-450.
doi: 10.1016/j.jep.2017.01.017. Epub 2017 Jan 12.
Abstract
Lychnophora passerina (Mart ex DC) Gardn (Asteraceae), popularly known as Brazilian arnica, is used in
Brazilian folk medicine to treat pain, rheumatism, bruises, inflammatory diseases and insect bites.
AIM OF THE STUDY:
Investigate the influence of the seasons on the anti-inflammatory and anti-hyperuricemic activities of
ethanolic extract of L. passerina and the ratio of the goyazensolide content, main chemical constituent
of the ethanolic extract, with these activities.
Ethanolic extracts of aerial parts of L. passerina were obtained from seasons: summer (ES), autumn (EA),
winter (EW) and spring (EP). The sesquiterpene lactone goyazensolide, major metabolite, was quantified
in ES, EA, EW and EP by a developed and validated HPLC-DAD method. The in vivo anti-hyperuricemic
and anti-inflammatory effects of the ethanolic extracts from L. passerina and goyazensolide were
assayed on experimental model of oxonate-induced hyperuricemia in mice, liver xanthine oxidase (XOD)
inhibition and on carrageenan-induced paw edema in mice.
RESULTS:
HPLC method using aqueous solution of acetic acid 0.01% (v/v) and acetonitrile with acetic acid 0.01%
(v/v) as a mobile phase in a gradient system, with coumarin as an internal standard and DAD detection
at 270nm was developed. The validation parameters showed linearity in a range within 10.0-
150.0µg/ml, with intraday and interday precisions a range of 0.61-3.82. The accuracy values of intraday
and interday analysis within 87.58-100.95%. EA showed the highest goyazensolide content. From the
third to the sixth hour after injection of carrageenan, treatments with all extracts at the dose of
125mg/kg were able to reduce edema. Goyazensolide (10mg/kg) showed significant reduction of paw
swelling from the second hour assay. This sesquiterpene lactone was more active than extracts and
presented similar effect to indomethacin. Treatments with ES, EA and EP (125mg/kg) and goyazensolide
(10mg/kg) reduced serum urate levels compared to hyperuricemic control group and were able to
inhibit liver XOD activity. One of the mechanisms by which ES, EA, EP and goyazensolide exercise their
anti-hyperuricemic effect is by the inhibition of liver XOD activity. Goyazensolide was identified as the
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main compound present in ES, EA, EW and EP and it is shown to be one of the chemical constituents
responsible for the anti-inflammatory and anti-hyperuricemic effects of the ethanolic extracts.
CONCLUSION:
The anti-inflammatory and anti-hyperuricemic activities of the ethanolic extracts from L. passerina were
not proportionally influenced by the variation of goyazensolide content throughout the seasons. The
involvement of goyazensolide on in vivo anti-inflammatory and anti-hyperuricemic activities of
L.passerina extracts was confirmed, as well as the possibility of participation of other constituents on
these effects. This study demonstrated that the aerial parts of L. passerina may be collected in any
season for use as anti-inflammatory agent. For use in hyperuricemia, the best seasons for the collection
are summer, autumn and spring. The ethanolic extract of L. passerina and goyazensolide can be
considered promising agents in the therapeutic of inflammation, hyperuricemia and gout.
KEYWORDS:
Gout; Hyperuricemia; Inflammation; Lychnophora passerina; Seasonality
Mexican Arnica (Heterotheca inuloides Cass. Asteraceae: Astereae):

Ethnomedical uses, chemical constituents and biological properties.
Rodríguez-Chávez JL, et al. J Ethnopharmacol. 2017 Jan 4;195:39-63. doi:
10.1016/j.jep.2016.11.021. Epub 2016 Nov 12.
Abstract
Heterotheca inuloides Cass. (Asteraceae) has been traditionally used to treat a wide range of diseases in
Mexico in the treatment of rheumatism, topical skin inflammation, muscular pain colic, and other
painful conditions associated with inflammatory processes, additionally has been used to treat dental
diseases, and gastrointestinal disorders. This species has also been used for the treatment of cancer and
diabetes. This review provides up-to-date information on the botanical characterization, traditional
uses, chemical constituents, as well as the biolological activities of H. inuloides.
MATERIAL AND METHODS:
A literature search was conducted by analyzing the published scientific material. Information related to
H. inuloides was collected from various primary information sources, including books, published articles
in peer-reviewed journals, monographs, theses and government survey reports. The electronic search of
bibliographic information was gathered from accepted scientific databases such as Scienfinder, ISI Web
of Science, Scielo, LILACS, Redalyc, Pubmed, SCOPUS and Google Scholar.
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RESULTS:
To date, more than 140 compounds have been identified from H. inuloides, including cadinane
sesquiterpenes, flavonoids, phytosterols, triterpenes, benzoic acid derivatives, and other types of
compounds. Many biological properties associated with H. inuloides. Many studies have shown that the
extracts and some compounds isolated from this plant exhibit a broad spectrum of biological activities
such as antioxidant, antitumor, anti-inflammatory, cytotoxic, and chelating activities, as well as
insecticidal and phytotoxic activity. To date, reports on the toxicity of H. inuloides are limited.
CONCLUSIONS:
A comprehensive analysis of the literature obtained through the above-mentioned sources confirmed
that ethnomedical uses of H. inuloides have been recorded in Mexico to treat rheumatism, pain, and
conditions associated with inflammatory processes. Pharmacological studies have demonstrated the
activity of certain compounds associated with the traditional use of the plant such as the anti-
inflammatory and cytotoxic activities of the species. The available literature showed that cadinene
sesquiterpenes are the major bioactive components of H. inuloides with potential pharmacological
activities. Further investigations are needed to fully understand the mode of action of the major active
constituents.
Physiotherapy and a Homeopathic Complex for Chronic Low-back Pain Due to

Osteoarthritis: A Randomized, Controlled Pilot Study.
Morris M, Pellow J, Solomon EM, Tsele-Tebakang T. Altern Ther Health Med. 2016
Jan-Feb;22(1):48-56.
Abstract
CONTEXT:
Osteoarthritis (OA) is a common cause of chronic low-back pain (CLBP) and can be managed with drug
therapy and physiotherapy. Homeopathic remedies may assist managing OA; however, research that
supports their effectiveness is limited.
OBJECTIVES:
The study aimed to investigate the efficacy of a homeopathic complex in combination with
physiotherapy in treating CLBP due to OA.
DESIGN:
The study was a 6-wk, randomized, double-blind, placebo-controlled pilot.

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SETTING:
The study took place in a private physiotherapy practice in Gauteng, South Africa.
PARTICIPANTS:
The participants were 30 males and females, aged 45-75 y, who were receiving physiotherapy treatment
for OA of the lumbar spine from a therapist in private practice.
INTERVENTIONS:
The intervention and control groups both received standard physiotherapy treatment-massage, thermal
therapy, and joint mobilization-every 2 wk. In addition, the treatment group received a homeopathic
complex-6cH each of Arnica montana, Bryonia alba, Causticum, Kalmia latifolia, Rhus toxicodendron,
and Calcarea fluorica. The control group a received a placebo.
OUTCOME MEASURES:
The primary measure was a visual analogue scale (VAS) for pain. Secondary outcome measures included
the Oswestry Disability Index (ODI), an evaluation of each patient's range of motion (ROM) of the lumbar
spine, and a determination of each patient's need for pain medication.
RESULTS:
Intergroup analysis revealed that the treatment group significantly outperformed the control group with
regard to pain, daily functioning, and ROM. No difference existed between the groups, however, in the
need for conventional pain medication.
CONCLUSIONS:
The study was too small to be conclusive, but results suggest the homeopathic complex, together with
physiotherapy, can significantly improve symptoms associated with CLBP due to OA.
Herbal Medicine for Low Back Pain: A Cochrane Review.

Gagnier JJ, et al. Spine (Phila Pa 1976). 2016 Jan;41(2):116-33. doi:
10.1097/BRS.0000000000001310.
Abstract
STUDY DESIGN:
Systematic review of randomized controlled trials (RCTs).
OBJECTIVES:
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To determine the effectiveness of herbal medicine for nonspecific low back pain (LBP).
SUMMARY OF BACKGROUND DATA:
Many people with chronic LBP use complementary and alternative medicine (CAM), visit CAM
practitioners, or both. Several herbal medicines have been purported for use in treating people with
LBP. This is an update of a Cochrane Review first published in 2006.
METHODS:
We searched numerous electronic databases up to September 2014; checked reference lists in review
articles, guidelines and retrieved trials; and personally contacted individuals with expertise in this area.
We included RCTs examining adults (over 18 years of age) suffering from acute, sub-acute, or chronic
nonspecific LBP. The interventions were herbal medicines that we defined as plants used for medicinal
purposes in any form. Primary outcome measures were pain and function. Two review authors assessed
risk of bias, GRADE criteria (GRADE 2004), and CONSORT compliance and a random subset were
compared with assessments by a third individual. Two review authors assessed clinical relevance and
resolved any disagreements by consensus.
RESULTS:
Fourteen RCTs (2050 participants) were included. Capsicum frutescens (cayenne) reduces pain more
than placebo. Although Harpagophytum procumbens (devil's claw), Salix alba (white willow bark),
Symphytum officinale L. (comfrey), Solidago chilensis (Brazilian arnica), and lavender essential oil also
seem to reduce pain more than placebo, evidence for these substances was of moderate quality at best.
No significant adverse events were noted within the included trials.
CONCLUSIONS:
Additional well-designed large trials are needed to test these herbal medicines against standard
treatments. In general, the completeness of reporting in these trials was poor. Trialists should refer to
the CONSORT statement extension for reporting trials of herbal medicine interventions.
Cumulative therapeutic effects of phytochemicals in Arnica montana flower

extract alleviated collagen-induced arthritis: inhibition of both pro-
inflammatory mediators and oxidative stress.
Sharma S, Arif M, Nirala RK, Gupta R, Thakur SC. J Sci Food Agric. 2016 Mar
30;96(5):1500-10. doi: 10.1002/jsfa.7252. Epub 2015 May 29.
Abstract
BACKGROUND:
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The plant Arnica montana is used in folk medicine to alleviate pain, inflammation and swelling of
muscles and joints associated with rheumatoid arthritis and other inflammatory conditions. The present
study aimed to investigate the therapeutic effects and mechanism of action of A. montana flower
methanol extract (AMME) against both inflammation and oxidative stress in a collagen-induced arthritis
(CIA) rat model.
RESULTS:
Oral administration of AMME was found to reduce clinical signs and improve the histological and
radiological status of the hind limb joints. AMME-treated rats had lower expression levels of nitric oxide,
tumor necrosis factor-α, interleukins (IL-1β, IL-6 and IL-12) and titer of anti-type II collagen antibody
compared with untreated CIA rats. Furthermore, by inhibiting these mediators, AMME also contributed
towards the reversal of disturbed antioxidant levels and peroxidative damage.
CONCLUSION:
The alleviation of arthritis in rats was very likely due to the combined action of phenolic and flavonoid
compounds, the major constituents identified by gas chromatography/mass spectrometry (GC/MS)
analysis. The study also shed some light on mechanisms involved in diminution of inflammatory
mediators and free radical-generating toxicants and enhancement of the antioxidant armory, thereby
preventing further tissue damage, injury and synovial hyperproliferation in arthritis.
A Clinical Trial with Brazilian Arnica (Solidago chilensis Meyen) Glycolic

Extract in the Treatment of Tendonitis of Flexor and Extensor Tendons of
Wrist and Hand.
da Silva AG, et al. Phytother Res. 2015 Jun;29(6):864-9. doi: 10.1002/ptr.5323.
Epub 2015 Mar 11.
Abstract
One of the Brazilian arnicas, Solidago chilensis Meyen, is a species of the Asteraceae family. This plant is
known by this common name because it shares remarkably similar organoleptic properties with the
genus Arnica L., also within the family Asteraceae. We examined the effectiveness of the S. chilensis
fluid extract used externally for treating tendinitis of flexor and extensor tendons of wrist and hand in
placebo-controlled double-blind clinical pharmacological studies. This study was approved by the Ethical
Committee for Scientific Research in Human Beings at University Vila Velha-UVV. Two daily skin
applications on the arm skin of a gel cream containing a 5% glycolic plant extract were administered to
eight volunteers for 21 days. Among the volunteers, one of their arms was used as the placebo group,
and the other one was used as a test group. Statistical data analyses demonstrated a significant
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reduction in the perception of pain in the arms in the test group, when it was compared to those
receiving only the placebo.
Ashwagandha (Withania
somnifera)
Antihyperalgesic effects of ashwagandha (Withania somnifera root extract) in
rat models of postoperative and neuropathic pain.
Lim DW, Kim JG, Lim EY, Kim YT. Inflammopharmacology. 2018 Feb;26(1):207-
215. doi: 10.1007/s10787-017-0389-1. Epub 2017 Aug 28.
Abstract
The root of Withania somnifera, commonly known as ashwagandha, is a traditional herb in the Indian
Ayurvedic system of medicine and is used as a tonic. Here, we investigated whether W. somnifera root
extract exhibits analgesic effects in plantar incision (PI) and spared nerve injury (SNI) rat models.
Mechanical withdrawal threshold (MWT) was measured by von Frey filaments, and pain-related
behavior was determined after operation by ultrasonic vocalization (USV) measurements. Indeed, we
examined interferon-γ (IFN-γ) and interleukin-10 (IL-10) levels in the isolated dorsal root ganglia (DRG)
following SNI in rats using an ELISA cytokine assay. MWT significantly increased 6 and 24 h after PI in
rats receiving W. somnifera root extracts (100 and 300 mg/kg). Furthermore, the number of 22-27-kHz
USV, which are a distress response, was significantly reduced at 6 and 24 h after PI in W. somnifera-
treated rats (100 and 300 mg/kg). SNI-induced hyperalgesia and cytokine levels were significantly
alleviated after treating with W. somnifera root extracts (100 and 300 mg/kg) for 15 continuous days.
The main active compound, withaferin A, from the W. somnifera root extract has shown the CC
chemokine family Receptor 2 (CCR2) antagonistic effects on monocyte chemoattractant protein-1 (MCP-
1)-induced Ca2+ response in CCR2 stable cell line. These results indicate that W. somnifera root extract
has a potential analgesic effect in rat models for both postoperative and neuropathic pain and shows
potential as a drug or supplement for the treatment of pain.
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Efficacy & safety evaluation of Ayurvedic treatment (Ashwagandha powder &

Sidh Makardhwaj) in rheumatoid arthritis patients: a pilot prospective study.
Kumar G, Srivastava A, Sharma SK, Rao TD, Gupta YK. Indian J Med Res. 2015
Jan;141(1):100-6.
Abstract
BACKGROUND & OBJECTIVES:
In the traditional system of medicine in India Ashwagandha powder and Sidh Makardhwaj have been
used for the treatment of rheumatoid arthritis. However, safety and efficacy of this treatment have not
been evaluated. Therefore, the present study was carried out to evaluate the efficacy and safety of
Ayurvedic treatment (Ashwagandha powder and Sidh Makardhwaj) in patients with rheumatoid
arthritis.
METHODS:
One hundred and twenty five patients with joint pain were screened at an Ayurvedic hospital in New
Delhi, India. Eighty six patients satisfied inclusion criteria and were included in the study. Detailed
medical history and physical examination were recorded. Patients took 5g of Ashwagandha powder
twice a day for three weeks with lukewarm water or milk. Sidh Makardhwaj (100 mg) with honey was
administered daily for the next four weeks. The follow up of patients was carried out every two weeks.
The primary efficacy end point was based on American College of Rheumatology (ACR) 20 response.
Secondary end points were ACR50, ACR70 responses, change from baseline in disease activity score
(DAS) 28 score and ACR parameters. Safety assessments were hepatic function [alanine
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), bilirubin and ß2
microglobulin], renal function (urea and creatinine and NGAL) tests and urine mercury level.
RESULTS:
The study was completed by 90.7 per cent (78/86) patients. Patients with moderate and high disease
activity were 57.7 per cent (45/78) and 42.3 per cent (33/78), respectively. All patients were tested
positive for rheumatoid factor and increased ESR level. Ashwagandha and Sidh Makardhwaj treatment
decreased RA factor. A significant change in post-treatment scores of tender joint counts, swollen joint
counts, physician global assessment score, patient global assessment score, pain assessment score,
patient self assessed disability index score and ESR level were observed as compared to baseline scores.
ACR20 response was observed in 56.4 per cent (44/78) patients (American College of Rheumatology
criteria) and moderate response in 39.74 per cent (31/78) patients [European League Against
Rheumatism (EULAR) criteria]. Ayurvedic treatment for seven weeks in rheumatoid arthritis patients
showed normal kidney and liver function tests. However, increased urinary mercury levels were was
observed after treatment.
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INTERPRETATION & CONCLUSIONS:
The findings of the present study suggest that this Ayurvedic treatment (Ashwagandha powder and Sidh
Makardhwaj) has a potential to be used for the treatment of rheumatoid arthritis. However, due to
small sample size, short duration, non randomization and lack of a control group as study limitations,
further studies need to be done to confirm these findings.
Ayurvedic management in cervical spondylotic myelopathy.

Singh SK, Rajoria K. J Ayurveda Integr Med. 2017 Jan - Mar;8(1):49-53. doi:
10.1016/j.jaim.2016.08.011. Epub 2017 Mar 9.
Abstract
The age related spondylotic changes may result in direct compressive and ischemic dysfunction of the
spinal cord known as cervical spondylotic myelopathy (CSM). Symptoms often develop insidiously and
are characterized by neck stiffness, unilateral or bilateral deep aching neck, arm and shoulder pain, and
possibly stiffness or clumsiness while walking. The management available in current mainstream
medicine is not satisfactory. Various Ayurvedic treatments have been in use for these manifestations.
We present a case of CSM, which was treated with a combination of Panchakarma procedures and
Ayurvedic oral drugs. The patient was considered suffering from Greevastambha (neck stiffness) and
was treated with Shalishastika pinda svedana (sudation with medicated cooked bolus of rice) for one
month and Mustadi yapana basti (enema with medicated milk) for 16 days along with oral Ayurvedic
drugs such as Brihatavata chintamani rasa 50 mg, Ekangaveer ras-250 mg, Ardhangavatari rasa-125 mg
Amrita satva (dry extract of Tinospora cordifolia Willd)-500 mg, Muktasukti pisti-500 mg, Ashwagandha
churna (powder of Withania somnifera Dunal)-500 mg Dashmool kvatha ghana (solid extract of
Dashmool kvatha)-500 mg, Trayodashanga guggulu-575 mg, twice a day with honey and Eranda paka-10
g twice a day with milk. Patient's condition which was assessed for symptoms of CSM and Chile's
modified Japanese Orthopaedic Association (mJOA) score for cervical spondylotic myelopathy showed
substantial improvement. This study shows that the cases of CSM may be successfully managed with
Ayurvedic treatment.
ASHWAGANDHA
Vitamins & Supplements. WebMD. 2018.
https://www.webmd.com/vitamins/ai/ingredientmono-953/ashwagandha
Overview Information
Ashwagandha is a plant. The root and berry are used to make medicine.
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Ashwagandha has a lot of uses. But so far, there isn't enough information to judge whether it is effective
for any of them.
Ashwagandha is used for arthritis, anxiety, bipolar disorder, attention deficit hyperactivity disorder
(ADHD), balance, obsessive-compulsive disorder (OCD), trouble sleeping (insomnia), tumors,
tuberculosis, asthma, a skin condition marked by white patchiness (leukoderma), bronchitis, backache,
fibromyalgia, menstrual problems, hiccups, Parkinson's disease, under-active thyroid (hypothyroidism),
and chronic liver disease. It is also used to reduce side effects of medications used to treat cancer and
schizophrenia. Ashwagandha is used to reduce levels of fat and sugar in the blood.
Ashwagandha is also used as an "adaptogen" to help the body cope with daily stress, and as a general
tonic.
Some people also use ashwagandha for improving thinking ability, decreasing pain and swelling
(inflammation), and preventing the effects of aging. It is also used for fertility problems in men and
women and also to increase sexual desire.
Ashwagandha is applied to the skin for treating wounds, backache, and one-sided paralysis (hemiplegia).
12 Proven Health Benefits of Ashwagandha

Written by Franziska Spritzler, RD, CDE on June 11, 2018
https://www.healthline.com/nutrition/12-proven-ashwagandha-benefits
Ashwagandha is an incredibly healthy medicinal herb.
It’s classified as an "adaptogen," meaning that it can help your body manage stress.
Ashwagandha also provides all sorts of other benefits for your body and brain.
For example, it can lower blood sugar levels, reduce cortisol, boost brain function and help fight
symptoms of anxiety and depression.
Hypoglycemic, diuretic and hypocholesterolemic effect of winter cherry

(Withania somnifera, Dunal) root.
Andallu B, Radhika B. Indian J Exp Biol. 2000 Jun;38(6):607-9.
Abstract
Hypoglycemic, diuretic and hypocholesterolemic effects of roots of W. somnifera (ashvagandha) were

assessed on human subjects. Six mild NIDDM subjects and six mild hypercholesterolemic subjects were
106
treated with the powder of roots of W. somnifera for 30 days. Suitable parameters were studied in the
blood and urine samples of the subjects along with dietary pattern before and at the end of treatment
period. Decrease in blood glucose was comparable to that of an oral hypoglycemic drug. Significant
increase in urine sodium, urine volume, significant decrease in serum cholesterol, triglycerides, LDL (low
density lipoproteins) and VLDL (very low density lipoproteins) cholesterol were observed indicating that
root of W. somnifera is a potential source of hypoglycemic, diuretic and hypocholesterolemic agents.
Clinical observations revealed no adverse effects.
Natural products with hypoglycemic, hypotensive, hypocholesterolemic,

antiatherosclerotic and antithrombotic activities.
Wang HX1, Ng TB. Life Sci. 1999;65(25):2663-77.
Abstract
This article reviews compounds of botanical origin which are capable of lowering plasma levels of
glucose and cholesterol and blood pressure, as well as compounds inhibiting atherosclerosis and
thrombosis. Hypoglycemic natural products comprise flavonoids, xanthones, triterpenoids, alkaloids,
glycosides, alkyldisulfides, aminobutyric acid derivatives, guanidine, polysaccharides and peptides.
Hypotensive compounds include flavonoids, diterpenes, alkaloids, glycosides, polysaccharides and
proteins. Among natural products with hypocholesterolemic activity are beta-carotene, lycopene,
cycloartenol, beta-sitosterol, sitostanol, saponin, soybean protein, indoles, dietary fiber, propionate,
mevinolin (beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor) and polysaccharides.
Heparins, flavonoids, tocotrienols, beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors
(statins), garlic compounds and fungal proteases exert antithrombotic action. Statins and garlic
compounds also possess antiatherosclerotic activity.
Evaluation of anti-inflammatory effect of Withania somnifera root on collagen-

induced arthritis in rats.
Gupta A, Singh S. Pharm Biol. 2014 Mar;52(3):308-20. doi:
10.3109/13880209.2013.835325. Epub 2013 Nov 5.
Abstract
CONTEXT:
107
Withania somnifera (Linn.) Dunal (Solanaceae) has long been used as an herb in Ayurvedic and
indigenous medicine and has received intense attention in recent years for its chemopreventive
properties.
OBJECTIVE:
The present study focuses on the effect of W. somnifera root powder on the behavioral and radiological
changes in collagen-induced arthritic rats.
The rats were randomly divided into five groups: normal control, arthritic control, arthritic rats treated
with W. somnifera root powder (at dose levels 600 and 800 mg kg⁻¹) and arthritic rats treated with
methotrexate (at dose level 0.3 mg kg⁻¹). The treatment with W. somnifera (daily) and methotrexate
(weekly) was initiated from the 20th day post collagen immunization and continued up until the 45th
day. Arthritis was assessed macroscopically by measuring paw thickness, ankle size and body weight.
Arthritic pain was assessed by toe-spread and total print length of the affected paw. Functional recovery
due to the oral treatment of W. somnifera and methotrexate was assessed by sciatic functional index
and rota rod activity.
RESULTS:
Administration of W. somnifera root powder (600 mg kg⁻¹) to the arthritic rats significantly decreased
the severity of arthritis by effectively suppressing the symptoms of arthritis and improving the functional
recovery of motor activity and radiological score.
DISCUSSION AND CONCLUSION:
W. somnifera root has a protective effect against collagen-induced arthritis (CIA) in rats. The results
suggest that W. somnifera root powder acts as an anti-inflammatory and antioxidant agent in decreasing
the arthritic effects in collagen-induced arthritic rats.
Protective effects of Withania somnifera root on inflammatory markers and

insulin resistance in fructose-fed rats.
Samadi Noshahr Z, Shahraki MR, Ahmadvand H, Nourabadi D, Nakhaei A. Rep
Biochem Mol Biol. 2015 Apr;3(2):62-7.
Abstract
BACKGROUND:
108
We investigated the effects of Withania somnifera root (WS) on insulin resistance, tumor necrosis factor
α (TNF-α), and interleukin-6 (IL-6) in fructose-fed rats.
METHODS:
Forty-eight Wistar-Albino male rats were randomly divided into four groups (n=12); Group I as control,
Group II as sham-treated with WS by 62.5mg/g per diet, Group III fructose-fed rats received 10%W/V
fructose, and Group IV fructose- and WS-fed rats. After eight weeks blood samples were collected to
measure glucose, insulin, IL-6, and TNF-α levels in sera.
RESULTS:
Blood glucose, insulin, homeostasis model assessment for insulin resistance (HOMA-R), IL-6, and TNF-α
levels were all significantly greater in the fructose-fed rats than in the controls. Treatment with WS
significantly (P < 0.05) inhibited the fructose-induced increases in glucose, insulin, HOMA-R, IL-6, and
TNF-α.
CONCLUSION:
Our data suggest that WS normalizes hyperglycemia in fructose-fed rats by reducing inflammatory
markers and improving insulin sensitivity.
KEYWORDS:
IL-6; Insulin resistance; TNF- α; Withania somnifera
Exploratory study to evaluate tolerability, safety, and activity of Ashwagandha

(Withania somnifera) in healthy volunteers.
Raut AA, et al. J Ayurveda Integr Med. 2012 Jul;3(3):111-4. doi: 10.4103/0975-
9476.100168.
Abstract
Ashwagandha (Withania somnifera) (WS), a "rasayana" drug, is recommended for balavardhan and
mamsavardhan. The study was intended to evaluate dose-related tolerability, safety, and activity of WS
formulation in normal individuals. The design was prospective, open-labeled, variable doses in
volunteers. Eighteen apparently healthy volunteers (12M:6F, age:18-30 years, and BMI: 19-30) were
enrolled. After baseline investigations, they received WS capsules (Rx) (aqueous extract, 8:1) daily in two
divided doses with increase in daily dosage every 10 days for 30 days (750 mg/day ×10 days, 1 000
mg/day × 10 days, 1 250 mg/day × 10 days). Volunteers were assessed for symptoms/signs, vital
functions, hematological and biochemical organ function tests. Muscle activity was measured by hand
grip strength, quadriceps strength, and back extensor force. Exercise tolerance was determined using
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cycle ergometry. Lean body weight and fat% were computed from skin fold thickness measurement.
Adverse events were recorded, as volunteered by the subjects. Repeated measures ANOVA, McNemar's
test, and paired t test were employed. All but one volunteer tolerated WS without any adverse event.
One volunteer showed increased appetite, libido, and hallucinogenic effects with vertigo at the lowest
dose and was withdrawn from study. In six subjects, improvement in quality of sleep was found. Organ
function tests were in normal range before and after the intervention. Reduction in total- and LDL-
cholesterol and increase of strength in muscle activity was significant. Total body fat percentage showed
a reduction trend. WS, in escalated dose, was tolerated well. The formulation appeared safe and
strengthened muscle activity. In view of its traditional Rasayana use, further studies are planned to
evaluate potential of this drug in patients of sarcopenia.
A randomized, double blind placebo controlled study of efficacy and

tolerability of Withaina somnifera extracts in knee joint pain.
Ramakanth GS, Uday Kumar C, Kishan PV, Usharani P. J Ayurveda Integr Med.
2016 Jul - Sep;7(3):151-157. doi: 10.1016/j.jaim.2016.05.003. Epub 2016 Sep 16.
Abstract
BACKGROUND:
Root extracts of Withania somnifera (Ashwagandha) are known to possess analgesic, anti-inflammatory
and chondroprotective effects. An aqueous extract of roots plus leaves of this plant has shown to yield
higher percentages of withanolide glycosides and, accordingly, may possess better analgesic, anti-
inflammatory and chondroprotective effects than root alone extracts.
OBJECTIVES:
To evaluate efficacy and tolerability of a standardized aqueous extract of roots plus leaves of W.
somnifera in patients with knee joint pain and discomfort.
MATERIAL AND METHODS:
Sixty patients with knee joint pain and discomfort were randomized in a double-blind manner to W.
somnifera 250 mg, W. somnifera 125 mg and placebo, all given twice daily. Assessment was done by
Modified WOMAC, Knee Swelling Index (KSI), Visual Analogue Scale (VAS) at baseline and at the end of
4, 8, 12 weeks. Tolerability was assessed by incidence of adverse effects in treatment groups. Student's
't' test and ANOVA were used to compare mean change from baseline within and between the study
groups. A p < 0.05 was considered significant.
110
RESULTS:
At the end of 12 weeks, compared to baseline and placebo, significant reductions were observed in
mean mWOMAC and KSI in W. somnifera 250 mg (p < 0.001), W. somnifera 125 mg (p < 0.05) groups.
VAS scores for pain, stiffness and disability were significantly reduced in W. somnifera 250 mg (p <
0.001), W. somnifera 125 mg (p < 0.01) groups. W. somnifera 250 mg group showed earliest efficacy (at
4 weeks). All treatments were well tolerated.
CONCLUSIONS:
Both the doses of an aqueous extract of W. somnifera produced significant reduction in outcome
variables, with the 250 mg group showing significantly better response. In addition, the therapeutic
response appears to be dose-dependent and free of any significant GI disturbances.
Bee Propolis, Pollen, and

Honey
Antioxidant Potential of Propolis, Bee Pollen, and Royal Jelly: Possible Medical
Application.
Kocot J, Kiełczykowska M, Luchowska-Kocot D, Kurzepa J, Musik I. Oxid Med Cell
Longev. 2018 May 2;2018:7074209. doi: 10.1155/2018/7074209. eCollection
2018.
Abstract
Honeybees products comprise of numerous substances, including propolis, bee pollen, and royal jelly,
which have long been known for their medicinal and health-promoting properties. Their wide biological
effects have been known and used since antiquity. Bee products are considered to be a potential source
of natural antioxidants such as flavonoids, phenolic acids, or terpenoids. Nowadays, the still growing
concern in natural substances capable of counteracting the effects of oxidative stress underlying the
pathogenesis of numerous diseases, such as neurodegenerative disorders, cancer, diabetes, and
111
atherosclerosis, as well as negative effects of different harmful factors and drugs, is being observed.
Having regarded the importance of acquiring drugs from natural sources, this review is aimed at
updating the current state of knowledge of antioxidant capacity of selected bee products, namely,
propolis, bee pollen, and royal jelly, and of their potential antioxidant-related therapeutic applications.
Moreover, the particular attention has been attributed to the understanding of the mechanisms
underlying antioxidant properties of bee products. The influence of bee species, plant origin, geographic
location, and seasonality as well as type of extraction solutions on the composition of bee products
extracts were also discussed.
Biological Properties and Therapeutic Applications of Propolis.

Sforcin JM. Phytother Res. 2016 Jun;30(6):894-905. doi: 10.1002/ptr.5605. Epub
2016 Mar 14.
Abstract
Propolis is a resinous material collected by bees from bud and exudates of the plants, mixed with bee
enzymes, pollen and wax. In this review, the biological properties of propolis and some therapeutic
applications are discussed. The same biological activities have been investigated until today, using
samples from different geographic regions. Thus, the study of the biological properties of a given sample
should always be associated with its chemical composition and botanical source, representing a
particular sample of a given geographic area, exploring its biological potential and the role of its
constituents. Efforts have been carried out to explain propolis' mechanisms of action in vivo and in vitro,
but the majority of propolis' targets and actions are still unclear. The number of formulations containing
propolis and patents have increased, although propolis extracts have been used deliberately with
different recommendations, not always mentioning the chemical composition, vegetal source and the
methods of extraction. Clinical studies will help to obtain criterious recommendations in view of the
expected outcomes. Further investigation should explore the effects of common compounds found in
the samples from all over the world in an attempt to standardize the research on propolis and to obtain
new drugs.
Copyright © 2016 John Wiley & Sons, Ltd.
Honey, Propolis, and Royal Jelly: A Comprehensive Review of Their Biological

Actions and Health Benefits.
Pasupuleti VR, Sammugam L, Ramesh N, Gan SH. Oxid Med Cell Longev.
2017;2017:1259510. doi: 10.1155/2017/1259510. Epub 2017 Jul 26.
112
Abstract
BACKGROUND:
There are several health benefits that honeybee products such as honey, propolis, and royal jelly claim
toward various types of diseases in addition to being food.
SCOPE AND APPROACH:
In this paper, the effects of honey, propolis, and royal jelly on different metabolic diseases, cancers, and
other diseases have been reviewed. The modes of actions of these products have also been illustrated
for purposes of better understanding.
KEY FINDINGS AND CONCLUSIONS:
An overview of honey, propolis, and royal jelly and their biological potentials was highlighted. The
potential health benefits of honey, such as microbial inhibition, wound healing, and its effects on other
diseases, are described. Propolis has been reported to have various health benefits related to
gastrointestinal disorders, allergies, and gynecological, oral, and dermatological problems. Royal jelly is
well known for its protective effects on reproductive health, neurodegenerative disorders, wound
healing, and aging. Nevertheless, the exact mechanisms of action of honey, propolis, and royal jelly on
the abovementioned diseases and activities have not been not fully elucidated, and further research is
warranted to explain their exact contributions.
Tumor-suppressing potential of stingless bee propolis in in vitro and in vivo

models of differentiated-type gastric adenocarcinoma.
Desamero MJ, et al. Sci Rep. 2019 Dec 23;9(1):19635. doi: 10.1038/s41598-019-
55465-4.
Abstract
The protective property of propolis across a wide spectrum of diseases has long been realized, yet the
anti-tumor efficacy of this bioactive substance from Philippine stingless bees has remained poorly
understood. Here, we showed the tumor-suppressing potential of crude ethanolic extract of Philippine
stingless bee propolis (EEP) in in vitro models of gastric cancer highlighting the first indication of
remarkable subtype specificity towards differentiated-type human gastric cancer cell lines but not the
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diffuse-type. Mechanistically, this involved the profound modulation of several cell cycle related gene
transcripts, which correlated with the prominent cell cycle arrest at the G0/G1 phase. To reinforce our
data, a unique differentiated-type gastric cancer model, A4gnt KO mice, together with age-matched 60
week-old C57BL/6 J mice were randomly assigned to treatment groups receiving distilled water or EEP
for 30 consecutive days. EEP treatment induced significant regression of gross and histological lesions of
gastric pyloric tumors that consistently corresponded with specific transcriptional regulation of cell cycle
components. Also, the considerable p21 protein expression coupled with a marked reduction in rapidly
dividing BrdU-labeled S-phase cells unequivocally supported our observation. Altogether, these findings
support the role of Philippine stingless bee propolis as a promising adjunct treatment option in
differentiated-type gastric cancer.
Antioxidant activity of honey supplemented with bee products.

Juszczak L, Gałkowska D, Ostrowska M, Socha R. Nat Prod Res. 2016
Jun;30(12):1436-9. doi: 10.1080/14786419.2015.1057582. Epub 2015 Jul 8.
Abstract
The aim of this work was to evaluate the influence of supplementation of multiflower honey with bee
products on the phenolic compound content and on antioxidant activity. Average total phenolic and
flavonoids contents in the multiflower honeys were 36.06 ± 10.18 mg GAE/100 g and 4.48 ± 1.69 mg
QE/100 g, respectively. The addition of royal jelly did not affect significantly the phenolic compound
content and antioxidant activity. Supplementation of honey with other bee products, i.e. beebread,
propolis, pollen, resulted in significant increase in the total phenolic and flavonoids contents, and in
antiradical activity and reducing power, with the largest effect found for addition of beebread.
Significant linear correlations between the total phenolic and flavonoids contents and antiradical activity
and reducing power were found.
KEYWORDS:
antioxidant activity; antiradical properties; bee products; honey
The phytochemistry of the honeybee.

Bankova V, Popova M, Trusheva B. Phytochemistry. 2018 Nov;155:1-11. doi:
10.1016/j.phytochem.2018.07.007. Epub 2018 Jul 24.
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Abstract
Honeybees rely on plants for everything they need to keep the colony running; plant nectar and pollen
are their only carbohydrate and protein food sources. By foraging to satisfy their basic nutritional
demand, honeybees inevitably gather specialized plant metabolites as part of the nectar and pollen. In
general, these compounds possess biological activity which may become relevant in fighting pests and
pathogens in the hive. The third plant derived bee product, besides honey and bee pollen, is propolis
(bee glue), which comes from plant resins. It is not a food; it is used as a building material and a
defensive substance. Thus, the beehive is rich in specialized plant metabolites, produced by many
different plant species and the expression "Phytochemistry of honeybees" is not inappropriate.
However, it is virtually impossible to perform a detailed overview of the phytochemical features of
honey and pollen in a review article of this nature, for reasons of space. The present review deals with
propolis, because it is the bee product with highest concentration of specialized plant metabolites and
has valuable pharmacological activities. The most recent developments concerning plant sources of
propolis, bees' preferences to particular plants, the application of metabolomic approaches and
chemometrics to propolis research and the problems concerning standardization of propolis are
summarized. The overview covers the literature published in the last decade, after 2007.
Copyright © 2018 Elsevier Ltd. All rights reserved.
KEYWORDS:
Honeybee; Metabolomics; Propolis; Propolis plant sources
Biological and therapeutic properties of bee pollen: a review.

Denisow B, Denisow-Pietrzyk M. J Sci Food Agric. 2016 Oct;96(13):4303-9. doi:
10.1002/jsfa.7729. Epub 2016 Apr 19.
Abstract
Natural products, including bee products, are particularly appreciated by consumers and are used for
therapeutic purposes as alternative drugs. However, it is not known whether treatments with bee
products are safe and how to minimise the health risks of such products. Among others, bee pollen is a
natural honeybee product promoted as a valuable source of nourishing substances and energy. The
health-enhancing value of bee pollen is expected due to the wide range of secondary plant metabolites
(tocopherol, niacin, thiamine, biotin and folic acid, polyphenols, carotenoid pigments, phytosterols),
besides enzymes and co-enzymes, contained in bee pollen. The promising reports on the antioxidant,
115
anti-inflammatory, anticariogenic antibacterial, antifungicidal, hepatoprotective, anti-atherosclerotic,

immune enhancing potential require long-term and large cohort clinical studies. The main difficulty in
the application of bee pollen in modern phytomedicine is related to the wide species-specific variation
in its composition. Therefore, the variations may differently contribute to bee-pollen properties and
biological activity and thus in therapeutic effects. In principle, we can unequivocally recommend bee
pollen as a valuable dietary supplement. Although the bee-pollen components have potential bioactive
and therapeutic properties, extensive research is required before bee pollen can be used in therapy.
© 2016 Society of Chemical Industry.
KEYWORDS:
bee pollen; honey; inflammation, cancer; medicine; therapy
In vivo activity assessment of a "honey-bee pollen mix" formulation.

Küpeli Akkol E, Orhan DD, Gürbüz I, Yesilada E. Pharm Biol. 2010 Mar;48(3):253-
9. doi: 10.3109/13880200903085482.
Abstract
Honey-bee pollen mix (HBM) formulation is claimed to be effective for the treatment of asthma,
bronchitis, cancers, peptic ulcers, colitis, various types of infections including hepatitis B, and
rheumatism by the herb dealers in northeast Turkey. In the present study, in vivo antinociceptive, anti-
inflammatory, gastroprotective and antioxidant effects of pure honey and HBM formulation were
evaluated comparatively. HBM did not show any significant gastroprotective activity in a single
administration at 250 mg/kg dose, whereas a weak activity was observed after three days of successive
administration at 500 mg/kg dose. On the other hand, HBM displayed significant antinociceptive (p
<0.01) and anti-inflammatory (p <0.01) activities at 500 mg/kg dose orally without inducing any
apparent acute toxicity or gastric damage. HBM was also shown to possess potent antilipidperoxidant
activity (p <0.01) at 500 mg/kg dose against acetaminophen-induced liver necrosis model in mice. On
the other hand, pure honey did not exert any remarkable antinociceptive, anti-inflammatory and
gastroprotective activity, but a potent antilipidperoxidant activity (p <0.01) was determined. Results
have clearly proved that mixing pure honey with bee pollen significantly increased the healing potential
of honey and provided additional support for its traditional use. Total phenolic and flavonoid contents of
HBM were found to be 145 and 59.3 mg/100 g of honey, which were estimated as gallic acid and
quercetin equivalents, respectively.
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From the hive: Honey, a novel weapon against cancer.

Badolato M, Carullo G, Cione E, Aiello F, Caroleo MC. Eur J Med Chem. 2017 Dec
15;142:290-299. doi: 10.1016/j.ejmech.2017.07.064. Epub 2017 Aug 3.
Abstract
Nowadays there is a folk medicine branch called apitherapy that aims to treat diseases with bee
products, including honey. Honey has long been known for its medicinal and health promoting
properties. It encloses numerous types of phytochemicals with high phenolic and flavonoid content,
which contribute to its antioxidant and anti-inflammatory activities. Varieties and variants of
polyphenols in honey showed antiproliferative property against several types of cancer. This review
focuses on the latest discoveries about the key role of honey in different stages of carcinogenesis,
initiation, proliferation and progression, both in vitro and in vivo, as well as on its adjuvant effect in
cancer therapy. Although a possible application of honey and its active compounds as drugs against
cancer is still far away from clinical practice, scientific results highlight that they could be used as
immune booster for patients undergoing chemotherapy. They showed protective effects against the
common exasperating and disabling side effects, mostly mucositis.
Copyright © 2017 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
Cancer therapy; Chemoprevention; Honey
Antiproliferative effects of honey and of its polyphenols: a review.

Jaganathan SK, Mandal M. J Biomed Biotechnol. 2009;2009:830616. doi:
10.1155/2009/830616. Epub 2009 Jul 19.
Abstract
Honey has been used since long time both in medical and domestic needs, but only recently the
antioxidant property of it came to limelight. The fact that antioxidants have several preventative effects
against different diseases, such as cancer, coronary diseases, inflammatory disorders, neurological
degeneration, and aging, led to search for food rich in antioxidants. Chemoprevention uses various
dietary agents rich in phytochemicals which serve as antioxidants. With increasing demand for
antioxidant supply in the food, honey had gained vitality since it is rich in phenolic compounds and other
117
antioxidants like ascorbic acid, amino acids, and proteins. Some simple and polyphenols found in honey,
namely, caffeic acid (CA), caffeic acid phenyl esters (CAPE), Chrysin (CR), Galangin (GA), Quercetin (QU),
Kaempferol (KP), Acacetin (AC), Pinocembrin (PC), Pinobanksin (PB), and Apigenin (AP), have evolved as
promising pharmacological agents in treatment of cancer. In this review, we reviewed the
antiproliferative and molecular mechanisms of honey and above-mentioned polyphenols in various
cancer cell lines.
Activities of different types of Thai honey on pathogenic bacteria causing skin

diseases, tyrosinase enzyme and generating free radicals.
Jantakee K, Tragoolpua Y. Biol Res. 2015 Jan 16;48:4. doi: 10.1186/0717-6287-
48-4.
Abstract
BACKGROUND:
Honey is a natural product obtained from the nectar that is collected from flowers by bees. It has several
properties, including those of being food and supplementary diet, and it can be used in cosmetic
products. Honey imparts pharmaceutical properties since it has antibacterial and antioxidant activities.
The antibacterial and antioxidant activities of Thai honey were investigated in this study.
RESULTS:
The honey from longan flower (source No. 1) gave the highest activity on MRSA when compared to the
other types of honey, with a minimum inhibitory concentration of 12.5% (v/v) and minimum bactericidal
concentration of 25% (v/v). Moreover, it was found that MRSA isolate 49 and S. aureus were completely
inhibited by the 50% (v/v) longan honey (source No. 1) at 8 and 20 hours of treatment, respectively.
Furthermore, it was observed that the honey from coffee pollen (source No. 4) showed the highest
phenolic and flavonoid compounds by 734.76 mg gallic/kg of honey and 178.31 mg quercetin/kg of
honey, respectively. The antioxidant activity of the honey obtained from coffee pollen was also found to
be the highest, when investigated using FRAP and DPPH assay, with 1781.77 mg FeSO4•7H2O/kg of
honey and 86.20 mg gallic/kg of honey, respectively. Additionally, inhibition of tyrosinase enzyme was
found that honey from coffee flower showed highest inhibition by 63.46%.
CONCLUSIONS:
118
Honey demonstrates tremendous potential as a useful source that provides anti-free radicals, anti-
tyrosinase and anti-bacterial activity against pathogenic bacteria causing skin diseases.
Bone Broth
What is Bone Broth, and What Are The Benefits?
Freydis Hjalmarsdottir, MS. Healthline. February 21, 2016
https://www.healthline.com/nutrition/bone-broth-101
Bone broth is a highly nutritious stock made by simmering animal bones and connective tissue.
Using acid, such as vinegar or lemon juice, breaks down the collagen and connective tissue.
Here are some potential health benefits of bone broth:
Anti-inflammatory: The glycine in bone broth may have some anti-inflammatory and antioxidant effects.
Weight Loss: Bone broth is usually very low in calories, but can still help you feel full. This may be due to
its gelatin content, which can promote satiety.
Joint Health: Glucosamine and chondroitin, found in the broth, have been shown to improve joint health
and reduce symptoms of osteoarthritis.
Bone Health: Bone broth contains many nutrients that are important for bone health, including calcium,
magnesium and phosphorus.
Sleep and Brain Function: Glycine taken before bed has been shown to improve sleep and brain
function.
L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective

agent.
Zhong Z, et al. Curr Opin Clin Nutr Metab Care. 2003 Mar;6(2):229-40.
Abstract
119
PURPOSE OF REVIEW:
In recent years, evidence has mounted in favor of the antiinflammatory, immunomodulatory and
cytoprotective effects of the simplest amino acid L-glycine. This article will focus on the recent findings
about the responsible mechanisms of protection and review the beneficial effects of glycine in different
disease states.
RECENT FINDINGS:
Glycine protects against shock caused by hemorrhage, endotoxin and sepsis, prevents
ischemia/reperfusion and cold storage/reperfusion injury to a variety of tissues and organs including
liver, kidney, heart, intestine and skeletal muscle, and diminishes liver and renal injury caused by hepatic
and renal toxicants and drugs. Glycine also protects against peptidoglycan polysaccharide-induced
arthritis and inhibits gastric secretion and protects the gastric mucosa against chemically and stress-
induced ulcers. Glycine appears to exert several protective effects, including antiinflammatory,
immunomodulatory and direct cytoprotective actions. Glycine acts on inflammatory cells such as
macrophages to suppress activation of transcription factors and the formation of free radicals and
inflammatory cytokines. In the plasma membrane, glycine appears to activate a chloride channel that
stabilizes or hyperpolarizes the plasma membrane potential. As a consequence, agonist-induced
opening of L-type voltage-dependent calcium channels and the resulting increases in intracellular
calcium ions are suppressed, which may account for the immunomodulatory and antiinflammatory
effects of glycine. Lastly, glycine blocks the opening of relatively non-specific pores in the plasma
membrane that occurs as the penultimate event leading to necrotic cell death.
SUMMARY:
Multiple protective effects make glycine a promising treatment strategy for inflammatory diseases.
L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective

agent.
Zhong Z, et al. Curr Opin Clin Nutr Metab Care. 2003 Mar;6(2):229-40.
Abstract
PURPOSE OF REVIEW:
In recent years, evidence has mounted in favor of the antiinflammatory, immunomodulatory and
cytoprotective effects of the simplest amino acid L-glycine. This article will focus on the recent findings
120
about the responsible mechanisms of protection and review the beneficial effects of glycine in different
disease states.
RECENT FINDINGS:
Glycine protects against shock caused by hemorrhage, endotoxin and sepsis, prevents
ischemia/reperfusion and cold storage/reperfusion injury to a variety of tissues and organs including
liver, kidney, heart, intestine and skeletal muscle, and diminishes liver and renal injury caused by hepatic
and renal toxicants and drugs. Glycine also protects against peptidoglycan polysaccharide-induced
arthritis and inhibits gastric secretion and protects the gastric mucosa against chemically and stress-
induced ulcers. Glycine appears to exert several protective effects, including antiinflammatory,
immunomodulatory and direct cytoprotective actions. Glycine acts on inflammatory cells such as
macrophages to suppress activation of transcription factors and the formation of free radicals and
inflammatory cytokines. In the plasma membrane, glycine appears to activate a chloride channel that
stabilizes or hyperpolarizes the plasma membrane potential. As a consequence, agonist-induced
opening of L-type voltage-dependent calcium channels and the resulting increases in intracellular
calcium ions are suppressed, which may account for the immunomodulatory and antiinflammatory
effects of glycine. Lastly, glycine blocks the opening of relatively non-specific pores in the plasma
membrane that occurs as the penultimate event leading to necrotic cell death.
SUMMARY:
Multiple protective effects make glycine a promising treatment strategy for inflammatory diseases.
Combined chondroitin sulfate and glucosamine for painful knee

osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial
versus celecoxib.
Hochberg MC, et al. Ann Rheum Dis. 2016 Jan;75(1):37-44. doi:
10.1136/annrheumdis-2014-206792. Epub 2015 Jan 14.
Abstract
OBJECTIVES:
To compare the efficacy and safety of chondroitin sulfate plus glucosamine hydrochloride (CS+GH)
versus celecoxib in patients with knee osteoarthritis and severe pain.
121
METHODS:
Double-blind Multicentre Osteoarthritis interVEntion trial with SYSADOA (MOVES) conducted in France,
Germany, Poland and Spain evaluating treatment with CS+GH versus celecoxib in 606 patients with
Kellgren and Lawrence grades 2-3 knee osteoarthritis and moderate-to-severe pain (Western Ontario
and McMaster osteoarthritis index (WOMAC) score ≥301; 0-500 scale). Patients were randomised to
receive 400 mg CS plus 500 mg GH three times a day or 200 mg celecoxib every day for 6 months. The
primary outcome was the mean decrease in WOMAC pain from baseline to 6 months. Secondary
outcomes included WOMAC function and stiffness, visual analogue scale for pain, presence of joint
swelling/effusion, rescue medication consumption, Outcome Measures in Rheumatology Clinical Trials
and Osteoarthritis Research Society International (OMERACT-OARSI) criteria and EuroQoL-5D.
RESULTS:
The adjusted mean change (95% CI) in WOMAC pain was -185.7 (-200.3 to -171.1) (50.1% decrease) with
CS+GH and -186.8 (-201.7 to -171.9) (50.2% decrease) with celecoxib, meeting the non-inferiority margin
of -40: -1.11 (-22.0 to 19.8; p=0.92). All sensitivity analyses were consistent with that result. At 6
months, 79.7% of patients in the combination group and 79.2% in the celecoxib group fulfilled
OMERACT-OARSI criteria. Both groups elicited a reduction >50% in the presence of joint swelling; a
similar reduction was seen for effusion. No differences were observed for the other secondary
outcomes. Adverse events were low and similarly distributed between groups.
CONCLUSIONS:
CS+GH has comparable efficacy to celecoxib in reducing pain, stiffness, functional limitation and joint
swelling/effusion after 6 months in patients with painful knee osteoarthritis, with a good safety profile.
Glucosamine therapy for treating osteoarthritis.

Towheed TE, et al. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD002946.
Abstract
BACKGROUND:
Osteoarthritis (OA) is the most common form of arthritis, and it is often associated with significant
disability and an impaired quality of life.
122
OBJECTIVES:
To review all randomized controlled trials (RCTs) evaluating the effectiveness and toxicity of
glucosamine in OA.
SEARCH STRATEGY:
We searched MEDLINE, PREMEDLINE, EMBASE, AMED, ACP Journal Club, DARE, CDSR, and the CCTR. We
also wrote letters to content experts, and hand searched reference lists of identified RCTs and pertinent
review articles. All searches were updated in January 2005.
SELECTION CRITERIA:
Relevant studies met the following criteria: 1) RCTs evaluating the effectiveness and safety of
glucosamine in OA, 2) Both placebo controlled and comparative studies were eligible, 3) Both single
blinded and double blinded studies were eligible.
DATA COLLECTION AND ANALYSIS:
Data abstraction was performed independently by two investigators and the results were compared for
degree of agreement. Gotzsche's method and a validated tool (Jadad 1996) were used to score the
quality of the RCTs. Continuous outcome measures were pooled using standardized mean differences
(SMD) as the measure of effect size. Dichotomous outcome measures were pooled using relative risk
ratios (RR).
MAIN RESULTS:
Analysis restricted to eight studies with adequate allocation concealment failed to show benefit of
glucosamine for pain and WOMAC function. Collectively, the 20 analyzed RCTs found glucosamine
favoured placebo with a 28% (change from baseline) improvement in pain (SMD -0.61, 95% CI -0.95, -
0.28) and a 21% (change from baseline) improvement in function using the Lequesne index (SMD -0.51
95% CI -0.96, -0.05). However, the results are not uniformly positive, and the reasons for this remain
unexplained. WOMAC pain, function and stiffness outcomes did not reach statistical significance. In the
10 RCTs in which the Rotta preparation of glucosamine was compared to placebo, glucosamine was
found to be superior for pain (SMD -1.31, 95% CI -1.99, -0.64) and function using the Lequesne index
(SMD -0.51, 95% CI -0.96, -0.05). Pooled results for pain (SMD -0.15, 95% CI -0.35, 0.05) and function
using the WOMAC index (SMD 0.03, 95% CI -0.18, 0.25) in those RCTs in which a non-Rotta preparation
of glucosamine was compared to placebo did not reach statistical significance. In the four RCTs in which
123
the Rotta preparation of glucosamine was compared to an NSAID, glucosamine was superior in two, and
equivalent in two. Two RCTs using the Rotta preparation showed that glucosamine was able to slow
radiological progression of OA of the knee over a three year period (SMD 0.24, 95% CI 0.04, 0.43).
Glucosamine was as safe as placebo in terms of the number of subjects reporting adverse reactions
(RR=0.97, 95% CI, 0.88, 1.08).
AUTHORS' CONCLUSIONS:
This update includes 20 studies with 2570 patients. Pooled results from studies using a non-Rotta
preparation or adequate allocation concealment failed to show benefit in pain and WOMAC function
while those studies evaluating the Rotta preparation show that glucosamine was superior to placebo in
the treatment of pain and functional impairment resulting from symptomatic OA. WOMAC outcomes of
pain, stiffness and function did not show a superiority of glucosamine over placebo for both Rotta and
non-Rotta preparations of glucosamine. Glucosamine was as safe as placebo.
Update of
Glucosamine therapy for treating osteoarthritis. [Cochrane Database Syst Rev. 2001]
Subjective effects of glycine ingestion before bedtime on sleep quality
Kentaro INAGAWA , Takenori HIRAOKA, Tohru KOHDA, Wataru YAMADERA, Michio TAKAHASHI. Sleep
and Biological Rhythms. 09 February 2006.
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1479-8425.2006.00193.x
Abstract
The effects of glycine on sleep quality were examined in a randomized double-blinded cross-over trial.
The volunteers, with complaints about the quality of their sleep, ingested either glycine (3 g) or
placebo before bedtime, and their subjective feeling in the following morning was evaluated with the St.
Mary's Hospital Sleep Questionnaire and Space-Aeromedicine Fatigue Checklist. The glycine ingestion
significantly improved the following elements: “fatigue”, “liveliness and peppiness”, and “clear-
headedness”. These results suggest that glycine produced a good subjective feeling after awakening
from sleep.
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Oral ingestion of a hydrolyzed gelatin meal in subjects with normal weight and
in obese patients: Postprandial effect on circulating gut peptides, glucose and
insulin.
Rubio IG, Castro G, Zanini AC, Medeiros-Neto G. Eat Weight Disord. 2008
Mar;13(1):48-53.
Abstract
Gut hormones [ghrelin, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1)] are an important group of
hormones that target appetite control. They are released from endocrine L cells of the small bowel in
proportion to the volume, components and calories in a meal. In the current study, 20 g of gelatin
(flavored and sweetened) were given to obese patients (n=12) and lean subjects (n=10). Subsequently,
plasma samples were collected at-30- minute intervals up to 180 minutes and glucose, insulin, PYY, GLP-
1 and ghrelin were assayed using specific and sensitive immunofluorometric and radioimmunoassays. As
expected, obese patients had normal serum glucose levels, higher serum insulin, and lower plasma
concentration of ghrelin at all times compared to lean subjects. GLP-1 plasma levels were significantly
elevated at 60 minutes, peaking at 120 minutes in obese patients and lean subjects. As a consequence,
there was a significant rise in serum insulin levels with a significantly higher peak level at 60 min (obese)
and 30 min (lean). There were no significant changes in PYY plasma concentrations and no correlation
was found between body mass index and concentrations of ghrelin, PYY and GLP-1 in the group of obese
patients. In conclusion, a single gelatin meal induces a rise in plasma GLP-1 followed by an increase in
serum levels of insulin. These findings may be applied to maximize satiety in obese patients as a means
of improving adherence to calorie-controlled diets as well as provide better control of diabetic patients.
Boswellia
Abstract
125
KEYWORDS:
herbs; medicinal plants; osteoarthritis; rheumatoid arthritis
A randomized, double blind, placebo controlled, cross over study to evaluate

the analgesic activity of Boswellia serrata in healthy volunteers using
mechanical pain model.
Prabhavathi K, Chandra US, Soanker R, Rani PU. Indian J Pharmacol. 2014 Sep-
Oct;46(5):475-9. doi: 10.4103/0253-7613.140570.
Abstract
OBJECTIVE:
Experimental pain models in human healthy volunteers are advantageous for early evaluation of
analgesics. All efforts to develop nonsteroidal anti-inflammatory drugs (NSAIDs) which are devoid of
gastrointestinal and cardiovascular system effects are still far from achieving a breakthrough. Hence we
evaluated the analgesic activity of an ayurvedic drug, Boswellia serrata by using validated human pain
models which has shown its analgesic activity both in-vitro and preclinical studies to evaluate the
analgesic activity of single oral dose (125 mg, 2 capsules) of Boswellia serrata compared to placebo using
mechanical pain model in healthy human subjects.
After taking written informed consent, twelve healthy subjects were randomized (1:1) to receive single
oral dose of Boswellia serrata (Shallaki (®)) 125 mg, 2 capsules or identical placebo in a crossover design.
Mechanical pain was assessed using Ugo basile analgesymeter (by Randall Selitto test) at baseline and at
126
1 hr, 2 hrs and 3 hrs after test drug administration. Pain Threshold force and time and Pain Tolerance
force and time were evaluated. Statistical analysis was done by paired t-test.
RESULTS:
Twelve healthy volunteers have completed the study. Mean percentage change from baseline in Pain
Threshold force and time with Boswellia serrata when compared to placebo had significantly increased
[Force: 9.7 ± 11.0 vs 2.9 ± 3.4 (P = 0.05) and time: 9.7 ± 10.7 vs 2.8 ± 3.4 (P = 0.04)] at third hr. Mean
Percentage change from baseline in Pain Tolerance force and time with Boswellia serrata when
compared to placebo had significantly (P ≤ 0.01) increased at 1 hr, 2 hrs and 3 hrs.
CONCLUSION:
In the present study, Boswellia serrata significantly increased the Pain Threshold and Pain Tolerance
force and time compared to placebo. Both study medications were well tolerated. Further multiple dose
studies may be needed to establish the analgesic efficacy of the drug.
KEYWORDS:
Boswellia serrata; human pain models; randall selitto test; ugo basile analgesymeter
Dietary supplements for treating osteoarthritis: a systematic review and

meta-analysis.
Liu X, Machado GC, Eyles JP, Ravi V, Hunter DJ. Br J Sports Med. 2018
Feb;52(3):167-175. doi: 10.1136/bjsports-2016-097333. Epub 2017 Oct 10.
Abstract
OBJECTIVE:
To investigate the efficacy and safety of dietary supplements for patients with osteoarthritis.
DESIGN:
An intervention systematic review with random effects meta-analysis and meta-regression.
DATA SOURCES:
MEDLINE, EMBASE, Cochrane Register of Controlled Trials, Allied and Complementary Medicine and
Cumulative Index to Nursing and Allied Health Literature were searched from inception to April 2017.
STUDY ELIGIBILITY CRITERIA:
Randomised controlled trials comparing oral supplements with placebo for hand, hip or knee
osteoarthritis.
127
RESULTS:
Of 20 supplements investigated in 69 eligible studies, 7 (collagen hydrolysate, passion fruit peel extract,
Curcuma longa extract, Boswellia serrata extract, curcumin, pycnogenol and L-carnitine) demonstrated
large (effect size >0.80) and clinically important effects for pain reduction at short term. Another six
(undenatured type II collagen, avocado soybean unsaponifiables, methylsulfonylmethane, diacerein,
glucosamine and chondroitin) revealed statistically significant improvements on pain, but were of
unclear clinical importance. Only green-lipped mussel extract and undenatured type II collagen had
clinically important effects on pain at medium term. No supplements were identified with clinically
important effects on pain reduction at long term. Similar results were found for physical function.
Chondroitin demonstrated statistically significant, but not clinically important structural improvement
(effect size -0.30, -0.42 to -0.17). There were no differences between supplements and placebo for
safety outcomes, except for diacerein. The Grading of Recommendations Assessment, Development and
Evaluation suggested a wide range of quality evidence from very low to high.
CONCLUSIONS:
The overall analysis including all trials showed that supplements provided moderate and clinically
meaningful treatment effects on pain and function in patients with hand, hip or knee osteoarthritis at
short term, although the quality of evidence was very low. Some supplements with a limited number of
studies and participants suggested large treatment effects, while widely used supplements such as
glucosamine and chondroitin were either ineffective or showed small and arguably clinically
unimportant treatment effects. Supplements had no clinically important effects on pain and function at
medium-term and long-term follow-ups.
Five Herbs Plus Thiamine Reduce Pain and Improve Functional Mobility in
Patients With Pain: A Pilot Study.
Hedaya R. Altern Ther Health Med. 2017 Jan;23(1):14-19.
Abstract
Context • Five herbs-Urtica dioica (stinging nettle), Boswellia serrata, Equisetum arvense, Allium
sativum, and Apium graveolens-have been demonstrated to have activity at several anti-inflammatory
pathways and have analgesic properties that are effective in treating chronic musculoskeletal pain.
Objectives • The study intended to evaluate the clinical efficacy of a proprietary blend of U dioica, B
serrata, E arvense, A sativum, A graveolens, and thiamine (vitamin B1), or "the blend," in the treatment
of chronic musculoskeletal pain. Methods • The research team performed a prospective case study.
Setting • The study took place at the National Center for Whole Psychiatry in Chevy Chase, MD, USA.
PARTICIPANTS:
128
Participants were patients who had experienced baseline persistent musculoskeletal pain for at least 4
mo in ≥1 body parts without relief from traditional treatments. Intervention • Participants were
provided with a 14-d supply of the study's medication. Two 350-mg capsules were administered 2 ×/d
with food. The participants were instructed not to alter or add any therapies for their pain-associated
condition for the 14 d of the study. Outcome Measures • The primary outcome measure was the change
on a subjectively scored visual analogue scale (VAS), similar to the Western Ontario and McMaster
Universities Osteoarthritis Index. The VAS was used to assess pain and the impact of motion and
mobility at each location with pain. Each patient was administered the VAS rating scale to assess
physical function and pain status at baseline and at the end of 14 d or postintervention. Patients were
seen for follow-up at a minimum of 2 wk and underwent an interview, with the VAS rating scale being
readministered. Results • A total of 13 patients, involving 27 pain sites, qualified for the study, 5 males
and 8 females with a median age of 58 y. The primary sites of pain were (1) the knees-5 sites (18.5%), (2)
the shoulders-6 sites (16.6%), and (3) the back (sciatica)-5 sites (18.5%), with 11 miscellaneous locations
(40.7%) making up the rest of the sites, including the neck, jaw, foot, heel, and coccyx. The mean disease
duration was 5.61 y, with a range of 4 mo to 20 y. The average VAS pain subscale score was 58.04 at
baseline and 23.33 at follow-up. The mean difference between the 2 scores was 34.71 (confidence
interval [CI], 26.16-47.01). A significant reduction in the pain scores had occurred by the follow-up
assessment (t = 7.23, P < .05). The average VAS subscale score for functional mobility was 56.67 at
baseline and 28.70 at follow-up. The mean difference between the 2 mobility scores was 27.97 (CI,
17.86-38.88). A significant improvement in the ability to move had occurred in the affected areas by the
follow-up assessment (t = 5.97, P < .05). No adverse effects were reported. Conclusions • A clinically
significant reduction in perceived pain and improvement in functional mobility had occurred for the
intervention group as related to their chronic joint, back, and muscle pain. The complex of 5 herbs, plus
vitamin B1, was well tolerated, and the results suggest that the blend should be considered to be a
valuable alternative treatment in the management of chronic musculoskeletal pain.
Management of muscular dystrophy during osteoarthritis disorder: A topical

phytotherapeutic treatment protocol.
Ganguly A. Caspian J Intern Med. 2019 Spring;10(2):183-196. doi:
10.22088/cjim.10.2.183.
https://www.ncbi.nlm.nih.gov/pubmed/?term=Management+of+muscular+dystrophy+during+osteoart
hritis+disorder%3A+A+topical+phytotherapeutic+treatment+protocol.
Abstract
Background:
Creatine kinase-muscle (CK-MM) and aldolase A (AldoA) levels are proven to be realistic biochemical
markers to detect muscular dystrophy during osteoarthritic disorders (MD-OADs). The aim of this study
129
is to normalize the MD-OADs characterized by muscle weakness, atrophy, inflammatory disorders, pain
with chronic arthropathy by specialized topical phytotherapeutic treatment.
Methods:
Baseline data were collected and evaluated from 153 patients, aged 59.89±11.37years, and suffering
with MD-OADs for 7.89±1.90 years. Serum CK-MM and aldoA levels were measured at baseline and after
a six- week treatment using the appropriate kits. All patients underwent standardized physical,
radiographic examinations and completed a questionnaire. All the patients were treated with topical
application of phytoconstituents from the extracts of seven Indian medicinal plants namely Cissus
quadrangularis, Calotropis gigantea, Zingiber officinalis, Rosemarinus officinale, Boswellia serratia,
Curcuma longa and Withata somnifera mixed with sesame oil and beehives wax for six-week.
Results:
The elevated levels of biomarkers, CK-MM and aldoA, were reduced to their mean±SEM values
82.77±1.32 and 4.94±1.30U/L, respectively at the end of six-week treatment and the improvements of
deranged anatomical features, Pearson's correlation coefficients, international-approved pain related
abnormalities (VAS, WOMAC, KPS and KOOS) and reduction of weight at the end of treatment were all
highly significant (p<0.0001).
Conclusion:
It is firmly confirmed that MD-OADs resulted with the elevated levels of CK-MM, and AldoA, along with
deranged anatomical features (KGB, DTM, DCM, DAP, DBP, SLR, KFS and KES) and pain related
parameters (VAS, WOMAC-index, KPS, KOOS and BMI) can be successfully normalized by topical
phytotherapeutic treatment protocol.
A pilot, randomized, double-blind, placebo-controlled trial to assess the safety

and efficacy of a novel Boswellia serrata extract in the management of
osteoarthritis of the knee.
Majeed M, Majeed S, Narayanan NK, Nagabhushanam K. Phytother Res. 2019
May;33(5):1457-1468. doi: 10.1002/ptr.6338. Epub 2019 Mar 6.
https://www.ncbi.nlm.nih.gov/pubmed/?term=A+pilot%2C+randomized%2C+double-
blind%2C+placebo-
controlled+trial+to+assess+the+safety+and+efficacy+of+a+novel+Boswellia+serrata+extract+in+the+ma
nagement+of+osteoarthritis+of+the+knee.
Abstract
130
A double-blind, placebo-controlled human trial was conducted to evaluate the safety and efficacy of a
standardized oral supplementation of Boswellin®, a novel extract of Boswellia serrata extract (BSE)
containing 3-acetyl-11-keto-β-boswellic acid (AKBBA) with β-boswellic acid (BBA). A total of 48 patients
with osteoarthritis (OA) of the knee were randomized and allocated to the BSE and placebo groups for
intervention. Patients were administered BSE or placebo for a period of 120 days. The trial results
revealed that BSE treatment significantly improved the physical function of the patients by reducing pain
and stiffness compared with placebo. Radiographic assessments showed improved knee joint gap and
reduced osteophytes (spur) confirming the efficacy of BSE treatment. BSE also significantly reduced the
serum levels of high-sensitive C-reactive protein, a potential inflammatory marker associated with OA of
the knee. No serious adverse events were reported. This is the first study with BSE conducted for a
period of 120 days, longer than any other previous clinical trial on patients with OA of the knee. The
findings provide evidence that biologically active constituents of BSE, namely, AKBBA and BBA, act
synergistically to exert anti-inflammatory/anti-arthritic activity showing improvement in physical and
functional ability and reducing the pain and stiffness.
Natural Products for Promoting Joint Health and Managing Osteoarthritis.

Henrotin Y, Mobasheri A. Curr Rheumatol Rep. 2018 Sep 19;20(11):72. doi:
10.1007/s11926-018-0782-9.
Abstract
PURPOSE OF REVIEW:
Osteoarthritis, the most common joint disease, is associated with substantial medical costs, lost
productivity, and reduced quality of life. However, available pharmaceutical treatments have limitations
in terms of efficacy and long-term safety.
RECENT FINDINGS:
In vitro evidence suggests that some natural products may possess anti-inflammatory and anti-oxidative
properties and may inhibit the release of key osteoarthritis-related cytokines. There is, therefore,
ongoing interest in identifying natural products that safely promote joint health and treat osteoarthritis.
Numerous plant extracts, including curcumin, Boswellia extract, and pycnogenol, have shown effect
sizes (ES) for reducing pain and functional disability larger than those observed with analgesics and
products such as glucosamine and chondroitin. The ES for methylsulfonylmethane and avocado/soybean
unsaponifiables are also considered to be clinically relevant. Data from a small number of studies using
natural products for treating osteoarthritis are promising but require confirmation in further well-
designed clinical trials.
KEYWORDS:
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Boswellia serrata extract; Curcumin; Osteoarthritis; Plant extracts; Pycnogenol
A Placebo-Controlled Double-Blind Study Demonstrates the Clinical Efficacy of

a Novel Herbal Formulation for Relieving Joint Discomfort in Human Subjects
with Osteoarthritis of Knee.
Karlapudi V, Prasad Mungara AVV, Sengupta K, Davis BA, Raychaudhuri SP. J Med
Food. 2018 May;21(5):511-520. doi: 10.1089/jmf.2017.0065. Epub 2018 Apr 30.
Abstract
LI73014F2 is a novel composition prepared from extracts of Terminalia chebula fruit, Curcuma longa
rhizome, and Boswellia serrata gum resin with synergistic benefit in 5-Lipoxygenase (5-LOX) inhibition.
This herbal composition with strong anti-5-LOX activity exhibited significant pain relief as indicated
through improvements in weight-bearing capacity in a monosodium iodoacetate-induced osteoarthritis
(OA) model of Sprague-Dawley rats. A 90-day randomized, placebo-controlled double-blind study
evaluates the clinical efficacy and tolerability of LI73014F2 in the management of symptoms of OA of the
knee (Clinical Trial Registration No. CTRI/2014/01/004338). Subjects, (n = 105), were randomized into
three groups: placebo (n = 35), 200 mg/day of LI73014F2 (n = 35), and 400 mg/day of LI73014F2 (n = 35).
All study participants were evaluated for pain and physical function by using standard tools, that is,
Visual Analog Scale, Lequesne's Functional Index, and Western Ontario and McMaster Universities
Osteoarthritis Index (WOMAC) at the baseline (day 0) and on day 14 ± 3, 30 ± 3, 60 ± 3, and at the end of
the study (day 90 ± 3). In addition, routine examinations on biochemical parameters in serum, urine, and
hematological parameters were conducted on each visit to assess the safety of the study material. At
the end of the trial period, LI73014F2 conferred significant pain relief, improved physical function, and
quality of life in OA patients. In conclusion, preclinical and clinical data together strongly suggest that
the herbal formulation LI73014F2 is a safe and effective intervention for management of joint
discomfort, demonstrating efficacy as early as 14 days.
Efficacy of curcumin and Boswellia for knee osteoarthritis: Systematic review

and meta-analysis.
Bannuru RR, Osani MC, Al-Eid F, Wang C. Semin Arthritis Rheum. 2018
Dec;48(3):416-429. doi: 10.1016/j.semarthrit.2018.03.001. Epub 2018 Mar 10.
Abstract
PURPOSE:
132
The unfavorable safety profiles of commonly prescribed knee osteoarthritis (OA) treatments have led
clinicians and patients to seek safer alternatives. Research has suggested that curcuminoid and
boswellia formulations could moderate key inflammatory pathways that are associated with worsening
symptoms and disease progression. We conducted a systematic review and meta-analysis to assess the
efficacy and safety of these treatments vs. placebo or NSAIDs for knee OA.
METHODS:
We searched Medline, EMBASE, Google Scholar, Web of Science and the Cochrane database from
inception to February 21, 2018. We also hand searched reference lists and reviewed conference
proceedings. We included randomized clinical trials (RCTs) comparing curcuminoid or boswellia
formulations with placebo or NSAIDs for knee OA. We calculated standardized mean differences (SMD)
or risk ratios (RR) for all relevant outcomes. Meta-analyses were conducted using random effects
models. Heterogeneity was assessed using the I2 statistic.
RESULTS:
Eleven RCTs (N = 1009) were eligible for analysis. Study quality was low overall, and most included RCTs
were conducted on fewer than 100 participants. Both curcuminoid and boswellia formulations were
statistically significantly more effective than placebo for pain relief and functional improvement. There
were no significant differences between curcuminoids or boswellia and placebo in safety outcomes.
Curcuminoids showed no statistically significant differences in efficacy outcomes compared to NSAIDs;
patients receiving curcuminoids were significantly less likely to experience gastrointestinal adverse
events. No RCTs compared boswellia against approved NSAIDs.
CONCLUSIONS:
The results of our study suggest that curcuminoid and boswellia formulations could be a valuable
addition to the knee OA treatment regimens by relieving symptoms while reducing safety risks. The
current body of evidence is not adequate in size or quality to make any meaningful clinical practice
recommendations. Further research through large, high quality RCTs probably investigating the
synergistic effect of these products with other OA treatments is warranted.
KEYWORDS:
Boswellia; Curcumin; Knee osteoarthritis; Meta-analysis
Efficacy and safety of curcumin and its combination with boswellic acid in
osteoarthritis: a comparative, randomized, double-blind, placebo-controlled
study.
Haroyan A, et al. BMC Complement Altern Med. 2018 Jan 9;18(1):7. doi:
10.1186/s12906-017-2062-z.
133
Abstract
BACKGROUND:
The aim of this clinical trial was to assess the efficacy and safety of curcuminoid complex extract from
turmeric rhizome with turmeric volatile oil (CuraMed®) and its combination with boswellic acid extract
from Indian frankincense root (Curamin®) vs placebo for the treatment of 40- to 70-year-old patients
with osteoarthritis (OA).
METHODS:
The effects of CuraMed® 500-mg capsules (333 mg curcuminoids) and Curamin® 500-mg capsules (350
mg curcuminoids and 150 mg boswellic acid) taken orally three times a day for 12 weeks in 201 patients
was investigated in a three-arm, parallel-group, randomized, double-blinded, placebo-controlled trial.
Primary outcome efficacy measures included OA physical function performance-based tests, the
WOMAC recommended index of joint pain, morning stiffness, limitations of physical function, and the
patients' global assessment of disease severity.
RESULTS:
Favorable effects of both preparations compared to placebo were observed after only 3 months of
continuous treatment. A significant effect of Curamin® compared to placebo was observed both in
physical performance tests and the WOMAC joint pain index, while superior efficacy of CuraMed vs
placebo was observed only in physical performance tests. The effect size compared to placebo was
comparable for both treatment groups but was superior in the Curamin® group. The treatments were
well tolerated.
CONCLUSIONS:
Twelve-week use of curcumin complex or its combination with boswellic acid reduces pain-related
symptoms in patients with OA. Curcumin in combination with boswellic acid is more effective.
Combining Curcuma longa and Boswellia serrata extracts in Curamin® increases the efficacy of OA
treatment presumably due to synergistic effects of curcumin and boswellic acid.
A novel boswellic acids delivery form (Casperome®) in the management of

musculoskeletal disorders: a review.
Riva A, et al. Eur Rev Med Pharmacol Sci. 2017 Nov;21(22):5258-5263. doi:
10.26355/eurrev_201711_13849.
Abstract
134
Standard pharmacological treatment of musculoskeletal conditions is often associated with relevant side
effects. Botanical preparations endowed with a good tolerability profile, therefore, could have a role in
the management of these disorders. Among different natural products, Boswellia serrata extracts have
long been used for the treatment of musculoskeletal disorders, given their marked anti-inflammatory
activity and their ability to promote tissue regeneration. However, standard preparations of Boswellia
serrata show overall modest pharmacokinetic properties, a limitation which may ultimately lead to
reduced efficacy. In an effort to improve the pharmacokinetic properties, Casperome®, a lecithin-based
formulation of Boswellia serrata extract representing the whole natural bouquet, has been developed.
This formulation was effective in the treatment of Achilles tendonitis, epicondylitis, radiculopathies,
ankle sprains and sport injuries as shown in several clinical studies, the majority of which with a
randomized design and all evaluating a number of well-recognized parameters of efficacy for the
therapy of musculoskeletal disorder. All studies were consistent in showing a prompt decrease of pain
and improvement of functionality of the affected area after supplementation with Casperome®, without
any relevant adverse effect. Remarkably, these symptomatic improvements were paralleled by reduced
plasmatic levels of inflammatory markers and by a diminished need for rescue analgesics. On these
bases, Casperome® may have a role in the treatment of musculoskeletal disorders. Clinical studies in
other similar conditions (e.g., osteoarthritis) appear warranted to further investigate the efficacy of this
botanical product in more specific settings.
A commercialized dietary supplement alleviates joint pain in community

adults: a double-blind, placebo-controlled community trial.
Nieman DC, et al. Nutr J. 2013 Nov 25;12(1):154. doi: 10.1186/1475-2891-12-154.
Abstract
BACKGROUND:
The purpose of this study was to assess the effect of 8-weeks ingestion of a commercialized joint pain
dietary supplement (Instaflex™ Joint Support, Direct Digital, Charlotte, NC) compared to placebo on joint
pain, stiffness, and function in adults with self-reported joint pain. Instaflex™ is a joint pain supplement
containing glucosamine sulfate, methylsufonlylmethane (MSM), white willow bark extract (15% salicin),
ginger root concentrate, boswella serrata extract (65% boswellic acid), turmeric root extract, cayenne,
and hyaluronic acid.
METHODS:
Subjects included 100 men and women, ages 50-75 years, with a history (>3 months) of joint pain, and
were randomized to Instaflex™ or placebo (3 colored gel capsules per day for 8 weeks, double-blind
administration). Subjects agreed to avoid the use of non-steroidal anti-inflammatory drugs (NSAID) and
all other medications and supplements targeted for joint pain. Primary outcome measures were
135
obtained pre- and post-study and included joint pain severity, stiffness, and function (Western Ontario
and McMaster Universities [WOMAC]), and secondary outcome measures included health-related
quality of life (Short Form 36 or SF-36), systemic inflammation (serum C-reactive protein and 9 plasma
cytokines), and physical function (6-minute walk test). Joint pain symptom severity was assessed bi-
weekly using a 12-point Likert visual scale (12-VS).
RESULTS:
Joint pain severity was significantly reduced in Instaflex™ compared to placebo (8-week WOMAC, ↓37%
versus ↓16%, respecsvely, interacson effect P = 0.025), with group differences using the 12-VS
emerging by week 4 of the study (interaction effect, P = 0.0125). Improvements in ability to perform
daily activities and stiffness scores in Instaflex™ compared to placebo were most evident for the 74% of
subjects reporting knee pain (8-week WOMAC function score, ↓39% versus ↓14%, respecsvely,
interaction effect P = 0.027; ssffness score, ↓30% versus ↓12%, respecsvely, interaction effect
P = 0.081). Patterns of change in SF-36, systemic inflammation biomarkers, and the 6-minute walk test
did not differ significantly between groups during the 8-week study
CONCLUSIONS:
Results from this randomized, double blind, placebo-controlled community trial support the use of the
Instaflex™ dietary supplement in alleviating joint pain severity in middle-aged and older adults, with
mitigation of difficulty performing daily activities most apparent in subjects with knee pain.
Oral herbal medicines marketed in Brazil for the treatment of osteoarthritis:

A systematic review and meta-analysis.
Del Grossi Moura M, et al. Phytother Res. 2017 Nov;31(11):1676-1685. doi:
10.1002/ptr.5910. Epub 2017 Sep 5.
Abstract
Herbal medications are commonly used to manage symptoms associated with osteoarthritis (OA). This
systematic review evaluated the effectiveness and safety of oral medications used in Brazil for the
treatment of OA. Randomized clinical trials involving adults with OA treated by a herbal medicine or a
control group were eligible. The primary outcomes measured were pain, physical function, swelling,
stiffness and quality of life; and the secondary outcomes were adverse events, activity limitations and
treatment satisfaction. Sixteen studies were included (n = 1,741 patients) in the systematic review and
nine studies in the meta-analysis, representing 6 of the 13 herbal medicines studied: Boswellia serrata (n
= 2), Curcuma longa (n = 3), Harpagophytum procumbens (n = 1), Salix daphnoides (n = 3), Uncaria
guianensis (n = 2) and Zingiber officinale (n = 5). B. serrata was more effective than both placebo and
136
valdecoxib for improvement of pain and physical function. No difference was observed for H.
procumbens, C. longa and U. guianensis compared with control. Z. officinale showed improvement of
pain over placebo. The evidence was insufficient to support the effective and safe use of these herbal
medicines, because the quality of evidence of studies was low. This study guides managers of the
Brazilian public health system and prescribers in decision-making regarding the use of these herbal
medicines for OA.
KEYWORDS:
effectiveness; herbal medicine; osteoarthritis; safety
Methylsulfonylmethane and boswellic acids versus glucosamine sulfate in the

treatment of knee arthritis: Randomized trial.
Notarnicola A, et al. Int J Immunopathol Pharmacol. 2016 Mar;29(1):140-6. doi:
10.1177/0394632015622215. Epub 2015 Dec 18.
Abstract
Until now glucosamine sulfate (GS) has been the most widely used supplement and has been shown to
be efficacious in the treatment of osteoarthritis (OA). Methylsulfonylmethane (MSM) and boswellic
acids (BA) are new effective supplements for the management of inflammation and joint degeneration,
according to previous experimental studies. The aim of our study is to test the effectiveness of
association of MSM and BA in comparison with GS in knee arthritis.In this prospective randomized
clinical trial, MEBAGA (Methylsulfonylmethane and Boswellic Acids versus Glucosamine sulfate in the
treatment of knee Arthritis), 120 participants affected by arthritis of the knee were randomly assigned
to an experimental group (MB group) or a control group (GS group) treated for 60 days with 5 g of MSM
and 7.2 mg of BA or with 1500 mg of GS daily, respectively. At the 2-month (T1) and 6-months (T2)
follow-up , the efficacy of these two nutraceuticals was assessed using the visual analog pain scale (VAS)
and the Lequesne Index (LI) for joint function, along with the use of anti-inflammatory drugs (non-
steroidal anti-inflammatory drugs and anti-cyclooxygenase-2).The repeated measures ANOVA analysis
shows that for VAS, LI, and the use of anti-inflammatory drugs scores there are improvements due to
the time in the two groups (respectively, F=26.0; P<0.0001; F=4.15; P=0.02; F=3.38; P=0.04), with a
tendency to better values for the MB group at T2.On the basis of these preliminary data, we could
support the efficacy of the MSM in association with BA in the treatment of OA. These results are
consistent with the anti-inflammatory and chondroprotective effects previously occurred in
experimental studies. This new combination of integration (MSM and BS) has presented good results
and satisfactory in comparison with GS, until now the cornerstone of the treatment of arthritis in
according to guidelines.
137
KEYWORDS:
boswellic acid; glucosamine; knee; methylsulfonylmethane; osteoarthritis
Evaluation of the effect of Elaeagnus angustifolia alone and combined with

Boswellia thurifera compared with ibuprofen in patients with knee
osteoarthritis: a randomized double-blind controlled clinical trial.
Karimifar M, Soltani R, Hajhashemi V, Sarrafchi S. Clin Rheumatol. 2017
Aug;36(8):1849-1853. doi: 10.1007/s10067-017-3603-z. Epub 2017 Mar 27.
Abstract
Osteoarthritis (OA) is one of the most common articular disorders. Many patients do not respond to
acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), the mainstay of pharmacotherapy
for knee OA. The plants Elaeagnus angustifolia and Boswellia thurifera have anti-inflammatory and
analgesic properties. This study aimed to evaluate the effect of E. angustifolia alone and in combination
with B. thurifera compared with ibuprofen in patients with knee osteoarthritis. In a randomized double-
blind controlled clinical trial, 75 patients with knee OA were randomly and equally assigned to one of
three groups Elaeagnus (n = 23), Elaeagnus/Boswellia (n = 26), and ibuprofen (n = 26) to receive the
capsules of Elaeagnus, Elaeagnus/Boswellia, and ibuprofen, respectively, three times daily with meals
for 4 weeks. Pain severity based on VAS (visual analog scale, 0 to 10 scale) and the scores of LPFI
(Lequesne Pain and Function Index) and PGA (patient global assessment) were determined pre- and
post-intervention for all patients. All interventions had significant lowering effects on VAS, LPFI, and PGA
scores (P < 0.001 for all parameters) with no significant difference between groups in terms of effects on
all evaluated parameters. Consumption of E. angustifolia fruit extract either alone or in combination
with Boswellia oleo-gum resin extract could decrease pain and improve function in patients with knee
osteoarthritis comparable to ibuprofen.
KEYWORDS:
Boswellia thurifera; Clinical trial; Elaeagnus angustifolia; Ibuprofen; Knee osteoarthritis

138
Broad Spectrum Enzymes

Impaired Intestinal Permeability Contributes to Ongoing Bowel Symptoms in
Patients With Inflammatory Bowel Disease and Mucosal Healing.
Chang J, Leong RW, Wasinger VC, Ip M, Yang M, Phan TG. Gastroenterology. 2017
Sep;153(3):723-731.e1. doi: 10.1053/j.gastro.2017.05.056. Epub 2017 Jun 8.
Abstract
BACKGROUND & AIMS:
Many patients with inflammatory bowel diseases (IBD) have ongoing bowel symptoms of diarrhea or
abdominal pain despite mucosal healing. We investigated whether impaired intestinal permeability
contributes to these symptoms.
METHODS:
We performed a prospective study of intestinal permeability, measured by endoscopic confocal laser

endomicroscopy in 110 consecutive subjects (31 with ulcerative colitis [UC], 57 with Crohn's disease
[CD], and 22 healthy individuals [controls]) in Sydney, Australia from May 2009 and September 2015.
Symptomatic CD was defined by a CD Activity Index score of 150 or more and symptomatic UC by a
partial Mayo score of 2 or more. Mucosal healing was defined as CD Endoscopic Index of Severity of 0 in
CD or Mayo endoscopic sub-score of 0-1 for patients with UC. Intestinal permeability was quantified by
the Confocal Leak Score (CLS; range: 0=no impaired permeability to 100=complete loss of barrier
function). The primary endpoint was intestinal permeability in patients with symptomatic IBD in mucosal
healing vs patients with asymptomatic IBD in mucosal healing. We determined the sensitivity and
specificity of CLS in determining symptoms based on receiver operating characteristic analysis.
RESULTS:
Ongoing bowel symptoms were present in 16.3% of patients with IBD and mucosal healing (15.4% of
patients with CD, 17.4% with UC). Patients with symptomatic IBD had a significantly higher median CLS
(19.0) than patients with asymptomatic IBD (7.3; P < .001) or controls (5.9, P < .001). There were no
significant differences between patients with IBD in remission vs controls (P = .261). Median CLS was
significantly higher in patients with symptomatic than asymptomatic CD (17.7 vs 8.1; P = .009) and
patients with symptomatic than asymptomatic UC (22.2 vs 6.9; P = .021). A CLS of 13.1 or more
identified ongoing bowel symptoms in patients with IBD and mucosal healing with 95.2% sensitivity and
97.6% specificity; the receiver operating characteristic area under curve value was 0.88. Based on this
cutoff, 36.2% of patients with IBD in mucosal healing have increased intestinal permeability. On
139
regression analysis, every increase in CLS of 1.9 correlated with an additional diarrheal motion per day (P
= .008).
CONCLUSIONS:
In a prospective study of intestinal permeability in patients with IBD and mucosal healing, we associated
impaired intestinal permeability with ongoing bowel symptoms; increases in permeability correlated
with increased severity of diarrhea. Resolution of mucosal permeability beyond mucosal healing might
improve outcomes of patients with IDB (ANZCTR.org.au: ACTRN12613001248752).
Early-life enteric infections: relation between chronic systemic inflammation

and poor cognition in children.
Oriá RB, et al. Nutr Rev. 2016 Jun;74(6):374-86. doi: 10.1093/nutrit/nuw008.
Epub 2016 May 3.
Abstract
The intestinal microbiota undergoes active remodeling in the first 6 to 18 months of life, during which
time the characteristics of the adult microbiota are developed. This process is strongly influenced by the
early diet and enteric pathogens. Enteric infections and malnutrition early in life may favor microbiota
dysbiosis and small intestinal bacterial overgrowth, resulting in intestinal barrier dysfunction and
translocation of intestinal bacterial products, ultimately leading to low-grade, chronic, subclinical
systemic inflammation. The leaky gut-derived low-grade systemic inflammation may have profound
consequences on the gut-liver-brain axis, compromising normal growth, metabolism, and cognitive
development. This review examines recent data suggesting that early-life enteric infections that lead to
intestinal barrier disruption may shift the intestinal microbiota toward chronic systemic inflammation
and subsequent impaired cognitive development.
Roles of the gut in the metabolic syndrome: an overview.

Fändriks L J Intern Med. 2017 Apr;281(4):319-336. doi: 10.1111/joim.12584.
Epub 2016 Dec 19.
Abstract
The metabolic syndrome is a cluster of risk factors (central obesity, hyperglycaemia, dyslipidaemia and
arterial hypertension), indicating an increased risk of diabetes, cardiovascular disease and premature
140
mortality. The gastrointestinal tract is seldom discussed as an organ system of principal importance for
metabolic diseases. The present overview connects various metabolic research lines into an integrative
physiological context in which the gastrointestinal tract is included. Strong evidence for the involvement
of the gut in the metabolic syndrome derives from the powerful effects of weight-reducing (bariatric)
gastrointestinal surgery. In fact, gastrointestinal surgery is now recommended as a standard treatment
option for type 2 diabetes in obesity. Several gut-related mechanisms that potentially contribute to the
metabolic syndrome will be presented. Obesity can be caused by hampered release of satiety-signalling
gut hormones, reduced meal-associated energy expenditure and microbiota-assisted harvest of energy
from nondigestible food ingredients. Adiposity per se is a well-established risk factor for
hyperglycaemia. In addition, a leaky gut mucosa can trigger systemic inflammation mediating peripheral
insulin resistance that together with a blunted incretin response aggravates the hyperglycaemic state.
The intestinal microbiota is strongly associated with obesity and the related metabolic disease states,
although the mechanisms involved remain unclear. Enterorenal signalling has been suggested to be
involved in the pathophysiology of hypertension and postprandial triglyceride-rich chylomicrons; in
addition, intestinal cholesterol metabolism probably contributes to atherosclerosis. It is likely that in the
future, the metabolic syndrome will be treated according to novel pharmacological principles interfering
with gastrointestinal functionality.
Risk factors associated with intestinal permeability in an adult population: A

systematic review.
Leech B, McIntyre E, Steel A, Sibbritt D. Int J Clin Pract. 2019 Jun 26:e13385. doi:
10.1111/ijcp.13385. [Epub ahead of print]
Abstract
BACKGROUND:
Increased intestinal permeability (IP) involves the loss of integrity between the cells of the small
intestine. IP has been suggested to contribute to the pathogenesis and exacerbation of many chronic
diseases. Many potential risk factors for IP are proposed in contemporary literature. The purpose of this
review is to identify the most significant risk factors for IP.
METHODS:
A systematic search of literature published up until September 2018 in the PubMed, EMBASE, CINAHL,
and Scopus databases was conducted.
RESULTS:
A total of 47 articles met the inclusion criteria. Elevated levels of proinflammatory markers,
dyslipidaemia, hyperglycaemia, insulin resistance, anthropometric measurements resembling obesity,
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advanced disease severity, comorbidity and the consumption of a Western-style diet were identified as
the strongest risk factors for altered intestinal integrity. The risk of IP increases when coupled with a
multiple disease state or combined with other environmental risk factors. Furthermore, many of the
identified risk factors such as anthropometric measurements and biomarkers were external from
intestinal health and rather resembled a metabolic-like condition.
CONCLUSIONS:
This review identified a number of potential risk factors for IP, ranging from biomarkers to
anthropometric measurements, demographics, dietary intake and chronic diseases. These risk factors
warrant the attention of clinicians and other healthcare providers to aid the identification of potential
patients at risk of altered IP. Further research needs to examine whether the identified risk factors are
homogeneous with the diagnosis of IP or whether the disease state influences the association.
Interactions between gut bacteria and bile in health and disease.

Long SL, Gahan CGM, Joyce SA. Mol Aspects Med. 2017 Aug;56:54-65. doi:
10.1016/j.mam.2017.06.002. Epub 2017 Jun 21.
Abstract
Bile acids are synthesized from cholesterol in the liver and released into the intestine to aid the
digestion of dietary lipids. The host enzymes that contribute to bile acid synthesis in the liver and the
regulatory pathways that influence the composition of the total bile acid pool in the host have been well
established. In addition, the gut microbiota provides unique contributions to the diversity of bile acids in
the bile acid pool. Gut microbial enzymes contribute significantly to bile acid metabolism through
deconjugation and dehydroxylation reactions to generate unconjugated bile acids and secondary bile
acids. These microbial enzymes (which include bile salt hydrolase (BSH) and bile acid-inducible (BAI)
enzymes) are essential for bile acid homeostasis in the host and represent a vital contribution of the gut
microbiome to host health. Perturbation of the gut microbiota in disease states may therefore
significantly influence bile acid signatures in the host, especially in the context of gastrointestinal or
systemic disease. Given that bile acids are ligands for host cell receptors (including the FXR, TGR5 and
Vitamin D Receptor) alterations to microbial enzymes and associated changes to bile acid signatures
have significant consequences for the host. In this review we examine the contribution of microbial
enzymes to the process of bile acid metabolism in the host and discuss the implications for microbe-host
signaling in the context of C. difficile infection, inflammatory bowel disease and other disease states.
142
Gut microbiota functions: metabolism of nutrients and other food

components.
Rowland I, et al. Eur J Nutr. 2018 Feb;57(1):1-24. doi: 10.1007/s00394-017-1445-
8. Epub 2017 Apr 9.
Abstract
The diverse microbial community that inhabits the human gut has an extensive metabolic repertoire
that is distinct from, but complements the activity of mammalian enzymes in the liver and gut mucosa
and includes functions essential for host digestion. As such, the gut microbiota is a key factor in shaping
the biochemical profile of the diet and, therefore, its impact on host health and disease. The important
role that the gut microbiota appears to play in human metabolism and health has stimulated research
into the identification of specific microorganisms involved in different processes, and the elucidation of
metabolic pathways, particularly those associated with metabolism of dietary components and some
host-generated substances. In the first part of the review, we discuss the main gut microorganisms,
particularly bacteria, and microbial pathways associated with the metabolism of dietary carbohydrates
(to short chain fatty acids and gases), proteins, plant polyphenols, bile acids, and vitamins. The second
part of the review focuses on the methodologies, existing and novel, that can be employed to explore
gut microbial pathways of metabolism. These include mathematical models, omics techniques, isolated
microbes, and enzyme assays.
Digestive Enzyme Supplementation in Gastrointestinal Diseases

Gianluca Ianiro, Silvia Pecere, Valentina Giorgio, Antonio Gasbarrini, and
Giovanni Cammarota. Curr Drug Metab. 2016 Feb; 17(2): 187–193. Published
online 2016 Feb. doi: 10.2174/138920021702160114150137
Abstract
Background:
Digestive enzymes are able to break down proteins and carbohydrates and lipids, and their
supplementation may play a role in the management of digestive disorders, from lactose intolerance to
cystic fibrosis. To date, several formulations of digestive enzymes are available on the market, being
different each other in terms of enzyme type, source and origin, and dosage.
Methods:
This review, performed through a non-systematic search of the available literature, will provide an
overview of the current knowledge of digestive enzyme supplementation in gastrointestinal disorders,
143
discussion of the use of pancreatic enzymes, lactase (β-galactosidase) and conjugated bile acids, and
also exploring the future perspective of digestive enzyme supplementation.
Results:
Currently, the animal-derived enzymes represent an established standard of care, however the growing
study of plant-based and microbe-derived enzymes offers great promise in the advancement of
digestive enzyme therapy.
Conclusion:
New frontiers of enzyme replacement are being evaluated also in the treatment of diseases not
specifically related to enzyme deficiency, whereas the combination of different enzymes might
constitute an intriguing therapeutic option in the future.
Keywords: Bile acids, celiac disease, enzyme supplementation, gastrointestinal disease, lactose
intolerance, pancreatic insufficiency.
The role of enzyme supplementation in digestive disorders.

Roxas M. Altern Med Rev. 2008 Dec;13(4):307-14.
Abstract
This article reviews various forms of enzyme supplementation used clinically in digestive and absorption
disorders. Enzyme supplementation plays an integral role in the management of various digestive
disorders, particularly with regard to exocrine pancreatic insufficiency. However, application of enzymes
may also be beneficial for other conditions associated with poor digestion including lactose intolerance.
Historically, porcine and bovine pancreatic enzymes have been the preferred form of supplementation
for exocrine pancreatic insufficiency. Use of microbe-derived lipase has shown promise with studies
indicating benefit similar to pancreatic enzymes, but at a lower dosage concentration and with a
broader pH range. Safety and efficacy of enzymes derived from microbial species in the treatment of
conditions such as malabsorption and lactose intolerance is promising. Plant-based enzymes, such as
bromelain from pineapple, serve as effective digestive aids in the breakdown of proteins. Synergistic
effects have been observed using a combination of animal-based enzymes and microbe-derived
enzymes or bromelain.
Digestive and nutritional considerations in celiac disease: could

supplementation help?
Malterre T. Altern Med Rev. 2009 Sep;14(3):247-57.
144
Abstract
Due to the increased immune activation in the intestinal tract of people with celiac disease, the
digestive and absorptive processes of those affected may be compromised. Individuals with celiac
disease are more susceptible to pancreatic insufficiencies, dysbiosis, lactase insufficiencies, and folic
acid, vitamin B12, iron, and vitamin D deficiencies, as well as accelerated bone loss due to an increase in
inflammatory signaling molecules. Beyond strict maintenance of a gluten-free diet, research has shown
benefit with additional nutritional supplementation to assist in regulation of several of these
complications.
Camphor
The pharmacology of topical analgesics.
Barkin RL. Postgrad Med. 2013 Jul;125(4 Suppl 1):7-18.
Abstract
Pain management of patients continues to pose challenges to clinicians. Given the multiple dimensions
of pain--whether acute or chronic, mild, moderate, or severe, nociceptive or neuropathic--a multimodal
approach may be needed. Fortunately, clinicians have an array of nonpharmacologic and pharmacologic
treatment choices; however, each modality must be chosen carefully, because some often used oral
agents are associated with safety and tolerability issues that restrict their use in certain patients. In
particular, orally administered nonsteroidal antiinflammatory drugs, opioids, antidepressants, and
anticonvulsants are known to cause systemic adverse effects in some patients. To address this problem,
a number of topical therapies in various therapeutic classes have been developed to reduce systemic
exposure and minimize the risks of patients developing adverse events. For example, topical
nonsteroidal anti-inflammatory drug formulations produce a site-specific effect (ie, cyclo-oxygenase
inhibition) while decreasing the systemic exposure that may lead to undesired effects in patients.
Similarly, derivatives of acetylsalicylic acid (ie, salicylates) are used in topical analgesic formulations that
do not significantly enter the patient's systemic circulation. Salicylates, along with capsaicin, menthol,
and camphor, compose the counterirritant class of topical analgesics, which produce analgesia by
activating and then desensitizing epidermal nociceptors. Additionally, patches and creams that contain
the local anesthetic lidocaine, alone or co-formulated with other local anesthetics, are also used to
manage patients with select acute and chronic pain states. Perhaps the most common topical analgesic
modality is the cautious application of cutaneous cold and heat. Such treatments may decrease pain not
by reaching the target tissue through systemic distribution, but by acting more directly on the affected
145
tissue. Despite the tolerability benefits associated with avoiding systemic circulation, topically applied
analgesics are associated with application-site reactions in patients, such as dryness, erythema, burning,
and discoloration. Furthermore, some adverse events that have been observed in patients may be
suggestive of some degree of systemic exposure. This article reviews the mechanisms of action,
pharmacokinetics, and tolerability of topical treatments for the management of patient pain.
Topical therapies for knee osteoarthritis.

Rodriguez-Merchan EC. Postgrad Med. 2018 Sep;130(7):607-612. doi:
10.1080/00325481.2018.1505182. Epub 2018 Aug 29.
Abstract
BACKGROUND:
Symptomatic knee osteoarthritis (OA) involves millions of adults around the world.
PURPOSE:
To analyze the effectiveness and tolerability of topical therapies and their contemporary placement in
knee OA management criteria.
METHODS:
A Cochrane Library and PubMed (MEDLINE) search related to the role of topical therapies in knee OA
was carried out.
RESULTS:
Many types of local therapy have been reported, including nonsteroidal anti-inflammatory drugs
(NSAIDs) like diclofenac and ketoprofen; capsaicin, cream containing glucosamine sulfate, chondroitin
sulfate, and camphor; nimesulide; civamide cream 0.075%; menthol; drug-free gel containing ultra-
deformable phospholipid vesicles (TDT 064); 4Jointz utilizing Acteev technology; herbal therapies; gel of
medical leech (Hirudo medicinalis) saliva extract; and gel prepared using Lake Urmia mud. One
systematic review showed that topical diclofenac and topical ketoprofen can alleviate pain. However,
another systematic review found that topical diclofenac and ketoprofen had limited efficacy in knee OA
at 6 to 12 weeks. Many studies with a low level of evidence have reported some pain mitigation using
the rest of aforementioned topical therapies.
CONCLUSIONS:
Although some controversy exists on the role of topical NSAIDs, current management guidelines advise
topical NSAIDs as an option and even first-line therapy for knee OA treatment, particularly among
146
elderly patients. Topical NSAIDs may be contemplated as similar options to oral NSAIDs and are
associated with fewer gastrointestinal complications when compared with oral NSAIDs. Caution should
be taken with the use of both topical and oral NSAIDs, including close adherence to dosing regimens and
monitoring, especially for patients with previous complications of NSAIDs. The role of other topical
therapies needs further research.
KEYWORDS:
Knee; NSAIDs; osteoarthritis; pain; topical therapies
Camphor--a fumigant during the Black Death and a coveted fragrant wood in
ancient Egypt and Babylon--a review.
Chen W, Vermaak I, Viljoen A. Molecules. 2013 May 10;18(5):5434-54. doi:
10.3390/molecules18055434.
Abstract
The fragrant camphor tree (Cinnamomum camphora) and its products, such as camphor oil, have been
coveted since ancient times. Having a rich history of traditional use, it was particularly used as a
fumigant during the era of the Black Death and considered as a valuable ingredient in both perfume and
embalming fluid. Camphor has been widely used as a fragrance in cosmetics, as a food flavourant, as a
common ingredient in household cleaners, as well as in topically applied analgesics and rubefacients for
the treatment of minor muscle aches and pains. Camphor, traditionally obtained through the distillation
of the wood of the camphor tree, is a major essential oil component of many aromatic plant species, as
it is biosynthetically synthesised; it can also be chemically synthesised using mainly turpentine as a
starting material. Camphor exhibits a number of biological properties such as insecticidal, antimicrobial,
antiviral, anticoccidial, anti-nociceptive, anticancer and antitussive activities, in addition to its use as a
skin penetration enhancer. However, camphor is a very toxic substance and numerous cases of camphor
poisoning have been documented. This review briefly summarises the uses and synthesis of camphor
and discusses the biological properties and toxicity of this valuable molecule.
A randomized, double blind, placebo controlled trial of a topical cream

containing glucosamine sulfate, chondroitin sulfate, and camphor for
Cohen M, Wolfe R, Mai T, Lewis D. J Rheumatol. 2003 Mar;30(3):523-8.
Abstract
147
OBJECTIVE:
To assess the ability of a topical preparation of glucosamine sulfate and chondroitin sulfate to reduce
pain related to osteoarthritis (OA) of the knee.
METHODS:
Sixty-three patients were randomized to receive either a topical glucosamine and chondroitin
preparation or placebo to be used as required over an 8 week period. Efficacy was assessed using a
visual analog scale (VAS) for pain as well as the Western Ontario and McMaster Universities
Osteoarthritis Index (WOMAC), and the SF-36 questionnaire.
RESULTS:
VAS scores indicated a greater mean reduction in pain for the glucosamine/chondroitin preparation
group (mean change -3.4 cm, SD 2.6 cm) compared to the placebo group (mean change -1.6 cm, SD 2.7
cm) after 8 weeks. After 4 weeks the difference between active and placebo groups in their mean
reduction from baseline was 1.2 (95% CI 0.1 to 2.4, p = 0.03) and after 8 weeks was 1.8 (95% CI for
difference between groups, 0.6 to 2.9 cm; p = 0.002).
CONCLUSION:
Topical application of glucosamine and chondroitin sulfate is effective in relieving the pain from OA of
the knee and improvement is evident within 4 weeks.
CAMPHOR
https://www.webmd.com/vitamins/ai/ingredientmono-709/camphor
Camphor used to be made by distilling the bark and wood of the camphor tree. Today, camphor is
usually manufactured from turpentine oil. It is used in products such as Vicks VapoRub.
Camphor products can be rubbed on the skin (topical application) or inhaled. Be sure to read the label to
find out how the product should be administered.
People sometimes apply camphor to the skin to relieve pain and reduce itching. Some people inhale
camphor to reduce the urge to cough. There is some good evidence to support these uses. Camphor has
also been applied to the skin to treat toenail fungus, warts, insect bites, cold sores, and hemorrhoids,
but there is no good scientific research to support these other uses.
It is important not to apply camphor to broken skin, because it can enter the body quickly and reach
concentrations that are high enough to cause poisoning.
148
Although it is an UNSAFE practice, some people take camphor by mouth to help them cough up phlegm,
treat infections of the airway, treat intestinal gas (flatulence), and decrease body weight. Experts warn
against doing this because, when ingested, camphor can cause serious side effects, even death.
Camphor is a well-established folk remedy, and is commonly used. Camphorated oil (20% camphor in
cottonseed oil) was removed from the U.S. market in the 1980s because of safety concerns associated
with accidental intake by mouth. It continues to be available without a prescription in Canada.
Clinical efficacy of polyherbal formulation Eezpain spray for muscular pain

relief.
Nawaz A, et al. Pak J Pharm Sci. 2015 Jan;28(1):43-7.
Abstract
The topical herbal formulation Eezpain spray consisting of natural ingredients that have been clinically
proved for its analgesic and anti-inflammatory activity. The designed formulation on application knee
and wrist joints, back of neck and shoulder, forearms and lower back exhibited significant efficacy. A
total of 20 subjects both male and female applied Eezpain spray consisting of Gaultheria oil, Eucalyptus
oil, Turpentine oil, Clove Oil, Menthol and Camphor. All the active materials are cited that these have
analgesic activity in myalgia and neuralgia. The study design was prospective and opens as pilot study
followed the inclusion and exclusion criteria. All the sign and symptoms were noted at baseline and at
the end of 14 days treatment performance was evaluated. The statistical analysis was done by using
Microsoft Excel2007 and SPSS version 18.0. It is concluded that Eezpain spray has shown efficacy in mild
to moderate cases on applying locally to the affected parts to relieve pain from different ailments.
[Study on antiinflammatory effect of different chemotype of Cinnamomum

camphora on rat arthritis model induced by Freund's adjuvant].[Article in
Chinese]
Li 1, Huang L, Zhou A, Li X, Sun J. Zhongguo Zhong Yao Za Zhi. 2009
Dec;34(24):3251-4.
Abstract
OBJECTIVE:
To study the antiinflammatory effects of naphtha from different chemotypes of Cinnamomum

camphora and natural borneol on the rat arthritis model induced by Freund's adjuvant.
149
METHOD:
The arthritis model was induced by injecting Freund's adjuvant in rat voix pedis dermis and the rats were
randomly divided into seven groups: normal control group, model control group, triptergium wilfordii
control group, borneol chemotype naphtha group, camphor chemotype naphtha group, isocamphane
chemotype naphtha group and natural borneol group. Rats of the triptergium wilfordii control group
were given orally 8.1 mg x kg(-1) triptergium wilfordii for 35 days, rats of the normal control group and
model control group were given same volume water, and rats of other groups were given 80 mg x kg(-1)
corresponding drug. We observed the rat common condition, weighed the rat body weight weekly,
measured the degree of swelling of voix pedis every 4 days, weighed the thymus and spleen on the end
of life, and measured the contents of cell factor TNF-alpha, IL-2, and IL-6 in rat blood serum.
RESULT:
As far as the arthrosis degree of swelling and the contents of cell factor TNF-alpha, IL-2, IL-6 were
concerned, rats of model control group were higher than normal control group, and rats of other drug
groups were lower than the model control group. The order of inhibition ratios of the arthrosis degree
of swelling from high to low principle was isocamphane chemotype naphtha group, camphor chemotype
naphtha group, borneol chemotype naphtha group and natural borneol group. All medication
administration teams evidently reduced the contents of the IL-2 and IL-6, and the inhibition ratios were
higher than 38%. In the case of the contents of TNF-alpha and IL-2, all groups were not evidently
different. In the case of inhibition of IL-6, camphor chemotype naphtha group was better than borneol
chemotype naphtha group and natural borneol group, the latter was better than isocamphane
chemotype naphtha group. As far as the weight, thymus index and spleen index were concerned, all
medication administration groups were not different.
CONCLUSION:
The different chemotypes of C. camphora have anti-inflammatory effect on the rat arthritis model
induced by Freund's adjuvant, but pharmacological activity and mechanism of action are different. The
study points out the clinical curative effects of the chemotypes of the kindred medicinal plant are
different, and please consider the difference of chemotype in clinical application.
How to Use Camphor Safely: Benefits and Precautions

Medically reviewed by Alan Carter, PharmD on June 19, 2018 — Written by Emily
Cronkleton
https://www.healthline.com/health/what-is-camphor
Overview
150
Camphor (Cinnamomum camphora) is a terpene (organic compound) that’s commonly used in creams,
ointments, and lotions. Camphor oil is the oil extracted from the wood of camphor trees and processed
by steam distillation. It can be used topically to relieve pain, irritation, and itching. Camphor is also used
to relieve chest congestion and inflammatory conditions.
It has a strong odor and taste and is easily absorbed through the skin. Camphor is currently made out of
turpentine, but it’s still safe to use as long as you use it correctly. It has the potential for side effects,
especially if you use it in high doses. Never take camphor internally or apply it to broken skin, as it can
be toxic.
What is camphor used for?
Camphor has a wide variety of topical uses due to its antibacterial, antifungal, and anti-inflammatory
properties. It can be used to treat skin conditions, improve respiratory function, and relieve pain.
Continue reading to learn more about the different uses for camphor and its supporting scientific
evidence.
Capsasin
Abstract
151
Topical therapies for knee osteoarthritis.

Rodriguez-Merchan EC. Postgrad Med. 2018 Sep;130(7):607-612. doi:
10.1080/00325481.2018.1505182. Epub 2018 Aug 29.
Abstract
BACKGROUND:
Symptomatic knee osteoarthritis (OA) involves millions of adults around the world.
PURPOSE:
To analyze the effectiveness and tolerability of topical therapies and their contemporary placement in
knee OA management criteria.
METHODS:
A Cochrane Library and PubMed (MEDLINE) search related to the role of topical therapies in knee OA
was carried out.
RESULTS:
Many types of local therapy have been reported, including nonsteroidal anti-inflammatory drugs
(NSAIDs) like diclofenac and ketoprofen; capsaicin, cream containing glucosamine sulfate, chondroitin
sulfate, and camphor; nimesulide; civamide cream 0.075%; menthol; drug-free gel containing ultra-
deformable phospholipid vesicles (TDT 064); 4Jointz utilizing Acteev technology; herbal therapies; gel of
medical leech (Hirudo medicinalis) saliva extract; and gel prepared using Lake Urmia mud. One
systematic review showed that topical diclofenac and topical ketoprofen can alleviate pain. However,
152
another systematic review found that topical diclofenac and ketoprofen had limited efficacy in knee OA
at 6 to 12 weeks. Many studies with a low level of evidence have reported some pain mitigation using
the rest of aforementioned topical therapies.
CONCLUSIONS:
Although some controversy exists on the role of topical NSAIDs, current management guidelines advise
topical NSAIDs as an option and even first-line therapy for knee OA treatment, particularly among
elderly patients. Topical NSAIDs may be contemplated as similar options to oral NSAIDs and are
associated with fewer gastrointestinal complications when compared with oral NSAIDs. Caution should
be taken with the use of both topical and oral NSAIDs, including close adherence to dosing regimens and
monitoring, especially for patients with previous complications of NSAIDs. The role of other topical
therapies needs further research.
KEYWORDS:
Knee; NSAIDs; osteoarthritis; pain; topical therapies
Topical therapies in the management of chronic pain.

Stanos SP, Galluzzi KE. Postgrad Med. 2013 Jul;125(4 Suppl 1):25-33.
Abstract
Chronic pain, whether localized or generalized, is a widespread, often debilitating condition affecting >
25% of adults in the United States. Oral agents are the cornerstone of chronic pain treatment, but their
use may be limited in certain patients, particularly the elderly. Topical therapies offer advantages over
systemically administered medications, including the requirement of a lower total systemic daily dose
for patients to achieve pain relief, site-specific drug delivery, and avoidance of first-pass metabolism,
major drug interactions, infections, and systemic side effects. Several types of topical agents have been
shown to be useful in the treatment of patients with chronic pain. Both capsaicin and topical diclofenac
have been shown to be effective in the treatment of patients with chronic soft-tissue pain. In patients
with hand and knee osteoarthritis (OA), the American College of Rheumatology generally recommends
oral treatments (acetaminophen, oral nonsteroidal anti-inflammatory drugs [NSAIDs], tramadol, and
intra-articular corticosteroids) and topical NSAIDs equally, favoring topical agents only for patients who
have pre-existing gastrointestinal risk or are aged ≥ 75 years. Topical NSAIDs have been shown to
provide relief superior to that of placebo and comparable to that of oral ibuprofen. Similarly, ketoprofen
gel has been shown to be superior to placebo and similar to oral celecoxib in reducing pain in patients
with knee OA. Different formulations of topical diclofenac (including the diclofenac hydroxyethyl
pyrrolidine patch, diclofenac sodium gel, and diclofenac sodium topical solution 1.5% w/w with dimethyl
sulfoxide USP) have been shown to be superior to placebo and comparable to oral diclofenac in the
treatment of patients with pain due to knee OA, with a lower incidence of gastrointestinal complaints
153
than with the oral formulation. In patients with neuropathic pain, topical forms of both capsaicin and
lidocaine have been shown to be useful in the treatment of postherpetic neuralgia and diabetic
peripheral neuropathic pain. Lidocaine has also demonstrated efficacy in relieving patient pain due to
complex regional pain syndrome and may be useful in the treatment of patients with neuropathic pain
who have cancer, although clinical trial results have not been consistent. Data suggest that topical
therapies may offer a safe, well-tolerated, and effective alternative to systemic therapies in the
treatment of patients with chronic, localized musculoskeletal and neuropathic pain.
Topical therapy for osteoarthritis: clinical and pharmacologic perspectives.

Altman R, Barkin RL. Postgrad Med. 2009 Mar;121(2):139-47. doi:
10.3810/pgm.2009.03.1986.
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown efficacy in patients with osteoarthritis (OA)
pain but are also associated with a dose-dependent risk of gastrointestinal, cardiovascular, hematologic,
hepatic, and renal adverse events (AEs). Topical NSAIDs were developed to provide analgesia similar to
their oral counterparts with less systemic exposure and fewer serious AEs. Topical NSAIDs have long
been available in Europe for the management of OA, and guidelines of the European League Against
Rheumatism and the Osteoarthritis Research Society International specify that topical NSAIDs are
preferred over oral NSAIDs for patients with knee or hand OA of mild-to-moderate severity, few affected
joints, and/or a history of sensitivity to oral NSAIDs. In contrast, the guidelines of the American Pain
Society and American College of Rheumatology have in the past recommended topical methyl salicylate
and topical capsaicin, but not topical NSAIDs. This reflects the fact that the American guidelines were
written several years before the first topical NSAID was approved for use in the United States. Neither
salicylates nor capsaicin have shown significant efficacy in the treatment of OA. In October 2007,
diclofenac sodium 1% gel (Voltaren Gel) became the first topical NSAID for OA therapy approved in the
United States following a long history of use internationally. Topical diclofenac sodium 1% gel delivers
effective diclofenac concentrations in the affected joint with limited systemic exposure. Clinical trial
data suggest that diclofenac sodium 1% gel provides clinically meaningful analgesia in OA patients with a
low incidence of systemic AEs. This review discusses the pharmacology, clinical efficacy, and safety
profiles of diclofenac sodium 1% gel, salicylates, and capsaicin for the management of hand and knee
OA.
154
Conditional Recommendations for Specific Dietary Ingredients as an Approach

to Chronic Musculoskeletal Pain: Evidence-Based Decision Aid for Health Care
Providers, Participants, and Policy Makers.
Boyd C, Crawford C, Berry K, Deuster P; HERB Working Group. Pain Med. 2019 Apr
15. pii: pnz051. doi: 10.1093/pm/pnz051. [Epub ahead of print]
Abstract
OBJECTIVE:
Approximately 55-76% of Service members use dietary supplements for various reasons; although such
use has become popular for a wide range of pain conditions, decisions to use supplements are often
driven by information that is not evidence-based. This work evaluates whether the current research on
dietary ingredients for chronic musculoskeletal pain provides sufficient evidence to inform decisions for
practice and self-care, specifically for Special Operations Forces personnel.
METHODS:
A steering committee convened to develop research questions and factors required for decision-making.
Key databases were searched through August 2016. Eligible systematic reviews and randomized
controlled trials were assessed for methodological quality. Meta-analysis was applied where feasible.
GRADE was used to determine confidence in the effect estimates. A decision table was constructed to
make evidence-informed judgments across factors required for decision-making, and recommendations
were made for practice and self-care use.
RESULTS:
Nineteen dietary ingredients were included. Conditional evidence-based recommendations were made
for the use of avocado soybean unsaponifiables, capsaicin, curcuma, ginger, glucosamine, melatonin,
polyunsaturated fatty acids, and vitamin D. In these cases, desirable effects outweighed undesirable
effects, but there was uncertainty about the trade-offs, either because the evidence was low quality or
because benefits and downsides were closely balanced.
CONCLUSIONS:
The evidence showed that certain dietary ingredients, when taken as part of a balanced diet and/or as a
supplement (e.g., pill, tablet, capsule, cream), may alleviate musculoskeletal pain with no to minimal risk
of harm. This finding emphasizes and reinforces the critical importance of shared decision-making
between Operators and their health care providers.
KEYWORDS:
Dietary Ingredients; Dietary Supplements; Meta-analysis; Musculoskeletal Pain; Systematic Review

155
Capsaicin, Nociception and Pain.

Frias B, Merighi A. Molecules. 2016 Jun 18;21(6). pii: E797. doi:
10.3390/molecules21060797.
Abstract
Capsaicin, the pungent ingredient of the hot chili pepper, is known to act on the transient receptor
potential cation channel vanilloid subfamily member 1 (TRPV1). TRPV1 is involved in somatic and
visceral peripheral inflammation, in the modulation of nociceptive inputs to spinal cord and brain stem
centers, as well as the integration of diverse painful stimuli. In this review, we first describe the chemical
and pharmacological properties of capsaicin and its derivatives in relation to their analgesic properties.
We then consider the biochemical and functional characteristics of TRPV1, focusing on its distribution
and biological effects within the somatosensory and viscerosensory nociceptive systems. Finally, we
discuss the use of capsaicin as an agonist of TRPV1 to model acute inflammation in slices and other ex
vivo preparations.
KEYWORDS:
TRPV1 receptor; analgesia; capsaicin; nociception; resinferatoxin; sensitization; somatic pain; vanilloids;
visceral pain
Capsaicin: Current Understanding of Its Mechanisms and Therapy of Pain and

Other Pre-Clinical and Clinical Uses.
Fattori V, Hohmann MS, Rossaneis AC, Pinho-Ribeiro FA, Verri WA. Molecules.
2016 Jun 28;21(7). pii: E844. doi: 10.3390/molecules21070844.
Abstract
In this review, we discuss the importance of capsaicin to the current understanding of neuronal
modulation of pain and explore the mechanisms of capsaicin-induced pain. We will focus on the
analgesic effects of capsaicin and its clinical applicability in treating pain. Furthermore, we will draw
attention to the rationale for other clinical therapeutic uses and implications of capsaicin in diseases
such as obesity, diabetes, cardiovascular conditions, cancer, airway diseases, itch, gastric, and urological
disorders.
KEYWORDS:
156
TRPV1; analgesia; capsaicinoids; chili peppers; desensitization
Topical capsaicin (high concentration) for chronic neuropathic pain in adults.

Derry S, Rice AS, Cole P, Tan T, Moore RA. Cochrane Database Syst Rev. 2017 Jan
13;1:CD007393. doi: 10.1002/14651858.CD007393.pub4.
Abstract
BACKGROUND:
This review is an update of 'Topical capsaicin (high concentration) for chronic neuropathic pain in adults'
last updated in Issue 2, 2013. Topical creams with capsaicin are used to treat peripheral neuropathic
pain. Following application to the skin, capsaicin causes enhanced sensitivity, followed by a period with
reduced sensitivity and, after repeated applications, persistent desensitisation. High-concentration (8%)
capsaicin patches were developed to increase the amount of capsaicin delivered; rapid delivery was
thought to improve tolerability because cutaneous nociceptors are 'defunctionalised' quickly. The single
application avoids noncompliance. Only the 8% patch formulation of capsaicin is available, with a
capsaicin concentration about 100 times greater than conventional creams. High-concentration topical
capsaicin is given as a single patch application to the affected part. It must be applied under highly
controlled conditions, often following local anaesthetic, due to the initial intense burning sensation it
causes. The benefits are expected to last for about 12 weeks, when another application might be made.
OBJECTIVES:
To review the evidence from controlled trials on the efficacy and tolerability of topically applied, high-
concentration (8%) capsaicin in chronic neuropathic pain in adults.
SEARCH METHODS:
For this update, we searched CENTRAL, MEDLINE, Embase, two clinical trials registries, and a
pharmaceutical company's website to 10 June 2016.
SELECTION CRITERIA:
Randomised, double-blind, placebo-controlled studies of at least 6 weeks' duration, using high-

concentration (5% or more) topical capsaicin to treat neuropathic pain.
Two review authors independently searched for studies, extracted efficacy and adverse event data, and
examined issues of study quality and potential bias. Where pooled analysis was possible, we used
dichotomous data to calculate risk ratio and numbers needed to treat for one additional event, using
157
standard methods.Efficacy outcomes reflecting long-duration pain relief after a single drug application
were from the Patient Global Impression of Change (PGIC) at specific points, usually 8 and 12 weeks. We
also assessed average pain scores over weeks 2 to 8 and 2 to 12 and the number of participants with
pain intensity reduction of at least 30% or at least 50% over baseline, and information on adverse events
and withdrawals.We assessed the quality of the evidence using GRADE and created a 'Summary of
findings' table.
MAIN RESULTS:
We included eight studies, involving 2488 participants, two more studies and 415 more participants than
the previous version of this review. Studies were of generally good methodological quality; we judged
only one study at high risk of bias, due to small size. Two studies used a placebo control and six used
0.04% topical capsaicin as an 'active' placebo to help maintain blinding. Efficacy outcomes were
inconsistently reported, resulting in analyses for most outcomes being based on less than complete
data.For postherpetic neuralgia, we found four studies (1272 participants). At both 8 and 12 weeks
about 10% more participants reported themselves much or very much improved with high-
concentration capsaicin than with 'active' placebo, with point estimates of numbers needed to treat for
an additional beneficial outcome (NNTs) of 8.8 (95% confidence interval (CI) 5.3 to 26) with high-
concentration capsaicin and 7.0 (95% CI 4.6 to 15) with 'active' placebo (2 studies, 571 participants;
moderate quality evidence). More participants (about 10%) had average 2 to 8-week and 2 to 12-week
pain intensity reductions over baseline of at least 30% and at least 50% with capsaicin than control, with
NNT values between 10 and 12 (2 to 4 studies, 571 to 1272 participants; very low quality evidence).For
painful HIV-neuropathy, we found two studies (801 participants). One study reported the proportion of
participants who were much or very much improved at 12 weeks (27% with high-concentration
capsaicin and 10% with 'active' placebo). For both studies, more participants (about 10%) had average 2
to 12-week pain intensity reductions over baseline of at least 30% with capsaicin than control, with an
NNT of 11 (very low quality evidence).For peripheral diabetic neuropathy, we found one study (369
participants). It reported about 10% more participants who were much or very much improved at 8 and
12 weeks. One small study of 46 participants with persistent pain following inguinal herniorrhaphy did
not show a difference between capsaicin and placebo for pain reduction (very low quality evidence).We
downgraded the quality of the evidence for efficacy outcomes by one to three levels due to sparse data,
imprecision, possible effects of imputation methods, and susceptibility to publication bias.Local adverse
events were common, but not consistently reported. Serious adverse events were no more common
with active treatment (3.5%) than control (3.2%). Adverse event withdrawals did not differ between
groups, but lack of efficacy withdrawals were somewhat more common with control than active
treatment, based on small numbers of events (six to eight studies, 21 to 67 events; moderate quality
evidence, downgraded due to few events). No deaths were judged to be related to study medication.
High-concentration topical capsaicin used to treat postherpetic neuralgia, HIV-neuropathy, and painful
diabetic neuropathy generated more participants with moderate or substantial levels of pain relief than
control treatment using a much lower concentration of capsaicin. These results should be interpreted
158
with caution as the quality of the evidence was moderate or very low. The additional proportion who
benefited over control was not large, but for those who did obtain high levels of pain relief, there were
usually additional improvements in sleep, fatigue, depression, and quality of life. High-concentration
topical capsaicin is similar in its effects to other therapies for chronic pain.
Update of
Topical capsaicin (high concentration) for chronic neuropathic pain in adults. [Cochrane Database Syst
Rev. 2013]
Topical therapies in the management of chronic pain.

Stanos SP, Galluzzi KE. Postgrad Med. 2013 Jul;125(4 Suppl 1):25-33.
Abstract
Chronic pain, whether localized or generalized, is a widespread, often debilitating condition affecting >
25% of adults in the United States. Oral agents are the cornerstone of chronic pain treatment, but their
use may be limited in certain patients, particularly the elderly. Topical therapies offer advantages over
systemically administered medications, including the requirement of a lower total systemic daily dose
for patients to achieve pain relief, site-specific drug delivery, and avoidance of first-pass metabolism,
major drug interactions, infections, and systemic side effects. Several types of topical agents have been
shown to be useful in the treatment of patients with chronic pain. Both capsaicin and topical diclofenac
have been shown to be effective in the treatment of patients with chronic soft-tissue pain. In patients
with hand and knee osteoarthritis (OA), the American College of Rheumatology generally recommends
oral treatments (acetaminophen, oral nonsteroidal anti-inflammatory drugs [NSAIDs], tramadol, and
intra-articular corticosteroids) and topical NSAIDs equally, favoring topical agents only for patients who
have pre-existing gastrointestinal risk or are aged ≥ 75 years. Topical NSAIDs have been shown to
provide relief superior to that of placebo and comparable to that of oral ibuprofen. Similarly, ketoprofen
gel has been shown to be superior to placebo and similar to oral celecoxib in reducing pain in patients
with knee OA. Different formulations of topical diclofenac (including the diclofenac hydroxyethyl
pyrrolidine patch, diclofenac sodium gel, and diclofenac sodium topical solution 1.5% w/w with dimethyl
sulfoxide USP) have been shown to be superior to placebo and comparable to oral diclofenac in the
treatment of patients with pain due to knee OA, with a lower incidence of gastrointestinal complaints
than with the oral formulation. In patients with neuropathic pain, topical forms of both capsaicin and
lidocaine have been shown to be useful in the treatment of postherpetic neuralgia and diabetic
peripheral neuropathic pain. Lidocaine has also demonstrated efficacy in relieving patient pain due to
complex regional pain syndrome and may be useful in the treatment of patients with neuropathic pain
who have cancer, although clinical trial results have not been consistent. Data suggest that topical
therapies may offer a safe, well-tolerated, and effective alternative to systemic therapies in the
treatment of patients with chronic, localized musculoskeletal and neuropathic pain.
159
Uses of Capsaicin Cream

Medically reviewed by Dena Westphalen, PharmD on September 20, 2018 —
Written by Eleesha Lockett
https://www.healthline.com/health/capsaicin-cream
Overview
In addition to being a popular ingredient in spicy dishes worldwide, the chili pepper also has a surprising
role in the medical world.
Capsaicin is the compound found in peppers that gives them their infamous hot and spicy kick. This
compound is well-known for its pain-relieving properties. It works by affecting the neurotransmitter that
communicates pain signals to the brain. In this way, it can reduce the perception of pain.
Once the capsaicin is extracted from the pepper, it can be added to creams, gels, and even patches for
use as a pain-relief treatment.
Common uses
Capsaicin cream has been studied as a possible treatment option to reduce pain in a handful of
conditions.
Arthritis
In arthritis, dysfunction of the pain receptors causes the body to experience prolonged symptoms of
pain.
Capsaicin Cream
https://www.webmd.com/drugs/2/drug-4181/capsaicin-topical/details
Uses
This medication is used to treat minor aches and pains of the muscles/joints (e.g., arthritis, backache,
sprains). Capsaicin works by decreasing a certain natural substance in your body (substance P) that helps
pass pain signals to the brain.
How to use Capsaicin Cream

160
Use this medication on the skin only. Follow all directions on the product package. If you are uncertain
about any of the information, consult your doctor or pharmacist.
For the cream, gel, and lotion forms, apply a thin layer of medication to the affected area and rub in
gently and thoroughly. You may want to use a cotton ball/swab or latex glove to apply the medication to
avoid touching the medication with your hands.
Do not apply the medication in the eyes, mouth, nostrils, or genitals. If you do get the medication in
those areas, flush with plenty of water. Also, do not apply this medication to skin that is injured or
irritated (for example, cut, scraped, sunburned).
Chamomile
Medicinal plants and their isolated phytochemicals for the management of
chemotherapy-induced neuropathy: therapeutic targets and clinical
perspective.
Oveissi V, et al. Daru. 2019 Jun;27(1):389-406. doi: 10.1007/s40199-019-00255-6.
Epub 2019 Mar 9.
Abstract
BACKGROUND:
Chemotherapy, as one of the main approaches of cancer treatment, is accompanied with several
adverse effects, including chemotherapy-induced peripheral neuropathy (CIPN). Since current methods
to control the condition are not completely effective, new treatment options should be introduced.
Medicinal plants can be suitable candidates to be assessed regarding their effects in CIPN. Current paper
reviews the available preclinical and clinical studies on the efficacy of herbal medicines in CIPN.
METHODS:
Electronic databases including PubMed, Scopus, and Cochrane library were searched with the keywords
"neuropathy" in the title/abstract and "plant", "extract", or "herb" in the whole text. Data were
collected from inception until April 2018.
RESULTS:
161
Plants such as chamomile (Matricaria chamomilla L.), sage (Salvia officinalis L.), cinnamon (Cinnamomum
cassia (L.) D. Don), and sweet flag (Acorus calamus L.) as well as phytochemicals like matrine, curcumin,
and thioctic acid have demonstrated beneficial effects in animal models of CIPN via prevention of axonal
degeneration, decrease in total calcium level, improvement of endogenous antioxidant defense
mechanisms such as superoxide dismutase and reduced glutathione, and regulation of neural cell
apoptosis, nuclear factor-ĸB, cyclooxygenase-2, and nitric oxide signaling. Also, five clinical trials have
evaluated the effect of herbal products in patients with CIPN.
CONCLUSIONS:
There are currently limited clinical evidence on medicinal plants for CIPN which shows the necessity of
future mechanistic studies, as well as well-designed clinical trial for further confirmation of the safety
and efficacy of herbal medicines in CIPN. Graphical abstract Schematic mechanisms of medicinal plants
to prevent chemotherapy-induced neuropathy: NO: nitric oxide, TNF: tumor necrosis factor, PG:
prostaglandin, NF-ĸB: nuclear factor kappa B, LPO: lipid peroxidation, ROS: reactive oxygen species, COX:
cyclooxygenase, IL: interleukin, ERK: extracellular signal-related kinase, X: inhibition, ↓: inducson.
KEYWORDS:
Chemotherapeutic agents; Clinical studies; Inflammation; Medicinal plants; Neuropathy; Pain;

Phytochemicals; Phytotherapy
The natural plant flavonoid apigenin is a strong antioxidant that effectively

delays peripheral neurodegenerative processes.
Kim M, Jung J, Jeong NY, Chung HJ Anat Sci Int. 2019 Sep;94(4):285-294. doi:
10.1007/s12565-019-00486-2. Epub 2019 Apr 4.
Abstract
Oxidative stress contributes to the progression of neurodegenerative diseases of the central and
peripheral nervous systems, including Alzheimer's disease, Parkinson's disease, stroke, and diabetic
neuropathy. Despite the greater capability of peripheral nerves to regenerate compared with those in
the brain or spinal cord, chronic oxidative stress leads to irreversible neurodegeneration in peripheral
nerves. Thus, many efforts have been made to defend against irreversible peripheral nerve
degeneration and oxidative stress. Numerous phytochemicals have been revealed as antioxidants which
neutralize free radicals and reduce peripheral neurocellular damage. Among them, polyphenols alleviate
neurodegeneration by interacting with reactive oxygen species. Apigenin is a polyphenol found in plant-
derived foods, including parsley, thyme, celery, and chamomile tea. Apigenin has been reported to exert
antioxidative effects by scavenging free radicals. In particular, apigenin has a neuroprotective effect
against oxidative stress in neurological disorders, such as cerebral ischemia. However, to date, no
162
studies have shown an association of the inhibitory effect of apigenin with peripheral nerve
degeneration. In this work, we showed that apigenin has a neuroprotective effect against peripheral
nerve degeneration according to four key phenotypes: axonal degradation, myelin fragmentation, trans-
dedifferentiation, and proliferation of Schwann cells via Krox20- and extracellular signal-regulated
kinase-independent processes. Thus, apigenin could be a good candidate to treat peripheral
neurodegenerative diseases.
KEYWORDS:
Antioxidant; Apigenin; Axonal degeneration; Demyelination; Schwann cells
Plant-derived medicines for neuropathies: a comprehensive review of clinical

evidence.
Ebrahimi F, et al. Rev Neurosci. 2019 Jul 26;30(6):671-684. doi:
10.1515/revneuro-2018-0097.
Abstract
Neuropathy is defined as the damage to the peripheral or central nervous system accompanied by pain,
numbness, or muscle weakness, which can be due to congenital diseases or environmental factors such
as diabetes, trauma, or viral infections. As current treatments are not sufficiently able to control the
disease, studies focusing on the identification and discovery of new therapeutic agents are necessary.
Natural products have been used for a long time for the management of different neurological problems
including neuropathies. The aim of the present study is to review the current clinical data on the
beneficial effects of medicinal plants in neuropathy. Electronic databases including PubMed, Scopus,
and Cochrane Library were searched with the keywords 'neuropathy' in the title/abstract and 'plant' or
'extract' or 'herb' in the whole text from inception until August 2017. From a total of 3679 papers, 22
studies were finally included. Medicinal plants were evaluated clinically in several types of neuropathy,
including diabetic neuropathy, chemotherapy-induced peripheral neuropathy, carpal tunnel syndrome,
and HIV-associated neuropathy. Some studies reported the improvement in pain, nerve function, nerve
conduction velocity, and quality of life. Cannabis sativa (hemp), Linum usitatissimum (linseed oil),
capsaicin, and a polyherbal Japanese formulation called Goshajinkigan had the most evidence regarding
their clinical efficacy. Other investigated herbal medicines in neuropathy, such as Matricaria chamomilla
(chamomile), Curcuma longa (turmeric), and Citrullus colocynthis (colocynth), had only one clinical trial.
Thus, future studies are necessary to confirm the safety and efficacy of such natural medicines as a
complementary or alternative treatment for neuropathy.
KEYWORDS:
herbal medicine; medicinal plant; neuropathy; pain; traditional medicine

163
Evaluation of the effect of topical chamomile (Matricaria chamomilla L.)

oleogel as pain relief in migraine without aura: a randomized, double-blind,
placebo-controlled, crossover study.
Zargaran A, et al. Neurol Sci. 2018 Aug;39(8):1345-1353. doi: 10.1007/s10072-
018-3415-1. Epub 2018 May 28.
Abstract
Phytotherapy is a source of finding new remedies for migraine. Traditional chamomile oil (chamomile
extraction in sesame oil) is a formulation in Persian medicine (PM) for pain relief in migraine. An oleogel
preparation of reformulated traditional chamomile oil was prepared and then standardized based on
chamazulene (as a marker in essential oil) and apigenin via gas chromatography (GC) and high-
performance liquid chromatography (HPLC) methods, respectively. A crossover double-blind clinical trial
was performed with 100 patients. Each patient took two tubes of drug and two tubes of placebo during
the study. Visual analog scale (VAS) questionnaires were filled in by the patients and scores were given,
ranging from 0 to 10 (based on the severity of pain) during 24 h. Other complications like nausea,
vomiting, photophobia, and phonophobia were also monitored. There was 4.48 ± 0.01 μl/ml of
chamazulene and 0.233 mg/g of apigenin in the preparation (by correcting the amount with extraction
ratio). Thirty-eight patients in the drug-placebo and 34 patients in the placebo-drug groups (a total
number of 72 patients as per protocol) completed the process in the randomized controlled trial (RCT).
Adapted results from the questionnaires showed that pain, nausea, vomiting, photophobia, and
phonophobia significantly (p < 0.001) decreased by using chamomile oleogel on the patients after 30
min. Results supported the efficacy of chamomile oleogel as a pain relief in migraine without aura.
KEYWORDS:
Chamomile; Migraine; Neurological sciences; Persian medicine
Gel of chamomile vs. urea cream to prevent acute radiation dermatitis in

patients with head and neck cancer: a randomized controlled trial.
Ferreira EB, et al. J Adv Nurs. 2016 Aug;72(8):1926-34. doi: 10.1111/jan.12955.
Epub 2016 Mar 29.
Abstract
AIM:
164
To compare a gel made with chamomile (Chamomilla recutita) with a cream of urea as an intervention
to delay the time to occurrence of radiation dermatitis.
BACKGROUND:
Radiation dermatitis is one of the most common adverse effects of radiotherapy in patients with head
and neck cancer. It is characterized by erythema, itching, pain, skin breakage and burning sensation, and
there is no consensus on how to prevent it.
DESIGN:
The study is a randomized controlled clinical trial.
METHODS:
We will recruit 48 individuals with head and neck cancer who will be starting their radiotherapy and
randomize them to receive either gel of chamomile or cream of urea, as an intervention for prevention
of radiation dermatitis. Social-demographic data will be collected at baseline, and clinical data will be
collected before the initiation of radiotherapy. Participants will be followed weekly to assess
development of radiation dermatitis. The protocol is funded by Conselho Nacional de Pesquisa e
Desenvolvimento Científico (Brazil). The study was approved by a research ethics committee.
DISCUSSION:
Given the clinical relevance of preventing radiation dermatitis and the lack of evidence supporting
specific preventive interventions, it is important to study new products that might be efficacious to
prevent this complication. This article presents the protocol of a randomized controlled trial comparing
a gel made with chamomile (intervention) with a cream of urea (control) to prevent radiation dermatitis
in patients with head and neck cancer undergoing radiotherapy.
KEYWORDS:
chamomile; head and neck cancer; nursing care; radiation dermatitis; skin care; urea
GABA-modulating phytomedicines for anxiety: A systematic review of

preclinical and clinical evidence.
Savage K, Firth J, Stough C, Sarris J. Phytother Res. 2018 Jan;32(1):3-18. doi:
10.1002/ptr.5940. Epub 2017 Nov 23.
Abstract
Anxiety disorders are chronic and functionally disabling conditions with high psychological stress,
characterised by cognitive symptoms of excessive worry and focus difficulties and physiological
165
symptoms such as muscle tension and insomnia. Gamma-aminobutyric acid (GABA) is an inhibitory
neurotransmitter within the central nervous system and is a key target of pharmacotherapies in the
treatment of anxiety. Although current pharmaceutical treatments are often efficacious, they may cause
undesirable side effects including cognitive decrements and withdrawal symptoms. Plant-based
"phytomedicines" may provide novel treatment options, to act as an adjunctive or alternative to existing
anxiolytic medications. As such, we conducted a systematic review to assess the current body of
literature on anxiolytic phytomedicines and/or phytoconstituents. An open-ended search to 5 July 2017
was conducted using MEDLINE (PubMed), Scopus, and Cochrane library online databases and performed
in a stepped format from preclinical to clinical investigations. Eligible studies must have had (a) in vitro
evidence of GABA-modulating activity, (b) animal studies using anxiety models to test an anxiolytic
effect, and (c) human clinical trials. Ten phytomedicines were identified as having preclinical
investigations showing interaction with the GABA system, in addition to human clinical trials: kava,
valerian, pennywort, hops, chamomile, Ginkgo biloba, passionflower, ashwagandha, skullcap, and lemon
balm. Collectively, the literature reveals preclinical and clinical evidence for various phytomedicines
modulating GABA-pathways, with comparative anxiolytic effect to the current array of pharmaceuticals,
along with good safety and tolerability profiles.
KEYWORDS:
GABA; anxiety; anxiolytic; herbal; phytomedicine; phytotherapy
5 Ways Chamomile Tea Benefits Your Health

Written by Brianna Elliott, RD on August 18, 2017. Healthline.com.
https://www.healthline.com/nutrition/5-benefits-of-chamomile-tea
Chamomile tea is a popular beverage that also offers a variety of health benefits.
Chamomile is an herb that comes from the daisy-like flowers of the Asteraceae plant family. It has been
consumed for centuries as a natural remedy for several health conditions.
To make chamomile tea, the flowers are dried and then infused into hot water.
Many people enjoy chamomile tea as a caffeine-free alternative to black or green tea and for its earthy,
somewhat sweet taste.
Furthermore, chamomile tea is loaded with antioxidants that may play a role in lowering your risk of
several diseases, including heart disease and cancer.
Chamomile has properties that may aid sleep and digestion, as well.
This article will discuss 5 potential health benefits of drinking chamomile tea.
166
What Is Chamomile?
Vitamins & Supplements. WebMD. 2018
https://www.webmd.com/diet/supplement-guide-chamomile#1
Chamomile has been used as a traditional medicine for thousands of years to calm anxiety and settle
stomachs. In the U.S., chamomile is best known as an ingredient in herbal tea.
Why do people take chamomile?
Chamomile is considered a safe plant and has been used in many cultures for stomach ailments and as a
mild sedative. Some studies, primarily using combinations of chamomile with other plants, show it may
have health benefits. However, as with any combination product, it is hard to say that a benefit comes
from any one plant.
One product with chamomile and other herbal medicines has been shown to ease upset stomach,
heartburn, nausea, and vomiting. Another mixture with chamomile seems to help colicky babies.
Chondroitin Sulfate
10.1007/s11926-018-0782-9.
Abstract
PURPOSE OF REVIEW:
RECENT FINDINGS:
167
KEYWORDS:

Abstract
OBJECTIVE:
METHODS:
RESULTS:
CONCLUSION:
168
Nutrition, osteoarthritis and cartilage metabolism.

Messina OD, Vidal Wilman M, Vidal Neira LF. Aging Clin Exp Res. 2019
Jun;31(6):807-813. doi: 10.1007/s40520-019-01191-w. Epub 2019 Apr 13.
Abstract
BACKGROUND:
Osteoarthritis (OA) is a degenerative joint disease and a leading cause of adult disability. There is no
cure for OA and there is no effective treatment to stop its progression. Current pharmacologic
treatments such as analgesics and non-steroidal anti-inflammatory drugs may improve the pain and
offer some relief but they do not affect the progression of the disease. The chronic intake of these drugs
may result in severe adverse events. The aim of this review is to revise the effects of nutrition on
cartilage metabolism and OA progression.
METHODS:
A systematic literature search was performed including those related to macro- and micro-nutrients'
actions on cartilage and OA outcome. We selected peer-reviewed articles reporting the results of human
clinical trials.
RESULTS:
Glucosamine and chondroitin sulfate have shown to delay OA knee progression in several clinical trials.
The effectiveness of some products considered nutraceuticals has been widely reviewed in the
literature. This article presents a general description of the effectiveness and mechanism of action of
nutrients, vitamins, antioxidants and other natural components considered as part of the normal diet.
Many in vitro studies indicate the efficacy of specific nutrients in cartilage metabolism and its
involvement in OA. However, rigorous clinical studies needed to evaluate the efficacy of these
compounds in humans are still missing. The influence of nutrients and diet on the metabolism of
cartilage and OA could represent a long-term coadjuvant alternative in the management of patients with
OA. Effects of diet modifications on lipid and cholesterol profiles, adequate vitamin levels and weight
reduction in obese patients could influence the course of the disease.
CONCLUSION:
This review demonstrates that nutrition can improve the symptoms of OA. Glucosamine and chondroitin
sulfate have shown robustly to delay the progression of knee OA in several well-designed studies,
however more controlled clinical trials are needed to conclude that nutritional changes slow down the
progression of the disease.
KEYWORDS:
Cartilage; Cartilage metabolism; Nutrition; Osteoarthritis

169
What is the current status of chondroitin sulfate and glucosamine for the
treatment of knee osteoarthritis?
Henrotin Y, Marty M, Mobasheri A. Maturitas. 2014 Jul;78(3):184-7. doi:
10.1016/j.maturitas.2014.04.015. Epub 2014 May 1.
Abstract
Chondroitin sulfate and glucosamine sulfate exert beneficial effects on the metabolism of in vitro
models of cells derived from synovial joints: chondrocytes, synoviocytes and cells from subchondral
bone, all of which are involved in osteoarthritis (OA). They increase type II collagen and proteoglycan
synthesis in human articular chondrocytes and are able to reduce the production of some pro-
inflammatory mediators and proteases, to reduce the cellular death process, and improve the
anabolic/catabolic balance of the extracellular cartilage matrix (ECM). Clinical trials have reported a
beneficial effect of chondroitin sulfate and glucosamine sulfate on pain and function. The structure-
modifying effects of these compounds have been reported and analyzed in recent meta-analyses. The
results for knee OA demonstrate a small but significant reduction in the rate of joint space narrowing.
Chondroitin sulfate and glucosamine sulphate are recommended by several guidelines from
international societies for the management of knee and hip OA, while others do not recommend these
products or recommend only under condition. This comprehensive review clarifies the role of these
compounds in the therapeutic arsenal for patients with knee OA.
KEYWORDS:
Cartilage; Chondroitin; Glucosamine; Osteoarthritis
Chondroitin Sulfate and Glucosamine as Disease Modifying Anti-

Osteoarthritis Dru gs (DMOADs).
Mantovani V, Maccari F, Volpi N. Curr Med Chem. 2016;23(11):1139-51.
Abstract
Osteoarthritis is a disabling affliction expected to increase in the coming decades, and disease-
modifying osteoarthritis drugs (DMOADs) would be highly desirable adjuncts to symptomatic relief and
structure reconstruction as they may delay the disease process. Chondroitin sulfate and glucosamine
have been observed to exert beneficial effects on the metabolism of various cells involved in
osteoarthritis as well as in animal models and clinical trials. Clinical trials have reported beneficial effects
of both these biological agents, alone or in combination, on pain and functions as well as their structure-
170
modifying capacity reported and analyzed in recent meta-analyses. Nonetheless, the effectiveness of
these bioactive (macro)molecules as DMOADs reported from randomized trials is mismatched. Current
studies with varying levels of evidence suggest that chondroitin sulfate and glucosamine can modify the
disease progression but at the same time there are not absolute certainties on their efficacy in
modifying the course of the disease. This comprehensive review aims to clarify the role of these
compounds in the therapeutic molecules/ drugs useful to patients affected by osteoarthritis.
Predictive modeling of therapeutic response to chondroitin

sulfate/glucosamine hydrochloride in knee osteoarthritis.
Blanco FJ, et al. Ther Adv Chronic Dis. 2019 Aug 24;10:2040622319870013. doi:
10.1177/2040622319870013. eCollection 2019.
Abstract
Background:
In the present study, we explored potential protein biomarkers useful to predict the therapeutic
response of knee osteoarthritis (KOA) patients treated with pharmaceutical grade Chondroitin
sulfate/Glucosamine hydrochloride (CS+GH; Droglican, Bioiberica), in order to optimize therapeutic
outcomes.
Methods:
A shotgun proteomic analysis by iTRAQ labelling and liquid chromatography-mass spectrometry (LC-
MS/MS) was performed using sera from 40 patients enrolled in the Multicentre Osteoarthritis
interVEntion trial with Sysadoa (MOVES). The panel of proteins potentially useful to predict KOA
patient's response was clinically validated in the whole MOVES cohort at baseline (n = 506) using
commercially available enzyme-linked immunosorbent assays kits. Logistic regression models and
receiver-operating-characteristics (ROC) curves were used to analyze the contribution of these proteins
to our prediction models of symptomatic drug response in KOA.
Results:
In the discovery phase of the study, a panel of six putative predictive biomarkers of response to CS+GH
(APOA2, APOA4, APOH, ITIH1, C4BPa and ORM2) were identified by shotgun proteomics. Data are
available via ProteomeXchange with identifier PXD012444. In the verification phase, the panel was
verified in a larger set of KOA patients (n = 262). Finally, ITIH1 and ORM2 were qualified by a blind test in
the whole MOVES cohort at baseline. The combination of these biomarkers with clinical variables
predict the patients' response to CS+GH with a specificity of 79.5% and a sensitivity of 77.1%.
Conclusions:
171
Combining clinical and analytical parameters, we identified one biomarker that could accurately predict
KOA patients' response to CS+GH treatment. Its use would allow an increase in response rates and
safety for the patients suffering KOA.
KEYWORDS:
chondroitin sulfate/glucosamine hydrochloride; knee osteoarthritis; predictive biomarkers; proteomics
Avocado/Soybean Unsaponifiables, Glucosamine and Chondroitin Sulfate

Combination Inhibits Proinflammatory COX-2 Expression and Prostaglandin
E2 Production in Tendon-Derived Cells.
Grzanna MW, Au RY, Au AY, Rashmir AM, Frondoza CG. J Med Food. 2019 Sep 5.
doi: 10.1089/jmf.2019.0022. [Epub ahead of print]
Abstract
Tendinopathy, a common disorder in man and horses, is characterized by pain, dysfunction, and tendon
degeneration. Inflammation plays a key role in the pathogenesis of tendinopathy. Tendon cells produce
proinflammatory molecules that induce pain and tissue deterioration. Currently used nonsteroidal anti-
inflammatory drugs are palliative but have been associated with adverse side effects prompting the
search for safe, alternative compounds. This study determined whether tendon-derived cells' expression
of proinflammatory cyclooxygenase (COX)-2 and production of prostaglandin E2 (PGE2) could be
attenuated by the combination of avocado/soybean unsaponifiables (ASU), glucosamine (GLU), and
chondroitin sulfate (CS). ASU, GLU, and CS have been used in the management of osteoarthritis-
associated joint inflammation. Tenocytes in monolayer and microcarrier spinner cultures were
incubated with media alone, or with the combination of ASU (8.3 μg/mL), GLU (11 μg/mL), and CS
(20 μg/mL). Cultures were next incubated with media alone, or stimulated with interleukin-1β (IL-1β;
10 ng/mL) for 1 h to measure COX-2 gene expression, or for 24 h to measure PGE2 production,
respectively. Tenocyte phenotype was analyzed by phase-contrast microscopy, immunocytochemistry,
and Western blotting. Tendon-derived cells proliferated and produced extracellular matrix component
type I collagen in monolayer and microcarrier spinner cultures. IL-1β-induced COX-2 gene expression
and PGE2 production were significantly reduced by the combination of (ASU+GLU+CS). The suppression
of IL-1β-induced inflammatory response suggests that (ASU+GLU+CS) may help attenuate deleterious
inflammation in tendons.
How to treat osteoarthritis in obese patients?

Conrozier T. Curr Rheumatol Rev. 2019 Jun 24. doi:
10.2174/1573397115666190625105759. [Epub ahead of print]
172
Abstract
The close association between osteoarthritis (OA) and obesity is well established. The concomitant
increasing prevalence of the two diseases has major health, social and economic consequences.
However, to date there is no specific recommendation for the medical management of obese patients
with OA. Current recommendations only specify that obese patients must lose weight and practice
regular physical activity in addition to the usual care. OA symptoms improvement is clinically relevant
from a weight loss > 5% of the body weight. Weight loss improves not only OA symptoms but also
metabolic abnormalities and cardiovascular risk factors commonly altered in subjects with obesity. In
case of morbid obesity, bariatric surgery may be the only one alternative for pain relief. non-steroidal
anti-inflammatory drugs and corticosteroids must be avoided in patients with metabolic syndrome. In
such patients symptomatic slow acting drugs for OA (i.e. glucosamine, chondroitin...) and some anti-
oxidant drugs (i.e. curcumin...) may be helpful thanks to their excellent benefit/risk ratio and their mode
of action which may have a positive impact on both OA and metabolic disorders. Patients and physicians
should know that intra-articular treatments for OA (corticosteroids and hyaluronic acid) have a lower
success rate in obese patients than in patients with normal BMI. Spa therapy contributes to relief pain,
favour weight-loss and reduce metabolic abnormalities with a favourable risk/benefit balance.
KEYWORDS:
SYSADOA; anti-oxidant; bariatric surgery; body mass index; knee; metabolic syndrome spa; obesity;
osteoarthritis; weight-loss
Comparison of Glucosamine-Chondroitin Sulfate with and without

Methylsulfonylmethane in Grade I-II Knee Osteoarthritis: A Double Blind
Lubis AMT, Siagian C, Wonggokusuma E, Marsetyo AF, Setyohadi B. Acta Med
Indones. 2017 Apr;49(2):105-111.
Abstract
BACKGROUND:
Glucosamine, chondroitinsulfate are frequently used to prevent further joint degeneration in

osteoarthritis (OA). Methylsulfonylmethane (MSM) is a supplement containing organic sulphur and also
reported to slow anatomical joint progressivity in the knee OA. The MSM is often combined with
glucosamine and chondroitin sulfate. However, there are controversies whether glucosamine-
chondroitin sulfate or their combination with methylsulfonylmethane could effectively reduce pain in
OA. This study is aimed to compare clinical outcome of glucosamine-chondroitin sulfate (GC),
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glucosamine-chondroitin sulfate-methylsulfonylmethane (GCM), and placeboin patients with knee

osteoarthritis (OA) Kellgren-Lawrence grade I-II.
METHODS:
A double blind, randomized controlled clinical trial was conducted on 147 patients with knee OA
Kellgren-Lawrence grade I-II. Patients were allocated by permuted block randomization into three
groups: GC (n=49), GCM (n=50), or placebo (n=48) groups. GC group received 1500 mg of glucosamine +
1200 mg of chondroitin sulfate + 500 mg of saccharumlactis; GCM group received 1500 mg of
glucosamine + 1200 mg of chondroitin sulfate + 500 mg of MSM; while placebo group received three
matching capsules of saccharumlactis. The drugs were administered once daily for 3 consecutive months
VAS and WOMAC scores were measured before treatment, then at 4th, 8th and 12th week after
treatment.
RESULTS:
On statistical analysis it was found that at the 12th week, there are significant difference between three
treatment groups on the WOMAC score (p=0.03) and on the VAS score (p=0.004). When analyzed
between weeks, GCM treatment group was found statistically significant on WOMAC score (p=0.01) and
VAS score (p<0.001). Comparing the score difference between weeks, WOMAC score analysis showed
significant difference between GC, GCM, and placebo in week 4 (p=0.049) and week 12 (p=0.01). In
addition, VAS score also showed significant difference between groups in week 8 (p=0.006) and week 12
(p<0.001).
CONCLUSION:
Combination of glucosamine-chondroitinsulfate-methylsulfonylmethane showed clinical benefit for

patients with knee OAK ellgren-Lawrence grade I-II compared with GC and placebo. GC did not make
clinical improvement in overall groups of patients with knee OA Kellgren Lawrence grade I-II.
KEYWORDS:
Glucosamine; chondroitin sulfate; methylsufonylmethane; osteoarthritis
Effectiveness of Non-Animal Chondroitin Sulfate Supplementation in the

Treatment of Moderate Knee Osteoarthritis in a Group of Overweight Subjects:
A Randomized, Double-Blind, Placebo-Controlled Pilot Study.
Rondanelli M, et al. Nutrients. 2019 Aug 29;11(9). pii: E2027. doi:
10.3390/nu11092027.
Abstract
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Osteoarthritis (OA) is the most common form of arthritis in the world and is characterized by pain,
various disabilities and loss of quality of life. Chondroitin sulfate (CS) is recommended as first-line
therapy. CS of non-animal origin is of great interest for safety and sustainability reasons. This study aims
to investigate the anti-inflammatory effects, anti-pain and ability-enhancement of a short-term
supplementation with non-animal CS in overweight subjects with OA. In a randomized, double-blind,
placebo-controlled pilot study, 60 overweight adults with symptomatic OA were allocated to consume
600 mg of non-animal CS (n = 30) or a placebo (n = 30) daily for 12 consecutive weeks. The assessment
of knee-pain, quality of life, related inflammation markers and body composition was performed at 0, 4
and 12 weeks. The Tegner Lysholm Knee Scoring (TLKS) scale of the experimental group showed a
statistically significant increase (+10.64 points; confidence interval (95% confidence interval (CI) 5.57;
15.70; p < 0.01), while the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)
score decreased (-12.24 points; CI 95% -16.01; -8.38; p < 0.01). The results also showed a decrease in the
C-reactive protein (CRP) level (-0.14 mg/dL, CI 95% -0.26; -0.04; p < 0.01) and erythrocyte sedimentation
rate (ESR) level (-5.01 mm/h, CI 95% -9.18; -0.84, p < 0.01) as well as the visual analogue scale (VAS)
score in both knees. In conclusion, this pilot study demonstrates the effectiveness of non-animal CS
supplementation in overweight subjects with knee OA in improving knee function, pain and
inflammation markers.
CoQ10
Coenzyme Q10 in Cardiovascular and Metabolic Diseases: Current State of the
Problem
Vladlena I. Zozina, Serghei Covantev, Olga A. Goroshko, Liudmila M. Krasnykh,
and Vladimir G. Kukes. Curr Cardiol Rev. 2018 Aug; 14(3): 164–174. Published
online 2018 Aug. doi: 10.2174/1573403X14666180416115428
Abstract
The burden of cardiovascular and metabolic diseases is increasing with every year. Although the
management of these conditions has improved greatly over the years, it is still far from perfect. With all
of this in mind, there is a need for new methods of prophylaxis and treatment. Coenzyme Q10 (CoQ10)
is an essential compound of the human body. There is growing evidence that COQ10 is tightly linked to
cardiometabolic disorders. Its supplementation can be useful in a variety of chronic and acute disorders.
This review analyses the role of COQ10 in hypertension, ischemic heart disease, myocardial infarction,
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heart failure, viral myocarditis, cardiomyopathies, cardiac toxicity, dyslipidemia, obesity, type 2 diabetes
mellitus, metabolic syndrome, cardiac procedures and resuscitation.
Keywords: Coenzyme Q10, hypertension, ischemic heart disease, myocardial infarction, heart failure,
viral myocarditis, cardiomyopathies, cardiac toxicity, dyslipidemia, obesity, type 2 diabetes mellitus,
metabolic syndrome, cardiac procedures and resuscitation
CONCLUSION
There are many controversial data on the supplementation of COQ10 in different conditions. The
reported dosage of COQ10 differs in a wide range 100-300 mg for CV diseases. Limited data on the
amount of COQ10 absorbed in the gastrointestinal tract and its amount in the circulating blood were
observed. Rat model demonstrates significant impact at a higher dose when the plasma concentration is
increased by more than 80%. Future studies should be aimed at assessment of higher dosage of COQ10
administration as well as evaluation of its pharmacokinetics and pharmacodynamics. Overall, there
seems to be a beneficial role of COQ10 co-administration as a supplemental therapy in different cardiac
and metabolic conditions. The changes in the antioxidant systems in these conditions support the idea
that COQ10 may improve outcome, quality of life and decrease morbidity and mortality. Nevertheless,
the findings of some studies are based on preclinical or clinical studies with surrogate endpoints. This
subject should be addressed in the future. Finally, more randomized trials should be performed to
assess
the impact of COQ10 supplementation on survival.
Coenzyme Q10 and Heart Failure: A State-of-the-Art Review.

Sharma A, Fonarow GC, Butler J, Ezekowitz JA, Felker GM. Circ Heart Fail. 2016
Apr;9(4):e002639. doi: 10.1161/CIRCHEARTFAILURE.115.002639.
Abstract
Heart failure (HF) with either preserved or reduced ejection fraction is associated with increased
morbidity and mortality. Evidence-based therapies are often limited by tolerability, hypotension,
electrolyte disturbances, and renal dysfunction. Coenzyme Q10 (CoQ10) may represent a safe
therapeutic option for patients with HF. CoQ10 is a highly lipophilic molecule with a chemical structure
similar to vitamin K. Although being a common component of cellular membranes, CoQ10's most
prominent role is to facilitate the production of adenosine triphosphate in the mitochondria by
participating in redox reactions within the electron transport chain. Numerous trials during the past 30
years examining CoQ10 in patients with HF have been limited by small numbers and lack of
contemporary HF therapies. The recent publication of the Q-SYMBIO randomized controlled trial
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demonstrated a reduction in major adverse cardiovascular events with CoQ10 supplementation in a

contemporary HF population. Although having limitations, this study has renewed interest in evaluating
CoQ10 supplementation in patients with HF. Current literature suggests that CoQ10 is relatively safe
with few drug interactions and side effects. Furthermore, it is already widely available as an over-the-
counter supplement. These findings warrant future adequately powered randomized controlled trials of
CoQ10 supplementation in patients with HF. This state-of-the-art review summarizes the literature
about the mechanisms, clinical data, and safety profile of CoQ10 supplementation in patients with HF.
© 2016 American Heart Association, Inc.
KEYWORDS:
coenzyme Q10; drug interactions; electrolytes; heart failure; hypotension
Recent Developments in the Role of Coenzyme Q10 for Coronary Heart

Disease: a Systematic Review.
Ayers J, Cook J, Koenig RA, Sisson EM, Dixon DL. Curr Atheroscler Rep. 2018 May
16;20(6):29. doi: 10.1007/s11883-018-0730-1.
Abstract
PURPOSE OF REVIEW:
This review examines recent randomized clinical trials evaluating the role of coenzyme Q10 (CoQ10) in
the management of coronary heart disease.
RECENT FINDINGS:
CoQ10 is one of the most commonly used dietary supplements in the USA. Due to its antioxidant and
anti-inflammatory effects, CoQ10 has been studied extensively for possible use in managing coronary
heart disease. One of the most common applications of CoQ10 is to mitigate statin-associated muscle
symptoms (SAMS) based on the theory that SAMS are caused by statin depletion of CoQ10 in the
muscle. Although previous studies of CoQ10 for SAMS have produced mixed results, CoQ10 appears to
be safe. Because CoQ10 is a cofactor in the generation of adenosine triphosphate, supplementation has
also recently been studied in patients with heart failure, which is inherently an energy deprived state.
The Q-SYMBIO trial found that CoQ10 supplementation in patients with heart failure not only improved
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functional capacity, but also significantly reduced cardiovascular events and mortality. Despite these
positive findings, a larger prospective trial is warranted to support routine use of CoQ10. Less impressive
are the effects of CoQ10 on specific cardiovascular risk factors such as blood pressure, dyslipidemia, and
glycemic control. Current evidence does not support routine use of CoQ10 in patients with coronary
heart disease. Additional studies are warranted to fully determine the benefit of CoQ10 in patients with
heart failure before including it in guideline-directed medical therapy.
KEYWORDS:
Cardiovascular disease; Coenzyme Q10; Heart failure; Myalgia; Statins
CoQ10 increases mitochondrial mass and polarization, ATP and Oct4 potency
levels, and bovine oocyte MII during IVM while decreasing AMPK activity and
oocyte death
M. K. Abdulhasa, et al. J Assist Reprod Genet. 2017 Dec; 34(12): 1595–1607.
Published online 2017 Sep 12. doi: 10.1007/s10815-017-1027-y
Abstract
Purpose
We tested whether mitochondrial electron transport chain electron carrier coenzyme Q10 (CoQ10)
increases ATP during bovine IVM and increases %M2 oocytes, mitochondrial polarization/mass, and
Oct4, and decreases pAMPK and oocyte death.
Methods
Bovine oocytes were aspirated from ovaries and cultured in IVM media for 24 h with 0, 20, 40, or 60 μM
CoQ10. Oocytes were assayed for ATP by luciferase-based luminescence. Oocyte micrographs were
quantitated for Oct4, pAMPK (i.e., activity), polarization by JC1 staining, and mitochondrial mass by
MitoTracker Green staining.
Results
CoQ10 at 40 μM was optimal. Oocytes at 40 μM enabled 1.9-fold more ATP than 0 μM CoQ10. There
was 4.3-fold less oocyte death, 1.7-fold more mitochondrial charge polarization, and 3.1-fold more
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mitochondrial mass at 40 μM than at 0 μM CoQ10. Increased ATP was associated with 2.2-fold lower
AMPK thr172P activation and 2.1-fold higher nuclear Oct4 stemness/potency protein at 40 μM than at 0
μM CoQ10. CoQ10 is hydrophobic, and at all doses, 50% was lost from media into oil by ~ 12 h.
Replenishing CoQ10 at 12 h did not significantly diminish dead oocytes.
Conclusions
The data suggest that CoQ10 improves mitochondrial function in IVM where unwanted stress, higher
AMPK activity, and Oct4 potency loss are induced.
Keywords: CoQ10, Oct4 potency factors, AMPK, ATP, Death, Mitochondria
Cellular factories for coenzyme Q10 production

Sean Qiu En Lee, Tsu Soo Tan, Makoto Kawamukai, and Ee Sin Chen. Microb Cell
Fact. 2017; 16: 39. Published online 2017 Mar 2. doi: 10.1186/s12934-017-0646-4
Abstract
Coenzyme Q10 (CoQ10), a benzoquinone present in most organisms, plays an important role in the
electron-transport chain, and its deficiency is associated with various neuropathies and muscular
disorders. CoQ10 is the only lipid-soluble antioxidant found in humans, and for this, it is gaining
popularity in the cosmetic and healthcare industries. To meet the growing demand for CoQ10, there has
been considerable interest in ways to enhance its production, the most effective of which remains
microbial fermentation. Previous attempts to increase CoQ10 production to an industrial scale have thus
far conformed to the strategies used in typical metabolic engineering endeavors. However, the
emergence of new tools in the expanding field of synthetic biology has provided a suite of possibilities
that extend beyond the traditional modes of metabolic engineering. In this review, we cover the various
strategies currently undertaken to upscale CoQ10 production, and discuss some of the potential novel
areas for future research.
Keywords: Coenzyme Q10, Isoprenoid, Antioxidant, Industrial biosynthesis, Protein engineering,

Synthetic biology
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Coenzyme Q10
Albert E. Raizner, MD. Methodist Debakey Cardiovasc J. 2019 Jul-Sep; 15(3): 185–
191. doi: 10.14797/mdcj-15-3-185
Abstract
Coenzyme Q10 (CoQ10) is among the most widely used dietary and nutritional supplements on the
market. CoQ10 has several fundamental properties that may be beneficial in several clinical situations.
This article reviews the pertinent chemical, metabolic, and physiologic properties of CoQ10 and the
scientific data and clinical trials that address its use in two common clinical settings: statin-associated
myopathy syndrome (SAMS) and congestive heart failure (CHF).
Although clinical trials of CoQ10 in SAMS have conflicting conclusions, the weight of the evidence, as
seen in meta-analyses, supports the use of CoQ10 in SAMS overall. In CHF, there is a lack of large-scale
randomized clinical trial data regarding the use of statins in patients receiving contemporary treatment.
However, one relatively recent randomized clinical trial, Q-SYMBIO, suggests an adjunctive role for
CoQ10 in CHF. Recommendations regarding the use of CoQ10 in these clinical situations are presented.
Keywords: coenzyme Q10, CoQ10, ubiquinol, ubiquinone, statin myopathy, statin-associated muscle
symptoms, congestive heart failure
CoQ10 supplementation rescues nephrotic syndrome through normalization

of H2S oxidation pathway
Giulio Kleiner, et al. Biochim Biophys Acta Mol Basis Dis. Author manuscript;
available in PMC 2019 Nov 1. Published in final edited form as: Biochim Biophys
Acta Mol Basis Dis. 2018 Nov; 1864(11): 3708–3722. Published online 2018 Sep 6.
doi: 10.1016/j.bbadis.2018.09.002
Abstract
Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most
common phenotype associated with primary coenzyme Q10 (CoQ10) deficiency and is very responsive
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to CoQ10 supplementation, although the pathomechanism is not clear. Here, using a mouse model of
CoQ deficiency-associated NS, we show that long-term oral CoQ10 supplementation prevents kidney
failure by rescuing defects of sulfides oxidation and ameliorating oxidative stress, despite only
incomplete normalization of kidney CoQ levels and lack of rescue of CoQ-dependent respiratory
enzymes activities. Liver and kidney lipidomics, and urine metabolomics analyses, did not show CoQ
metabolites. To further demonstrate that sulfides metabolism defects cause oxidative stress in CoQ
deficiency, we show that silencing of sulfide quinone oxido-reductase (SQOR) in wild-type HeLa cells
leads to similar increases of reactive oxygen species (ROS) observed in HeLa cells depleted of the CoQ
biosynthesis regulatory protein COQ8A. While CoQ10 supplementation of COQ8A depleted cells
decreases ROS and increases SQOR protein levels, knock-down of SQOR prevents CoQ10 antioxidant
effects. We conclude that kidney failure in CoQ deficiency-associated NS is caused by oxidative stress
mediated by impaired sulfides oxidation and propose that CoQ supplementation does not significantly
increase the kidney pool of CoQ bound to the respiratory supercomplexes, but rather enhances the free
pool of CoQ, which stabilizes SQOR protein levels rescuing oxidative stress.
Keywords: Coenzyme Q10, CoQ deficiency, mitochondria, oxidative stress, sulfides
A high-throughput screen of real-time ATP levels in individual cells reveals

mechanisms of energy failure
Bryce A. Mendelsohn, et al. PLoS Biol. 2018 Aug; 16(8): e2004624. Published
online 2018 Aug 27. doi: 10.1371/journal.pbio.2004624
Abstract
Insufficient or dysregulated energy metabolism may underlie diverse inherited and degenerative
diseases, cancer, and even aging itself. ATP is the central energy carrier in cells, but critical pathways for
regulating ATP levels are not systematically understood. We combined a pooled clustered regularly
interspaced short palindromic repeats interference (CRISPRi) library enriched for mitochondrial genes, a
fluorescent biosensor, and fluorescence-activated cell sorting (FACS) in a high-throughput genetic screen
to assay ATP concentrations in live human cells. We identified genes not known to be involved in energy
metabolism. Most mitochondrial ribosomal proteins are essential in maintaining ATP levels under
respiratory conditions, and impaired respiration predicts poor growth. We also identified genes for
which coenzyme Q10 (CoQ10) supplementation rescued ATP deficits caused by knockdown. These
included CoQ10 biosynthetic genes associated with human disease and a subset of genes not linked to
CoQ10 biosynthesis, indicating that increasing CoQ10 can preserve ATP in specific genetic contexts. This
screening paradigm reveals mechanisms of metabolic control and genetic defects responsive to energy-
based therapies.
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High plasma coenzyme Q10 concentration is correlated with good left

ventricular performance after primary angioplasty in patients with acute
myocardial infarction
Ching-Hui Huang, MD, PhD, et al. Medicine (Baltimore). 2016 Aug; 95(31): e4501.
Published online 2016 Aug 7. doi: 10.1097/MD.0000000000004501
Abstract
Exogenous administration of coenzyme Q10 (CoQ10) has been shown in experimental models to have a
protective effect against ischemia–reperfusion injury. However, it is unclear whether follow-up plasma
CoQ10 concentration is prognostic of left ventricular (LV) performance after primary balloon angioplasty
in patients with acute ST segment elevation myocardial infarction (STEMI).
We prospectively recruited 55 patients with STEMI who were treated with primary coronary balloon
angioplasty. Plasma CoQ10 concentrations were measured before primary angioplasty (baseline) and 3
days, 7 days, and 1 month after STEMI using high-performance liquid chromatography.
Echocardiography was performed at baseline and at 6-month follow-up. The control group comprised 54
healthy age- and sex-matched volunteers.
Serial circulating CoQ10 concentrations significantly decreased with time in the STEMI group. The LV
ejection fraction at 6-month follow-up positively correlated with the 1-month plasma CoQ10 tertile.
Higher plasma CoQ10 concentrations at 1 month were associated with favorable LV remodeling and
systolic function 6 months after STEMI. Multiple linear regression analysis showed that changes in
CoQ10 concentrations at 1-month follow-up were predictive of LV systolic function 6 months after
STEMI. Changes in CoQ10 concentrations correlated negatively with baseline oxidized low-density
lipoprotein and fibrinogen concentrations and correlated positively with leukocyte mitochondrial copy
number at baseline.
Patients with STEMI who had higher plasma CoQ10 concentrations 1 month after primary angioplasty
had better LV performance at 6-month follow-up. In addition, higher plasma CoQ10 concentration was
associated with lower grade inflammatory and oxidative stress status. Therefore, plasma CoQ10
concentration may serve as a novel prognostic biomarker of LV systolic function after revascularization
therapy for acute myocardial infarction.
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Keywords: acute ST segment elevation myocardial infarction, left ventricular systolic function, plasma
coenzyme Q10
Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in

a male rat model of poor maternal nutrition and accelerated postnatal
growth1
Jane L Tarry-Adkins, et al. Am J Clin Nutr. 2016 Feb; 103(2): 579–588. Published
online 2015 Dec 30. doi: 10.3945/ajcn.115.119834
Abstract
Background: It is well established that low birth weight and accelerated postnatal growth increase the
risk of liver dysfunction in later life. However, molecular mechanisms underlying such developmental
programming are not well characterized, and potential intervention strategies are poorly defined.
Objectives: We tested the hypotheses that poor maternal nutrition and accelerated postnatal growth
would lead to increased hepatic fibrosis (a pathological marker of liver dysfunction) and that postnatal
supplementation with the antioxidant coenzyme Q10 (CoQ10) would prevent this programmed
phenotype.
Design: A rat model of maternal protein restriction was used to generate low-birth-weight offspring that
underwent accelerated postnatal growth (termed “recuperated”). These were compared with control
rats. Offspring were weaned onto standard feed pellets with or without dietary CoQ10 (1 mg/kg body
weight per day) supplementation. At 12 mo, hepatic fibrosis, indexes of inflammation, oxidative stress,
and insulin signaling were measured by histology, Western blot, ELISA, and reverse transcriptase–
polymerase chain reaction.
Results: Hepatic collagen deposition (diameter of deposit) was greater in recuperated offspring (mean ±
SEM: 12 ± 2 μm) than in controls (5 ± 0.5 μm) (P < 0.001). This was associated with greater inflammation
(interleukin 6: 38% ± 24% increase; P < 0.05; tumor necrosis factor α: 64% ± 24% increase; P < 0.05), lipid
peroxidation (4-hydroxynonenal, measured by ELISA: 0.30 ± 0.02 compared with 0.19 ± 0.05 μg/mL per
μg protein; P < 0.05), and hyperinsulinemia (P < 0.05). CoQ10 supplementation increased (P < 0.01)
hepatic CoQ10 concentrations and ameliorated liver fibrosis (P < 0.001), inflammation (P < 0.001), some
measures of oxidative stress (P < 0.001), and hyperinsulinemia (P < 0.01).
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Conclusions: Suboptimal in utero nutrition combined with accelerated postnatal catch-up growth caused
more hepatic fibrosis in adulthood, which was associated with higher indexes of oxidative stress and
inflammation and hyperinsulinemia. CoQ10 supplementation prevented liver fibrosis accompanied by
downregulation of oxidative stress, inflammation, and hyperinsulinemia.
Keywords: developmental programming, liver disease, coenzyme Q, low birth weight, accelerated
postnatal growth
Creatine
Creatine Supplementation and Upper Limb Strength Performance: A
Systematic Review and Meta-Analysis.
Lanhers C, et al. Sports Med. 2017 Jan;47(1):163-173. doi: 10.1007/s40279-016-
0571-4.
Abstract
BACKGROUND:
Creatine is the most widely used supplementation to increase performance in strength; however, the
most recent meta-analysis focused specifically on supplementation responses in muscles of the lower
limbs without regard to upper limbs.
OBJECTIVE:
We aimed to systematically review the effect of creatine supplementation on upper limb strength
performance.
METHODS:
We conducted a systematic review and meta-analyses of all randomized controlled trials comparing
creatine supplementation with a placebo, with strength performance measured in exercises shorter
than 3 min in duration. The search strategy used the keywords 'creatine', 'supplementation', and
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'performance'. Independent variables were age, sex and level of physical activity at baseline, while
dependent variables were creatine loading, total dose, duration, time interval between baseline (T0)
and the end of the supplementation (T1), and any training during supplementation. We conducted three
meta-analyses: at T0 and T1, and on changes between T0 and T1. Each meta-analysis was stratified
within upper limb muscle groups.
RESULTS:
We included 53 studies (563 individuals in the creatine supplementation group and 575 controls).
Results did not differ at T0, while, at T1, the effect size (ES) for bench press and chest press were 0.265
(95 % CI 0.132-0.398; p < 0.001) and 0.677 (95 % CI 0.149-1.206; p = 0.012), respectively. Overall,
pectoral ES was 0.289 (95 % CI 0.160-0.419; p = 0.000), and global upper limb ES was 0.317 (95 % CI
0.185-0.449; p < 0.001). Meta-analysis of changes between T0 and T1 gave similar results. The meta-
regression showed no link with characteristics of population or supplementation, demonstrating the
efficacy of creatine independently of all listed conditions.
CONCLUSION:
Creatine supplementation is effective in upper limb strength performance for exercise with a duration of
less than 3 min, independent of population characteristics, training protocols, and supplementary doses
or duration.
Creatine, Creatine Kinase, and Aging.

Sumien N, Shetty RA, Gonzales EB. Subcell Biochem. 2018;90:145-168. doi:
10.1007/978-981-13-2835-0_6.
Abstract
With an ever aging population, identifying interventions that can alleviate age-related functional
declines has become increasingly important. Dietary supplements have taken center stage based on
various health claims and have become a multi-million dollar business. One such supplement is creatine,
a major contributor to normal cellular physiology. Creatine, an energy source that can be endogenously
synthesized or obtained through diet and supplement, is involved primarily in cellular metabolism via
ATP replenishment. The goal of this chapter is to summarize how creatine and its associated enzyme,
creatine kinase, act under normal physiological conditions, and how altered levels of either may lead to
detrimental functional outcomes. Furthermore, we will focus on the effect of aging on the creatine
system and how supplementation may affect the aging process and perhaps reverse it.
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KEYWORDS:
Aging; Anti-aging intervention; Creatine; Creatine kinase; Motor and cognitive function; Muscle function;
Supplementation
Creatine and its potential therapeutic value for targeting cellular energy
impairment in neurodegenerative diseases.
Adhihetty PJ1, Beal MF. Neuromolecular Med. 2008;10(4):275-90. doi:
10.1007/s12017-008-8053-y. Epub 2008 Nov 13.
Abstract
Substantial evidence indicates bioenergetic dysfunction and mitochondrial impairment contribute either
directly and/or indirectly to the pathogenesis of numerous neurodegenerative disorders. Treatment
paradigms aimed at ameliorating this cellular energy deficit and/or improving mitochondrial function in
these neurodegenerative disorders may prove to be useful as a therapeutic intervention. Creatine is a
molecule that is produced both endogenously, and acquired exogenously through diet, and is an
extremely important molecule that participates in buffering intracellular energy stores. Once creatine is
transported into cells, creatine kinase catalyzes the reversible transphosphorylation of creatine via ATP
to enhance the phosphocreatine energy pool. Creatine kinase enzymes are located at strategic
intracellular sites to couple areas of high energy expenditure to the efficient regeneration of ATP. Thus,
the creatine kinase/phosphocreatine system plays an integral role in energy buffering and overall
cellular bioenergetics. Originally, exogenous creatine supplementation was widely used only as an
ergogenic aid to increase the phosphocreatine pool within muscle to bolster athletic performance.
However, the potential therapeutic value of creatine supplementation has recently been investigated
with respect to various neurodegenerative disorders that have been associated with bioenergetic
deficits as playing a role in disease etiology and/or progression which include; Alzheimer's, Parkinson's,
amyotrophic lateral sclerosis (ALS), and Huntington's disease. This review discusses the contribution of
mitochondria and bioenergetics to the progression of these neurodegenerative diseases and
investigates the potential neuroprotective value of creatine supplementation in each of these
neurological diseases. In summary, current literature suggests that exogenous creatine supplementation
is most efficacious as a treatment paradigm in Huntington's and Parkinson's disease but appears to be
less effective for ALS and Alzheimer's disease.
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Creatine supplementation in the aging population: effects on skeletal muscle,

bone and brain.
Gualano B, Rawson ES, Candow DG, Chilibeck PD. Amino Acids. 2016
Aug;48(8):1793-805. doi: 10.1007/s00726-016-2239-7. Epub 2016 Apr 23.
Abstract
This narrative review aims to summarize the recent findings on the adjuvant application of creatine
supplementation in the management of age-related deficits in skeletal muscle, bone and brain
metabolism in older individuals. Most studies suggest that creatine supplementation can improve lean
mass and muscle function in older populations. Importantly, creatine in conjunction with resistance
training can result in greater adaptations in skeletal muscle than training alone. The beneficial effect of
creatine upon lean mass and muscle function appears to be applicable to older individuals regardless of
sex, fitness or health status, although studies with very old (>90 years old) and severely frail individuals
remain scarce. Furthermore, there is evidence that creatine may affect the bone remodeling process;
however, the effects of creatine on bone accretion are inconsistent. Additional human clinical trials are
needed using larger sample sizes, longer durations of resistance training (>52 weeks), and further
evaluation of bone mineral, bone geometry and microarchitecture properties. Finally, a number of
studies suggest that creatine supplementation improves cognitive processing under resting and various
stressed conditions. However, few data are available on older adults, and the findings are discordant.
Future studies should focus on older adults and possibly frail elders or those who have already
experienced an age-associated cognitive decline.
KEYWORDS:
Bone, skeletal muscle, brain; Dietary supplement; Elderly; Exercise
Creatine supplementation: can it improve quality of life in the elderly without

associated resistance training?
Moon A, Heywood L, Rutherford S, Cobbold C. Curr Aging Sci. 2013 Dec;6(3):251-
7.
Abstract
INTRODUCTION:
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Ageing is associated with decreased muscle mass, strength, power and function, and reduction in bone
density and mineral content, leading to reduced independence and increased risk of falls. Creatine
supplementation is reported to improve muscular strength and performance with training in younger
athletes, and therefore could benefit older individuals.
AIMS:
This review critically appraises the current literature on whether creatine supplementation enhances
muscular performance and function, body composition, bone mineral density and content in older
adults without the addition of resistance training, and thus determines whether creatine
supplementation can lead to an improved lifestyle for the sedentary elderly population.
RESULTS:
There is conflicting evidence regarding the usefulness of creatine supplementation in older subjects.
Generally, however, creatine supplementation, without associated resistance training, seems to
enhance muscular strength, power and endurance, increase lean body mass (LBM) and improve the
functional capacity of the elderly. Furthermore, it has been demonstrated that increased muscle mass
due to creatine supplementation can result in increased local bone density. It appears that the effect of
creatine supplementation is more beneficial in larger muscles and less effective in smaller muscles,
however there are exceptions. The mechanism by which creatine supplementation works requires
further research, however it is likely that the effects of creatine are related to creatine kinase activity,
providing enhanced energy production for greater muscular contraction.
CONCLUSIONS:
These data indicate that creatine supplementation without associated training in the elderly could
potentially delay atrophy of muscle mass, improve endurance and strength, and increase bone strength,
and thus may be a safe therapeutic strategy to help decrease loss in functional performance of everyday
tasks.
Cerebral energetic effects of creatine supplementation in humans.

Pan JW, Takahashi K. Am J Physiol Regul Integr Comp Physiol. 2007
Apr;292(4):R1745-50. Epub 2006 Dec 21.
Abstract
188
There has been considerable interest in the use of creatine (Cr) supplementation to treat neurological
disorders. However, in contrast to muscle physiology, there are relatively few studies of creatine
supplementation in the brain. In this report, we use high-field MR (31)P and (1)H spectroscopic imaging
of human brain with a 7-day protocol of oral Cr supplementation to examine its effects on cerebral
energetics (phosphocreatine, PCr; ATP) and mitochondrial metabolism (N-acetyl aspartate, NAA; and
Cr). We find an increased ratio of PCr/ATP (day 0, 0.80 +/- 0.10; day 7, 0.85 +/- 09), with this change
largely due to decreased ATP, from 2.7 +/- 0.3 mM to 2.5 +/- 0.3 mM. The ratio of NAA/Cr also
decreased (day 0, 1.32 +/- 0.17; day 7 1.18 +/- 0.13), primarily from increased Cr (9.6 +/- 1.9 to 10.1 +/-
2.0 mM). The Cr-induced changes significantly correlated with the basal state, with the fractional
increase in PCr/ATP negatively correlating with the basal PCr/ATP value (R = -0.74, P < 0.001). As NAA is
a measure of mitochondrial function, there was also a significant negative correlation between basal
NAA concentrations with the fractional change in PCr and ATP. Thus healthy human brain energetics is
malleable and shifts with 7 days of Cr supplementation, with the regions of initially low PCr showing the
largest increments in PCr. Overall, Cr supplementation appears to improve high-energy phosphate
turnover in healthy brain and can result in either a decrease or an increase in high-energy phosphate
concentrations.
Effect of Ten Weeks of Creatine Monohydrate Plus HMB Supplementation on

Athletic Performance Tests in Elite Male Endurance Athletes.
Fernández-Landa J, et al. Nutrients. 2020 Jan 10;12(1). pii: E193. doi:
10.3390/nu12010193.
Abstract
Creatine monohydrate (CrM) and β-hydroxy β-methylbutyrate (HMB) are common ergogenic aids in the
field of sports and are frequently used in an isolated way. However, there are a few studies that have
investigated the effect of combining both supplements on different variables related to performance,
with controversial results. Therefore, the main purpose of this study was to determine the efficacy and
the degree of potentiation of 10 weeks of CrM plus HMB supplementation on sports performance,
which was measured by an incremental test to exhaustion in elite male traditional rowers. In this
placebo-controlled, double-blind trial, 10-week study, participants (n = 28) were randomized to a
placebo group (PLG; n = 7), CrM group (0.04 g/kg/day of CrM; n = 7), HMB group (3 g/day of HMB; n = 7)
and CrM-HMB group (0.04 g/kg/day of CrM plus 3 g/day of HMB; n = 7). Before and after 10 weeks of
different treatments, an incremental test was performed on a rowing ergometer to calculate the power
that each rower obtained at the anaerobic threshold (WAT), and at 4 mmol (W4) and 8 mmol (W8) of
blood lactate concentration. There were no significant differences in WAT and W4 among groups or in
body composition. However, it was observed that the aerobic power achieved at W8 was significantly
higher in the CrM-HMB group than in the PLG, CrM and HMB groups (p < 0.001; η2p = 0.766). Likewise, a
synergistic effect of combined supplementation was found for the sum of the two supplements
189
separately at WAT (CrM-HMBG = 403.19% vs. CrMG+HMBG = 337.52%), W4 (CrM-HMBG = 2736.17% vs.
CrMG+HMBG = 1705.32%) and W8 (CrM-HMBG = 1293.4% vs. CrMG+HMBG = 877.56%). In summary,
CrM plus HMB supplementation over 10 weeks showed a synergistic effect on aerobic power (measured
as WAT, W4, and W8) during an incremental test but had no influence muscle mass.
KEYWORDS:
aerobic power; body composition; lactate threshold; muscle mass; muscle recovery; sport nutrition;
supplementation
Delta Tocotrienol (Delta

Fraction Vitamin E)
The use of delta-tocotrienol and lovastatin for anti-osteoporotic therapy.
Abdul-Majeed S, Mohamed N, Soelaiman IN. Life Sci. 2015 Mar 15;125:42-8. doi:
10.1016/j.lfs.2014.12.012. Epub 2014 Dec 20.
Abstract
AIMS:
Statins are competitive inhibitors of HMGCoA reductase and are commonly used as
antihypercholesterolemic agents. Experimental studies clearly demonstrate the beneficial effects of
statins on bone. Tocotrienols have also been shown to have anti-osteoporotic effects on the skeletal
system. This study was conducted to observe the effect of a combination of delta-tocotrienol and
lovastatin on structural bone histomorphometry and bone biomechanical strength in a postmenopausal
rat model at clinically tolerable doses, and to compare it with the effect of delta-tocotrienol or
lovastatin.
MAIN METHODS:
190
Forty-eight female Sprague Dawley rats were randomly divided into six groups: baseline control; sham-
operated control; ovariectomised control; ovariectomised+11mg/kg lovastatin;
ovariectomised+60mg/kg delta-tocotrienol and ovariectomised+60mg/kg delta-tocotrienol+11mg/kg
lovastatin. These treatments were given via oral gavage daily for eight weeks. After sacrificing the rats,
the left and right femurs were dissected and processed for bone histomorphometric analysis and a bone
biomechanical test, respectively.
KEY FINDINGS:
Delta-tocotrienol in combination with lovastatin significantly improved the trabecular volume,

trabecular number, trabecular thickness and trabecular separation; and it significantly increased bone
strength in oestrogen-deficient rats. Delta-tocotrienol alone enhanced bone formation and maintained
bone strength in ovariectomised rats. Delta-tocotrienol plus lovastatin treatment promoted better
trabecular volume and trabecular number and received higher load than delta-tocotrienol alone.
Lovastatin alone was not effective.
SIGNIFICANCE:
Thus, the combination of delta-tocotrienol and lovastatin has the potential to be used for anti-
osteoporotic therapy in postmenopausal women.
Copyright © 2014 Elsevier Inc. All rights reserved.
KEYWORDS:
Biomechanical test; Bone histomorphometry; Bone strength; HMGCoA reductase; Lovastatin;

Osteoporosis; Ovariectomised; Postmenopausal women; Statins; Tocotrienols; Trabecular
Effects of Delta-tocotrienol Supplementation on Liver Enzymes, Inflammation,

Oxidative stress and Hepatic Steatosis in Patients with Nonalcoholic Fatty
Liver Disease.
Pervez MA, Khan DA, Ijaz A, Khan S. Turk J Gastroenterol. 2018 Mar;29(2):170-
176. doi: 10.5152/tjg.2018.17297.
191
Abstract
BACKGROUND/AIMS:
Non-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and is associated
with increased morbidity and mortality. Currently, there is no definitive treatment for this disease. δ-
Tocotrienol has potent anti-inflammatory and antioxidant properties and may reduce liver injury in
NAFLD. The present study aims to evaluate the efficacy and safety of δ-tocotrienol in the treatment of
NAFLD.
The present study was a randomized, double-blind, placebo-controlled pilot study conducted in patients
aged > 20 years, belonging to both sexes, having ultrasound-proven fatty liver disease, having a fatty
liver index (FLI) of ≥ 60, and persistent elevation of alanine transaminase. A total of 71 patients were
assigned to receive either oral δ-tocotrienol (n=35, 300 mg twice daily) or placebo (n=36) for 12 weeks.
At the baseline and at the end of the study, clinical and biochemical parameters, including lipid profile,
liver function tests, high-sensitivity C-reactive protein (hs-CRP), and malondialdehyde (MDA) were
measured. Body mass index and FLI were calculated, and ultrasound grading of hepatic steatosis was
performed.
RESULTS:
Out of 71 enrolled patients, 64 patients, 31 in the δ-tocotrienol group and 33 in the placebo group,
completed the study. After 12 weeks of supplementation, δ-tocotrienol showed greater efficacy than
placebo by decreasing serum aminotransferases, hs-CRP, MDA, and FLI score (p<0.001). However, it did
not improve hepatic steatosis on ultrasound examination. No adverse effects were reported.
CONCLUSION:
δ-Tocotrienol was safe, and it effectively improved aminotransferase levels and inflammatory and
oxidative stress markers in patients with NAFLD. Large-scale randomized clinical trials are warranted to
further support these findings.
Omega 3-DHA and Delta-Tocotrienol Modulate Lipid Droplet Biogenesis and

Lipophagy in Breast Cancer Cells: the Impact in Cancer Aggressiveness.
Pizato N, et al. Nutrients. 2019 May 28;11(6). pii: E1199. doi:
10.3390/nu11061199.
192
Abstract
Omega 3-docosahexaenoic acid (DHA) and vitamin E Delta-tocotrienol (Delta-T3) are extensively studied
as protective nutrients against cancer development. Little is known about the biological mechanisms
targeted by these bioactive molecules on lipid droplet (LD) biogenesis, an important breast cancer
aggressiveness marker, and the occurrence of lipophagy in breast cancer cells. The aim of this study was
to investigate the effect of DHA, Delta-T3 and DHA plus Delta-T3 co-treatment in LD biogenesis and
lipophagy process in triple negative breast cancer cell line MDA-MB-231. Cells were treated with 50 μM
DHA and/or 5 μM Delta-T3. Our results demonstrated that DHA can trigger an increase in LD biogenesis
and co-treatment with Delta-T3 was able to reduce this LD biogenesis. In addition, we showed that a
higher cytoplasmic LD content is associated with a higher breast cancer cells malignance and
proliferation. Reduction of cytoplasmic LD content by silencing ADRP (adipose differentiation-related
protein), a structural LD protein, also decreased cell proliferation in MDA-MB-231 cells. Treatment with
DHA and Delta-T3 alone or co-treatment did not reduce cell viability. Moreover, we showed here that
DHA can trigger lipophagy in MDA-MB-231 cells and DHA plus Delta-T3 co-treatment was able to
enhance this lipophagy process. Our findings demonstrated that co-treatment with DHA plus Delta-T3 in
MDA-MB-231 cells could reduce LD biogenesis and potentiate lipophagy in these cells, possibly having a
positive impact to inhibit breast cancer malignancy. Therefore, suitable doses of DHA and Delta-T3
vitamin E isoform supplementation can be a prominent tool in therapeutic treatments against breast
cancer.
KEYWORDS:
breast cancer; docosahexaenoic acid (DHA), delta-tocotrienol (Delta-T3), lipid droplets; lipophagy
Beneficial effects of δ-tocotrienol against oxidative stress in osteoblastic cells:

studies on the mechanisms of action.
Casati L. et al. Eur J Nutr. 2019 Jul 6. doi: 10.1007/s00394-019-02047-9. [Epub
ahead of print]
Abstract
PURPOSE:
Natural antioxidants are considered as promising compounds in the prevention/treatment of

osteoporosis. We studied the ability of purified δ-tocotrienol (δ-TT) isolated from a commercial palm oil
(Elaeis guineensis) fraction to protect osteoblast MC3T3-E1 and osteocyte MLO-Y4 cells against tert-
butyl hydroperoxide (t-BHP)-induced oxidative damage and the mechanisms involved in its protective
action in MC3T3-E1.
193
METHODS:
MC3T3-E1 and MLO-Y4 cells were treated with δ-TT (1.25-20 µg/ml for 2 h) followed by t-BHP at 250 µM
or 125 µM for 3 h, respectively. MTT test was used to measure cell viability. Apoptotic cells were stained
with Hoechst-33258 dye. Intracellular ROS levels were measured by dichlorofluorescein CM-DCFA. The
OPT fluorimetric assay was used to detect the reduced glutathione to oxidized glutathione ratio
(GSH/GSSG) contents.
RESULTS:
δ-TT significantly prevented the effects of t-BHP on cell viability and apoptosis reaching a maximum
protective activity at 10 and 5 µg/ml in MC3T3-E1 and MLO-Y4 cells, respectively. This protective effect
was due to a reduction of intracellular ROS levels and an increase in the defense systems shown by the
increase in the GSH/GSSG. GSH loss induced by an inhibitor of GSH synthesis significantly reduced the δ-
TT-positive effect on ROS levels. δ-TT prevention of oxidative damage was completely removed by
combined treatment with the specific inhibitors of PI3K/AKT (LY294002) and Nrf2 (ML385).
CONCLUSIONS:
The δ-TT protective effect against oxidative damage in MC3T3-E1 cells is due to a reduction of
intracellular ROS levels and an increase of the GSH/GSSG ratio, and involves an interaction between the
PI3K/Akt-Nrf2 signaling pathways.
KEYWORDS:
MC3T3-E1 cells; MLO-Y4 cells; Oxidative stress; Signaling pathways; Tocotrienol
Vitamin E and Alzheimer's disease: the mediating role of cellular aging.

Casati M, et al. Aging Clin Exp Res. 2019 May 3. doi: 10.1007/s40520-019-01209-
3. [Epub ahead of print]
Abstract
BACKGROUND:
194
Vitamin E represents a potent antioxidant and anti-inflammatory system, playing a role in Alzheimer's
disease (AD). Different plasma concentrations of the forms of vitamin E are observed in AD compared to
cognitively healthy subjects.
AIM:
Since these modifications may modulate the markers of oxidative stress and cellular aging, we aim to
explore the relationship between vitamin E forms and leukocyte telomere length (LTL) in AD.
METHODS:
53 AD subjects and 40 cognitively healthy controls (CTs) were enrolled. The vitamin E forms (α-, β-, γ-
and δ-tocopherol, α-, β-, γ- and δ-tocotrienol), the ratio of α-tocopherylquinone/α-tocopherol and 5-
nitro-γ-tocopherol/γ-tocopherol (markers of oxidative/nitrosative damage) and LTL were measured.
RESULTS AND DISCUSSION:
Regression model was used to explore the associations of vitamin E forms and LTL with AD. The
interaction of LTL in the association between vitamin E forms and AD was tested. AD subjects showed
significantly lower concentrations of α-, β-, γ- and δ-tocopherol, α- and δ-tocotrienol, total tocopherols,
total tocotrienols and total vitamin E compared to CTs. AD subjects showed higher values of
nitrosative/oxidative damage. The adjusted analyses confirmed a significant relationship of AD with
plasma concentrations of α- and β-tocopherols, δ-tocotrienol, total tocopherols, total tocotrienol, total
vitamin E and oxidative/nitrosative damage. However, nitrosative damage was significantly associated
with AD only in subjects with higher LTL and not in those expressing marked cellular aging.
CONCLUSIONS:
Our study confirms the role of vitamin E in AD pathology and indicates that nitrosative damage
influences the association with AD only in subjects characterized by longer LTL.
KEYWORDS:
Alzheimer’s disease; Nitrosative stress; Oxidative stress; Telomere length; Vitamin E

195
High plasma levels of vitamin E forms and reduced Alzheimer's disease risk in
advanced age.
Mangialasche F, et al. J Alzheimers Dis. 2010;20(4):1029-37. doi: 10.3233/JAD-
2010-091450.
Abstract
In this study we investigated the association between plasma levels of eight forms of vitamin E and
incidence of Alzheimer's disease (AD) among oldest-old individuals in a population-based setting. A
dementia-free sample of 232 subjects aged 80+ years, derived from the Kungsholmen Project, was
followed-up to 6 years to detect incident AD. Plasma levels of vitamin E (alpha-, beta-, gamma, and
delta-tocopherol; alpha-, beta-, gamma-, and delta-tocotrienol) were measured at baseline. Vitamin E
forms-AD association was analyzed with Cox proportional hazard model after adjustment for several
potential confounders. Subjects with plasma levels of total tocopherols, total tocotrienols, or total
vitamin E in the highest tertile had a reduced risk of developing AD in comparison to persons in the
lowest tertile. Multi-adjusted hazard ratios (HRs) and 95% confidence interval (CI) were 0.55 (0.32-0.94)
for total tocopherols, 0.46 (0.23-0.92) for total tocotrienols, and 0.55 (0.32-0.94) for total vitamin E.
When considering each vitamin E form, the risk of developing AD was reduced only in association with
high plasma levels of beta-tocopherol (HR: 0.62, 95% CI 0.39-0.99), whereas alpha-tocopherol, alpha-
tocotrienol, and beta-tocotrienol showed only a marginally significant effect in the multiadjusted model
[HR (95% CI): alpha-tocopherol: 0.72 (0.48-1.09); alpha-tocotrienol: 0.70 (0.44-1.11); beta-tocotrienol:
0.69 (0.45-1.06)]. In conclusion, high plasma levels of vitamin E are associated with a reduced risk of AD
in advanced age. The neuroprotective effect of vitamin E seems to be related to the combination of
different forms, rather than to alpha-tocopherol alone, whose efficacy in interventions against AD is
currently debated.
Annatto (Bixa orellana) δ-TCT supplementation protected against embryonic

DNA damages through alterations in PI3K/ Akt-Cyclin D1 pathway.
Mutalip SSM, Rajikin MH, Rahim SA, Khan NMN. Int J Vitam Nutr Res. 2018
Feb;88(1-2):16-26. doi: 10.1024/0300-9831/a000492. Epub 2019 Mar 20.
Abstract
Protective action by annatto-derived delta-tocotrienol (δ-TCT) and soy-derived alpha-tocopherol (α-

TOC) through the regulation of PI3K/Akt-Cyclin D1 pathway against the nicotine-induced DNA damages
is the focus of the present study. Nicotine, which has been widely reported to have numerous adverse
effects on the reproductive system, was used as reproductive toxicant. 48 female balb/c mice (6-8
weeks) (23-25 g) were randomly divided into 8 groups (G1-G8; n = 6) and treated with either nicotine
196
or/and annatto δ-TCT/soy α-TOC for 7 consecutive days. On Day 8, the females were superovulated and
mated before euthanized for embryo collection (46 hours post-coitum). Fifty 2-cell embryos from each
group were used in gene expression analysis using Affymetrix QuantiGene Plex2.0 assay. Findings
indicated that nicotine (G2) significantly decreased (p < 0.05) the number of produced 2-cell embryos
compared to control (G1). Intervention with mixed annatto δ-TCT (G3) and pure annatto δ-TCT (G4)
significantly increased the number of produced 2-cell embryos by 127 % and 79 % respectively
compared to G2, but these were lower than G1. Concurrent treatment with soy α-TOC (G5) decreased
embryo production by 7 %. Supplementations with δ-TCT and α-TOC alone (G6-G8) significantly
increased (p < 0.05) the number of produced 2-cell embryos by 50 %, 36 % and 41 % respectively,
compared to control (G1). These results were found to be associated with the alterations in the
PI3K/Akt-Cyclin D1 gene expressions, indicating the inhibitory effects of annatto δ-TCT and soy α-TOC
against the nicotinic embryonic damages. To our knowledge, this is the first attempt on studying the
benefits of annatto δ-TCT on murine preimplantation 2-cell embryos.
KEYWORDS:
Murine preimplantation embryos; annatto delta-tocotrienol; reproductive toxicant; tocopherols; vitamin

E
Natural forms of vitamin E and metabolites-regulation of cancer cell death and

underlying mechanisms.
Jiang Q. IUBMB Life. 2019 Apr;71(4):495-506. doi: 10.1002/iub.1978. Epub 2018
Dec 11.
Abstract
The disappointing results from large clinical studies of α-tocopherol (αT), the major form of vitamin E in
tissues, for prevention of chronic diseases including cancer have cast doubt on not only αT but also
other forms of vitamin E regarding their role in preventing carcinogenesis. However, basic research has
shown that specific forms of vitamin E such as γ-tocopherol (γT), δ-tocopherol (δT), γ-tocotrienol (γTE)
and δ-tocotrienol (δTE) can inhibit the growth and induce death of many types of cancer cells, and are
capable of suppressing cancer development in preclinical cancer models. For these activities, these
vitamin E forms are much stronger than αT. Further, recent research revealed novel anti-inflammatory
and anticancer effects of vitamin E metabolites including 13'-carboxychromanols. This review focuses on
anti-proliferation and induction of death in cancer cells by vitamin E forms and metabolites, and discuss
mechanisms underlying these anticancer activities. The existing in vitro and in vivo evidence indicates
that γT, δT, tocotrienols and 13'-carboxychromanols have anti-cancer activities via modulating key
signaling or mediators that regulate cell death and tumor progression, such as eicosanoids, NF-κB,
STAT3, PI3K, and sphingolipid metabolism. These results provide useful scientific rationales and
197
mechanistic understanding for further translation of basic discoveries to the clinic with respect to
potential use of these vitamin E forms and metabolites for cancer prevention and therapy.
© 2018 IUBMB Life, 71(4):495-506, 2019.
KEYWORDS:
apoptosis; autophagy; biology; breast cancer; cancer prevention; ceramides; colon cancer; food;
inflammation; long-chain carboxychromanol; medicine; prostate cancer; sphingolipids; tocopherols;
tocotrienols
Devil’s Claw
Review of Anti-Inflammatory Herbal Medicines.
Ghasemian M, Owlia S, Owlia MB. Adv Pharmacol Sci. 2016;2016:9130979. doi:
10.1155/2016/9130979. Epub 2016 May 10.
Abstract
Medicinal plants and their secondary metabolites are progressively used in the treatment of diseases as
a complementary medicine. Inflammation is a pathologic condition that includes a wide range of
diseases such as rheumatic and immune-mediated conditions, diabetes, cardiovascular accident, and
etcetera. We introduce some herbs which their anti-inflammatory effects have been evaluated in clinical
and experimental studies. Curcuma longa, Zingiber officinale, Rosmarinus officinalis, Borago officinalis,
evening primrose, and Devil's claw are some of the introduced medicinal herbs in this review. Since the
treatment of inflammation is not a one-dimensional remedy, this review tries to reach a
multidimensional therapeutic approach to inflammation with the help of herbal medicine and
modification in lifestyle.
198
Devil's claw (Harpagophytum procumbens) and chronic inflammatory

diseases: A concise overview on preclinical and clinical data.
Menghini L, et al. Phytother Res. 2019 Sep;33(9):2152-2162. doi:
10.1002/ptr.6395. Epub 2019 Jul 4.
Devil's Claw is a traditional medicine that has been long used a wide range of health conditions,
including indigestion, fever, allergic reactions, and rheumatism. The main compounds are iridoid
glycosides, including harpagoside, harpagide, and procumbide. However, harpagoside is the most
responsible for therapeutic activity, and its content is used as reference standard. Here, we analyzed
and summarized preclinical and clinical studies focusing on therapeutic efficacy of devil's claw
preparations in pathological conditions in which inflammation plays a key causative role.
KEYWORDS:
arthritis; atherosclerosis; inflammatory bowel disease; neurodegenerative diseases; osteoporosis; type 1

diabetes
Kynurenic acid content in anti-rheumatic herbs.

Zgrajka W, Turska M, Rajtar G, Majdan M, Parada-Turska J. Ann Agric Environ
Med. 2013;20(4):800-2.
Abstract
INTRODUCTION:
The use of herbal medicines is common among people living in rural areas and increasingly popular in
urbanized countries. Kynurenic acid (KYNA) is a metabolite of kynurenine possessing anti-inflammatory,
anti-oxidative and pain reliving properties. Previous data indicated that the content of KYNA in the
synovial fluid of patients with rheumatoid arthritis is lower than in patients with osteoarthritis.
Rheumatoid arthritis is a chronic, systemic inflammatory disorder affecting about 1% of the world's
population.
AIM:
The aim of the presented study was to investigate the content of KYNA in 11 herbal preparations used in
rheumatic diseases.

199
The following herbs were studied: bean pericarp, birch leaf, dandelion root, elder flower, horsetail herb,
nettle leaf, peppermint leaf and willow bark. An anti-rheumatic mixture of the herbs Reumatefix and
Reumaflos tea were also investigated. The herbs were prepared according to producers' directions. In
addition, the herbal supplement Devil's Claw containing root of Harpagophytum was used. KYNA
content was measured using the high-performance liquid chromatography method, and KYNA was
detected fluorometrically.
RESULTS:
KYNA was found in all studied herbal preparations. The highest content of KYNA was found in
peppermint, nettle, birch leaf and the horsetail herb. The lowest content of KYNA was found in willow
bark, dandelion root and in the extract from the root of Harpagophytum.
CONCLUSION:
These findings indicate that the use of herbal preparations containing a high level of KYNA can be
considered as a supplementary measure in rheumatoid arthritis therapy, as well as in rheumatic
diseases prevention.
Natural products and their (semi-)synthetic forms in treatment of migraine:

History and current status.
Tauchen J. Curr Med Chem. 2019 Jan 25. doi:
Abstract
BACKGROUND:
Migraine may be described as a headache with moderate to extreme pain that is often accompanied by
incapacitating neurological symptoms. It is estimated that 12% of the world population suffers from
migraine. Although a number of drugs have been used for treatment of migraine, most of these are not
effective for every patient and may have undesirable side-effects. Thus there is an enormous unmet
need in current migraine therapy for discovering safer and more effective agents.
METHODS:
The information summarized in this review was obtained through extensive literature review and search
of relevant books and articles with the use of Web of Knowledge and SciVerse Scopus databases.
RESULTS:
200
Greater understanding of the molecular mechanisms underlying the etiopathogenesis of migraine is

helpful in identifying novel targets for antimigraine drugs such as cannabinoid, histamine, and melatonin
receptors. In the past, natural product-derived constituents have served as an invaluable source of
numerous medicinally useful antimigraine agents and it may be expected that further promising drug
candidates from natural products will be discovered for antimigraine pharmacotherapy with better
efficacy and fewer adverse-effects.
CONCLUSIONS:
The discovery of novel targets in migraine therapy has opened new horizons for compounds that have
not been clinically tested or that previously failed in clinical trials as potential antimigraine drugs.
Ginkgolide B, melatonin, histamine, oxytocin, various ribosomal peptide toxins, kavalactones, devil's
claw-derived compounds, salvinorin A and petasin are among those agents that show considerable
promise as novel drugs in migraine prevention and treatment. It is necessary to conduct more research
to better understand their antimigraine action, to confirm their effectiveness and safety, and to
introduce them into clinical practice.
KEYWORDS:
headache; migraine disorders natural compounds; nociception; novel targets; pain
Bioactive Compounds and Extracts from Traditional Herbs and Their Potential
Anti-Inflammatory Health Effects.
Serrano A, Ros G, Nieto G. Medicines (Basel). 2018 Jul 16;5(3). pii: E76. doi:
10.3390/medicines5030076.
Abstract
The inflammatory processes associated with several chronic illnesses like cardiovascular disease and
cancer have been the focus of mechanistic studies of the pathogenicity of these diseases and of the use
of different pharmacological and natural methods to prevent them. In this study we review the current
evidence regarding the effectiveness of natural extracts from as-yet little-studied traditional botanical
species in alleviating the inflammation process associated with several chronic diseases. Additionally,
the intention is to expose the known pathways of action and the potential synergistic effects of the
constituent compounds of the discussed extracts. It is noted that the here-studied extracts, which
include black garlic rich in S-allylcystein, polyphenols from cat's claw (Uncaria tomentosa), devil's claw
(Harpagophytum procumbens), camu-camu (Myrciaria dubia), and blackcurrant (Ribes nigrum), and
citrus fruit extracts rich in hesperidin, have similar or greater effects than other, more extensively
studied extracts such as tea and cocoa. The combined use of all of these extracts can give rise to
synergetic effects with greater biological relevance at lower doses.
201
KEYWORDS:
Harpagophytum procumbens; Myrciaria dubia; Ribes nigrum; Uncaria tomentosa; anti-inflammatory;

chronic diseases; hesperidin; medicinal plants
Natural or Plant Products for the Treatment of Neurological Disorders:

Current Knowledge.
Parvez MK Curr Drug Metab. 2018;19(5):424-428. doi:
10.2174/1389200218666170710190249.
Abstract
BACKGROUND:
In recent decades, complementary and alternative medicine (CAM) has become very popular in the
treatment of several chronic diseases. Natural products as one of the CAM modalities offer potential
opportunities to discover lead compounds for novel drug development. The use of CAM or natural
products in the prevention of neurodegenerative diseases is comparatively a newer area.
METHOD:
A structured online literature search for peer-reviewed research articles was conducted on the PubMed,
Europe PMC, Medline and Google Scholar portals, using phrases: natural products for neurologic
disorders, phytomedicine for neurodegenerative diseases, natural therapeutics for neurological
symptopms etc. Results: The retrieved data showed the natural therapeutics with anti-oxidative and
anti-inflammatory salutations evidently plays a crucial role in protecting neurons. Of these, the most
promising are caffeine, trigonelline, shogaol, curcumin, resveratrol, baicalein, wogonin, ginsenosides,
tanshinones, withanolides, picrosides, parthenolide, cannabinoids, Devil's claw and white willow bark,
including Chinese formulations Renshen Shouwu and Shengmai San. Though several herbs and their
active ingredients have been studied in laboratory and clinical settings, only a few have been
investigated for their molecular mechanisms of action. Notably, despite the promising and safe
therapeutic benefits of CAM/herbal medicines, there exists a possible risk when combining them with
prescription drugs. As a result, many drugs have shown changes in blood pressure, hepatotoxicity,
seizures etc. when combined with certain herbs.
CONCLUSION:
Certainly, extensive work is needed to make sure that patients should take a regimen of protective and
restorative therapy under an experienced healthcare professional. This article updates on the current
knowledge of promising natural products used in neurological disorders.
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KEYWORDS:
Alzheimer's disease; Complementary and alternative medicine; Parkinson's Disease; natural products;
neurological disorders; neuroprotection.
Anti-Osteoporotic Activity of Harpagoside by Upregulation of the BMP2 and

Wnt Signaling Pathways in Osteoblasts and Suppression of Differentiation in
Osteoclasts.
Chung HJ, et al. J Nat Prod. 2017 Feb 24;80(2):434-442. doi:
10.1021/acs.jnatprod.6b00964. Epub 2017 Jan 20.
Abstract
Harpagoside (1) is an iridoid glycoside isolated from the radix of Harpagophytum procumbens var.
sublobatum, commonly called Devil's claw. The anti-osteoporotic effect of 1 was investigated in both in
vitro cell cultures and in vivo using an ovariectomized (OVX) mouse model. Compound 1 induced bone
formation by stimulating osteoblast proliferation, alkaline phosphatase activity, and mineralization in
osteoblastic MC3T3-E1 cells. Treatment with 1 increased the mRNA and protein expression of bone
formation biomarkers through regulation of the BMP2 and Wnt signaling pathway in MC3T3-E1 cells.
Compound 1 also suppressed the RANKL-induced osteoclastogenesis of cultured mouse bone marrow
cells. Oral administration of 1 restored the OVX-induced destruction of trabecular bone. The bone
mineral density of the femur was also increased significantly by 1. The elevated serum levels of
osteocalcin, C-terminal telopeptide, and tartrate-resistant acid phosphatase in the OVX mice were
decreased by treatment with 1. These findings suggest that compound 1 may protect against bone loss
induced by OVX in mice by regulating stimulation of osteoblast differentiation and inhibition of
osteoclast resorption. Therefore, harpagoside (1) is a potential candidate for management of
postmenopausal osteoporosis.
Harpagoside Content in Devil's Claw Extracts.

Kondamudi N, Turner MW, McDougal OM. Nat Prod Commun. 2016
Sep;11(9):1215-1216.
Abstract
Devil's claw is a common ingredient in nutraceutical products for the treatment of inflammation due to
arthritis. The secondary root extract of Harpagophymn piocumbens contains bioactive iridoid glycosides
known as harpagosides. Recent scrutiny of the nutraceutical industry claims that products listing devil's
203
claw on their labels should refer only to H. procumbens, while the closely related, and less expensive, H.
zeyheri is not to be classified as devil's claw. .This assertion is in contrast to botanists who claim that
either species of Harpagophytum can be generically referred to as devil's claw. The current research
aimed to determine the chemical composition of extracts from H. procumbens and H. zeyheri, with the
intent to identify whether the bioactive harpagosides were similarly present between species, and how
their presence resembled or deviated from commercially available H. procumbens extracts commonly
used in -nutraceutical products. A microwave extraction followed by high performance liquid
chromatography analysis of root samples from botanical specimens of H. procimbens and H. zeyheri
identified similar quantities of harpagoside, regardless of species. The chemical composition between
root extracts for each.species was found to contain varying quantities of non-harpagoside constituents,
however their harpagoside content was comparable. These findings are intended to inform
policymakers, nutraceutical manufacturers, and the general public of the distinction between myth and
reality regarding devil's claw supplements.

10.1097/BRS.0000000000001310.
https://journals.lww.com/spinejournal/Abstract/2007/01010/Herbal_Medicine_for_Low_Back_Pain__A
_Cochrane.14.aspx
Abstract
STUDY DESIGN:
OBJECTIVES:
METHODS:
204
RESULTS:
CONCLUSIONS:
DMSO (Dimethyl
Sulphoxide)
Thermal Sensitivity and Dimethyl Sulfoxide (DMSO).
Takeda K1, Pokorski M, Okada Y. Adv Exp Med Biol. 2016;921:45-50. doi:
10.1007/5584_2016_228.
Abstract
Dimethyl sulfoxide (DMSO) is commonly used as a solvent for hydrophobic substances, but the
compound's innate bioactivity is an area of limited understanding. In this investigation we seek to
determine the analgesic potential of DMSO. We addressed the issue by assessing the perception of
thermal pain stimulus, using a 55 °C hotplate design, in conscious mice. The latency of withdrawal
behaviors over a range of incremental accumulative intraperitoneal DMSO doses (0.5-15.5 g/kg) in the
same mouse was taken as a measure of thermal endurance. The findings were that the latency, on
205
average, amounted to 15-30 s and it differed inappreciably between the sequential DMSO conditions.
Nor was it different from the pre-DMSO control conditions. Thus, DMSO did not influence the cutaneous
thermal pain perception. The findings do not lend support to those literature reports that point to the
plausible antinociceptive potential of DMSO as one of a plethora of its innate bioactivities. However, the
findings concern the mouse's footpad nociceptors which have specific morphology and stimulus
transduction pathways, which cannot exclude DMSO's antinociceptive influence on other types of pain
or in other types of skin. Complex and as yet unresolved neural mechanisms of perception of cutaneous
noxious heat stimulus should be further explored with alternative experimental designs.
KEYWORDS:
Analgesia; Dimethyl sulfoxide; Nociception; Noxious heat; Pain; Perception; Thermal stimulus
A Novel Compound Analgesic Cream (Ketamine, Pentoxifylline, Clonidine,

DMSO) for Complex Regional Pain Syndrome Patients.
Russo MA, Santarelli DM. Pain Pract. 2016 Jan;16(1):E14-20. doi:
10.1111/papr.12404. Epub 2015 Nov 7.
Abstract
BACKGROUND:
Evidence suggests that complex regional pain syndrome (CRPS) is a manifestation of microvascular
dysfunction. Topical combinations of α2-adrenergic receptor agonists or nitric oxide donors with
phosphodiesterase or phosphatidic acid inhibitors formulated to treat microvascular dysfunction have
been shown to reduce allodynia in a rat model of CRPS-I. Driven by these findings, we assessed the
outcomes of CRPS patients treated with a compound analgesic cream (CAC) consisting of ketamine 10%,
pentoxifylline 6%, clonidine 0.2%, and dimethyl sulfoxide 6% to 10%.
METHODS:
An audit was conducted on 13 CRPS patients who trialed the CAC. A detailed report was compiled for
each patient which comprised baseline characteristics, including CRPS description, previous treatments,
and pain scores (numerical pain rating scale; 0 to 10). Recorded outcomes consisted of pain scores,
descriptive outcomes, and concurrent medications/treatments, for which basic analysis was performed
to determine the effectiveness of the CAC. Case reports are presented for 3 patients with varying
outcomes.
RESULTS:
206
Nine patients (69%) reported pain/symptom reduction (4.4 ± 2.1 vs. 6.3 ± 1.9) with use of the CAC. Six
patients reported sustained benefits after 2 months of CAC use, and 2 patients reported complete
resolution of pain/symptoms: one had early CRPS-I and the other received a partial CRPS diagnosis. An
otherwise medication refractory and intolerant patient found partial benefit with the CAC.
CONCLUSIONS:
These results demonstrate promise for this topical combination as a useful treatment in multimodal
therapy for patients with CRPS, with the potential to resolve pain/symptoms in early CRPS patients.
KEYWORDS:
NO donor; clonidine; complex regional pain syndrome; dimethyl sulfoxide; ketamine; nitric oxide
complex regional pain syndrome; pentoxifylline; topical analgesic
Dimethyl sulfoxide (DMSO) as intravesical therapy for interstitial

cystitis/bladder pain syndrome: A review.
Rawls WF, Cox L, Rovner ES. Neurourol Urodyn. 2017 Sep;36(7):1677-1684. doi:
10.1002/nau.23204. Epub 2017 Feb 21.
Abstract
AIMS:
The purpose of this review is to update the current understanding of dimethyl sulfoxide (DMSO) and its
role in the treatment of interstitial cystitis (IC).
METHODS:
A systematic review was conducted using the PRIMSA checklist to identify published articles involving
intravesical DMSO for the treatment of IC.
RESULTS:
Thirteen cohort studies and three randomized-controlled trials were identified. Response rates relying
on subjective measurement scores range from 61 to 95%. No increased efficacy was found with
"cocktail" DMSO therapy. Great variation existed in diagnostic criteria, DMSO instillation protocols and
response measurements.
CONCLUSIONS:
The current evidence backing DMSO is a constellation of cohort studies and a single randomized-
controlled trial versus placebo. The optimal dose, dwell time, type of IC most likely to respond to DMSO,
207
definitions of success/failure and the number of treatments are not universally agreed upon.
Improvements in study design, phenotyping patients based on symptoms, as well as the emergence of
reliable biomarkers of the disease may better guide the use of DMSO in the future.
KEYWORDS:
dimethyl sulfoxide; interstitial cystitis; intravesical administration
Dimethylsulfoxide
Memorial Sloan Kettering Cancer Center. MSKCC.org. March 15, 2016.
https://www.mskcc.org/cancer-care/integrative-medicine/herbs/dimethylsulfoxide
Dimethylsulfoxide (DMSO) is a widely used chemical solvent because of its high polarity. It is also used in
the laboratories as a cryopreservative. DMSO is readily absorbed by the skin and has been studied as a
vehicle for topical drugs. It is thought to have analgesic and anti-inflammatory properties and has been
used topically to relieve pain and to treat arthritis.
Small scale studies conducted in the early 1980s suggested that DMSO may help relieve peripheral
neuropathy and post-thoracotomy pain . But a systematic review of DMSO reported a lack of definitive
evidence against osteoarthritis and painful bladder syndrome/interstitial cystitis.
DMSO has been used to prevent or treat extravasations of chemotherapeutic agents. It may also slow
down the progression of cancer cells; however, data are inconsistent.
DMSO has been shown to cause neural damage in animals (9). Topical application results in a strong
garlic taste in the mouth (10). Intravesical DMSO is an approved prescription drug for the treatment of
interstitial cystitis. DMSO is not approved for use in other forms due to lack of efficacy and safety data.
Uses:
Cancer treatment
Chemotherapy side effects
Pain
Rheumatoid arthritis
Sedation
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What Is DMSO?
Medically reviewed by Judith Marcin, MD on August 4, 2016 — Written by Joe
Bowman.Healthline.com.
https://www.healthline.com/health/what-is-dmso
Overview
The story of dimethyl sulfoxide (DMSO) is an unusual one. This by-product of the paper making process
was discovered in Germany in the late 19th century. It’s a colorless liquid that gained notoriety for its
ability to penetrate skin and other biological membranes.
Scientists discovered that they could use DMSO as a transportation device to pass small molecules
through skin. Since then, scientists have researched the potential benefits and risks of using DMSO to
treat a variety of conditions. This research is ongoing.
Benefits
Some doctors began to use DMSO to treat cases of skin inflammation and diseases such as scleroderma
because of its ability to penetrate skin. Scleroderma is a rare disorder that causes your skin to harden.
Some studies have found that DMSO may also be useful for treating certain side effects of
chemotherapy, reports the Memorial Sloan Kettering Cancer Center (MSKCC). Specifically, DMSO may
help treat chemotherapy extravasations.
Research
Preliminary research evidence reported in PLOS ONE also suggests that DMSO might be effective for
treating Alzheimer's disease, a condition with no known cure.
According to MSKCC, some researchers suggests that DMSO might also be useful for:
• reducing pain and inflammation caused by arthritis

• treating bladder pain and inflammation
• slowing the progression of cancer
However, more research is needed to assess the potential benefits and risks of using DMSO to treat
these conditions. To date, the Food and Drug Administration (FDA) has officially approved the use of
DMSO in humans for only one purpose: to treat interstitial cystitis.
DMSO
Vitamins & Supplements. WebMD. 2018
https://www.webmd.com/vitamins-and-supplements/dmso-uses-and-risks#1
209
DMSO, or dimethyl sulfoxide, is a by-product of paper making. It comes from a substance found in
wood.
DMSO has been used as an industrial solvent since the mid-1800s. From about the mid-20th century,
researchers have explored its use as an anti-inflammatory agent.
The FDA has approved DMSO as a prescription medication for treating symptoms of painful bladder
syndrome. It's also used under medical supervision to treat several other conditions, including shingles.
DMSO is easily absorbed by the skin. It's sometimes used to increase the body's absorption of other
medications.
DMSO is available without a prescription most often in gel or cream form. It can be purchased in health
food stores, by mail order, and on the Internet.
While it can sometimes be found as an oral supplement, its safety is unclear. DMSO is primarily used by
applying it to the skin.
DMSO has been used to try to relieve the pain of osteoarthritis. It has also been promoted as an
"alternative" cancer treatment.
Systematic review of the nutritional supplements dimethyl sulfoxide (DMSO)

and methylsulfonylmethane (MSM) in the treatment of osteoarthritis.
Brien S, Prescott P, Bashir N, Lewith H, Lewith G. Osteoarthritis Cartilage. 2008
Nov;16(11):1277-88. doi: 10.1016/j.joca.2008.03.002. Epub 2008 Apr 15.
Abstract
OBJECTIVE:
Conventional treatment of osteoarthritis (OA) with non-steroidal anti-inflammatory drugs is associated

with serious gastrointestinal side effects and in view of the recent withdrawal of some cyclo-oxygenase-
2 inhibitors, identifying safer alternative treatment options is needed. The objective of this systematic
review is to evaluate the existing evidence from randomised controlled trials of two chemically related
nutritional supplements, dimethyl sulfoxide (DMSO) and methylsulfonylmethane (MSM) in the
treatment of OA to determine their efficacy and safety profile.
METHODS:
The electronic databases [Cochrane Library, Medline, Embase, Amed, Cinahl and NeLH (1950 to
November 2007)] were searched. The search strategy combined terms: osteoarthritis, degenerative
joint disorder, dimethyl sulfoxide, DMSO, methylsulfonylmethane, MSM, clinical trial; double-blind,
210
single blind, RCT, placebo, randomized, comparative study, evaluation study, control. Inclusion and
exclusion criteria were applied. Data were extracted and quality was assessed using the JADAD scale.
RESULTS:
Six studies were included [evaluating a total of 681 patients with OA of the knee for DMSO (N=297 on
active treatment); 168 patients for MSM (N=52 on active treatment)]. Two of the four DMSO trials, and
both MSM trials reported significant improvement in pain outcomes in the treatment group compared
to comparator treatments, however, methodological issues and concerns over optimal dosage and
treatment period, were highlighted.
CONCLUSION:
No definitive conclusion can currently be drawn for either supplement. The findings from all the DMSO
studies need to be viewed with caution because of poor methodology including; possible unblinding,
and questionable treatment duration and dose. The data from the more rigorous MSM trials provide
positive but not definitive evidence that MSM is superior to placebo in the treatment of mild to
moderate OA of the knee. Further studies are now required to identify both the optimum dosage and
longer-term safety of MSM and DMSO, and definitive efficacy trials.
Dimethyl Sulfoxide (DMSO) and Methylsulfonylmethane (MSM) for

Osteoarthritis
National Center for Complementary and Integrative Health (NCCIH).
NCIH.nih.gov. September 24, 2017
https://nccih.nih.gov/health/supplements/dmso-msm
Dimethyl sulfoxide (DMSO) and methylsulfonylmethane (MSM) are two chemically related substances
that have been studied for osteoarthritis. DMSO is used topically (applied to the skin). MSM is sold as a
dietary supplement, either alone or in combination with other ingredients such as glucosamine.
Bottom Line
Only a small amount of research has been conducted on DMSO or MSM for osteoarthritis. No
conclusions can be reached about whether either of these substances is helpful.
Safety
The safety of DMSO and MSM is uncertain because little research has been done on this topic. Side
effects of DMSO include digestive upset, skin irritation, and a garlic-like taste, breath, and body odor.
Side effects of MSM include allergic reactions, digestive upsets, and skin rashes.
If you’re using or considering DMSO or MSM for osteoarthritis, consult your health care provider.
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Feverfew
Widespread pain reliever profile of a flower extract of Tanacetum
parthenium.
Di Cesare Mannelli L, et al. Phytomedicine. 2015 Jul 15;22(7-8):752-8. doi:
10.1016/j.phymed.2015.05.006. Epub 2015 May 27.
Abstract
BACKGROUND:
Tanacetum parthenium L., commonly called Feverfew, is known for anti-inflammatory and anti-migraine
properties.
PURPOSE:
Aimed to individuate new therapeutical strategies to control acute and persistent pain induced by
different origins we tested two hydroalcoholic extracts obtained from Feverfew flowers and leaves,
respectively.
STUDY DESIGN:
Extracts were characterized according to the European Pharmacopoeia monograph. Both the extracts
were tested after acute per os administration in the dose range 30-1000 mg kg(-1). The anti-nociceptive
properties were evaluated by the Writhing test in mice.
RESULTS:
The number of abdominal contractions was dose dependently reduced by the flower extract. It reduced
mechanical hypersensitivity (Paw pressure test) related to the acute inflammatory phase induced by
carrageenan similarly to diclofenac and ibuprofen. In the osteoarthritis model induced by intra articular
injection of monoiodoacetate (MIA) the flower extract significantly increased the pain threshold peaking
30 min after treatment. Moreover, it was effective in the chronic constriction injury model of
neuropathic pain showing activity similar to the anti-epileptic drug gabapentin. The flower extract
activity was confirmed in rat models of chemotherapy-induced neuropathic pain. The mechanical
hypersensitivity induced by repeated treatments with the anticancer drug oxaliplatin and with the
antiviral dideoxycytidine was significantly reduced after a single injection of Feverfew flower extract.
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The leaf extract showed lesser efficacy and potency and it was devoid of any effect in carrageenan-,
MIA- and chemotherapy-induced pain.
CONCLUSION:
The present Feverfew flower extract behaves as a potent pain reliever in acute, inflammatory, articular
and neuropathic pain. It appears as a natural strategy potentially suitable for the treatment of different
kinds of pain.
Nutraceuticals in Migraine: A Summary of Existing Guidelines for Use.

Rajapakse T, Pringsheim T. Headache. 2016 Apr;56(4):808-16. doi:
10.1111/head.12789. Epub 2016 Mar 7.
Abstract
BACKGROUND:
The use of nutraceuticals or food/herbal products for health benefits is expanding in adults with
migraine as they seek relief from pain in an effective and tolerable manner not always afforded by
current conventional pharmacologic therapies. Guidelines from the American Academy of
Neurology/American Headache Society, Canadian Headache Society, and European Federation of
Neurological Societies have discussed nutraceuticals in varying degrees of detail with at times conflicting
recommendations.
CONCLUSION:
This review serves to provide a summary of existing guidelines for the use of certain nutraceuticals
including riboflavin, coenzyme Q10, magnesium, butterbur, feverfew, and omega-3 polyunsaturated
fatty acids. The review will also discuss the regulation of nutraceuticals in North America and the current
controversy regarding butterbur and its safety.
Migraine Headache Prophylaxis.

Ha H, Gonzalez A. Am Fam Physician. 2019 Jan 1;99(1):17-24.
Abstract
Migraines impose significant health and financial burdens. Approximately 38% of patients with episodic
migraines would benefit from preventive therapy, but less than 13% take prophylactic medications.
213
Preventive medication therapy reduces migraine frequency, severity, and headache-related distress.
Preventive therapy may also improve quality of life and prevent the progression to chronic migraines.
Some indications for preventive therapy include four or more headaches a month, eight or more
headache days a month, debilitating headaches, and medication-overuse headaches. Identifying and
managing environmental, dietary, and behavioral triggers are useful strategies for preventing migraines.
First-line medications established as effective based on clinical evidence include divalproex, topiramate,
metoprolol, propranolol, and timolol. Medications such as amitriptyline, venlafaxine, atenolol, and
nadolol are probably effective but should be second-line therapy. There is limited evidence for
nebivolol, bisoprolol, pindolol, carbamazepine, gabapentin, fluoxetine, nicardipine, verapamil,
nimodipine, nifedipine, lisinopril, and candesartan. Acebutolol, oxcarbazepine, lamotrigine, and
telmisartan are ineffective. Newer agents target calcitonin gene-related peptide pain transmission in the
migraine pain pathway and have recently received approval from the U.S. Food and Drug
Administration; however, more studies of long-term effectiveness and adverse effects are needed. The
complementary treatments petasites, feverfew, magnesium, and riboflavin are probably effective.
Nonpharmacologic therapies such as relaxation training, thermal biofeedback combined with relaxation
training, electromyographic feedback, and cognitive behavior therapy also have good evidence to
support their use in migraine prevention.
St. John's Wort seed and feverfew flower extracts relieve painful diabetic
neuropathy in a rat model of diabetes.
Galeotti N, et al. 2014 Jan;92:23-33. doi: 10.1016/j.fitote.2013.10.003. Epub 2013
Oct 12.
Abstract
Painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes and the few
approved therapies for the management of pain have limited efficacy and side effects. With the aim to
explore and develop new pharmacological treatments, we investigated the antihyperalgesic properties
of St. John's Wort (SJW) and feverfew in streptozotocin (STZ)-diabetic rats. Acute administration of a
SJW seed extract reversed mechanical hyperalgesia with a prolonged effect. A SJW extract obtained
from the aerial portion of the plant and a feverfew flower extract partially relieved neuropathic pain
whereas a feverfew leaf extract was ineffective. The antihyperalgesic efficacy of these herbal drugs was
comparable to that of clinically used antihyperalgesic drugs (carbamazepine, lamotrigine, l-acetyl-
levocarnitine). Further examinations of SJW and feverfew composition revealed that hyperforin and
hypericin might be responsible for the antihyperalgesic properties of SJW whereas the efficacy of
feverfew seems to be related to the presence of parthenolide. Rats undergoing treatment with SJW and
feverfew did not show any behavioral side effect or sign of altered locomotor activity. Our results
suggest that SJW and feverfew extracts may become new therapeutic perspectives for painful DPN.
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A double-blind placebo-controlled pilot study of sublingual feverfew and

ginger (LipiGesic™ M) in the treatment of migraine.
Cady RK, et al. Headache. 2011 Jul-Aug;51(7):1078-86. doi: 10.1111/j.1526-
4610.2011.01910.x. Epub 2011 Jun 1.
Abstract
BACKGROUND:
Therapeutic needs of migraineurs vary considerably from patient to patient and even attack to attack.
Some attacks require high-end therapy, while other attacks have treatment needs that are less
immediate. While triptans are considered the "gold standard" of migraine therapy, they do have
limitations and many patients are seeking other therapeutic alternatives. In 2005, an open-label study of
feverfew/ginger suggested efficacy for attacks of migraine treated early during the mild headache phase
of the attack.
METHODS/MATERIALS:
In this multi-center pilot study, 60 patients treated 221 attacks of migraine with sublingual
feverfew/ginger or placebo. All subjects met International Headache Society criteria for migraine with or
without aura, experiencing 2-6 attacks of migraine per month within the previous 3 months. Subjects
had <15 headache days per month and were not experiencing medication overuse headache. Inclusion
required that subjects were able to identify a period of mild headache in at least 75% of attacks.
Subjects were required to be able to distinguish migraine from non-migraine headache. Subjects were
randomized 3:1 to receive either sublingual feverfew/ginger or a matching placebo and were instructed
but not required to treat with study medication at the earliest recognition of migraine.
RESULTS:
Sixty subjects treated 208 evaluable attacks of migraine over a 1-month period; 45 subjects treated 163
attacks with sublingual feverfew/ginger and 15 subjects treated 58 attacks with a sublingual placebo
preparation. Evaluable diaries were completed for 151 attacks of migraine in the population using
feverfew/ginger and 57 attacks for those attacks treated with placebo. At 2 hours, 32% of subjects
receiving active medication and 16% of subjects receiving placebo were pain-free (P= .02). At 2 hours,
63% of subjects receiving feverfew/ginger found pain relief (pain-free or mild headache) vs 39% for
placebo (P= .002). Pain level differences on a 4-point pain scale for those receiving feverfew/ginger vs
placebo were -0.24 vs -0.04 respectively (P= .006). Feverfew/ginger was generally well tolerated with
oral numbness and nausea being the most frequently occurring adverse event.
CONCLUSION:
215
Sublingual feverfew/ginger appears safe and effective as a first-line abortive treatment for a population
of migraineurs who frequently experience mild headache prior to the onset of moderate to severe
headache.
Fish Oil
Fish Oil and Osteoarthritis: Current Evidence.
Boe C, Vangsness CT. Am J Orthop (Belle Mead NJ). 2015 Jul;44(7):302-5.
Abstract
According to the 2005 US census, osteoarthritis (OA) was the leading cause of disability in the United
States, affecting more than 50 million people. Current treatments are targeted at reducing symptoms of
the inflammatory reaction that occurs after destruction of essential joint cartilage. However, these
treatments do not prevent significant pain and activity restriction. We reviewed the literature to address
claims that fish oil supplementation can prevent or decrease severity of OA. Our extensive search of
databases covered all relevant terms related to omega-3-containing supplements and their effects on
OA. We hypothesized there would be insufficient clinical studies to justify recommending
supplementation to patients.Laboratory studies have shown that eicosapentaenoic acid and
docosahexaenoic acid reduce proinflammatory mediators and increase joint lubrication in vitro. In
addition, canine trials have shown clinically significant reductions in various symptom parameters.
Results of human clinical trials have not been consistently significant. Well-designed clinical trials are
needed to substantiate or refute the potential benefit of fish oils in OA treatment. Long-term studies are
needed to assess the possibility of prevention. In addition, standardization of the fish oil industry is
needed for consistency of therapy.Senftleber NK, et al. Nutrients. 2017 Jan 6;9(1). pii: E42. doi:
10.3390/nu9010042.
Abstract
Arthritis patients often take fish oil supplements to alleviate symptoms, but limited evidence exists
regarding their efficacy. The objective was to evaluate whether marine oil supplements reduce pain
and/or improve other clinical outcomes in patients with arthritis. Six databases were searched
systematically (24 February 2015). We included randomized trials of oral supplements of all marine oils
compared with a control in arthritis patients. The internal validity was assessed using the Cochrane Risk
216
of Bias tool and heterogeneity was explored using restricted maximum of likelihood (REML)-based meta-
regression analysis. Grading of Recommendations Assessment, Development and Evaluation (GRADE)
was used to rate the overall quality of the evidence. Forty-two trials were included; 30 trials reported
complete data on pain. The standardized mean difference (SMD) suggested a favorable effect (-0.24;
95% confidence interval, CI, -0.42 to -0.07; heterogeneity, I² = 63%. A significant effect was found in
patients with rheumatoid arthritis (22 trials; -0.21; 95% CI, -0.42 to -0.004) and other or mixed diagnoses
(3 trials; -0.63; 95% CI, -1.20 to -0.06), but not in osteoarthritis patients (5 trials; -0.17; 95% CI, -0.57-
0.24). The evidence for using marine oil to alleviate pain in arthritis patients was overall of low quality,
but of moderate quality in rheumatoid arthritis patients.
Acute antinociceptive effect of fish oil or its major compounds,

eicosapentaenoic and docosahexaenoic acids on diabetic neuropathic pain
depends on opioid system activation.
Redivo DDB, Jesus CHA, Sotomaior BB, Gasparin AT, Cunha JM. Behav Brain Res.
2019 Oct 17;372:111992. doi: 10.1016/j.bbr.2019.111992. Epub 2019 May 30.
Abstract
Diabetic neuropathic pain is one of the most common and debilitating complications of diabetes whose
available treatments are poorly effective. Currently, omega-3 polyunsaturated fatty acids (ω-3 PUFAs)
have been widely studied as a treatment of many types of pain, including inflammatory, spontaneous
and neuropathic pain. However, little is known about the potential antinociceptive effect of ω-3 PUFAs
(fish oil; FO or its major fatty acids, eicosapentaenoic -EPA and docosahexaenoic acids-DHA), in diabetic
neuropathic pain as well as the mechanisms involved. To test, streptozotocin (STZ) -induced diabetic
male Wistar rats were submitted to acute treatment with FO, EPA or DHA at the second and fourth
weeks after diabetes induction (at the beginning and peak of development of mechanical allodynia,
respectively). The cumulative effect of these compounds after a sub-chronic treatment for two weeks
was also evaluated as well as the role of central μ-opioid receptors. It was observed that acute oral
treatment with FO (0.5, 1 or 3 g/kg), EPA or DHA (100, 200 or 400 mg/kg) at the 2nd or at the 4th week
after STZ significantly reverted the mechanical allodynia of diabetic animals, without altering the
hyperglycemia or reduced weight gain. Moreover, the sub-chronic treatment with FO, EPA or DHA
induced a sustained antinociceptive effect in diabetic animals. Intriguingly, the intrathecal treatment
with a μ-opioid receptor antagonist (CTOP; 10 μg/rat) completely prevented the acute effect of FO, EPA
or DHA. Taken together, our data suggest that ω-3 PUFAs may represent a promising therapeutic
outcome for diabetic neuropathic pain, probably acting through the opioid system activation.
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Anti-pain and anti-inflammation like effects of Neptune krill oil and fish oil
against carrageenan induced inflammation in mice models: Current statues
and pilot study.
Zadeh-Ardabili PM, Rad SK. Biotechnol Rep (Amst). 2019 Apr 18;22:e00341. doi:
10.1016/j.btre.2019.e00341. eCollection 2019 Jun.
Abstract
Although inflammation is a reactive to injurious stimuli and considered as beneficial process in body, but
it causes some discomforts, such as pain. Murine dietary contains appreciable amounts of fatty acids
and antioxidants which encourages researchers to focus on their potential therapeutic effects. This
study is aimed to examine the analgesic and anti-inflammatory activity of Neptune krill oil (NKO) and fish
oil (FO) in rodent model which are two well-known sources of rich content of n-3 polyunsaturated fatty
acids (n-3 PUFAs), mostly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). NKO and FO
were used at the same dose of 500 mg and also balanced at similar doses of EPA: 12 in NKO vs. 12 in FO
wt%, DHA: 7 NKO vs. 8 FO wt%. Application of NKO and FO in acetic acid-induced writhing effect, hot
plate, and formalin induced test, indicated the nociceptive activity of the two tested drugs in
comparison with normal saline. Also, the anti-inflammatory effect of these supplements was confirmed
by carrageenan test. Analysis of cytokines levels in the blood samples of the mice after induction
inflammation by carrageenan indicated decreased levels of those proteins compared to that in the
normal groups. Both tested drugs, effectively could reduce severe inflammation and pain in rodents in
comparison with the references drugs (depends on the tests); however, NKO was found to be more
effective.
KEYWORDS:
Anti-inflammation; Anti-nociceptive; DHA; EPA; Fish oil; IL-6; Neptune krill oil; TNF-α; n-3 PUFAs
Supplementation of eicosapentaenoic acid-rich fish oil attenuates muscle

stiffness after eccentric contractions of human elbow flexors.
Tsuchiya Y, Yanagimoto K, Ueda H, Ochi E. J Int Soc Sports Nutr. 2019 Apr
15;16(1):19. doi: 10.1186/s12970-019-0283-x.
Abstract
BACKGROUND:
218
This study aimed to investigate the effect of supplementation of fish oil rich in eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA) on the damage of the biceps brachii after eccentric contractions
(ECCs) of the elbow flexors, particularly focusing on muscle stiffness.
METHODS:
Sixteen men were included in this double-blind, placebo-controlled, parallel design study and the
participants were randomly assigned to the EPA and DHA supplement group (EPA, n = 8) and placebo
group (PL, n = 8). They consumed either EPA 600 mg and DHA 260 mg per day or placebo supplement for
8 weeks prior to exercise. Moreover, they performed six sets of 10 ECCs at 100% maximal voluntary
contraction (MVC) using a dumbbell. Changes in MVC torque, range of motion (ROM), upper arm
circumference, muscle soreness, muscle echo intensity, and muscle stiffness were assessed before
exercise; immediately after exercise; and 1, 2, and 5 days after exercise.
RESULTS:
MVC torque and ROM were significantly higher in the EPA group than in the PL group after ECCs
(p < 0.05). Muscle soreness, upper arm circumference, and muscle echo intensity were significantly
higher in the PL group than in the EPA group after ECCs (p < 0.05). In addition, muscle stiffness at 150°
was significantly higher in the PL group than in the EPA group immediately after ECCs (p < 0.05).
CONCLUSION:
The present study showed that EPA and DHA supplementation has a positive role in inhibiting muscle
stiffness after ECCs.
TRIAL REGISTRATION:
This trial (UMIN000028165) was registered on 10th/July/2017.
KEYWORDS:
Echo intensity; Eicosapentaenoic acid; Muscle function; Muscle soreness; Muscle swelling; Omega-3
polyunsaturated fatty acids; Shear elastic modulus; Shear wave elastography
Dynamic changes to lipid mediators support transitions among macrophage

subtypes during muscle regeneration.
Giannakis N, et al. Nat Immunol. 2019 May;20(5):626-636. doi: 10.1038/s41590-
019-0356-7. Epub 2019 Apr 1.
Abstract
219
Muscle damage elicits a sterile immune response that facilitates complete regeneration. Here, we used
mass spectrometry-based lipidomics to map the mediator lipidome during the transition from
inflammation to resolution and regeneration in skeletal muscle injury. We observed temporal regulation
of glycerophospholipids and production of pro-inflammatory lipid mediators (for example, leukotrienes
and prostaglandins) and specialized pro-resolving lipid mediators (for example, resolvins and lipoxins)
that were modulated by ibuprofen. These time-dependent profiles were recapitulated in sorted
neutrophils and Ly6Chi and Ly6Clo muscle-infiltrating macrophages, with a distinct pro-resolving
signature observed in Ly6Clo macrophages. RNA sequencing of macrophages stimulated with resolvin
D2 showed similarities to transcriptional changes found during the temporal transition from Ly6Chi
macrophage to Ly6Clo macrophage. In vivo, resolvin D2 increased Ly6Clo macrophages and functional
improvement of the regenerating muscle. These results reveal dynamic lipid mediator signatures of
innate immune cells and provide a proof of concept for their exploitable effector roles in muscle
regeneration.
FISH OIL
https://www.webmd.com/vitamins/ai/ingredientmono-993/fish-oil
Fish oil can be obtained by eating fish or taking supplements. Fish that are especially rich in the
beneficial oils known as omega-3 fatty acids include mackerel, herring, tuna, salmon, cod liver, whale
blubber, and seal blubber. Two of the most important omega-3 fatty acids contained in fish oil are
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
Certain fish oil is used as a prescription medicine to lower triglycerides levels.
Fish oil is most often used in supplements for conditions related to the heart and blood system. Fish oil
is also used for many kidney-related problems. Fish may have earned its reputation as "brain food"
because some people eat fish to help with various conditions linked with nerve and brain function. Some
people use fish oil for eye conditions that can lead to blindness. Fish oil supplements have also been
tried for many other conditions.
Phytalgic, a food supplement, vs placebo in patients with osteoarthritis of the

knee or hip: a randomised double-blind placebo-controlled clinical trial.
Jacquet A, et al. Arthritis Res Ther. 2009;11(6):R192. doi: 10.1186/ar2891. Epub
2009 Dec 16.
Abstract
220
INTRODUCTION:
The medicinal treatment of osteoarthritis (OA) is mostly symptomatic to relieve pain and incapacity with
analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), drugs with well-known risks.
Complementary medicines might reduce the symptoms of OA and decrease the need for NSAIDs. This
study tested the effects of a food supplement, Phytalgic, on pain and function in patients with
osteoarthritis and their use of analgesic and NSAIDs.
METHODS:
A randomized double-blind parallel-groups clinical trial compared Phytalgic (fish-oil, vitamin E, Urtica
dioica) to a placebo for three months, in 81 patients with OA of the knee or hip using NSAIDs and/or
analgesics regularly. The main outcome measures were use of NSAIDs (in Defined Daily Doses per day -
DDD/day) or analgesics (in 500 mg paracetamol-equivalent tablets per week (PET/week) measured each
month, and Western Ontario-McMaster University Osteo-Arthritis Index (WOMAC) function scales.
RESULTS:
After three months of treatment, the mean use of analgesics in the active arm (6.5 PET/week) vs. the
placebo arm (16.5) was significantly different (P < 0.001) with a group mean difference of -10.0 (95% CI:
-4.9 to -15.1). That of NSAIDs in the active arm (0.4 DDD/day) vs the placebo arm (1.0 DDD/day) was
significantly different (P = 0.02) with a group mean difference of - 0.7 DDD/day (95% CI: -0.2 to -1.2).
Mean WOMAC scores for pain, stiffness and function in the active arm (respectively 86.5, 41.4 and
301.6) vs the placebo arm (resp. 235.3, 96.3 and 746.5) were significantly different (P < 0.001) with
group mean differences respectively of -148.8 (95% CI: -97.7 to -199.9), -54.9 (95% CI: -27.9 to -81.9)
and -444.8 (95% CI: -269.1 to -620.4).
CONCLUSIONS:
The food supplement tested appeared to decrease the need for analgesics and NSAIDs and improve the
symptoms of osteoarthritis.
13 Benefits of Taking Fish Oil

Written by Ruairi Robertson, PhD on December 18, 2018. Healthline.com
https://www.healthline.com/nutrition/13-benefits-of-fish-oil
Fish oil is the fat or oil that's extracted from fish tissue.
It usually comes from oily fish, such as herring, tuna, anchovies, and mackerel. Yet it's sometimes
produced from the livers of other fish, as is the case with cod liver oil.
221
The World Health Organization (WHO) recommends eating 1–2 portions of fish per week. This is
because the omega-3 fatty acids in fish provide many health benefits, including protection against a
number of diseases.
However, if you don't eat 1–2 servings of fish per week, fish oil supplements can help you get enough
omega-3s.
Around 30% of fish oil is made up of omega-3s, while the remaining 70% is made up of other fats.
What’s more, fish oil usually contains some vitamin A and D.
It's important to note that the types of omega-3s found in fish oil have greater health benefits than the
omega-3s found in some plant sources.
The main omega-3s in fish oil are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), while
the omega-3 in plant sources is mainly alpha-linolenic acid (ALA).
Although ALA is an essential fatty acid, EPA and DHA have many more health benefits.
It's also important to get enough omega-3s because the Western diet has replaced a lot of omega-3s
with other fats like omega-6s. This distorted ratio of fatty acids may contribute to numerous diseases.
Marine Oil Supplements for Arthritis Pain: A Systematic Review and Meta-
Analysis of Randomized Trials.
Senftleber NK, et al. Nutrients. 2017 Jan 6;9(1). pii: E42. doi:
10.3390/nu9010042.
https://www.ncbi.nlm.nih.gov/pubmed/?term=Marine+Oil+Supplements+for+Arthritis+Pain%3A+A+Syst
ematic+Review+and+Meta-Analysis+of+Randomized+Trials.
Abstract
Arthritis patients often take fish oil supplements to alleviate symptoms, but limited evidence exists
regarding their efficacy. The objective was to evaluate whether marine oil supplements reduce pain
and/or improve other clinical outcomes in patients with arthritis. Six databases were searched
systematically (24 February 2015). We included randomized trials of oral supplements of all marine oils
compared with a control in arthritis patients. The internal validity was assessed using the Cochrane Risk
of Bias tool and heterogeneity was explored using restricted maximum of likelihood (REML)-based meta-
regression analysis. Grading of Recommendations Assessment, Development and Evaluation (GRADE)
was used to rate the overall quality of the evidence. Forty-two trials were included; 30 trials reported
complete data on pain. The standardized mean difference (SMD) suggested a favorable effect (-0.24;
95% confidence interval, CI, -0.42 to -0.07; heterogeneity, I² = 63%. A significant effect was found in
patients with rheumatoid arthritis (22 trials; -0.21; 95% CI, -0.42 to -0.004) and other or mixed diagnoses
(3 trials; -0.63; 95% CI, -1.20 to -0.06), but not in osteoarthritis patients (5 trials; -0.17; 95% CI, -0.57-
222
0.24). The evidence for using marine oil to alleviate pain in arthritis patients was overall of low quality,
but of moderate quality in rheumatoid arthritis patients.
Fish Oil Increases Specialized Pro-resolving Lipid Mediators in PAD (The

OMEGA-PAD II Trial).
Ramirez JL, et al. J Surg Res. 2019 Jun;238:164-174. doi:
10.1016/j.jss.2019.01.038. Epub 2019 Feb 13.
Abstract
BACKGROUND:
N-3 polyunsaturated fatty acid (PUFA) supplementation has been associated with reduced mortality and
inflammation in patients with cardiovascular disease. There are limited data on the effects of n-3 PUFA
supplementation in patients with peripheral artery disease (PAD).
The OMEGA-PAD II trial was a double-blinded, randomized, placebo-controlled trial to assess the effect
of 3 mo of high-dose oral n-3 PUFA supplementation on inflammation, endothelial function, and walking
ability in patients with PAD.
RESULTS:
Twenty-four patients with claudication received 4.4 g/d of fish oil or placebo for 3 mo. Outcomes
measured included high-sensitivity C-reactive protein levels, the omega-3 index, endothelial function as
measured via flow-mediated vasodilation, walking impairment questionnaire, and a 6-min walk test.
Plasma levels of specialized pro-resolving lipid mediators (SPMs) were measured by liquid-
chromatography-tandem mass spectrometry. In patients treated with fish oil, the absolute mean
omega-3 index significantly increased from baseline (fish oil: 7.2 ± 1.2%, P < 0.001; placebo: -0.4 ± 0.9%,
P = 0.31; between-group P < 0.001). Furthermore, there were significant increases in several pathway
markers of SPM biosynthesis, including several mono-hydroxyeicosapentaenoic acids and mono-
hydroxydocosahexaenoic acids. We also observed significant increases in the SPM lipoxin A5 (fish oil:
0.57 ± 0.70 pg/mL, P = 0.05; placebo: 0.01 ± 0.38 pg/mL, P = 0.93; between-group P = 0.04) and resolvin
E3 (fish oil: 154 ± 171 pg/mL, P = 0.04; placebo: 32 ± 54 pg/mL, P = 0.08; between-group P = 0.04). There
were no significant changes in high-sensitivity C-reactive protein, flow-mediated vasodilation, walking
impairment questionnaire, or 6-min walk test in the fish oil group.
CONCLUSIONS:
223
Fish oil increases SPMs in plasma of patients with PAD. Further studies are required to determine
whether these early changes translate to clinical improvements in patients with PAD.
KEYWORDS:
Fish oils; Other pharmacotherapy; Peripheral artery disease; Specialized pro-resolving lipid mediators; n-
3 polyunsaturated fatty acids
Ginger
A double-blind placebo-controlled pilot study of sublingual feverfew and
ginger (LipiGesic™ M) in the treatment of migraine.
Cady RK, et al. Headache. 2011 Jul-Aug;51(7):1078-86. doi: 10.1111/j.1526-
4610.2011.01910.x. Epub 2011 Jun 1.
Abstract
BACKGROUND:
Therapeutic needs of migraineurs vary considerably from patient to patient and even attack to attack.
Some attacks require high-end therapy, while other attacks have treatment needs that are less
immediate. While triptans are considered the "gold standard" of migraine therapy, they do have
limitations and many patients are seeking other therapeutic alternatives. In 2005, an open-label study of
feverfew/ginger suggested efficacy for attacks of migraine treated early during the mild headache phase
of the attack.
METHODS/MATERIALS:
In this multi-center pilot study, 60 patients treated 221 attacks of migraine with sublingual
feverfew/ginger or placebo. All subjects met International Headache Society criteria for migraine with or
without aura, experiencing 2-6 attacks of migraine per month within the previous 3 months. Subjects
had <15 headache days per month and were not experiencing medication overuse headache. Inclusion
required that subjects were able to identify a period of mild headache in at least 75% of attacks.
Subjects were required to be able to distinguish migraine from non-migraine headache. Subjects were
224
randomized 3:1 to receive either sublingual feverfew/ginger or a matching placebo and were instructed
but not required to treat with study medication at the earliest recognition of migraine.
RESULTS:
Sixty subjects treated 208 evaluable attacks of migraine over a 1-month period; 45 subjects treated 163
attacks with sublingual feverfew/ginger and 15 subjects treated 58 attacks with a sublingual placebo
preparation. Evaluable diaries were completed for 151 attacks of migraine in the population using
feverfew/ginger and 57 attacks for those attacks treated with placebo. At 2 hours, 32% of subjects
receiving active medication and 16% of subjects receiving placebo were pain-free (P= .02). At 2 hours,
63% of subjects receiving feverfew/ginger found pain relief (pain-free or mild headache) vs 39% for
placebo (P= .002). Pain level differences on a 4-point pain scale for those receiving feverfew/ginger vs
placebo were -0.24 vs -0.04 respectively (P= .006). Feverfew/ginger was generally well tolerated with
oral numbness and nausea being the most frequently occurring adverse event.
CONCLUSION:
Sublingual feverfew/ginger appears safe and effective as a first-line abortive treatment for a population
of migraineurs who frequently experience mild headache prior to the onset of moderate to severe
headache.
Gingerols and shogaols: Important nutraceutical principles from ginger.

Semwal RB, Semwal DK, Combrinck S, Viljoen AM. Phytochemistry. 2015
Sep;117:554-568. doi: 10.1016/j.phytochem.2015.07.012. Epub 2015 Jul 27.
Abstract
Gingerols are the major pungent compounds present in the rhizomes of ginger (Zingiber officinale
Roscoe) and are renowned for their contribution to human health and nutrition. Medicinal properties of
ginger, including the alleviation of nausea, arthritis and pain, have been associated with the gingerols.
Gingerol analogues are thermally labile and easily undergo dehydration reactions to form the
corresponding shogaols, which impart the characteristic pungent taste to dried ginger. Both gingerols
and shogaols exhibit a host of biological activities, ranging from anticancer, anti-oxidant, antimicrobial,
anti-inflammatory and anti-allergic to various central nervous system activities. Shogaols are important
biomarkers used for the quality control of many ginger-containing products, due to their diverse
biological activities. In this review, a large body of available knowledge on the biosynthesis, chemical
synthesis and pharmacological activities, as well as on the structure-activity relationships of various
gingerols and shogaols, have been collated, coherently summarised and discussed. The manuscript
highlights convincing evidence indicating that these phenolic compounds could serve as important lead
molecules for the development of therapeutic agents to treat various life-threatening human diseases,
225
particularly cancer. Inclusion of ginger or ginger extracts in nutraceutical formulations could provide
valuable protection against diabetes, cardiac and hepatic disorders.
KEYWORDS:
Anti-inflammatory; Anticancer; Antidiabetic; Ginger; Gingerols; Nutraceutical; Shogaols; Zingiber

officinale
Ginger (Zingiber officinale) as an Analgesic and Ergogenic Aid in Sport: A

Systemic Review.
Wilson PB. J Strength Cond Res. 2015 Oct;29(10):2980-95. doi:
10.1519/JSC.0000000000001098.
Abstract
Ginger is a popular spice used to treat a variety of maladies, including pain. Nonsteroidal anti-
inflammatory drugs (NSAIDs) are frequently used by athletes to manage and prevent pain;
unfortunately, NSAIDs contribute to substantial adverse effects, including gastrointestinal (GI)
dysfunction, exercise-induced bronchoconstriction, hyponatremia, impairment of connective tissue
remodeling, endurance competition withdrawal, and cardiovascular disease. Ginger, however, may act
as a promoter of GI integrity and as a bronchodilator. Given these potentially positive effects of ginger, a
systematic review of randomized trials was performed to assess the evidence for ginger as an analgesic
and ergogenic aid for exercise training and sport. Among 7 studies examining ginger as an analgesic, the
evidence indicates that roughly 2 g·d(-1) of ginger may modestly reduce muscle pain stemming from
eccentric resistance exercise and prolonged running, particularly if taken for a minimum of 5 days.
Among 9 studies examining ginger as an ergogenic aid, no discernable effects on body composition,
metabolic rate, oxygen consumption, isometric force generation, or perceived exertion were observed.
Limited data suggest that ginger may accelerate recovery of maximal strength after eccentric resistance
exercise and reduce the inflammatory response to cardiorespiratory exercise. Major limitations to the
research include the use of untrained individuals, insufficient reporting on adverse events, and no direct
comparisons with NSAID ingestion. While ginger taken over 1-2 weeks may reduce pain from eccentric
resistance exercise and prolonged running, more research is needed to evaluate its safety and efficacy
as an analgesic for a wide range of athletic endeavors.
Double-blind placebo-controlled randomized clinical trial of ginger (Zingiber

officinale Rosc.) in the prophylactic treatment of migraine.
Martins LB, et al. Cephalalgia. 2019 Aug 9:333102419869319. doi:
226
Abstract
BACKGROUND:
Previous studies have shown an analgesic effect of ginger in the acute treatment of migraine, and there
is anecdotal evidence of its efficacy in migraine prophylaxis.
OBJECTIVE:
This study aimed to evaluate the potential of ginger to prevent migraine attacks.
METHODS:
This double-blind, placebo-controlled randomized clinical trial took place at the Headache Clinic,
Universidade Federal de Minas Gerais (Belo Horizonte, Minas Gerais, Brazil), involving 107 patients. Only
subjects diagnosed with episodic migraine, aged between 18 and 60 years old, and who were not taking
any prophylactic medication, were enrolled in the study. After one month of observation, subjects
selected for the study were randomized 1:1 into placebo and treatment groups. Patients received
capsules three times per day of 200 mg of dry extract of ginger (5% active ingredient) or placebo
(cellulose) for three months. Visits were performed monthly and the patients were asked to fill in a
migraine diary. The adherence to treatment was evaluated by counting capsules.
RESULTS:
The percentage of patients who responded to treatment (i.e. a reduction of 50% in the number of
migraine attacks at the end of treatment) did not differ between the groups. There was a decrease in
the number of days with severe pain, analgesic use for acute migraine and duration of migraine attacks
in both groups, without significant difference between ginger and placebo groups.
CONCLUSIONS:
Ginger provides no greater benefit in the prophylactic treatment of migraine when compared to
placebo. This trial is registered at ClinicalTrials.gov (NCT02570633).
KEYWORDS:
Migraine; ginger; prophylactic treatment
Ginger for health care: An overview of systematic reviews.

Li H, et al. Complement Ther Med. 2019 Aug;45:114-123. doi:
10.1016/j.ctim.2019.06.002. Epub 2019 Jun 5.
227
Abstract
OBJECTIVES:
To summarize the evidence from systematic reviews (SRs) and meta-analyses that evaluated the efficacy
of ginger in treating any conditions and critically assess the quality of these evidence.
METHODS:
A systematic search of the literature was conducted from inception until February 28, 2019 using the
PubMed, EMBASE, Web of science, Cochrane library, and four Chinese databases. Literature selection
and data extraction were conducted by two independent reviewers. The quality of SRs was evaluated
using the AMSTAR-2 tool. The GRADE system was used to assess the quality of evidence.
RESULTS:
Twenty-seven SRs were included. The number of included studies were various, range from 3 to 27. The
condition with the most included SRs was nausea and vomiting (n = 12, 44.4%). Many SRs showed a
promising efficacy of ginger, including nausea and vomiting, metabolic syndrome and pain, while the
effect of ginger for platelet aggregation failed to draw a certain conclusion. The quality of SRs was
heterogeneous. All of included SRs well complied with the Item 1 ("research questions included the
components of PICO") and Item 3 ("explained selection of the study designs for inclusion"). Twenty
review failed to provide registration information. Only one SR reported the sources of funding for
studies included.
CONCLUSIONS:
In our overview, most of SRs suggest ginger is a promising herbal medicine for health care, which is
beneficial for nausea and vomiting, metabolic syndrome and pain. However, considering the limited
quality of included evidence and heterogeneity of different clinical trials, more well-design studies are
required to confirm the conclusion further.
Does diet play a role in reducing nociception related to inflammation and

chronic pain?
Bjørklund G, et al. Nutrition. 2019 Oct;66:153-165. doi:
10.1016/j.nut.2019.04.007. Epub 2019 Apr 26.
Abstract
Dietary habits are fundamental issues to assess when modulating health and well-being; however,
different nutritional panels may help individuals prevent acute and chronic pain. Many substances,
known to be active antioxidants and anti-inflammatory compounds, should serve this fundamental task.
228
Antinociceptive and analgesic natural compounds include flavonoids, terumbone from ginger root,
curcuminoids, ω-3 polyunsaturated fatty acids, and taurine. Furthermore, correct intake of trace
elements and minerals is strategic to reduce inflammation-related pain. This review addresses these
items in an effort to suggest new criteria for proper dietary supplementation to prevent pain.
Ginger for Arthritis: Does It Work?

March 27, 2017 — Written by Emily Cronkleton. Healthline.com.
https://www.healthline.com/health/ginger-for-arthritis
Ginger is a flowering plant. Its root is often used for cooking. Its sharp, distinct flavor is unmistakable,
and many people appreciate its aromatic taste.
In addition to its culinary uses, ginger has served as a folk medicine for centuries.
Ginger has anti-inflammatory, antioxidant, and anticancer properties. Because of this, it’s thought to
boost your overall immunity.
For people with arthritis, its anti-inflammatory properties are of particular benefit. Ginger contains anti-
inflammatory compounds that function in the same way as COX-2 inhibitors. COX-2 inhibitors are drugs
used to treat pain and inflammation.

Abstract
BACKGROUND:
METHODS:
229
RESULTS:
interaction effect P = 0.027; ssffness score, ↓30% versus ↓12%, respectively, interaction effect
CONCLUSIONS:
GINGER
https://www.webmd.com/vitamins/ai/ingredientmono-961/ginger
Ginger is a plant with leafy stems and yellowish green flowers. The ginger spice comes from the roots of
the plant. Ginger is native to warmer parts of Asia, such as China, Japan, and India, but now is grown in
parts of South American and Africa. It is also now grown in the Middle East to use as medicine and with
food.
230
Ginger is commonly used for various types of "stomach problems," including motion sickness, morning
sickness, colic, upset stomach, gas, diarrhea, irritable bowel syndrome (IBS), nausea, nausea caused by
cancer treatment, nausea caused by HIV/AIDS treatment, nausea and vomiting after surgery, as well as
loss of appetite.
Other uses include pain relief from rheumatoid arthritis (RA), osteoarthritis, menstrual pain, and other
conditions. However, there is not strong evidence to support the use of ginger for these conditions.

Abstract
OBJECTIVE:
METHODS:
RESULTS:
231
CONCLUSIONS:
KEYWORDS:
Glucosamine
Efficacy and safety of glucosamine sulfate in the management of
osteoarthritis: Evidence from real-life setting trials and surveys.
Bruyère O, Altman RD, Reginster JY. Semin Arthritis Rheum. 2016 Feb;45(4
Suppl):S12-7. doi: 10.1016/j.semarthrit.2015.11.011. Epub 2015 Dec 2.
https://www.ncbi.nlm.nih.gov/pubmed
Abstract
The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO)
treatment algorithm recommends chronic symptomatic slow-acting drugs for osteoarthritis (SYSADOAs)
including glucosamine sulfate (GS) and chondroitin sulfate (CS) as first-line therapy for knee
osteoarthritis (OA). Numerous studies are published on the use of SYSADOAs in OA; however, the
efficacy of this class is still called into question largely due to the regulatory status, labeling and
availability of these medications which differ substantially across the world. Examination of the evidence
for the prescription patented crystalline GS (pCGS) formulation at a dose of 1500mg once-daily
demonstrates superiority over other GS and glucosamine hydrochloride (GH) formulations and dosage
regimens. Thus, the ESCEO task force advocates differentiation of prescription pCGS over other
glucosamine preparations. Long-term clinical trials and real-life studies show that pCGS may delay joint
structural changes, suggesting potential benefit beyond symptom control when used early in the
management of knee OA. Real-life pharmacoeconomic studies demonstrate a long-term reduction in the
need for additional pain analgesia and non-steroidal anti-inflammatory drugs (NSAIDs) with pCGS, with a
significant reduction of over 50% in costs associated with medications, healthcare consultations and
examinations over 12 months. Furthermore, treatment with pCGS for at least 12 months leads to a
232
reduction in the need for total joint replacement for at least 5 years following treatment cessation.
Thus, pCGS (1500mg od) is a logical choice to maximize clinical benefit in OA patients, with
demonstrated medium-term control of pain and lasting impact on disease progression.
A retrospective observational study of glucosamine sulfate in addition to

conventional therapy in hand osteoarthritis patients compared to
conventional treatment alone.
Tenti S, Giordano N, Mondanelli N, Giannotti S, Maheu E, Fioravanti A. Aging Clin
Exp Res. 2019 Aug 19. doi: 10.1007/s40520-019-01305-4. [Epub ahead of print]
Abstract
BACKGROUND:
The optimal management of hand osteoarthritis (HOA) is still challenging.
AIM:
To evaluate the effects of glucosamine sulfate (GS) in addition to conventional therapy compared to
conventional therapy alone in HOA.
METHODS:
This 6-month retrospective study included 108 patients with concomitant knee and hand OA. Fifty-five
patients (GS Group) were treated for six consecutive months with crystalline GS (1500 mg once/day) in
addition to conventional therapy for HOA [exercise combined with acetaminophen and/or non-steroidal
anti-inflammatory drugs (NSAIDs)] and 53 patients (Control Group) with the conventional therapy alone.
Primary outcomes were the difference between groups in the change of hand pain on a Visual Analogue
Scale (VAS) and in the Functional Index for Hand Osteoarthritis (FIHOA) from baseline to 6 months.
Secondary outcomes were Health Assessment Questionnaire (HAQ), medical outcomes study 36-item
short form (SF-36) and symptomatic drug consumption.
RESULTS:
The patients who received GS presented a significant decrease (p < 0.001) in VAS pain and FIHOA scores
compared with the Control Group at 3 and 6 months. Furthermore, GS therapy was associated to a
significant improvement of HAQ score and to a significant reduction of acetaminophen and NSAID
consumption during the follow-up. No differences in the number of side effects were observed between
the groups.
DISCUSSION:
233
GS could represent a potential successful therapy for HOA and should be tried in large randomized
placebo and active controlled trials.
CONCLUSIONS:
The combination of GS with conventional treatment seems to be more effective in improving pain and
function than conventional HOA treatment alone.
TRIAL REGISTRATION:
ClinicalTrials.gov, http://www.clinicaltrials.gov date of registration: April 9, 2019, NCT03911570. The

present trial was retrospectively registered.
KEYWORDS:
Crystalline glucosamine sulfate; Hand osteoarthritis; Pain; Retrospective study; Symptomatic slow-acting
drugs for osteoarthritis
How to treat osteoarthritis in obese patients?

Conrozier T. Curr Rheumatol Rev. 2019 Jun 24. doi:
Abstract
The close association between osteoarthritis (OA) and obesity is well established. The concomitant
increasing prevalence of the two diseases has major health, social and economic consequences.
However, to date there is no specific recommendation for the medical management of obese patients
with OA. Current recommendations only specify that obese patients must lose weight and practice
regular physical activity in addition to the usual care. OA symptoms improvement is clinically relevant
from a weight loss > 5% of the body weight. Weight loss improves not only OA symptoms but also
metabolic abnormalities and cardiovascular risk factors commonly altered in subjects with obesity. In
case of morbid obesity, bariatric surgery may be the only one alternative for pain relief. non-steroidal
anti-inflammatory drugs and corticosteroids must be avoided in patients with metabolic syndrome. In
such patients symptomatic slow acting drugs for OA (i.e. glucosamine, chondroitin...) and some anti-
oxidant drugs (i.e. curcumin...) may be helpful thanks to their excellent benefit/risk ratio and their mode
of action which may have a positive impact on both OA and metabolic disorders. Patients and physicians
should know that intra-articular treatments for OA (corticosteroids and hyaluronic acid) have a lower
success rate in obese patients than in patients with normal BMI. Spa therapy contributes to relief pain,
favour weight-loss and reduce metabolic abnormalities with a favourable risk/benefit balance.
KEYWORDS:
234
SYSADOA; anti-oxidant; bariatric surgery; body mass index; knee; metabolic syndrome spa; obesity;
osteoarthritis; weight-loss

10.1007/s11926-018-0782-9.
Abstract
PURPOSE OF REVIEW:
RECENT FINDINGS:
KEYWORDS:

Abstract
235
OBJECTIVE:
METHODS:
RESULTS:
CONCLUSIONS:
KEYWORDS:
Avocado/Soybean Unsaponifiables, Glucosamine and Chondroitin Sulfate

Combination Inhibits Proinflammatory COX-2 Expression and Prostaglandin
E2 Production in Tendon-Derived Cells.
Grzanna MW, Au RY, Au AY, Rashmir AM, Frondoza CG. J Med Food. 2019 Sep 5.
doi: 10.1089/jmf.2019.0022. [Epub ahead of print]
236
Abstract
Tendinopathy, a common disorder in man and horses, is characterized by pain, dysfunction, and tendon
degeneration. Inflammation plays a key role in the pathogenesis of tendinopathy. Tendon cells produce
proinflammatory molecules that induce pain and tissue deterioration. Currently used nonsteroidal anti-
inflammatory drugs are palliative but have been associated with adverse side effects prompting the
search for safe, alternative compounds. This study determined whether tendon-derived cells' expression
of proinflammatory cyclooxygenase (COX)-2 and production of prostaglandin E2 (PGE2) could be
attenuated by the combination of avocado/soybean unsaponifiables (ASU), glucosamine (GLU), and
chondroitin sulfate (CS). ASU, GLU, and CS have been used in the management of osteoarthritis-
associated joint inflammation. Tenocytes in monolayer and microcarrier spinner cultures were
incubated with media alone, or with the combination of ASU (8.3 μg/mL), GLU (11 μg/mL), and CS
(20 μg/mL). Cultures were next incubated with media alone, or stimulated with interleukin-1β (IL-1β;
10 ng/mL) for 1 h to measure COX-2 gene expression, or for 24 h to measure PGE2 production,
respectively. Tenocyte phenotype was analyzed by phase-contrast microscopy, immunocytochemistry,
and Western blotting. Tendon-derived cells proliferated and produced extracellular matrix component
type I collagen in monolayer and microcarrier spinner cultures. IL-1β-induced COX-2 gene expression
and PGE2 production were significantly reduced by the combination of (ASU+GLU+CS). The suppression
of IL-1β-induced inflammatory response suggests that (ASU+GLU+CS) may help attenuate deleterious
inflammation in tendons.
Predictive modeling of therapeutic response to chondroitin

sulfate/glucosamine hydrochloride in knee osteoarthritis.
Blanco FJ, et al. Ther Adv Chronic Dis. 2019 Aug 24;10:2040622319870013. doi:
10.1177/2040622319870013. eCollection 2019.
Abstract
Background:
In the present study, we explored potential protein biomarkers useful to predict the therapeutic
response of knee osteoarthritis (KOA) patients treated with pharmaceutical grade Chondroitin
sulfate/Glucosamine hydrochloride (CS+GH; Droglican, Bioiberica), in order to optimize therapeutic
outcomes.
Methods:
A shotgun proteomic analysis by iTRAQ labelling and liquid chromatography-mass spectrometry (LC-
MS/MS) was performed using sera from 40 patients enrolled in the Multicentre Osteoarthritis
237
interVEntion trial with Sysadoa (MOVES). The panel of proteins potentially useful to predict KOA
patient's response was clinically validated in the whole MOVES cohort at baseline (n = 506) using
commercially available enzyme-linked immunosorbent assays kits. Logistic regression models and
receiver-operating-characteristics (ROC) curves were used to analyze the contribution of these proteins
to our prediction models of symptomatic drug response in KOA.
Results:
In the discovery phase of the study, a panel of six putative predictive biomarkers of response to CS+GH
(APOA2, APOA4, APOH, ITIH1, C4BPa and ORM2) were identified by shotgun proteomics. Data are
available via ProteomeXchange with identifier PXD012444. In the verification phase, the panel was
verified in a larger set of KOA patients (n = 262). Finally, ITIH1 and ORM2 were qualified by a blind test in
the whole MOVES cohort at baseline. The combination of these biomarkers with clinical variables
predict the patients' response to CS+GH with a specificity of 79.5% and a sensitivity of 77.1%.
Conclusions:
Combining clinical and analytical parameters, we identified one biomarker that could accurately predict
KOA patients' response to CS+GH treatment. Its use would allow an increase in response rates and
safety for the patients suffering KOA.
KEYWORDS:
chondroitin sulfate/glucosamine hydrochloride; knee osteoarthritis; predictive biomarkers; proteomics

Abstract
OBJECTIVE:
METHODS:
238
RESULTS:
CONCLUSION:
What is the current status of chondroitin sulfate and glucosamine for the
treatment of knee osteoarthritis?
Henrotin Y, Marty M, Mobasheri A. Maturitas. 2014 Jul;78(3):184-7. doi:
10.1016/j.maturitas.2014.04.015. Epub 2014 May 1.
Abstract
Chondroitin sulfate and glucosamine sulfate exert beneficial effects on the metabolism of in vitro
models of cells derived from synovial joints: chondrocytes, synoviocytes and cells from subchondral
bone, all of which are involved in osteoarthritis (OA). They increase type II collagen and proteoglycan
synthesis in human articular chondrocytes and are able to reduce the production of some pro-
inflammatory mediators and proteases, to reduce the cellular death process, and improve the
anabolic/catabolic balance of the extracellular cartilage matrix (ECM). Clinical trials have reported a
beneficial effect of chondroitin sulfate and glucosamine sulfate on pain and function. The structure-
modifying effects of these compounds have been reported and analyzed in recent meta-analyses. The
results for knee OA demonstrate a small but significant reduction in the rate of joint space narrowing.
Chondroitin sulfate and glucosamine sulphate are recommended by several guidelines from
international societies for the management of knee and hip OA, while others do not recommend these
products or recommend only under condition. This comprehensive review clarifies the role of these
compounds in the therapeutic arsenal for patients with knee OA.
KEYWORDS:
239
Cartilage; Chondroitin; Glucosamine; Osteoarthritis
Chondroitin Sulfate and Glucosamine as Disease Modifying Anti-

Osteoarthritis Drugs (DMOADs).
Mantovani V, Maccari F, Volpi N. Curr Med Chem. 2016;23(11):1139-51.
Abstract
Osteoarthritis is a disabling affliction expected to increase in the coming decades, and disease-
modifying osteoarthritis drugs (DMOADs) would be highly desirable adjuncts to symptomatic relief and
structure reconstruction as they may delay the disease process. Chondroitin sulfate and glucosamine
have been observed to exert beneficial effects on the metabolism of various cells involved in
osteoarthritis as well as in animal models and clinical trials. Clinical trials have reported beneficial effects
of both these biological agents, alone or in combination, on pain and functions as well as their structure-
modifying capacity reported and analyzed in recent meta-analyses. Nonetheless, the effectiveness of
these bioactive (macro)molecules as DMOADs reported from randomized trials is mismatched. Current
studies with varying levels of evidence suggest that chondroitin sulfate and glucosamine can modify the
disease progression but at the same time there are not absolute certainties on their efficacy in
modifying the course of the disease. This comprehensive review aims to clarify the role of these
compounds in the therapeutic molecules/ drugs useful to patients affected by osteoarthritis.

10.1177/0394632015622215. Epub 2015 Dec 18.
Abstract
240
KEYWORDS:

Abstract
BACKGROUND:
METHODS:
241
RESULTS:
interaction effect P = 0.027; stiffness score, ↓30% versus ↓12%, respecsvely, interacson effect
CONCLUSIONS:

Indones. 2017 Apr;49(2):105-111.
Abstract
BACKGROUND:

242

METHODS:
a double blind, randomized controlled clinical trial was conducted on 147 patients with knee OA
treatment.
RESULTS:
on statistical analysis it was found that at the 12th week, there are significant difference between three
(p<0.001).
CONCLUSION:
combination of glucosamine-chondroitinsulfate-methylsulfonylmethane showed clinical benefit for

KEYWORDS:
Nutrition, osteoarthritis and cartilage metabolism.

Messina OD, Vidal Wilman M, Vidal Neira LF. Aging Clin Exp Res. 2019
Jun;31(6):807-813. doi: 10.1007/s40520-019-01191-w. Epub 2019 Apr 13.
Abstract
243
BACKGROUND:
Osteoarthritis (OA) is a degenerative joint disease and a leading cause of adult disability. There is no
cure for OA and there is no effective treatment to stop its progression. Current pharmacologic
treatments such as analgesics and non-steroidal anti-inflammatory drugs may improve the pain and
offer some relief but they do not affect the progression of the disease. The chronic intake of these drugs
may result in severe adverse events. The aim of this review is to revise the effects of nutrition on
cartilage metabolism and OA progression.
METHODS:
A systematic literature search was performed including those related to macro- and micro-nutrients'
actions on cartilage and OA outcome. We selected peer-reviewed articles reporting the results of human
clinical trials.
RESULTS:
Glucosamine and chondroitin sulfate have shown to delay OA knee progression in several clinical trials.
The effectiveness of some products considered nutraceuticals has been widely reviewed in the
literature. This article presents a general description of the effectiveness and mechanism of action of
nutrients, vitamins, antioxidants and other natural components considered as part of the normal diet.
Many in vitro studies indicate the efficacy of specific nutrients in cartilage metabolism and its
involvement in OA. However, rigorous clinical studies needed to evaluate the efficacy of these
compounds in humans are still missing. The influence of nutrients and diet on the metabolism of
cartilage and OA could represent a long-term coadjuvant alternative in the management of patients with
OA. Effects of diet modifications on lipid and cholesterol profiles, adequate vitamin levels and weight
reduction in obese patients could influence the course of the disease.
CONCLUSION:
This review demonstrates that nutrition can improve the symptoms of OA. Glucosamine and chondroitin
sulfate have shown robustly to delay the progression of knee OA in several well-designed studies,
however more controlled clinical trials are needed to conclude that nutritional changes slow down the
progression of the disease.
KEYWORDS:
Cartilage; Cartilage metabolism; Nutrition; Osteoarthritis

244
Glutathione
Glutathione and glutathione analogues; therapeutic potentials.
Wu JH, Batist G . Biochim Biophys Acta. 2013 May;1830(5):3350-3. doi:

10.1016/j.bbagen.2012.11.016. Epub 2012 Nov 28.
Abstract
BACKGROUND:
Glutathione (GSH) and related enzymes are critical to cell protection from toxins, both endogenous and
environmental, including a number of anti-cancer cytotoxic agents.
SCOPE OF REVIEW:
Enhancing GSH and associated enzymes represents a longtime and persistent aim in the search for
cytoprotective strategies against cancer, neurologic degeneration, pulmonary and inflammatory
conditions, as well as cardiovascular ailments. The challenge is to identify effective GSH analogues or
precursors that generate mimic molecules with glutathione's cellular protective effects. This review will
provide an update on these efforts. Much effort has also been directed at depleting cellular GSH and
related cytoprotective effects, in order to sensitize established tumors to the cytotoxic effects of anti-
cancer agents. Efforts to deplete GSH have been limited by the challenge of selectivity doing so in tumor
and not in normal tissue so as to avoid enhancing the toxicity of anti-cancer drugs. This review will also
provide an update of efforts at overcoming the challenge of targeting the desired GSH depletion to
tumor cells.
MAJOR CONCLUSIONS:
This chapter provides a brief background and update of progress in the development and use of GSH
analogues in the therapeutic setting, including the pharmacological aspects of these compounds.
GENERAL SIGNIFICANCE:
245
This is an area of enormous research activity, and major advances promise the advent of novel
therapeutic opportunities in the near future. This article is part of a Special Issue entitled Cellular
functions of glutathione.
Copyright © 2012 Elsevier B.V. All rights reserved.
Glutathione and infection.

Morris D, et al. Biochim Biophys Acta. 2013 May;1830(5):3329-49. doi:
10.1016/j.bbagen.2012.10.012. Epub 2012 Oct 23.
Abstract
BACKGROUND:
The tripeptide γ-glutamylcysteinylglycine or glutathione (GSH) has demonstrated protective abilities

against the detrimental effects of oxidative stress within the human body, as well as protection against
infection by exogenous microbial organisms.
SCOPE OF REVIEW:
In this review we describe how GSH works to modulate the behavior of many cells including the cells of
the immune system, augmenting the innate and the adaptive immunity as well as conferring protection
against microbial, viral and parasitic infections. This article unveils the direct antimicrobial effects of GSH
in controlling Mycobacterium tuberculosis (M. tb) infection within macrophages. In addition, we
summarize the effects of GSH in enhancing the functional activity of various immune cells such as
natural killer (NK) cells and T cells resulting in inhibition in the growth of M. tb inside monocytes and
macrophages. Most importantly we correlate the decreased GSH levels previously observed in
individuals with pulmonary tuberculosis (TB) with an increase in the levels of pro-inflammatory
cytokines which aid in the growth of M. tb.
MAJOR CONCLUSIONS:
In conclusion, this review provides detailed information on the protective integral effects of GSH along
with its therapeutic effects as they relate to the human immune system and health.
246
GENERAL SIGNIFICANCE:
It is important to note that the increases in the levels of pro-inflammatory cytokines are not only
detrimental to the host due to the sequel that follow such as fever and cachexia, but also due to the
alteration in the functions of immune cells. The additional protective effects of GSH are evident after
sequel that follows the depletion of this antioxidant. This is evident in a condition such as Cystic Fibrosis
(CF) where an increased oxidant burden inhibits the clearance of the affecting organism and results in
oxidant-induced anti-protease inhibition. GSH has a similar protective effect in protozoans as it does in
human cells. Thus GSH is integral to the survival of some of the protozoans because some protozoans
utilize the compound trypanothione [T(SH)2] as their main antioxidant. T(SH)2 in turn requires GSH for
its production. Hence a decrease in the levels of GSH (by a known inhibitor such as buthionine
sulfoximine [BSO] can have adverse effects of the protozoan parasites. This article is part of a Special
Issue entitled Cellular functions of glutathione.
Glutathione and adaptive immune responses against Mycobacterium

tuberculosis infection in healthy and HIV infected individuals.
Guerra C, et al. PLoS One. 2011;6(12):e28378. doi: 0.1371/journal.pone.0028378.
Epub 2011 Dec 2.
Abstract
Glutathione (GSH), a tripeptide antioxidant, is essential for cellular homeostasis and plays a vital role in
diverse cellular functions. Individuals who are infected with Human immuno deficiency virus (HIV) are
known to be susceptible to Mycobacterium tuberculosis (M. tb) infection. We report that by enhancing
GSH levels, T-cells are able to inhibit the growth of M. tb inside macrophages. In addition, those GSH-
replenished T cell cultures produced increased levels of Interleukin-2 (IL-2), Interleukin-12 (IL-12), and
Interferon-gamma (IFN-γ), cytokines, which are known to be crucial for the control of intracellular
pathogens. Our study reveals that T lymphocytes that are derived from HIV infected individuals are
deficient in GSH, and that this deficiency correlates with decreased levels of Th1 cytokines and
enhanced growth of M. tb inside human macrophages.
247
Liposomal Glutathione Supplementation Restores TH1 Cytokine Response to

Mycobacterium tuberculosis Infection in HIV-Infected Individuals.
Ly J, et al. J Interferon Cytokine Res. 2015 Nov;35(11):875-87. doi:
10.1089/jir.2014.0210. Epub 2015 Jul 2.
Abstract
Cytokines are signaling biomolecules that serve as key regulators of our immune system. CD4(+) T-cells
can be grouped into 2 major categories based on their cytokine profile: T-helper 1 (TH1) subset and T-
helper 2 (TH2) subset. Protective immunity against HIV infection requires TH1-directed CD4 T-cell
responses, mediated by cytokines, such as interleukin-1β (IL-1β), IL-12, interferon-γ (IFN-γ), and tumor
necrosis factor-α (TNF-α). Cytokines released by the TH1 subset of CD4 T-cells are considered important
for mediating effective immune responses against intracellular pathogens such as Mycobacterium
tuberculosis (M. tb). Oxidative stress and redox imbalance that occur during HIV infection often lead to
inappropriate immune responses. Glutathione (GSH) is an antioxidant present in nearly all cells and is
recognized for its function in maintaining redox homeostasis. Our laboratory previously reported that
individuals with HIV infection have lower levels of GSH. In this study, we report a link between lower
levels of GSH and dysregulation of TH1- and TH2-associated cytokines in the plasma samples of HIV-
positive subjects. Furthermore, we demonstrate that supplementing individuals with HIV infection for
13 weeks with liposomal GSH (lGSH) resulted in a significant increase in the levels of TH1 cytokines, IL-
1β, IL-12, IFN-γ, and TNF-α. lGSH supplementation in individuals with HIV infection also resulted in a
substantial decrease in the levels of free radicals and immunosuppressive cytokines, IL-10 and TGF-β,
relative to those in a placebo-controlled cohort. Finally, we determined the effects of lGSH
supplementation in improving the functions of immune cells to control M. tb infection by conducting in
vitro assays using peripheral blood mononuclear cells collected from HIV-positive individuals at post-
GSH supplementation. Our studies establish a correlation between low levels of GSH and increased
susceptibility to M. tb infection through TH2-directed response, which may be relieved with lGSH
supplementation enhancing the TH1 response.
Demonstration of the Antioxidant Capabilities of a Product Formulated With

Antioxidants Stabilized in Their Reduced Form
Draelos ZD, Pachuk CJ. J Drugs Dermatol. 2020 Jan 1;19(1):46-49. doi:
10.36849/JDD.2020.3947.
Abstract
Oxidative damage from reactive oxygen species is instrumental in aging. Topical antioxidants are used in
many cosmeceuticals to provide appearance benefits; however, the activity of these antioxidants may
248
be questionable. This research validated the activity of L-ascorbic acid and L-glutathione in the studied
facial product and correlated this activity with clinical appearance improvement following 12 weeks of
use.
Glutathione Benefits
Whelan, Corey. Reviewed by Wilson, Debra Rose, PhD, MSN, RN, IBCLC, AHN-BC,
CHT. Healthline. November 21, 2017.
https://www.healthline.com/health/glutathione-benefits
Overview
Glutathione is an antioxidant produced in cells. It’s comprised largely of three amino acids: glutamine,
glycine, and cysteine.
Glutathione levels in the body may be reduced by a number of factors, including poor nutrition,
environmental toxins, and stress. Its levels also decline with age.
In addition to being produced naturally by the body, glutathione can be given intravenously, topically, or
as an inhalant. It’s also available as an oral supplement in capsule and liquid form. However, oral
ingestion of glutathione may not be as effectiveTrusted Source as intravenous delivery for some
conditions.
Takeaway
Glutathione is a powerful antioxidant that’s made in the body’s cells. Its levels decrease as a result of
aging, stress, and toxin exposure. Boosting glutathione may provide many health benefits, including
reduction of oxidative stress.
What are the benefits of glutathione?

Galen, Nicole. Reviewed by Alan Carter, Pharm.D. Medical News Today. December
10, 2018
https://www.medicalnewstoday.com/articles/323936.php
Glutathione is a powerful antioxidant found in every cell in the body. It is made of three types of
molecules known as amino acids.
Amino acids combine in different patterns to make all of the proteins in the body.
One unique thing about glutathione is that the body is able to make it in the liver, which is not true of
most antioxidants.
249
Glutathione has many important functions, including:
• making DNA, the building blocks of proteins and cells

• supporting immune function
• forming sperm cells
• breaking down some free radicals
• helping certain enzymes function
• regenerating vitamins C and E
• transporting mercury out of the brain
• helping the liver and gallbladder deal with fats
• assisting regular cell death (a process known as apoptosis)
Researchers have found links between low levels of glutathione and some diseases. It is possible to
increase glutathione levels through oral or intravenous (IV) supplementation.
What Is Glutathione? A Detailed Guide to the Antioxidant and Supplement

Sheryl Huggins Salomon. Medically Reviewed by Kelly Kennedy, RD. Everyday
Health. January 4, 2019.
https://www.everydayhealth.com/diet-nutrition/diet/glutathione-definition-uses-benefits-more/
Glutathione (gloo-tah-thy-ohn) is an amino acid compound that is naturally present in cells throughout
the body. (1) Cysteine, glutamic acid, and glycine are the three amino acids that make it up. Glutathione
acts as an antioxidant, preventing and delaying cell damage; as well as to detoxify chemicals within the
liver, according to the U.S. National Library of Medicine. (1) It is also important to immune system health
and the regulation of cell growth and death, per an article published in May 2013 in the journal
Biochimica et Biophysica Acta. (2) Furthermore, the amino acid compound has the ability to bind itself to
drugs, notes the National Center for Biotechnology Information, to make them easier for the body to
excrete. (3) But levels of glutathione in the body appear to decrease with age, experts say.
Without a doubt, the biggest health benefits of glutathione are the result of its antioxidant properties.
Oxidative stress, which occurs when the balance of free radicals and antioxidants skews in favor of free
radicals, can result in cell damage, according to the National Cancer Institute. (4) Research shows this
process is linked to cancer, autoimmune disorders, cataracts, rheumatoid arthritis, cardiovascular and
neurodegenerative diseases, and accelerated aging itself.
250
Hemp Extract with CBD

evidence.
10.1515/revneuro-2018-0097.
Abstract
KEYWORDS:

Current Knowledge.
10.2174/1389200218666170710190249.
251
Abstract
BACKGROUND:
METHOD:
CONCLUSION:
KEYWORDS:
Clinicians' Guide to Cannabidiol and Hemp Oils.

VanDolah HJ, Bauer BA2 Mauck KF. Mayo Clin Proc. 2019 Sep;94(9):1840-1851.
doi: 10.1016/j.mayocp.2019.01.003. Epub 2019 Aug 22.
252
Abstract
Cannabidiol (CBD) oils are low tetrahydrocannabinol products derived from Cannabis sativa that have
become very popular over the past few years. Patients report relief for a variety of conditions,
particularly pain, without the intoxicating adverse effects of medical marijuana. In June 2018, the first
CBD-based drug, Epidiolex, was approved by the US Food and Drug Administration for treatment of rare,
severe epilepsy, further putting the spotlight on CBD and hemp oils. There is a growing body of
preclinical and clinical evidence to support use of CBD oils for many conditions, suggesting its potential
role as another option for treating challenging chronic pain or opioid addiction. Care must be taken
when directing patients toward CBD products because there is little regulation, and studies have found
inaccurate labeling of CBD and tetrahydrocannabinol quantities. This article provides an overview of the
scientific work on cannabinoids, CBD, and hemp oil and the distinction between marijuana, hemp, and
the different components of CBD and hemp oil products. We summarize the current legal status of CBD
and hemp oils in the United States and provide a guide to identifying higher-quality products so that
clinicians can advise their patients on the safest and most evidence-based formulations. This review is
based on a PubMed search using the terms CBD, cannabidiol, hemp oil, and medical marijuana. Articles
were screened for relevance, and those with the most up-to-date information were selected for
inclusion.
A selective review of medical cannabis in cancer pain management.

Blake A, et al. Ann Palliat Med. 2017 Dec;6(Suppl 2):S215-S222. doi:
10.21037/apm.2017.08.05. Epub 2017 Aug 23.
Abstract
Insufficient management of cancer-associated chronic and neuropathic pain adversely affects patient
quality of life. Patients who do not respond well to opioid analgesics, or have severe side effects from
the use of traditional analgesics are in need of alternative therapeutic op-tions. Anecdotal evidence
suggests that medical cannabis has potential to effectively manage pain in this patient population. This
review presents a selection of representative clinical studies, from small pilot studies conducted in 1975,
to double-blind placebo-controlled trials conducted in 2014 that evaluated the efficacy of cannabinoid-
based therapies containing tetrahydrocannabinol (THC) and cannabidiol (CBD) for reducing cancer-
associated pain. A review of literature published on Medline between 1975 and 2017 identified five
clinical studies that evaluated the effect of THC or CBD on controlling cancer pain, which have been
reviewed and summarised. Five studies that evaluated THC oil capsules, THC:CBD oromucosal spray
(nabiximols), or THC oromucosal sprays found some evidence of cancer pain reduction associated with
these therapies. A variety of doses ranging from 2.7-43.2 mg/day THC and 0-40 mg/day CBD were
administered. Higher doses of THC were correlated with increased pain relief in some studies. One study
found that significant pain relief was achieved in doses as low as 2.7-10.8 mg THC in combination with
253
2.5-10.0 mg CBD, but there was conflicting evidence on whether higher doses provide superior pain
relief. Some reported side effects include drowsiness, hypotension, mental clouding, and nausea and
vomiting. There is evidence suggesting that medical cannabis reduces chronic or neu-ropathic pain in
advanced cancer patients. However, the results of many studies lacked statistical power, in some cases
due to limited number of study subjects. Therefore, there is a need for the conduct of further double-
blind, placebo-controlled clinical trials with large sample sizes in order to establish the optimal dosage
and efficacy of different cannabis-based therapies.
KEYWORDS:
Medical cannabis; cancer; pain
Topical Medical Cannabis: A New Treatment for Wound Pain-Three Cases of

Pyoderma Gangrenosum.
Maida V, Corban J. J Pain Symptom Manage. 2017 Nov;54(5):732-736. doi:
10.1016/j.jpainsymman.2017.06.005. Epub 2017 Aug 14.
Abstract
Pain associated with integumentary wounds is highly prevalent, yet it remains an area of significant
unmet need within health care. Currently, systemically administered opioids are the mainstay of
treatment. However, recent publications are casting opioids in a negative light given their high side
effect profile, inhibition of wound healing, and association with accidental overdose, incidents that are
frequently fatal. Thus, novel analgesic strategies for wound-related pain need to be investigated. The
ideal methods of pain relief for wound patients are modalities that are topical, lack systemic side effects,
noninvasive, self-administered, and display rapid onset of analgesia. Extracts derived from the cannabis
plant have been applied to wounds for thousands of years. The discovery of the human
endocannabinoid system and its dominant presence throughout the integumentary system provides a
valid and logical scientific platform to consider the use of topical cannabinoids for wounds. We are
reporting a prospective case series of three patients with pyoderma gangrenosum that were treated
with topical medical cannabis compounded in nongenetically modified organic sunflower oil. Clinically
significant analgesia that was associated with reduced opioid utilization was noted in all three cases.
Topical medical cannabis has the potential to improve pain management in patients suffering from
wounds of all classes.
KEYWORDS:
CBD; THC; Topical medical cannabis; endocannabinoid system; medical cannabis oil; opioid-sparing
analgesia; pyoderma gangrenosum; volitional incident pain; wound-related pain
254
Cannabidiol: promise and pitfalls.

Welty TE, Luebke A, Gidal BE. Epilepsy Curr. 2014 Sep;14(5):250-2. doi:
10.5698/1535-7597-14.5.250.
Abstract
Over the past few years, increasing public and political pressure has supported legalization of medical
marijuana. One of the main thrusts in this effort has related to the treatment of refractory epilepsy-
especially in children with Dravet syndrome-using cannabidiol (CBD). Despite initiatives in numerous
states to at least legalize possession of CBD oil for treating epilepsy, little published evidence is available
to prove or disprove the efficacy and safety of CBD in patients with epilepsy. This review highlights some
of the basic science theory behind the use of CBD, summarizes published data on clinical use of CBD for
epilepsy, and highlights issues related to the use of currently available CBD products. Cannabidiol is the
major nonpsychoactive component of Cannabis sativa. Over the centuries, a number of medicinal
preparations derived from C. sativa have been employed for a variety of disorders, including gout,
rheumatism, malaria, pain, and fever. These preparations were widely employed as analgesics by
Western medical practitioners in the 19(th) century (1). More recently, there is clinical evidence
suggesting efficacy in HIV-associated neuropathic pain, as well as spasms associated with multiple
sclerosis (1).
Plant-derived cannabinoids modulate the activity of transient receptor

potential channels of ankyrin type-1 and melastatin type-8.
De Petrocellis L, et al. J Pharmacol Exp Ther. 2008 Jun;325(3):1007-15. doi:
10.1124/jpet.107.134809. Epub 2008 Mar 19.
Abstract
The plant cannabinoids (phytocannabinoids), cannabidiol (CBD), and Delta(9)-tetrahydrocannabinol

(THC) were previously shown to activate transient receptor potential channels of both vanilloid type 1
(TRPV1) and ankyrin type 1 (TRPA1), respectively. Furthermore, the endocannabinoid anandamide is
known to activate TRPV1 and was recently found to antagonize the menthol- and icilin-sensitive
transient receptor potential channels of melastatin type 8 (TRPM8). In this study, we investigated the
effects of six phytocannabinoids [i.e., CBD, THC, CBD acid, THC acid, cannabichromene (CBC), and
cannabigerol (CBG)] on TRPA1- and TRPM8-mediated increase in intracellular Ca2+ in either HEK-293
cells overexpressing the two channels or rat dorsal root ganglia (DRG) sensory neurons. All of the
compounds tested induced TRPA1-mediated Ca2+ elevation in HEK-293 cells with efficacy comparable
with that of mustard oil isothiocyanates (MO), the most potent being CBC (EC(50) = 60 nM) and the least
potent being CBG and CBD acid (EC(50) = 3.4-12.0 microM). CBC also activated MO-sensitive DRG
255
neurons, although with lower potency (EC(50) = 34.3 microM). Furthermore, although none of the
compounds tested activated TRPM8-mediated Ca2+ elevation in HEK-293 cells, they all, with the
exception of CBC, antagonized this response when it was induced by either menthol or icilin. CBD, CBG,
THC, and THC acid were equipotent (IC(50) = 70-160 nM), whereas CBD acid was the least potent
compound (IC(50) = 0.9-1.6 microM). CBG inhibited Ca2+ elevation also in icilin-sensitive DRG neurons
with potency (IC(50) = 4.5 microM) similar to that of anandamide (IC(50) = 10 microM). Our findings
suggest that phytocannabinoids and cannabis extracts exert some of their pharmacological actions also
by interacting with TRPA1 and TRPM8 channels, with potential implications for the treatment of pain
and cancer.
The marijuana component cannabidiol inhibits beta-amyloid-induced tau

protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in
PC12 cells.
Esposito G1 De Filippis D, Carnuccio R, Izzo AA, Iuvone T. J Mol Med (Berl). 2006
Mar;84(3):253-8. Epub 2005 Dec 31.
Abstract
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. A massive
accumulation of beta-amyloid (Abeta) peptide aggregates has been proposed as pivotal event in AD.
Abeta-induced toxicity is accompanied by a variegated combination of events including oxidative stress.
The Wnt pathway has multiple actions in the cascade of events triggered by Abeta, and drugs that
rescue Wnt activity may be considered as novel therapeutics for AD treatment. Cannabidiol, a non-
psychoactive marijuana component, has been recently proposed as an antioxidant neuroprotective
agent in neurodegenerative diseases. Moreover, it has been shown to rescue PC12 cells from toxicity
induced by Abeta peptide. However, the molecular mechanism of cannabidiol-induced neuroprotective
effect is still unknown. Here, we report that cannabidiol inhibits hyperphosphorylation of tau protein in
Abeta-stimulated PC12 neuronal cells, which is one of the most representative hallmarks in AD. The
effect of cannabidiol is mediated through the Wnt/beta-catenin pathway rescue in Abeta-stimulated
PC12 cells. These results provide new molecular insight regarding the neuroprotective effect of
cannabidiol and suggest its possible role in the pharmacological management of AD, especially in view of
its low toxicity in humans.
7 Benefits and Uses of CBD Oil (Plus Side Effects)

Written by Jillian Kubala, MS, RD on February 26, 2018. Healthline.com.
https://www.healthline.com/nutrition/cbd-oil-benefits
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Cannabidiol is a popular natural remedy used for many common ailments.
Better known as CBD, it is one of over 100 chemical compounds known as cannabinoids found in the
cannabis or marijuana plant, Cannabis sativa .
Tetrahydrocannabinol (THC) is the main psychoactive cannabinoid found in cannabis, and causes the
sensation of getting “high” that’s often associated with marijuana. However, unlike THC, CBD is not
psychoactive.
This quality makes CBD an appealing option for those who are looking for relief from pain and other
symptoms without the mind-altering effects of marijuana or certain pharmaceutical drugs.
CBD oil is made by extracting CBD from the cannabis plant, then diluting it with a carrier oil like coconut
or hemp seed oil.
It’s gaining momentum in the health and wellness world, with some scientific studies confirming it may
ease symptoms of ailments like chronic pain and anxiety.
Endocannabinoid system: An overview of its potential in current medical

practice.
Mouslech Z1, Valla V. Neuro Endocrinol Lett. 2009;30(2):153-79.
Abstract
The endocannabinoid system (ECS) is a lipid signalling system, comprising of the endogenous cannabis-
like ligands (endocannabinoids) anandamide (AEA) and 2-arachidonoylglycerol (2-AG), which derive from
arachidonic acid. These bind to a family of G-protein-coupled receptors, called CB1 and CB2. The
cannabinoid receptor 1 (CB1R) is distributed in brain areas associated with motor control, emotional
responses, motivated behaviour and energy homeostasis. In the periphery, the same receptor is
expressed in the adipose tissue, pancreas, liver, GI tract, skeletal muscles, heart and the reproduction
system. The CB2R is mainly expressed in the immune system regulating its functions. Endocannabinoids
are synthesized and released upon demand in a receptor-dependent way. They act as retrograde
signalling messengers in GABAergic and glutamatergic synapses and as modulators of postsynaptic
transmission, interacting with other neurotransmitters. Endocannabinoids are transported into cells by a
specific uptake system and degraded by the enzymes fatty acid amide hydrolase (FAAH) and
monoacylglycerol lipase (MAGL). The ECS is involved in various pathophysiological conditions in central
and peripheral tissues. It is implicated in the hormonal regulation of food intake, cardiovascular,
gastrointestinal, immune, behavioral, antiproliferative and mammalian reproduction functions. Recent
advances have correlated the ECS with drug addiction and alcoholism. The growing number of
preclinical and clinical data on ECS modulators is bound to result in novel therapeutic approaches for a
number of diseases currently treated inadequately. The ECS dysregulation has been correlated to
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obesity and metabolic syndrome pathogenesis. Rimonabant is the first CB1 blocker launched to treat
cardiometabolic risk factors in obese and overweight patients. Phase III clinical trials showed the drug's
ability to regulate intra-abdominal fat tissue levels, lipidemic, glycemic and inflammatory parameters.
However, safety conerns have led to its withrawal. The role of endocannabinoids in mammalian
reproduction is an emerging research area given their implication in fertilization, preimplantation
embryo and spermatogenesis. The relevant preclinical data on endocannabinoid signalling open up new
perspectives as a target to improve infertility and reproductive health in humans.
Pharmacotherapeutic considerations for use of cannabinoids to relieve pain

in patients with malignant diseases
Marija Darkovska-Serafimovska, et al. J Pain Res. 2018; 11: 837–842. Published
online 2018 Apr 23. doi: 10.2147/JPR.S160556.
Abstract
Purpose
The aim of this review was to assess the efficacy of cannabis preparations for relieving pain in patients
with malignant diseases, through a systematic review of randomized controlled trials (RCTs), which were
predominantly double-blind trials that compared cannabis preparation to a placebo.
Methods
An electronic search of all literature published until June 2017 was made in MEDLINE/PubMed, Embase,
The Cochrane Controlled Trials Register and specific web pages devoted to cannabis.
Results
Fifteen of the 18 trials demonstrated a significant analgesic effect of cannabinoids as compared to

placebo. The most commonly reported adverse effects were generally well tolerated, mild to moderate.
The main side effects were drowsiness, nausea, vomiting and dry mouth. There is evidence that
cannabinoids are safe and modestly effective in neuropathic pain and also for relieving pain in patients
with malignant diseases. The proportion of “responders” (patients who at the end of 2 weeks of
treatment reported ≥30% reduction in pain intensity on a scale of 0–10, which is considered to be
clinically important) was 43% in comparison with placebo (21%).
Conclusion
The target dose for relieving pain in patients with malignant diseases is most likely about 10 actuations
per day, which is about 27 mg tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD), and the highest
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approved recommended dose is 12 actuations per day (32 mg THC/30 mg CBD). Further large studies of
cannabinoids in homogeneous populations are required.
Keywords: cancer management, chronic pain, cannabidiol, tetrahydrocannabinol, medical marihuana,

nabiximols, cannabinoid receptors
An Update of Current Cannabis-Based Pharmaceuticals in Pain Medicine

Ivan Urits, et al. Pain Ther. 2019 Jun; 8(1): 41–51. Published online 2019 Feb 5.
doi: 10.1007/s40122-019-0114-4
Abstract
Cannabis users have long reported therapeutic properties of the plant for a variety of conditions, some
of which include nausea, emesis, seizures, cancer, neurogenic diseases and pain control. Research has
elucidated many cannabinoid pharmacodynamic and pharmacokinetic properties, expanding the
potential use of cannabinoids as a medical therapy. Due to the inconsistent delivery and control of the
active components involved with smoking, pharmaceutical companies are investigating and prioritizing
routes other than smoke inhalation for therapeutic use of cannabinoids. In this relatively new field of
pharmaceutical development, ongoing drug development promises great benefit from targeted
endocannabinoid receptor agonism. Available in Canada and Europe, nabiximols, a specific extract from
the Cannabis plant, has demonstrated great benefit in the treatment of pain related to spasticity in
multiple sclerosis, cancer and otherwise chronic pain conditions. The cannabidiol oral solution
Epidiolex®, which is available in the USA, is indicated for management of refractory epilepsy but may
offer therapeutic relief to chronic pain conditions as well. Current investigative drugs, such as those
developed by Cara Therapeutics and Zynerba Pharmaceuticals, are synthetic cannabinoids which show
promise to specifically target neuropsychiatric conditions and chronic pain symptoms such as
neuropathy and allodynia. The objective of this review is to provide clinicians with an update of
currently available and promising developmental cannabis pharmaceutical derivatives which may stand
to greatly benefit patients with otherwise difficult-to-treat chronic conditions.
Keywords: Cannabidiol, Cannabinoids, Epidiolex, Nabiximols, Tetrahydrocannabinol
Endocannabinoid System: A Multi-Facet Therapeutic Target.

Kaur R, Ambwani SR, Singh S. Curr Clin Pharmacol. 2016;11(2):110-7.
259
Abstract
Cannabis sativa is also popularly known as marijuana. It has been cultivated and used by man for
recreational and medicinal purposes since many centuries. Study of cannabinoids was at bay for very
long time and its therapeutic value could not be adequately harnessed due to its legal status as
proscribed drug in most of the countries. The research of drugs acting on endocannabinoid system has
seen many ups and downs in the recent past. Presently, it is known that endocannabinoids has role in
pathology of many disorders and they also serve "protective role" in many medical conditions. Several
diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia,
cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson's disease,
Huntington's disease, Alzheimer's disease and Tourette's syndrome could possibly be treated by drugs
modulating endocannabinoid system. Presently, cannabinoid receptor agonists like nabilone and
dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC
combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis.
In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under
investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a
promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect
profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale
was also suspended across the EU in 2008. Recent discontinuation of clinical trial related to FAAH
inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging
for the research fraternity. Despite some mishaps in clinical trials related to drugs acting on
endocannabinoid system, still lot of research is being carried out to explore and establish the
therapeutic targets for both cannabinoid receptor agonists and antagonists. One challenge is to develop
drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that act
selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development
of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.
Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2
receptor targets for cannabinoids. In order to successfully exploit the therapeutic potential of
endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms
of identification of the exact cellular location of cannabinoid receptors and their role as "protective" and
"disease inducing substance", time-dependent changes in the expression of cannabinoid receptors.
Cannabis and cannabinoids: pharmacology and rationale for clinical use.

Pertwee RG. Forsch Komplementarmed. 1999 Oct;6 Suppl 3:12-5.
Abstract
It is now known that there are at least two types of cannabinoid receptors. These are CB1 receptors,
present mainly on central and peripheral neurones, and CB2 receptors, present mainly on immune cells.
Endogenous cannabinoid receptor agonists ('endocannabinoids') have also been identified. The
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discovery of this 'endogenous cannabinoid system' has led to the development of selective CB1 and CB2
receptor ligands and fueled renewed interest in the clinical potential of cannabinoids. Two cannabinoid
CB1 receptor agonists are already used clinically, as antiemetics or as appetite stimulants. These are D 9
- tetrahydrocannabinol (THC) and nabilone. Other possible uses for CB1 receptor agonists include the
suppression of muscle spasm/spasticity associated with multiple sclerosis or spinal cord injury, the relief
of chronic pain and the management of glaucoma and bronchial asthma. CB1 receptor antagonists may
also have clinical applications, e. g. as appetite suppressants and in the management of schizophrenia or
disorders of cognition and memory. So too may CB2 receptor ligands and drugs that activate
cannabinoid receptors indirectly by augmenting endocannabinoid levels at cannabinoid receptors. When
taken orally, THC seems to undergo variable absorption and to have a narrow 'therapeutic window'
(dose range in which it is effective without producing significant unwanted effects). This makes it
difficult to predict an oral dose that will be both effective and tolerable to a patient and indicates a need
for better cannabinoid formulations and modes of administration. For the therapeutic potential of
cannabis or CB1 receptor agonists to be fully exploited, it will be important to establish objectively and
conclusively (a) whether these agents have efficacy against selected symptoms that is of clinical
significance and, if so, whether the benefits outweigh the risks, (b) whether cannabis has therapeutic
advantages over individual cannabinoids, (c) whether there is a need for additional drug treatments to
manage any of the disorders against which cannabinoids are effective, and (d) whether it will be possible
to develop drugs that have reduced psychotropic activity and yet retain the ability to act through CB1
receptors to produce their sought-after effects.
Cannabinoids.
Grotenhermen F. Curr Drug Targets CNS Neurol Disord. 2005 Oct;4(5):507-30.
Abstract
Since the discovery of an endogenous cannabinoid system, research into the pharmacology and
therapeutic potential of cannabinoids has steadily increased. Two subtypes of G-protein coupled
cannabinoid receptors, CB(1) and CB(1), have been cloned and several putative endogenous ligands
(endocannabinoids) have been detected during the past 15 years. The main endocannabinoids are
arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG), derivatives of arachidonic
acid, that are produced "on demand" by cleavage of membrane lipid precursors. Besides
phytocannabinoids of the cannabis plant, modulators of the cannabinoid system comprise synthetic
agonists and antagonists at the CB receptors and inhibitors of endocannabinoid degradation.
Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues,
including immune system, reproductive and gastrointestinal tracts, sympathetic ganglia, endocrine
glands, arteries, lung and heart. There is evidence for some non-receptor dependent mechanisms of
cannabinoids and for endocannabinoid effects mediated by vanilloid receptors. Properties of CB
receptor agonists that are of therapeutic interest include analgesia, muscle relaxation,
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immunosuppression, anti-inflammation, antiallergic effects, improvement of mood, stimulation of

appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and
antineoplastic effects. The current main focus of clinical research is their efficacy in chronic pain and
neurological disorders. CB receptor antagonists are under investigation for medical use in obesity and
nicotine addiction. Additional potential was proposed for the treatment of alcohol and heroine
dependency, schizophrenia, conditions with lowered blood pressure, Parkinson's disease and memory
impairment in Alzheimer's disease.
Randomized, controlled trial of cannabis-based medicine in central pain in

multiple sclerosis.
Rog DJ, Nurmikko TJ, Friede T, Young CA. Neurology. 2005 Sep 27;65(6):812-9.
Abstract
BACKGROUND:
Central pain in multiple sclerosis (MS) is common and often refractory to treatment.
METHODS:
We conducted a single-center, 5-week (1-week run-in, 4-week treatment), randomized, double-blind,

placebo-controlled, parallel-group trial in 66 patients with MS and central pain states (59 dysesthetic,
seven painful spasms) of a whole-plant cannabis-based medicine (CBM), containing delta-9-
tetrahydrocannabinol:cannabidiol (THC:CBD) delivered via an oromucosal spray, as adjunctive analgesic
treatment. Each spray delivered 2.7 mg of THC and 2.5 of CBD, and patients could gradually self-titrate
to a maximum of 48 sprays in 24 hours.
RESULTS:
Sixty-four patients (97%) completed the trial, 34 received CBM. In week 4, the mean number of daily
sprays taken of CBM (n = 32) was 9.6 (range 2 to 25, SD = 6.0) and of placebo (n = 31) was 19.1 (range 1
to 47, SD = 12.9). Pain and sleep disturbance were recorded daily on an 11-point numerical rating scale.
CBM was superior to placebo in reducing the mean intensity of pain (CBM mean change -2.7, 95% CI: -
3.4 to -2.0, placebo -1.4 95% CI: -2.0 to -0.8, comparison between groups, p = 0.005) and sleep
disturbance (CBM mean change -2.5, 95% CI: -3.4 to -1.7, placebo -0.8, 95% CI: -1.5 to -0.1, comparison
between groups, p = 0.003). CBM was generally well tolerated, although more patients on CBM than
placebo reported dizziness, dry mouth, and somnolence. Cognitive side effects were limited to long-
term memory storage.
CONCLUSIONS:
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Cannabis-based medicine is effective in reducing pain and sleep disturbance in patients with multiple
sclerosis related central neuropathic pain and is mostly well tolerated.
Preliminary assessment of the efficacy, tolerability and safety of a cannabis-

based medicine (Sativex) in the treatment of pain caused by rheumatoid
arthritis.
Blake DR, Robson P, Ho M, Jubb RW, McCabe CS. Rheumatology (Oxford). 2006
Jan;45(1):50-2. Epub 2005 Nov 9.
Abstract
OBJECTIVES:
To assess the efficacy of a cannabis-based medicine (CBM) in the treatment of pain due to rheumatoid
arthritis (RA).
METHODS:
We compared a CBM (Sativex) with placebo in a randomized, double-blind, parallel group study in 58
patients over 5 weeks of treatment. The CBM was administered by oromucosal spray in the evening and
assessments were made the following morning. Efficacy outcomes assessed were pain on movement,
pain at rest, morning stiffness and sleep quality measured by a numerical rating scale, the Short-Form
McGill Pain Questionnaire (SF-MPQ) and the DAS28 measure of disease activity.
RESULTS:
Seventy-five patients were screened and 58 met the eligibility criteria. Thirty-one were randomized to
the CBM and 27 to placebo. Mean (S.D.) daily dose achieved in the final treatment week was 5.4 (0.84)
actuations for the CBM and 5.3 (1.18) for placebo. In comparison with placebo, the CBM produced
statistically significant improvements in pain on movement, pain at rest, quality of sleep, DAS28 and the
SF-MPQ pain at present component. There was no effect on morning stiffness but baseline scores were
low. The large majority of adverse effects were mild or moderate, and there were no adverse effect-
related withdrawals or serious adverse effects in the active treatment group.
CONCLUSIONS:
In the first ever controlled trial of a CBM in RA, a significant analgesic effect was observed and disease
activity was significantly suppressed following Sativex treatment. Whilst the differences are small and
variable across the population, they represent benefits of clinical relevance and show the need for more
detailed investigation in this indication.
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Distinct interactions of cannabidiol and morphine in three nociceptive

behavioral models in mice.
Neelakantan H, et al. Behav Pharmacol. 2015 Apr;26(3):304-14. doi:
10.1097/FBP.0000000000000119.
Abstract
Cannabinoid and opioid agonists can display overlapping behavioral effects and the combination of
these agonists is known to produce enhanced antinociception in several rodent models of acute and
chronic pain. The present study investigated the antinociceptive effects of the nonpsychoactive
cannabinoid, cannabidiol (CBD) and the µ-opioid agonist morphine, both alone and in combination,
using three behavioral models in mice, to test the hypothesis that combinations of morphine and CBD
would produce synergistic effects. The effects of morphine, CBD, and morphine/CBD combinations were
assessed in the following assays: (a) acetic acid-stimulated stretching; (b) acetic acid-decreased operant
responding for palatable food; and (c) hot plate thermal nociception. Morphine alone produced
antinociceptive effects in all three models of acute nociception, whereas CBD alone produced
antinociception only in the acetic acid-stimulated stretching assay. The nature of the interactions
between morphine and CBD combinations were assessed quantitatively based on the principle of dose
equivalence. Combinations of CBD and morphine produced synergistic effects in reversing acetic acid-
stimulated stretching behavior, but subadditive effects in the hot plate thermal nociceptive assay and
the acetic acid-decreased operant responding for palatable food assay. These results suggest that
distinct mechanisms of action underlie the interactions between CBD and morphine in the three
different behavioral assays and that the choice of appropriate combination therapies for the treatment
of acute pain conditions may depend on the underlying pain type and stimulus modality.
Holy Basil/Tulsi (Ocimum

tenuiflorum)
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Medicinal herbs in the treatment of neuropathic pain: a review.

Forouzanfar F, Hosseinzadeh H. Iran J Basic Med Sci. 2018 Apr;21(4):347-358.
doi: 10.22038/IJBMS.2018.24026.6021.
Abstract
Chronic neuropathic pain is a common significant and debilitating problem that presents a major
challenge to health-care. Despite the large number of available drugs, there are no curative
conventional treatments for neuropathic pain. Nowadays, more attention has been focused on the
herbal formulation in the field of drug discovery. Therefore, we performed an extensive review about
herbal drugs and plants that exhibited protective effects on neuropathic pain. In this review, the
beneficial effects of each plant in different neuropathic pain model, either in animals or in patients are
reported. Moreover, the possible involved mechanisms for the protective effects are discussed. The
more common plants which are used for the treatment of neuropathic pain are included as: Acorus
calamus, Artemisia dracunculus, Butea monosperma, Citrullus colocynthis, Curcuma longa, Crocus
sativus, Elaeagnus angustifolia, Ginkgo biloba, Mitragyna speciosa, Momordica charantia, Nigella sativa,
Ocimum sanctum, Phyllanthus amarus, Pterodon pubescens Benth, Rubia cordifolia and Salvia
officinalis. Furthermore, the most pathways which are known to be involved in pain relief by means of
herbal remedies are anti-oxidant activity, anti-inflammatory, anti-apoptotic, neuroprotective and
calcium inhibitory actions. In conclusion, this review suggests that some herbal plants can be suitable
candidates for the treatment of neuropathic pain.
KEYWORDS:
Analgesic; Antinociceptive; Chronic pain; Herbal medicine Neuropathic pain
HOLY BASIL
WebMD. Vitamins and Supplements. 2018.
https://www.webmd.com/vitamins/ai/ingredientmono-1101/holy-basil
Holy basil is a plant. It is originally from India but now grows in Australia, West Africa, and some Middle
Eastern countries. It is used in Ayurvedic medicine as an "adaptogen" to counter life's stresses. It is
considered a sacred plant by the Hindus and is often planted around Hindu shrines. The Hindu name for
holy basil, Tulsi, means "the incomparable one." Medicine is made from the leaves, stems, and seeds.
Holy basil is commonly used by mouth to help with anxiety and stress. It is also used for diabetes and
high cholesterol. But there is limited scientific research to support these and other uses.
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In cooking, holy basil is often added to stir-fry dishes and spicy soups because of its peppery taste.
Cookbooks sometimes call it "hot basil."
How does it work?
Chemicals in holy basil are thought to decrease pain and swelling (inflammation). Other chemicals might
lower blood sugar in people with diabetes.
There is interest in using holy basil seed oil for cancer. Early research suggests that the oil can slow
progression and improve survival rate in animals with certain types of cancer. Researchers think this
benefit may be explained by the oil's ability to act as an antioxidant.
Tulsi - Ocimum sanctum: A herb for all reasons

Marc Maurice Cohen. J Ayurveda Integr Med. 2014 Oct-Dec; 5(4): 251–259. doi:
10.4103/0975-9476.146554
Abstract
The predominant cause of global morbidity and mortality is lifestyle-related chronic diseases, many of
which can be addressed through Ayurveda with its focus on healthy lifestyle practices and regular
consumption of adaptogenic herbs. Of all the herbs used within Ayurveda, tulsi (Ocimum sanctum Linn)
is preeminent, and scientific research is now confirming its beneficial effects. There is mounting
evidence that tulsi can address physical, chemical, metabolic and psychological stress through a unique
combination of pharmacological actions. Tulsi has been found to protect organs and tissues against
chemical stress from industrial pollutants and heavy metals, and physical stress from prolonged physical
exertion, ischemia, physical restraint and exposure to cold and excessive noise. Tulsi has also been
shown to counter metabolic stress through normalization of blood glucose, blood pressure and lipid
levels, and psychological stress through positive effects on memory and cognitive function and through
its anxiolytic and anti-depressant properties. Tulsi's broad-spectrum antimicrobial activity, which
includes activity against a range of human and animal pathogens, suggests it can be used as a hand
sanitizer, mouthwash and water purifier as well as in animal rearing, wound healing, the preservation of
food stuffs and herbal raw materials and traveler's health. Cultivation of tulsi plants has both spiritual
and practical significance that connects the grower to the creative powers of nature, and organic
cultivation offers solutions for food security, rural poverty, hunger, environmental degradation and
climate change. The use of tulsi in daily rituals is a testament to Ayurvedic wisdom and provides an
example of ancient knowledge offering solutions to modern problems.
Keywords: Adaptogen, Ayurveda, holy basil, lifestyle, Ocimum sanctum, stress, tulsi
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Ocimum sanctum Linn. A reservoir plant for therapeutic applications: An

overview.
Pattanayak P, Behera P, Das D, Panda SK. Pharmacogn Rev. 2010 Jan;4(7):95-105.
doi: 10.4103/0973-7847.65323.
Abstract
The medicinal plants are widely used by the traditional medicinal practitioners for curing various
diseases in their day to day practice. In traditional system of medicine, different parts (leaves, stem,
flower, root, seeds and even whole plant) of Ocimum sanctum Linn. have been recommended for the
treatment of bronchitis, malaria, diarrhea, dysentery, skin disease, arthritis, eye diseases, insect bites
and so on. The O. sanctum L. has also been suggested to possess anti-fertility, anticancer, antidiabetic,
antifungal, antimicrobial, cardioprotective, analgesic, antispasmodic and adaptogenic actions. Eugenol
(1-hydroxy-2-methoxy-4-allylbenzene), the active constituents present in O. sanctum L. have been found
to be largely responsible for the therapeutic potentials. The pharmacological studies reported in the
present review confirm the therapeutic value of O. sanctum L. The results of the above studies support
the use of this plant for human and animal disease therapy and reinforce the importance of the ethno-
botanical approach as a potential source of bioactive substances.
Anti-Inflammatory, gastrointestinal and hepatoprotective effects of Ocimum

sanctum Linn: an ancient remedy with new application.
Kamyab AA, Eshraghian A. Inflamm Allergy Drug Targets. 2013 Dec;12(6):378-84.
Abstract
Herbal medicine has a long background equal to history of humankind. Several plants have been used as
remedies in ancient Persian, Egyptian, Chinese and Indian civilizations. The plant Ocimum sanctum Linn.
(Tulsi) is one of these medicinal plants with a wide variety of applications in traditional medicine. In
modern era, it has been shown to be effective against diabetes mellitus, hypertension, cancers,
bronchitis, and found to have anti-microbial properties. Several experimental studies have confirmed its
anti-inflammatory properties and its role in modulation of both cellular and humeral immunity. Recently
its efficacy against inflammatory response, hepatic injury and gastric ulcer has been elucidated in animal
studies. In liver, essential oils and extracts of Ocimum sanctum could prevent oxidative stress by
increasing glutathione peroxidae and catalase and were also effective in prevention of hepatic steatosis.
In gastric epithelial tissue different derivatives of Ocimum sanctum had anti-ulcer and anti-secretory
characteristics and could heal gastric ulceration. These beneficial properties of this medicinal plant can
mainly originate from its major biochemically active constituents like eugenol, carvacrol, ursolic acid, β-
267
caryophyllene and rosmarinic acid. Here in, we reviewed current literature about anti-inflammatory,
gastric and hepatoprotective properties of Ocimum sanctum.
Validation of traditional claim of Tulsi, Ocimum sanctum Linn. as a medicinal

plant.
Gupta SK, Prakash J, Srivastava S. Indian J Exp Biol. 2002 Jul;40(7):765-73.
Abstract
In several ancient systems of medicine including Ayurveda, Greek, Roman, Siddha and Unani, Ocimum
sanctum has vast number of therapeutic applications such as in cardiopathy, haemopathy, leucoderma,
asthma, bronchitis, catarrhal fever, otalgia, hepatopathy, vomiting, lumbago, hiccups, ophthalmia,
gastropathy, genitourinary disorders, ringworm, verminosis and skin diseases etc. The present review
incorporates the description of O. sanctum plant, its chemical constituents, and various pharmacological
activities.
Therapeutic uses of Ocimum sanctum Linn (Tulsi) with a note on eugenol and
its pharmacological actions: a short review.
Prakash P, Gupta N. Indian J Physiol Pharmacol. 2005 Apr;49(2):125-31.
Abstract
The medicinal plants are widely used by the traditional medical practitioners for curing various diseases
in their day to day practice. In traditional systems of medicine, different parts (leaves, stem, flower,
root, seeds and even whole plant) of Ocimum sanctum Linn (known as Tulsi in Hindi), a small herb seen
throughout India, have been recommended for the treatment of bronchitis, bronchial asthma, malaria,
diarrhea, dysentery, skin diseases, arthritis, painful eye diseases, chronic fever, insect bite etc. The
Ocimum sanctum L. has also been suggested to possess antifertility, anticancer, antidiabetic, antifungal,
antimicrobial, hepatoprotective, cardioprotective, antiemetic, antispasmodic, analgesic, adaptogenic
and diaphoretic actions. Eugenol (1-hydroxy-2-methoxy-4-allylbenzene), the active constituent present
in Ocimum sanctum L., has been found to be largely responsible for the therapeutic potentials of Tulsi.
Although because of its great therapeutic potentials and wide occurrence in India the practitioners of
traditional systems of medicine have been using Ocimum sanctum L. for curing various ailments, a
rational approach to this traditional medical practice with modern system of medicine is, however, not
much available. In order to establish the therapeutic uses of Ocimum sanctum L. in modern medicine, in
last few decades several Indian scientists and researchers have studied the pharmacological effects of
268
steam distilled, petroleum ether and benzene extracts of various parts of Tulsi plant and eugenol on
immune system, reproductive system, central nervous system, cardiovascular system, gastric system,
urinary system and blood biochemistry and have described the therapeutic significance of Tulsi in
management of various ailments. These pharmacological studies have established a scientific basis for
therapeutic uses of this plant.
The Health Benefits of Holy Basil

August 30, 2017 — Written by Brian Krans and Ana Gotter. Healthline.com
https://www.healthline.com/health/food-nutrition/basil-benefits
Not your basic basil
Holy basil (Ocimum tenuiflorum) isn’t like the sweet basil in your mom’s marinara sauce or the Thai herb
you use to flavor a steaming bowl of pho. This green leafy plant, also known as Ocimum sanctum L. and
tulsi, is native to Southeast Asia. It has a history within Indian medicine as a treatment for many
conditions, from eye diseases to ringworms.
From the leaves to the seed, holy basil is considered a tonic for the body, mind, and spirit. Different
parts of the plant are recommended for treating different conditions:
Use its fresh flowers for bronchitis.
Use the leaves and seeds, with black pepper, for malaria.
Use the whole plant for diarrhea, nausea, and vomiting.
Use the pill and ointment form for eczema.
Use an alcohol extract for stomach ulcers and eye diseases.
Use an essential oil made from the leaves for insect bites.
Ameliorative potential of Ocimum sanctum in chronic constriction injury-

induced neuropathic pain in rats.
Kaur G1, Bali A, Singh N, Jaggi AS. An Acad Bras Cienc. 2015 Mar;87(1):417-29.
doi: 10.1590/0001-3765201520130008. Epub 2015 Feb 10.
Abstract
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The present study was designed to investigate the ameliorative potential of Ocimum sanctum and its
saponin rich fraction in chronic constriction injury-induced neuropathic pain in rats. The chronic
constriction injury was induced by placing four loose ligatures around the sciatic nerve, proximal to its
trifurcation. The mechanical hyperalgesia, cold allodynia, paw heat hyperalgesia and cold tail
hyperalgesia were assessed by performing the pinprick, acetone, hot plate and cold tail immersion tests,
respectively. Biochemically, the tissue thio-barbituric acid reactive species, super-oxide anion content
(markers of oxidative stress) and total calcium levels were measured. Chronic constriction injury was
associated with the development of mechanical hyperalgesia, cold allodynia, heat and cold hyperalgesia
along with an increase in oxidative stress and calcium levels. However, administration of Ocimum
sanctum (100 and 200 mg/kg p.o.) and its saponin rich fraction (100 and 200 mg/kg p.o.) for 14 days
significantly attenuated chronic constriction injury-induced neuropathic pain as well as decrease the
oxidative stress and calcium levels. It may be concluded that saponin rich fraction of Ocimum sanctum
has ameliorative potential in attenuating painful neuropathic state, which may be attributed to a
decrease in oxidative stress and calcium levels.
Horsetail
Horsetail
Vitamins &Supplements. WebMD.com. 2018.
https://www.webmd.com/vitamins/ai/ingredientmono-843/horsetail
Horsetail is a plant. The above ground parts are used to make medicine.
Horsetail is used for "fluid retention" (edema), kidney and bladder stones, urinary tract infections, the
inability to control urination (incontinence), and general disturbances of the kidney and bladder.
It is also used for balding; tuberculosis; jaundice; hepatitis; brittle fingernails; joint diseases; gout;
osteoarthritis; weak bones (osteoporosis); high cholesterol levels; frostbite; weight loss; heavy
menstrual periods; and uncontrolled bleeding (hemorrhage) of the nose, lung, or stomach.
Horsetail is applied directly to the skin to treat wounds and burns.
Horsetail is sometimes used in cosmetics and shampoos.
How does it work?

270
The chemicals in horsetail may have antioxidant and anti-inflammatory effects. Horsetail contains
chemicals that work like "water pills" (diuretics) and increase urine output.
Horsetail – Benefits and Side Effects

Thordur Sturluson. The Herbal Resource. Herbal-suppliment-resource.com. 2018.
https://www.herbal-supplement-resource.com/horsetail-herb.html
Horsetail contains silicic acid, saponins, flavonoids, sterols, tannins, potassium, aluminum salts,
manganese, magnesium, sulfur and calcium.
Historically, horsetail has been used to stop bleeding, repair broken bones and as an herbal remedy for
arthritis.
It has also been beneficial in the treatment of dropsy, gravel and kidney infections, including ulceration
and ulcers in the urinary passages.
Because horsetail has the ability to increase urine production, (a diuretic), it gained popularity as an
herbal treatment of kidney stones, edema and urinary tract infections as well as cystitis.
Equisetum arvense L. Extract Induces Antibacterial Activity and Modulates

Oxidative Stress, Inflammation, and Apoptosis in Endothelial Vascular Cells
Exposed to Hyperosmotic Stress.
Pallag A, et al. Oxid Med Cell Longev. 2018 Feb 14;2018:3060525. doi:
10.1155/2018/3060525. eCollection 2018.
Abstract
Background:
The antimicrobial activity of the Equisetum arvense L. extract and the mechanisms involved in the in
vitro effects on endothelial vascular cells exposed to hyperosmotic stress were evaluated.
Methods:
Antimicrobial activity was evaluated by disk diffusion method and minimum inhibitory concentration
(MIC) determination, and oxidative stress, inflammation, and apoptosis, in pretreatment with Equisetum
arvense L., caffeic acid, and cathechin, were quantified.
Results:
271
The results have shown that Equisetum arvense L. exhibited antibacterial effects only on pathogenic
gram-positive cocci. The modulatory activity of Equisetum arvense L. on endothelial cells exposed to
hypertonic medium was different and depended on the concentration used. Low concentrations of
tested compounds exerted antioxidant effect and diminished the activity of caspase-8 and also
increased IκB expression while in high doses, Equisetum arvense L. was prooxidant, induced apoptosis,
and decreased IL-6 secretion.
Conclusions:
These experimental findings suggest that Equisetum arvense L. has antibacterial effects on gram-
positive cocci and, administered in low dose, may be a new therapeutic approach for diseases
associated with hypertonic conditions or oxidative stress and apoptosis.
Equisetum arvense (common horsetail) modulates the function of

inflammatory immunocompetent cells.
Gründemann C, et al. BMC Complement Altern Med. 2014 Aug 4;14:283. doi:
10.1186/1472-6882-14-283.
Abstract
BACKGROUND:
In Europe, extracts of Equisetum arvense (common horsetail) have a long tradition in the treatment of
inflammatory disorders. To understand the molecular basis for its use, we investigated the
immunomodulatory capacity of a standardized commercially available common horsetail extract on
human primary lymphocyte function in vitro.
METHODS:
The standardized extract of Equisetum arvense was phytochemically characterized. Effects on

proliferation, viability and activity of mitogen-activated human lymphocytes were assessed in
comparison to cyclosporine A using annexin V/propidium iodide staining assays and flow cytometry-
based surface receptor characterization, respectively. Intracellular levels of effector molecules (IL-2, IFN-
γ and TNF-α) were analyzed with cytokine assays.
RESULTS:
T cell proliferation was inhibited dose dependently by the Equisetum extract without induction of
apoptosis or necrosis. This effect was mediated through inhibition of lymphocyte activation, specifically
by diminishing CD69 and IL-2 surface receptor expression and intracellular IL-2 production. Furthermore,
272
treatment with Equisetum arvense inhibited effector functions, as indicated by reduced production of
IFN-γ and TNF-α.
CONCLUSIONS:
The data indicate that the used extract of Equisetum arvense interferes with the polyfunctionality of
immunocompetent cells thereby providing an anti-inflammatory mode-of-action.
Equisetum arvense hydromethanolic extracts in bone tissue regeneration: in

vitro osteoblastic modulation and antibacterial activity.
Bessa Pereira C, et al. Cell Prolif. 2012 Aug;45(4):386-96. doi: 10.1111/j.1365-
2184.2012.00826.x. Epub 2012 Jun 1.
Abstract
OBJECTIVES:
Equisetum arvense preparations have long been used to promote bone healing. The aim of this work
was to evaluate osteogenic and antibacterial effects of E. arvense hydromethanolic extracts.
Dried aerial components of E. arvense were extracted using a mixture of methanol:water (1:1), for 26
days, yielding three extracts that were tested (10-1000 μg/ml) in human osteoblastic cells: E1, E2 and
EM (a mixture of E1 and E2, 1:1). Cell cultures, performed on cell culture plates or over hydroxyapatite
(HA) substrates, were assessed for osteoblastic markers. In addition, effects of the extracts on
Staphylococcus aureus were addressed.
RESULTS:
Solution E1 caused increased viability/proliferation and ALP activity at 50-500 μg/ml, and deleterious
effects at levels ≥1000 μg/ml. E2 inhibited cell proliferation at levels ≥500 μg/ml. EM presented a profile
between those observed with E1 and E2. In addition, E1, E2 and EM, 10-1000 μg/ml, inhibited expansion
of S. aureus. Furthermore, E1, tested in HA substrates colonized with osteoblastic cells, causing increase
in cell population growth (10-100 μg/ml). E1 also exhibited antibacterial activity against S. aureus
cultured over HA.
CONCLUSIONS:
Results showed that E. arvense extracts elicited inductive effects on human osteoblasts while inhibiting
activity of S. aureus, suggesting a potentially interesting profile regarding bone regeneration strategies.
273
Anabolic therapy with Equisetum arvense along with bone mineralising

nutrients in ovariectomized rat model of osteoporosis.
Kotwal SD, Badole SR. Indian J Pharmacol. 2016 May-Jun;48(3):312-5. doi:
10.4103/0253-7613.182880.
Abstract
OBJECTIVE:
Equisetum arvense has been used to treat bone diseases. The traditional supplementation of calcium
and Vitamin D for osteoporosis patients is insufficient considering the rise in patients every year. We
have observed that extending the calcium and Vitamin D supplement with L-lysine, L-proline, L-arginine,
and L-ascorbic acid (N) positively affects bone mineralization in ovariectomized rat. Here, we report a
further extension of the above supplement with E. arvense.
The changes in serum biomarkers, bone mineral content, and femur bone histology were studied and
compared to the standard drug for osteoporosis, namely raloxifene (RAL).
RESULTS:
We report a significant change in formation and resorption markers of bone as well as in cortical bone
thickness and trabecular width in N and N + EA groups. The treatment N + EA also restored lipid profile
near to normal level compared to ovariectomized group.
CONCLUSIONS:
Treatment N + EA was found to be as effective as RAL in reversing the osteoporotic changes.
KEYWORDS:
Bone mineralizing nutrients; Equisetum arvense; osteoporosis prevention
Does Horsetail Help You Pee?

Medically reviewed by Natalie Butler, RD, LD on June 2, 2016 — Written by Rena
Goldman. Healthline.com
https://www.healthline.com/health/does-horsetail-help-you-pee
How it works
274
Horsetail is believed to contain chemicals that increase the amount of urine the body produces.
Researchers aren’t yet sure exactly how or why the herb may work. There is little solid evidence to
prove that it is effective. A recent studyTrusted Source compared horsetail to a common diuretic,
hydrochlorothiazide, and found the herb to be as effective as the medication without causing excessive
electrolyte loss. However, the study was very small, so the results are not considered conclusive.
Horsetail has been used medicinally since as long ago as ancient Greece. Beyond its potential benefits as
a diuretic, horsetail has also been used for skin and nail care, wound healing, osteoporosis, and bone
repairTrusted Source. Some researchers hypothesize that the plant’s possible health benefits may be
due to a mineral called silica. The mineral helps your body store calcium needed to heal bones, and to
build strong fingernails and hair.
Silica gives horsetail a coarse texture that also makes it useful for cleaning. For this reason, the herb is
used in some beauty products such as facial cleansers and shampoos.

Abstract
Osteoporosis Alternative Treatments

Medically reviewed by Gerhard Whitworth, RN on July 30, 2019 — Written by the
Healthline Editorial Team and Kathryn Watson
https://www.healthline.com/health/osteoporosis-alternative-treatments
275
Horsetail is a plant with possible medicinal properties. The silicon in horsetail is believed to help with
bone loss by stimulating bone regeneration. Although clinical trials to support this assertion are lacking,
horsetail is still recommended by some holistic doctors as an osteoporosis treatment.
Horsetail can be taken as a tea, tincture, or herbal compress. It can interact negatively with alcohol,
nicotine patches, and diuretics, and it’s important to stay properly hydrated when you’re using it.
Abstract
PARTICIPANTS:
276

Med. 2013;20(4):800-2.
Abstract
INTRODUCTION:
population.
AIM:
rheumatic diseases.
RESULTS:
277
CONCLUSION:
Kava
Kava for Generalized Anxiety Disorder: A Review of Current Evidence.
Ooi SL, Henderson P, Pak SC. J Altern Complement Med. 2018 Aug;24(8):770-780.
doi: 10.1089/acm.2018.0001. Epub 2018 Apr 11.
Abstract
BACKGROUND:
Generalized anxiety disorder (GAD) is a chronic and debilitating condition characterized by persistent
and overpowering anxiety. Treatment of GAD with antidepressants and benzodiazepines is only
moderately effective and not free from side effects. Kava (Piper methysticum) has been explored as a
potential phytotherapeutic option for GAD.
OBJECTIVES:
To perform a systematic review and meta-analysis of the available evidence on Kava as a treatment for
GAD.
METHODS:
Systematic search of English-language publications from major databases for clinical trials reporting the
effects of Kava for the treatment of GAD.
278
RESULTS:
Twelve articles were included in this review. Evidence supporting Kava as an effective treatment for GAD
was found in two placebo-controlled trials and a reference-controlled trial. One negative trial
demonstrated that Kava was not more effective than placebo. Meta-analyses of the results of three
placebo-controlled trials (n = 130) favored Kava for GAD treatment with effect sizes between 0.59 and
0.99 (standard mean difference) without reaching statistical significance. Kava is an appealing treatment
option to GAD patients who are more attune to natural remedies or lifestyle approaches to reduce
stress. Positive patient experiences and improvement of vagal cardiac control due to Kava treatment
were also reported in the literature. Kava is safe and well tolerated for short-term (4-8 weeks)
therapeutic use at a dosage of 120-280 mg per day of Kavalactones, regardless of dosage schedule.
CONCLUSIONS:
Current evidence, although promising, is insufficient to confirm the effect of Kava for GAD treatment
beyond placebo. New evidence is expected from a large, multisite ongoing trial.
KEYWORDS:
Kava; generalized anxiety disorder; meta-analysis; phytomedicine; systematic review
Activity and mechanism of flavokawain A in inhibiting P-glycoprotein

expression in paclitaxel resistance of lung cancer.
Li J, et al. Oncol Lett. 2020 Jan;19(1):379-387. doi: 10.3892/ol.2019.11069. Epub
2019 Nov 8.
Abstract
Lung cancer is one of the most common cancers, which is the leading cause of cancer-related death
among various cancers worldwide. Flavokawain A (FKA), a chalcone found in the kava plant, exerts
potent anticancer activity. However, the activity and mechanisms of FKA in inhibiting the viability of
paclitaxel (PTX)-resistant lung cancer A549 (A549/T) have not been investigated. In the present study,
the effect of FKA on the viability of A549/T and hepatotoxicity in normal liver epithelial cells was
detected by Cell Counting Kit-8 assay. Flow cytometry, western blot analysis and Annexin V-FITC/PI
apoptosis detection kit were used to assess cell apoptosis. The effect of FKA on permeability-
glycoprotein (P-gp) expression was measured by reverse transcription-PCR and western blot analysis.
279
The results indicated that FKA dose-dependently inhibited cell proliferation and induced cell apoptosis in
PTX-resistant A549/T cells, with an IC50 value of ~21 µM, while the IC50 value of A549/T cells to PTX was
34.64 µM. FKA had no hepatic toxicity in liver epithelial cells. P-gp, which contributes to the
chemoresistant phenotype, was not expressed in A549 cells but was remarkably enhanced in A549/T
cells. FKA (30 µM) decreased P-gp protein expression at 24 h by 3-fold. Furthermore, FKA
downregulated P-gp expression by blocking the PI3K/Akt pathway. These findings suggest FKA as a
potential candidate for the treatment of PTX-resistant lung cancer.
Copyright: © Li et al.
Kava for generalised anxiety disorder: A 16-week double-blind, randomised,

placebo-controlled study.
Sarris J, et al. Aust N Z J Psychiatry. 2019 Dec 8:4867419891246. doi:
Abstract
OBJECTIVE:
Previous randomised, double-blind, placebo-controlled studies have shown that Kava (a South Pacific
medicinal plant) reduced anxiety during short-term administration. The objective of this randomised,
double-blind, placebo-controlled study was to perform a larger, longer-term trial assessing the efficacy
and safety of Kava in the treatment of generalised anxiety disorder and to determine whether gamma-
aminobutyric acid transporter (SLC6A1) single-nucleotide polymorphisms were moderators of response.
METHODS:
The trial was a phase III, multi-site, two-arm, 16-week, randomised, double-blind, placebo-controlled
study investigating an aqueous extract of dried Kava root administered twice per day in tablet form
(standardised to 120 mg of kavalactones twice/day) in 171 currently non-medicated anxious participants
with diagnosed generalised anxiety disorder. The trial took place in Australia.
RESULTS:
An analysis of 171 participants revealed a non-significant difference in anxiety reduction between the
Kava and placebo groups (a relative reduction favouring placebo of 1.37 points; p = 0.25). At the
280
conclusion of the controlled phase, 17.4% of the Kava group were classified as remitted (Hamilton
Anxiety Rating Scale score < 7) compared to 23.8% of the placebo group (p = 0.46). No SLC6A1
polymorphisms were associated with treatment response, while carriers of the rs2601126 T allele
preferentially respond to placebo (p = 0.006). Kava was well tolerated aside from poorer memory (Kava
= 36 vs placebo = 23; p = 0.044) and tremor/shakiness (Kava = 36 vs placebo = 23; p = 0.024) occurring
more frequently in the Kava group. Liver function test abnormalities were significantly more frequent in
the Kava group, although no participant met criteria for herb-induced hepatic injury.
CONCLUSION:
While research has generally supported Kava in non-clinical populations (potentially for more
'situational' anxiety as a short-term anxiolytic), this particular extract was not effective for diagnosed
generalised anxiety disorder.
KEYWORDS:
Generalised anxiety disorder; Kava; Piper methysticum; anxiety; gamma-aminobutyric acid;

pharmacogenetics; polymorphisms
Kava and its Kavalactones Inhibit Norepinephrine-induced Intracellular

Calcium Influx in Lung Cancer Cells.
Botello JF, Corral P, Bian T, Xing C. Planta Med. 2020 Jan;86(1):26-31. doi:
10.1055/a-1035-5183. Epub 2019 Nov 11.
Abstract
Kava, the extract of the roots of Piper methysticum, has been traditionally consumed in the South Pacific
islands for its natural relaxing property. Epidemiological data suggests that kava consumption may
reduce human cancer risk, and in vitro and in vivo models suggest chemopreventive potential against
carcinogen-induced tumorigenesis. Therefore, knowledge about its molecular mechanisms and
responsible ingredient(s) for these beneficial properties will better guide kava's use for the management
of these disorders. Psychological stress typically results in increased production of stress hormones, such
as norepinephrine (NE), which activate adrenergic receptors (ARs). Psychological stress has also been
associated with increased cancer incidence and poor clinical outcomes in cancer patients.
Mechanistically, binding of NE to ARs induces intracellular calcium influx, which activates downstream
signaling pathways involved in both stress and cancer development. In this study, we characterized the
effect of kava and its components, 3 fractions and 6 major kavalactones, on NE-induced intracellular
281
calcium influx in H1299, a human non-small cell lung carcinoma cell line. Results show that kava extract
effectively inhibits NE-mediated intracellular calcium influx in H1299 cells, potentially through
antagonizing β-AR signaling. This inhibitory activity is recapitulated by the major kavalactones in kava.
Among the 6 major kavalactones, DHK demonstrated the best potency. Taken together, our study
suggests a novel mechanism through which kava and its ingredients potentially offer the anxiolytic and
cancer-preventive activity.
Georg Thieme Verlag KG Stuttgart · New York.
Cyclization of flavokawain B reduces its activity against human colon cancer

cells.
Palko-Łabuz A, et al. Hum Exp Toxicol. 2019 Oct 22:960327119882986. doi:
Abstract
Chalcones are naturally occurring compounds exhibiting biological activity through multiple
mechanisms. Flavokawain B is one of chalcones found in kava plant. In our studies, we focused on the
anticancer activity of flavokawain B in colorectal cancer cells LoVo and its resistant to doxorubicin
subline-LoVo/Dx. Strong cytotoxic activity of flavokawain B and its ability to inhibit the proliferation in
both cell lines was detected. These effects accompanied with induction cell cycle arrest in G2/M phase
and the presence of SubG1 fraction. Flavokawain B at low concentration led to increase of caspase-3
activity. The chalcone-induced apoptosis was also confirmed by DNA fragmentation. In our work, the
conversion of flavokawain B to corresponding flavanone-5,7-dimetoxyflavanone-was shown to be more
extensive in cancer than in non-cancer cells. We found that the cyclization of the chalcone was related
to the significant decrease in the cytotoxicity. Cell proliferation and cell cycle progression were not
impaired significantly in the studied cancer cells incubated with 5,7-dimethoxyflavanone. We did not
observe apoptosis in the cells incubated with flavanone. The results from biological studies agreed with
the theoretical activity that emerges from structural parameters.
KEYWORDS:
Chalcone; apoptosis; cancer; cytotoxicity; flavanone; molecular parameter

282
Identification of a Kavain Analog with Efficient Anti-inflammatory Effects.

Huck O, et al. Sci Rep. 2019 Sep 10;9(1):12940. doi: 10.1038/s41598-019-49383-
8.
Abstract
Kavain, a compound derived from Piper methysticum, has demonstrated anti-inflammatory properties.
To optimize its drug properties, identification and development of new kavain-derived compounds was
undertaken. A focused library of analogs was synthesized and their effects on Porphyromonas gingivalis
(P. gingivalis) elicited inflammation were evaluated in vitro and in vivo. The library contained
cyclohexenones (5,5-dimethyl substituted cyclohexenones) substituted with a benzoate derivative at the
3-position of the cyclohexanone. The most promising analog identifed was a methylated derivative of
kavain, Kava-205Me (5,5-dimethyl-3-oxocyclohex-1-en-1-yl 4-methylbenzoate.) In an in vitro assay of
anti-inflammatory effects, murine macrophages (BMM) and THP-1 cells were infected with P. gingivalis
(MOI = 20:1) and a panel of cytokines were measured. Both cell types treated with Kava-205Me (10 to
200 μg/ml) showed significantly and dose-dependently reduced TNF-α secretion induced by P. gingivalis.
In BMM, Kava-205Me also reduced secretion of other cytokines involved in the early phase of
inflammation, including IL-12, eotaxin, RANTES, IL-10 and interferon-γ (p < 0.05). In vivo, in an acute
model of P. gingivalis-induced calvarial destruction, administration of Kava-205Me significantly
improved the rate of healing associated with reduced soft tissue inflammation and osteoclast activation.
In an infective arthritis murine model induced by injection of collagen-antibody (ArthriomAb) + P.
gingivalis, administration of Kava-205Me was able to reduce efficiently paw swelling and joint
destruction. These results highlight the strong anti-inflammatory properties of Kava-205Me and
strengthen the interest of testing such compounds in the management of P. gingivalis elicited
inflammation, especially in the management of periodontitis.
Reduction of Articular and Systemic Inflammation by Kava-241 in a

Porphyromonas gingivalis-Induced Arthritis Murine Model.
Huck O, et al. Infect Immun. 2018 Aug 22;86(9). pii: e00356-18. doi:
10.1128/IAI.00356-18. Print 2018 Sep.
Abstract
Rheumatoid arthritis (RA) is an inflammatory disease that has been linked to several risk factors,
including periodontitis. Identification of new anti-inflammatory compounds to treat arthritis is needed.
We had previously demonstrated the beneficial effect of Kava-241, a kavain-derived compound, in the
management of Porphyromonas gingivalis-induced periodontitis. The present study evaluated systemic
and articular effects of Kava-241 in an infective arthritis murine model triggered by P. gingivalis bacterial
283
inoculation and primed with a collagen antibody cocktail (CIA) to induce joint inflammation and tissular
destruction. Clinical inflammation score and radiological analyses of the paws were performed
continuously, while histological assessment was obtained at sacrifice. Mice exposed to P. gingivalis and a
CIA cocktail and treated concomitantly with Kava-241 exhibited a reduced clinical inflammatory score
and a decreased number of inflammatory cells and osteoclasts within joint. Kava-241 treatment also
decreased significantly tumor necrosis factor alpha (TNF-α) in serum from mice injected with a Toll-like
receptor 2 or 4 (TLR-2/4) ligand, P. gingivalis-lipopolysaccharide (LPS). Finally, bone marrow-derived
macrophages infected with P. gingivalis and exposed to Kava-241 displayed reduced TLR-2/4, reduced
mitogen-activated protein kinase (MAPK)-related signal elements, and reduced LPS-induced TNF-α
factor (LITAF), all explaining the observed reduction of TNF-α secretion. Taken together, these results
emphasized the novel properties of Kava-241 in the management of inflammatory conditions, especially
TNF-α-related diseases such as infective RA.
Copyright © 2018 American Society for Microbiology.
Lomatium
Antibacterial activity of components from Lomatium californicum.
Chou SC, Everngam MC, Sturtz G, Beck JJ. Phytother Res. 2006 Feb;20(2):153-6.
Abstract
The isolation, characterization and bioactivity testing of compounds from Lomatium californicum (Nutt.)
are described. Ethyl acetate and hexane extracts of the roots of L. californicum were subjected to
vacuum liquid chromatography (VLC), flash column chromatography (FCC) and separation by normal-
and reverse-phase high-performance liquid chromatography (HPLC). Six compounds were isolated
successfully and characterized by 1D and 2D nuclear magnetic resonance (NMR) experimentation. The
bioactivity of the known compounds (+)-falcarindiol, coniferyl ferulate, ferulic acid and (Z)-ligustilide
were confirmed against the Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus. The
known compounds senkyunolide I and trans-neocnidilide were also isolated but in too small a quantity
for similar testing.
Copyright 2006 John Wiley & Sons, Ltd.

284
Phytotoxic and antifungal compounds from two Apiaceae species, Lomatium

californicum and Ligusticum hultenii, rich sources of Z-ligustilide and apiol,
respectively.
Meepagala KM, Sturtz G, Wedge DE, Schrader KK, Duke SO. J Chem Ecol. 2005
Jul;31(7):1567-78.
Abstract
The seeds of two Apiaceae species, Ligusticum hultenii and Lomatium californicum, were investigated.
Preliminary bioassays indicated that methylene chloride extracts of seeds of both species contained
selective phytotoxic activity against monocots and antifungal activity against Colletotrichum fragariae.
Active constituents were isolated by bioassay-guided fractionation, and the structures were elucidated
by NMR and GC-MS as apiol and Z-ligustilide, isolated from L. hultenii and L. californicum, respectively.
Apiol and Z-ligustilide had I50 values of about 80 and 600 microM, respectively, for inhibition of the
growth of Lemna paucicostata. The methylene chloride (CH2Cl2) extracts of the seeds and the isolated
and purified compounds were tested against the 2-methylisobomeol-producing cyanobacterium (blue-
green alga) Oscillatoria perornata, and the green alga Selenastrum capricornutum. The CH2Cl2 extracts
of both Apiaceae species and apiol were weakly toxic to both species of phytoplankton, while Z-
ligustilide was toxic to both with a lowest complete inhibitory concentration (LCIC) of 53 microM. Seeds
of L. californicum and L. hultenii were found to be rich sources of Z-ligustilide (97 mg/g of dry seed) and
apiol (40 mg/g of dry seed), respectively.
Antiviral screening of British Columbian medicinal plants.

McCutcheon AR, et al. J Ethnopharmacol. 1995 Dec 1;49(2):101-10.
Abstract
One hundred methanolic plant extracts were screened for antiviral activity against seven viruses. Twelve
extracts were found to have antiviral activity at the non-cytotoxic concentrations tested. The extracts of
Rosa nutkana and Amelanchier alnifolia, both members of the Rosaceae, were very active against an
enteric coronavirus. A root extract of another member of the Rosaceae, Potentilla arguta, completely
inhibited respiratory syncytial virus. A Sambucus racemosa branch tip extract was also very active
against respiratory syncytial virus while the inner bark extract of Oplopanax horridus partially inhibited
this virus. An extract of Ipomopsis aggregata demonstrated very good activity against parainfluenza virus
type 3. A Lomatium dissectum root extract completely inhibited the cytopathic effects of rotavirus. In
addition to these, extracts prepared from the following plants exhibited antiviral activity against
285
herpesvirus type 1: Cardamine angulata, Conocephalum conicum, Lysichiton americanum, Polypodium

glycyrrhiza and Verbascum thapsus.
Suksdorfin: an anti-HIV principle from Lomatium suksdorfii, its structure-

activity correlation with related coumarins, and synergistic effects with anti-
AIDS nucleosides.
Lee TT, et al. Bioorg Med Chem. 1994 Oct;2(10):1051-6.
Abstract
Suksdorfin (1), which is isolated from the fruit of Lomatium suksdorfii, was found to be able to inhibit
HIV-1 replication in the T cell line, H9, with an average EC50 value of 2.6 +/- 2.1 microM. In addition,
suksdorfin was also suppressive during acute HIV-1 infections of peripheral blood mononuclear cells,
monocyte/macrophages and the promonocytic cell line, U937. Combinations of 1 and the anti-HIV
nucleosides ddI and ddC demonstrated statistical synergy in inhibiting HIV-1 replication (ddC > ddI).
However, the viral inhibition mediated by combining 1 with AZT was not statistically synergistic.
Furthermore, the presence of suksdorfin did not antagonize the suppression mediated by the three
nucleoside reverse transcriptase inhibitors. Comparison of the structure and activity of 1 with those of
ten related compounds indicated that the dihydroseselin type of pyranocoumarin possessing a 4'-
isovaleryl group is important to suksdorfin's enhanced anti-HIV activity.
Native American food and medicinal plants, 8. Water-soluble constituents of

Lomatium dissectum.
VanWagenen BC, Huddleston J, Cardellina JH 2nd. J Nat Prod. 1988 Jan-
Feb;51(1):136-41.
Abstract
A continuing investigation of the umbellifer Lomatium dissectum has resulted in the isolation of a known
flavonoid [1] and three coumarin glycosides [2-4], two of which are previously unreported. One of these
new compounds [4] contains apiose, a sugar uncommon in the coumarins. The ichthyotoxicity of the
plant extracts has been traced to the tetronic acids isolated earlier in this study.
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Maca
Medicinal effects of Peruvian maca (Lepidium meyenii): a review.
da Silva Leitão Peres N, et al. Food Funct. 2020 Jan 17. doi: 10.1039/c9fo02732g.
[Epub ahead of print]
Abstract
Peruvian maca (Lepidium meyenii) is a root native to the Andean region, cultivated for at least 2000
years. Maca is rich in fiber, a large number of essential amino acids, fatty acids, and other nutrients,
including vitamin C, copper, iron, and calcium. Besides these essential nutrients, this root contains
bioactive compounds responsible for benefits to the human body, which has caused a considerable
increase in its consumption in the last 20 years worldwide. This review documents the Peruvian maca
composition and the recent findings regarding the medicinal effects of this root in sexual dysfunction
regulation, neuroprotective effects, action in memory enhancement, antidepressant, antioxidant, anti-
cancer, and anti-inflammatory activities, and skin protection.
Effect of Lepidium meyenii (Maca), a root with aphrodisiac and fertility-

enhancing properties, on serum reproductive hormone levels in adult healthy
men.
Gonzales GF, et al. J Endocrinol. 2003 Jan;176(1):163-8.
Abstract
Lepidium meyenii (Maca) is a Peruvian hypocotyl that grows exclusively between 4000 and 4500 m in
the central Andes. Maca is traditionally employed in the Andean region for its supposed aphrodisiac
and/or fertility-enhancing properties. This study was a 12-week double-blind, placebo-controlled,
randomized, parallel trial in which active treatment with different doses of Maca Gelatinizada was
compared with a placebo. The study aimed to test the hypothesis that Maca has no effect on serum
reproductive hormone levels in apparently healthy men when administered in doses used for
aphrodisiac and/or fertility-enhancing properties. Men aged between 21 and 56 Years received 1500 mg
287
or 3000 mg Maca. Serum levels of luteinizing hormone, follicle-stimulating hormone, prolactin, 17-alpha
hydroxyprogesterone, testosterone and 17-beta estradiol were measured before and at 2, 4, 8 and 12
weeks of treatment with placebo or Maca (1.5 g or 3.0 g per day). Data showed that compared with
placebo Maca had no effect on any of the hormones studied nor did the hormones show any changes
over time. Multiple regression analysis showed that serum testosterone levels were not affected by
treatment with Maca at any of the times studied (P, not significant). In conclusion, treatment with Maca
does not affect serum reproductive hormone levels.
Physicochemical and functional properties of a protein isolate from maca

(Lepidium meyenii) and the secondary structure and immunomodulatory
activity of its major protein component.
Wu L , Zhang M , Xin X , Lai F , Wu H . Food Funct. 2019 May 22;10(5):2894-2905.
doi: 10.1039/c8fo02490a.
Abstract
Maca protein isolate (MPI) was extracted from maca root, and its physicochemical and functional
properties, and the secondary structure and immunomodulatory activity of its major protein
component, MMP, were investigated. The MPI lacked essential amino acids compared with soybean
protein isolate (SPI) and casein, but was rich in cysteine and proline. The MPI had rich free sulfhydryl
(20.6 μmol g-1), and its surface hydrophobicity (H0, 812.4), oil absorption capacity (7.4 g g-1), foaming
capacity (100%) and emulsifying activity (58.2 m2 g-1) were higher than that of SPI. However, the
thermal stability (Td, 87.4 °C), foaming stability (75%) and emulsifying stability (26.3 min) of the MPI
were weaker than that of the SPI. MMP was a pentamer with a molecular weight of 22 kDa and rich in β-
sheets. MMP could significantly enhance the phagocytic capacity and promote the NO, TNF-α and IL-6
secretion of RAW 264.7 cells, involving toll-like receptor 4 and complement receptor 3 mainly.
Lepidium meyenii (Maca) in male reproduction.

Tafuri S, et al. Nat Prod Res. 2019 Dec 5:1-10. doi:
Abstract
Lepidium meyenii (Maca) is an edible root plant that grows in the Andean region of Peru. For centuries,
the plant has been used as a dietary supplement for its nutritional and therapeutic properties. Maca are
rich in high value nutritional elements and secondary metabolites (macaridine, macamides and
glucosinolates) with high biological activity. Several studies demonstrated various biological effects of
Maca mainly in the field of fertility. The aim of this review is to summarize the state of knowledge on the
288
properties of Maca on male reproduction. Literature data was performed in PubMed with researches
published from 2000 to 2019. The research showed results related to the effects of Maca on the quality
and quantity of the semen, sexual behaviour and disorders of the male genital tract. Despite the
numerous studies carried out on different animal species, further research is needed to clarify the
mechanisms of action of Maca.
KEYWORDS:
Lepidium meyenii; Maca; fertility; nutraceuticals; spermatogenesis
Chemical composition and health effects of maca (Lepidium meyenii).

Wang S, Zhu F. Food Chem. 2019 Aug 1;288:422-443. doi:
10.1016/j.foodchem.2019.02.071. Epub 2019 Feb 22.
Abstract
Maca (Lepidium meyenii Walpers) has emerged as a popular functional plant food due to various
claimed health effects. This review details the major (i.e., starch, dietary fiber, and protein) and minor
constituents (i.e., minerals, non-starch polysaccharides, polyphenols (flavonolignans), macaenes,
macamides, glucosinolates, and alkaloids) of maca (root and aerial parts). Diverse health effects of maca
are also summarized. Various bioactivities of maca include enhanced reproductive health, antifatigue,
antioxidation, neuroprotection, antimicrobial activity, anticancer, hepatoprotection,
immunomodulation, and improving skin health and digestive system's function. Plant genetics, botanical
parts, processing, extraction, and experimental protocols represent the major factors affecting the
chemical composition, physicochemical attributes, and health effects of maca-based products. However,
clinical studies to support the claimed health effects of maca and related mechanisms appear to be
lacking. Product innovation and diversification in food and non-food utilization of different parts of maca
to maximize the value perceptions are suggested.
KEYWORDS:
Antioxidant; Bioactivity; Chemical analysis; Health-promoting; Lepidium peruvianum; Polyphenol;

Underutilized species
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A double-blind placebo-controlled trial of maca root as treatment for

antidepressant-induced sexual dysfunction in women.
Dording CM, et al. Evid Based Complement Alternat Med. 2015;2015:949036. doi:
10.1155/2015/949036. Epub 2015 Apr 14.
Abstract
OBJECTIVE:
We sought to demonstrate that maca root may be an effective treatment for antidepressant-induced
sexual dysfunction (AISD) in women.
METHOD:
We conducted a 12-week, double-blind, placebo-controlled trial of maca root (3.0 g/day) in 45 female

outpatients (mean age of 41.5 ± 12.5 years) with SSRI/SNRI-induced sexual dysfunction whose
depression remitted. Endpoints were improvement in sexual functioning as per the Arizona Sexual
Experience Scale (ASEX) and the Massachusetts General Hospital Sexual Function Questionnaire (MGH-
SFQ).
RESULTS:
45 of 57 consented females were randomized, and 42 (30 premenopausal and 12 postmenopausal

women) were eligible for a modified intent-to-treat analysis based on having had at least one
postmedication visit. Remission rates by the end of treatment were higher for the maca than the
placebo group, based on attainment of an ASEX total score ≤ 10 (9.5% for maca versus 4.8% for
placebo), attaining an MGH-SFQ score ≤ 12 (30.0% for maca versus 20.0% for placebo) and reaching an
MGH-SFQ score ≤ 8 (9.5% for maca versus 5.0% for placebo). Higher remission rates for the maca versus
placebo group were associated with postmenopausal status. Maca was well tolerated.
CONCLUSION:
Maca root may alleviate SSRI-induced sexual dysfunction in postmenopausal women. This trial is
registered with NCT00568126.
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Magnesium
Migraine Headache Prophylaxis.
Ha H, Gonzalez A. Am Fam Physician. 2019 Jan 1;99(1):17-24.
Abstract
Migraines impose significant health and financial burdens. Approximately 38% of patients with episodic
migraines would benefit from preventive therapy, but less than 13% take prophylactic medications.
Preventive medication therapy reduces migraine frequency, severity, and headache-related distress.
Preventive therapy may also improve quality of life and prevent the progression to chronic migraines.
Some indications for preventive therapy include four or more headaches a month, eight or more
headache days a month, debilitating headaches, and medication-overuse headaches. Identifying and
managing environmental, dietary, and behavioral triggers are useful strategies for preventing migraines.
First-line medications established as effective based on clinical evidence include divalproex, topiramate,
metoprolol, propranolol, and timolol. Medications such as amitriptyline, venlafaxine, atenolol, and
nadolol are probably effective but should be second-line therapy. There is limited evidence for
nebivolol, bisoprolol, pindolol, carbamazepine, gabapentin, fluoxetine, nicardipine, verapamil,
nimodipine, nifedipine, lisinopril, and candesartan. Acebutolol, oxcarbazepine, lamotrigine, and
telmisartan are ineffective. Newer agents target calcitonin gene-related peptide pain transmission in the
migraine pain pathway and have recently received approval from the U.S. Food and Drug
Administration; however, more studies of long-term effectiveness and adverse effects are needed. The
complementary treatments petasites, feverfew, magnesium, and riboflavin are probably effective.
Nonpharmacologic therapies such as relaxation training, thermal biofeedback combined with relaxation
training, electromyographic feedback, and cognitive behavior therapy also have good evidence to
support their use in migraine prevention.
10 Evidence-Based Health Benefits of Magnesium

Written by Franziska Spritzler, RD, CDE on September 3, 2018. Healthline.com.
https://www.healthline.com/nutrition/10-proven-magnesium-benefits
Magnesium is a mineral found in the earth, sea, plants, animals and humans.
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About 60% of the magnesium in your body is found in bone, while the rest is in muscles, soft tissues and
fluids, including blood.
In fact, every cell in your body contains it and needs it to function.
One of magnesium's main roles is acting as a cofactor or "helper molecule" in the biochemical reactions
continuously performed by enzymes.
In fact, it’s involved in more than 600 reactions in your body, including :
• Energy creation: Helps convert food into energy.

• Protein formation: Helps create new proteins from amino acids.
• Gene maintenance: Helps create and repair DNA and RNA.
• Muscle movements: Is part of the contraction and relaxation of muscles.
Nervous system regulation: Helps regulate neurotransmitters, which send messages throughout your
brain and nervous system.
Unfortunately, studies suggest that about 50% of people in the US and Europe get less than the
recommended daily amount of magnesium.
MAGNESIUM
https://www.webmd.com/vitamins/ai/ingredientmono-998/magnesium
Magnesium is required for the proper growth and maintenance of bones. Magnesium is also required
for the proper function of nerves, muscles, and many other parts of the body. In the stomach,
magnesium helps neutralize stomach acid and moves stools through the intestine.
Magnesium supplementation improves indicators of low magnesium status

and inflammatory stress in adults older than 51 years with poor quality sleep.
Nielsen FH, Johnson LK, Zeng H. Magnes Res. 2010 Dec;23(4):158-68. doi:
10.1684/mrh.2010.0220. Epub 2011 Jan 4.
Abstract
Low magnesium status has been associated with numerous conditions characterized as having a chronic
inflammatory stress component. Some animal findings indicate that a moderate magnesium deficiency,
similar to which apparently commonly occurs in humans, may enhance inflammatory or oxidative stress
292
induced by other factors, including disrupted sleep/sleep deprivation. Thus, an experiment was
performed with 100 adults (22 males and 78 females) aged 59 ± 8 years (range 51 to 85 years) with poor
sleep quality revealed by a Pittsburg Sleep Quality Index (PSQI) score higher than five. The participants
were randomly assigned to two groups matched by gender, age, and overall PSQI score. After baseline
assessment (week one) of body mass index (BMI), diet, blood and urine biochemical variables, and sleep
quality, one group was given a 320 mg magnesium/day supplement as magnesium citrate and the other
group a sodium citrate placebo for seven weeks. Final assessments were made five and seven weeks
(which were combined for statistical analysis to reduce intra-individual variation) after supplement
initiation for the 96 participants who completed the study as designed. Based on food diaries, 58% of
the participants were consuming less than the US. Estimated Average Requirement (EAR) for
magnesium. Consuming less than the EAR was associated with a significantly higher BMI and plasma C-
reactive protein (CRP) concentration. Only 40 participants had plasma CRP concentrations higher than
3.0 mg/L (an indication of chronic inflammatory stress). Overall PSQI scores improved (10.4 to 6.6, p <
0.0001) and erythrocyte magnesium increased (4.75 to 5.05 pg/cell, p = 0.01) regardless of magnesium
or placebo supplementation. Magnesium vs placebo supplementation did not significantly affect serum
magnesium when all participants were included in the analysis. When only the 37 participants with
serum magnesium concentrations < 1.8 mg/dL (indication of deficient magnesium status) were
analyzed, magnesium supplementation, but not the placebo, increased serum magnesium
concentrations. Magnesium supplementation vs placebo decreased plasma CRP in participants with
baseline values > 3.0 mg/L. The findings show that many individuals have a low magnesium status
associated with increased chronic inflammatory stress that could be alleviated by increased magnesium
intake. Because dietary magnesium intake did not change during the experimental period, another
factor, possibly a placebo effect, improved sleep quality, which resulted in increased erythrocyte
magnesium. This factor prevented the determination of whether magnesium deficiency contributes to
poor sleep quality. The findings, however, suggest an association between magnesium status and sleep
quality that needs further study to definitively determine whether a low magnesium status is a cause or
an effect of poor sleep quality.
Magnesium supplementation, metabolic and inflammatory markers, and

global genomic and proteomic profiling: a randomized, double-blind,
controlled, crossover trial in overweight individuals.
Chacko SA, et al. Am J Clin Nutr. 2011 Feb;93(2):463-73. doi:
10.3945/ajcn.110.002949. Epub 2010 Dec 15.
Abstract
BACKGROUND:
293
Dietary magnesium intake has been favorably associated with reduced risk of metabolic outcomes in
observational studies; however, few randomized trials have introduced a systems-biology approach to
explore molecular mechanisms of pleiotropic metabolic actions of magnesium supplementation.
OBJECTIVE:
We examined the effects of oral magnesium supplementation on metabolic biomarkers and global
genomic and proteomic profiling in overweight individuals.
DESIGN:
We undertook this randomized, crossover, pilot trial in 14 healthy, overweight volunteers [body mass
index (in kg/m(2)) ≥25] who were randomly assigned to receive magnesium citrate (500 mg elemental
Mg/d) or a placebo for 4 wk with a 1-mo washout period. Fasting blood and urine specimens were
collected according to standardized protocols. Biochemical assays were conducted on blood specimens.
RNA was extracted and subsequently hybridized with the Human Gene ST 1.0 array (Affymetrix, Santa
Clara, CA). Urine proteomic profiling was analyzed with the CM10 ProteinChip array (Bio-Rad
Laboratories, Hercules, CA).
RESULTS:
We observed that magnesium treatment significantly decreased fasting C-peptide concentrations

(change: -0.4 ng/mL after magnesium treatment compared with +0.05 ng/mL after placebo treatment; P
= 0.004) and appeared to decrease fasting insulin concentrations (change: -2.2 μU/mL after magnesium
treatment compared with 0.0 μU/mL after placebo treatment; P = 0.25). No consistent patterns were
observed across inflammatory biomarkers. Gene expression profiling revealed up-regulation of 24 genes
and down-regulation of 36 genes including genes related to metabolic and inflammatory pathways such
as C1q and tumor necrosis factor-related protein 9 (C1QTNF9) and pro-platelet basic protein (PPBP).
Urine proteomic profiling showed significant differences in the expression amounts of several peptides
and proteins after treatment.
CONCLUSION:
Magnesium supplementation for 4 wk in overweight individuals led to distinct changes in gene

expression and proteomic profiling consistent with favorable effects on several metabolic pathways.
This trial was registered at clinicaltrials.gov as NCT00737815.
Effects of magnesium depletion on inflammation in chronic disease.

Nielsen FH. Curr Opin Clin Nutr Metab Care. 2014 Nov;17(6):525-30. doi:
10.1097/MCO.0000000000000093.
Abstract
294
PURPOSE OF REVIEW:
To update findings supporting the opinion that commonly occurring subclinical magnesium deficiency
induced by a low dietary intake is a predisposing factor for chronic inflammatory stress that contributes
to the incidence of chronic diseases such as cardiovascular disease and diabetes.
RECENT FINDINGS:
Both deficient magnesium intakes (<250 mg/day) and serum magnesium concentrations (≤ 0.75 mmol/l)
have been associated with elevated serum C-reactive protein concentration, a widely used indicator of
inflammation. Achieving magnesium intakes or serum magnesium concentrations that indicate an
adequate magnesium status generally attenuates elevated serum C-reactive protein to concentrations
that are not indicative of chronic low-grade inflammation. Individuals that are obese or have chronic
diseases for which low-grade inflammation is a risk factor are commonly found to be magnesium-
deficient.
SUMMARY:
Subclinical magnesium deficiency caused by low dietary intake often occurring in the population is a
predisposing factor for chronic inflammatory stress that is conducive for chronic disease. Magnesium
deficiency should be considered a nutrient of significant concern for health and well-being.
Magnesium, inflammation, and obesity in chronic disease.

Nielsen FH. Nutr Rev. 2010 Jun;68(6):333-40. doi: 10.1111/j.1753-
4887.2010.00293.x.
Abstract
About 60% of adults in the United States do not consume the estimated average requirement for
magnesium, but widespread pathological conditions attributed to magnesium deficiency have not been
reported. Nevertheless, low magnesium status has been associated with numerous pathological
conditions characterized as having a chronic inflammatory stress component. In humans, deficient
magnesium intakes are mostly marginal to moderate (approximately 50% to <100% of the
recommended dietary allowance). Animal experiments indicate that signs of marginal-to-moderate
magnesium deficiency can be compensated or exacerbated by other factors influencing inflammatory
and oxidative stress; recent studies suggest a similar happening in humans. This suggestion may have
significance in obesity, which is characterized as having a chronic low-grade inflammation component
and an increased incidence of a low magnesium status. Marginal-to-moderate magnesium deficiency
through exacerbating chronic inflammatory stress may be contributing significantly to the occurrence of
chronic diseases such as atherosclerosis, hypertension, osteoporosis, diabetes mellitus, and cancer.
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Burning magnesium, a sparkle in acute inflammation: gleams from

experimental models.
Castiglioni S, Cazzaniga A, Locatelli L, Maier JA. Magnes Res. 2017 Feb 1;30(1):8-
15. doi: 10.1684/mrh.2017.0418.
Abstract
Magnesium contributes to the regulation of inflammatory responses. Here, we focus on the role of
magnesium in acute inflammation. Although present knowledge is incomplete to delineate an accurate
scenario and a schedule of the events occurring under magnesium deficiency, it emerges that low
magnesium status favors the induction of acute inflammation by sensitizing sentinel cells to the noxious
agent, and then by participating to the orchestration of the vascular and cellular events that
characterize the process.
KEYWORDS:
acute inflammation; endothelial cells; leukocytes; magnesium
Exacerbated immune stress response during experimental magnesium

deficiency results from abnormal cell calcium homeostasis.
Malpuech-Brugère C, et al. Life Sci. 1998;63(20):1815-22.
Abstract
The aim of this study was to assess the potential mechanism underlying the enhanced inflammatory
processes during magnesium deficit. In this study, exacerbated response to live bacteria and platelet
activating factors was shown in rats fed a magnesium-deficient diet. Peritoneal cells from these animals
also showed enhanced superoxide anion production and calcium mobilising potency following in vitro
stimulation. The latter effect occurred very early in the course of magnesium deficiency. These studies
first showed that an abnormal calcium handling induced by extracellular magnesium depression in vivo
may be at the origin of exacerbated inflammatory response.
Inflammatory response following acute magnesium deficiency in the rat.

Malpuech-Brugère C, et al. Biochim Biophys Acta. 2000 Jun 15;1501(2-3):91-8.
296
Abstract
The importance of inflammatory processes in the pathology of Mg deficiency has been recently
reconsidered but the sequence of events leading to the inflammatory response remains unclear. Thus,
the purpose of the present study was to characterize more precisely the acute phase response following
Mg deficiency in the rat. Weaning male Wistar rats were pair-fed either a Mg-deficient or a control diet
for either 4 or 8 days. The characteristic allergy-like crisis of Mg-deficient rats was accompanied by a
blood leukocyte response and changes in leukocytes subpopulations. A significant increase in
interleukin-6 (IL-6) plasma level was observed in Mg-deficient rats compared to rats fed a control diet.
The inflammatory process was accompanied by an increase in plasma levels of acute phase proteins. The
concentrations of alpha2-macroglobulin and alpha1-acid glycoprotein in the plasma of Mg-deficient rats
were higher than in control rats. This was accompanied in the liver by an increase in the level of mRNA
coding for these proteins. Moreover, Mg-deficient rats showed a significant increase in plasma
fibrinogen and a significant decrease in albumin concentrations. Macrophages found in greater number
in the peritoneal cavity of Mg-deficient rats were activated endogenously and appeared to be primed
for superoxide production following phorbol myristate acetate stimulation. A high plasma level of IL-6
could be detected as early as day 4 for the Mg-deficient diet. Substance P does not appear to be the
initiator of inflammation since IL-6 increase was observed without plasma elevation of this
neuropeptide. The fact that the inflammatory response was an early consequence of Mg deficiency
suggests that reduced extracellular Mg might be responsible for the activated state of immune cells.
Magnesium sulfate inhibits inflammation through P2X7 receptors in human

umbilical vein endothelial cells.
Ozen M, et al. Pediatr Res. 2019 Sep 7. doi: 10.1038/s41390-019-0557-7. [Epub
ahead of print]
Abstract
INTRODUCTION:
Magnesium sulfate (MgSO4) is utilized for fetal neuroprotection in preterm birth but its mechanism of
action is still poorly understood. P2X7 receptor (P2X7R) is required for secretion of IL-1β, and can be
blocked by divalent cations such as magnesium (Mg) and its own antagonist, Brilliant Blue G (BBG). We
sought to determine whether during inflammation MgSO4 can block endothelial IL-1β secretion, using
an in vitro model.
METHODS:
Human umbilical vein endothelial cell (HUVEC) cultures were treated with varying doses of LPS, 2'(3)-Ο-
(4-Benzoylbenzoyl) adenosine-5'-triphosphate (BzATP), BBG and MgSO4 for 3- or 24 h. We determined
297
cell cytotoxicity, apoptosis, IL-1β mRNA expression, IL-1β production and secretion and P2X7R
expression on HUVECs.
RESULTS:
We demonstrated that MgSO4 is efficacious in blocking IL-1β-mediated-inflammation in HUVECs, at

both the initiation and propagation phases of inflammation. MgSO4 exerts these anti-inflammatory
effects via downregulation of P2X7Rs on HUVECs.
CONCLUSION:
LPS-exposure increases IL-1β production and secretion in HUVECs, which is further intensified by P2X7R
agonist, BzATP while MgSO4 inhibits IL-1β in both presence and absence of BzATP. This effect is similar
to the results of P2X7R antagonist, BBG, suggesting that the anti-inflammatory effects of MgSO4 is
through P2X7R.
Menthol (Mint, Mentha)

8 Health Benefits of Mint
Written by Keith Pearson, PhD, RD on December 13, 2017. Healthline.com.
https://www.healthline.com/nutrition/mint-benefits
Mint is the name for over a dozen plant species, including peppermint and spearmint that belong to the
genus Mentha.
These plants are particularly known for the cooling sensation they impart. They can be added to foods in
both fresh and dried forms.
Mint is a popular ingredient in several foods and beverages, ranging from teas and alcoholic drinks to
sauces, salads and desserts.
While eating the plant offers some health benefits, research shows that several of mint’s health benefits
come from applying it to the skin, inhaling its aroma or taking it as a capsule.
WILD MINT
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https://www.webmd.com/vitamins/ai/ingredientmono-189/wild-mint
Wild mint is an herb. The leaves are used to make medicine.
People take wild mint tea for diarrhea and menstrual cramps. It is also used as a drying agent
(astringent) and stimulant.
TRPM8 is the principal mediator of menthol-induced analgesia of acute and

inflammatory pain.
Liu B, Fan L, Balakrishna S, Sui A, Morris JB, Jordt SE. Pain. 2013
Oct;154(10):2169-77. doi: 10.1016/j.pain.2013.06.043. Epub 2013 Jun 29.
Abstract
Menthol, the cooling natural product of peppermint, is widely used in medicinal preparations for the
relief of acute and inflammatory pain in sports injuries, arthritis, and other painful conditions. Menthol
induces the sensation of cooling by activating TRPM8, an ion channel in cold-sensitive peripheral
sensory neurons. Recent studies identified additional targets of menthol, including the irritant receptor,
TRPA1, voltage-gated ion channels and neurotransmitter receptors. It remains unclear which of these
targets contribute to menthol-induced analgesia, or to the irritating side effects associated with menthol
therapy. Here, we use genetic and pharmacological approaches in mice to probe the role of TRPM8 in
analgesia induced by L-menthol, the predominant analgesic menthol isomer in medicinal preparations.
L-menthol effectively diminished pain behavior elicited by chemical stimuli (capsaicin, acrolein, acetic
acid), noxious heat, and inflammation (complete Freund's adjuvant). Genetic deletion of TRPM8
completely abolished analgesia by L-menthol in all these models, although other analgesics
(acetaminophen) remained effective. Loss of L-menthol-induced analgesia was recapitulated in mice
treated with a selective TRPM8 inhibitor, AMG2850. Selective activation of TRPM8 with WS-12, a
menthol derivative that we characterized as a specific TRPM8 agonist in cultured sensory neurons and in
vivo, also induced TRPM8-dependent analgesia of acute and inflammatory pain. L-menthol- and WS-12-
induced analgesia was blocked by naloxone, suggesting activation of endogenous opioid-dependent
analgesic pathways. Our data show that TRPM8 is the principal mediator of menthol-induced analgesia
of acute and inflammatory pain. In contrast to menthol, selective TRPM8 agonists may produce
analgesia more effectively, with diminished side effects.
KEYWORDS:
Acetic acid; Acrolein; Analgesia; Capsaicin; Heat; Inflammatory pain; Menthol; TRPA1; TRPM8; TRPV1;
Visceral pain
299
The role and mechanism of action of menthol in topical analgesic products.

Pergolizzi JV Jr, Taylor R Jr, LeQuang JA, Raffa RB; NEMA Research Group. J Clin
Pharm Ther. 2018 Jun;43(3):313-319. doi: 10.1111/jcpt.12679. Epub 2018 Mar
10.
Abstract
WHAT IS KNOWN AND OBJECTIVE:
Menthol has been used as a non-opioid pain reliever since ancient times. A modern understanding of its
molecular mechanism of action could form the basis for generating targets for discovery of novel non-
opioid analgesic drugs.
METHODS:
The PubMed database was queried using search words related to menthol, pain and analgesia. The
results were limited to relevant preclinical studies and clinical trials and reviews published in English
during the past 5 years, which yielded 31 reports. The bibliographies of these articles were sources of
additional supporting articles.
RESULTS:
Menthol is a selective activator of transient receptor potential melastatin-8 (TRPM8) channels and is
also a vasoactive compound. As a topical agent, it acts as a counter-irritant by imparting a cooling effect
and by initially stimulating nociceptors and then desensitizing them. Topically applied menthol may also
activate central analgesic pathways. At high concentrations, menthol may generate cold allodynia.
WHAT IS NEW AND CONCLUSIONS:
Recent elucidation of TRPM8 channels has provided a molecular basis for understanding the molecular
action of menthol and its ability to produce both a cooling sensation and reduction in pain associated
with a wide variety of pain(ful) conditions. The more modern mechanistic understanding of menthol and
its pharmacologic mechanism of action may lead to an expanded role for this substance in the search for
replacements for opioid analgesics, particularly those that can be applied topically.
KEYWORDS:
TRPM8; analgesic; calcium channel; menthol; non-opioid analgesic; topical analgesic

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Menthol: a refreshing look at this ancient compound.

Patel T1, Ishiuji Y, Yosipovitch G. J Am Acad Dermatol. 2007 Nov;57(5):873-8.
Epub 2007 May 10.
Abstract
Menthol is a naturally occurring cyclic terpene alcohol of plant origin, which has been used since
antiquity for medicinal purposes. Its use in dermatology is ubiquitous, where it is frequently part of
topical antipruritic, antiseptic, analgesic, and cooling formulations. Despite its widespread use, it was
only recently that the mechanism by which menthol elicits the same cool sensation as low temperature
was elucidated upon, with the discovery of the TRPM8 receptor. Although almost 5 years have passed
since the discovery of this receptor, many dermatologists are still unaware of menthol's underlying
target. The purpose of this review is to highlight the recent advances in the mechanism of action of
menthol and to provide an overview of its dermatologic application

Abstract
301
Comparison of the Effect of Topical Application of Rosemary and Menthol for

Musculoskeletal Pain in Hemodialysis Patients.
Keshavarzian S, Shahgholian N. Iran J Nurs Midwifery Res. 2017 Nov-
Dec;22(6):436-441. doi: 10.4103/ijnmr.IJNMR_163_16.
Abstract
Background:
Pain is the most common problem experienced by hemodialysis patients, especially musculoskeletal
pain in lower extremities, which is usually not completely treated and adversely affects their quality of
life. The present study was conducted with the aim to determine and compare the effects of topical
application of menthol and rosemary for musculoskeletal pain in hemodialysis patients.
Materials and Methods:
The present single-blind clinical trial recruited 105 eligible patients undergoing hemodialysis in selected
hospitals affiliated to Isfahan University of Medical Sciences; patients were selected by convenient
sampling. Participants' severity of pain was determined prior to intervention. They were then randomly
divided into rosemary, menthol, and placebo groups. All three groups applied medication on the site of
pain on their legs three times a day for three days and recorded the severity of pain four hours after
morning and afternoon applications. The statistical analysis of data was performed using SPSS 18.
Results:
The mean score of severity of pain before the intervention was not significantly different among the
three groups (p = 0.83), but it became significantly different after intervention (p = 0.001). Significant
differences were observed in mean severity of pain before and after intervention in rosemary and
menthol groups (p < 0.001), but not in the placebo group (p = 0.21).
Conclusions:
302
Topical application of menthol and rosemary can alleviate severity and frequency of recurrence of
musculoskeletal pain in hemodialysis patients; however, according to the results of the study, none had
precedence over the other.
KEYWORDS:
Hemodialysis; Iran; menthol; pain; rosemary
Efficacy and safety profile of a topical methyl salicylate and menthol patch in
adult patients with mild to moderate muscle strain: a randomized, double-
blind, parallel-group, placebo-controlled, multicenter study.
Higashi Y, Kiuchi T, Furuta K. Clin Ther. 2010 Jan;32(1):34-43. doi:
10.1016/j.clinthera.2010.01.016.
Abstract
BACKGROUND:
An occlusive patch formulation containing 10% methyl salicylate and 3% l-menthol was recently
approved by the US Food and Drug Administration for the treatment of mild to moderate pain. Despite
widespread use of counterirritants, including methyl salicylate and menthol, for topical pain relief,
published efficacy and safety data regarding the use of the agents alone or in combination are limited.
OBJECTIVE:
The goal of this study was to determine the efficacy and safety profile of a patch containing 10% methyl
salicylate and 3% l-menthol compared with a placebo patch in adult patients with mild to moderate
muscle strain.
METHODS:
Eligible patients were men or women aged >or=18 years with a clinical diagnosis of mild to moderate
muscle strain. Patients were randomly assigned to receive either 1 active patch or 1 placebo patch
applied to the skin at the affected area (ie, shoulder, upper back, upper arm, neck, calf, thigh, forearm,
abdomen). Pain intensity was assessed on a 100-mm visual analog scale while at rest and with
movement for 12 hours after patch application. The primary efficacy end point was the summed pain
intensity difference score through 8 hours (SPID8) with movement. Analyses included use of descriptive
statistics and an ANOVA model. Safety data, including adverse events, and secondary efficacy end points
were also evaluated.
RESULTS:
303
A total of 208 patients (104 men, 104 women; age range, 18-78 years) were randomized to 1 of 2 study
groups (105 in the active-patch group [mean age, 37.3 years], 103 in the placebo-patch group [mean
age, 38.1 years]). The primary efficacy analysis (SPID8 with movement) indicated that patients receiving
the active patch experienced significantly greater pain relief (approximately 40%) than those patients
receiving a placebo patch (mean [SD], 182.6 [131.2] vs 130.1 [144.1]; P = 0.005). Analysis of the per-
protocol population also found significantly more relief (P = 0.024) in the active-patch group (176.2
[131.4]; n = 92) versus the placebo-patch group (130.2 [144.0]; n = 96). Statistical analysis of secondary
efficacy measures supported the primary end-point results. The number of patients experiencing any
type of adverse event was comparable between study groups (active patch, 6.7% [7 events]; placebo
patch, 5.8% [6 events]). No serious adverse events were reported during the study.
CONCLUSION:
A single, 8-hour application of a patch containing methyl salicylate and l-menthol provided significant
relief of pain associated with mild to moderate muscle strain in these adult patients compared with
patients receiving a placebo patch.
Comparison of diclofenac gel, ibuprofen gel, and ibuprofen gel with

levomenthol for the topical treatment of pain associated with musculoskeletal
injuries.
Wade AG, Crawford GM, Young D, Corson S, Brown C. J Int Med Res. 2019 Jul
29:300060519859146. doi: 10.1177/0300060519859146. [Epub ahead of print]
KEYWORDS:
Analgesic; diclofenac; ibuprofen; levomenthol; menthol; pain relief; topical
Delayed Onset Muscle Soreness and Topical Analgesic Alter Corticospinal

Excitability of the Biceps Brachii.
Stefanelli L, et al. Med Sci Sports Exerc. 2019 May 29. doi:
10.1249/MSS.0000000000002055. [Epub ahead of print]
Abstract
INTRODUCTION:
304
The interactive effect of delayed onset muscle soreness (DOMS) and a topical analgesic on corticospinal
excitability was investigated.
METHODS:
Thirty-two participants completed Experiments A (No DOMS) and B (DOMS). For each experiment
participants were randomly assigned to two groups: 1) topical analgesic gel (Topical Analgesic, n=8), or
2) placebo gel (Placebo, n=8) group. Prior to the application of gel (pre-gel), as well as 5, 15, 30, and 45
min post-gel, motor evoked potential (MEP) area, latency, and silent period, as well as cervicomedullary
MEP (CMEP) and maximal compound motor unit action potential (Mmax) areas and latencies were
measured. In addition, pressure-pain threshold (PPT) was measured pre-DOMS and at the same time
points in Experiment B.
RESULTS:
In Experiment A, neither group showed a significant change for any outcome measure. In Experiment B,
both groups exhibited a significant decrease in PPT from pre-DOMS to pre-gel. Following the application
of topical analgesic, but not placebo, there was a significant increase in PPT at 45 min post-gel,
respectively compared to pre-gel and a main effect of time for the silent period to increase compared to
pre-gel. Participants with DOMS had reduced MEP and CMEP areas, and increased corticospinal silent
periods compared to those who did not have DOMS.
CONCLUSION:
These findings suggest that DOMS reduced corticospinal excitability and following the administration of
menthol-based topical analgesic there was a reduction in pain, which was accompanied by increased
corticospinal inhibition.
Milk Thistle
Silybum marianum (milk thistle) and its main constituent, silymarin, as a
potential therapeutic plant in metabolic syndrome: A review.
Tajmohammadi A, Razavi BM, Hosseinzadeh H. Phytother Res. 2018
Oct;32(10):1933-1949. doi: 10.1002/ptr.6153. Epub 2018 Jul 17.
305
Abstract
Metabolic syndrome describes a complex metabolic risk factors including obesity, hypertension,
dyslipidemia, and diabetes. This syndrome is diagnosed by medical conditions such as weight gain, high
blood pressure, high blood glucose, and disturbance in lipid profile. Metabolic syndrome has become as
an important and increasing global health problem, so finding potentially novel solutions with less
adverse effects is favorable for health problems. Herbal therapy plays an important role for treatment of
different diseases. Silybum marianum is a plant that is used for centuries as a herbal treatment in liver
and biliary tract diseases. Silymarin is the main component of S. marianum and derived from fruits and
seeds of S. marianum (milk thistle). S. marianum has been found to exhibit antioxidant, lipid-lowering,
antihypertensive, antidiabetic, antiatherosclerotic, anti-obesity, and hepatoprotective effects.
Therefore, the aim of this review is to summarize different animal and human studies regarding the
effect of S. marianum in metabolic syndrome and to identify the underlying mechanisms of action.
© 2018 John Wiley & Sons, Ltd.
KEYWORDS:
Silybum marianum; diabetes; dyslipidemia; hypertension; metabolic syndrome; milk thistle; obesity;
silibyn; silymarin
Effects of silymarin on metabolic syndrome: a review.

Vahabzadeh M, Amiri N, Karimi G. J Sci Food Agric. 2018 Oct;98(13):4816-4823.
doi: 10.1002/jsfa.9115. Epub 2018 Jun 27.
Abstract
Metabolic syndrome is one of the rising global health problems and medical challenges due to several
clinical complications it may cause, for example increasing the risk of myocardial infarction and
hypertension. However, great attention has been directed toward determining the worthiness of herbal
medicines. There are emerging studies on preventive and therapeutic effects of silymarin on different
components of metabolic syndrome. Extracted from the dried seeds of milk thistle plant (Silybum
marianum L.), silymarin has been used in the treatment of different diseases for many years. Several
protective effects have been identified for this herb such as decreasing insulin resistance, regulating
blood pressure and lipid profile, as well as antioxidant and cytoprotective effects. This review aims to
discuss available human and experimental researches into the promising effects of silymarin on different
elements of metabolic syndrome. All related human and experimental papers published from 2012 to
date were included in this review. Reviewing different human and experimental studies into the effects
of silymarin on metabolic syndrome, we deduced that silymarin possesses promising effects on different
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components of this syndrome. Although the complete mechanism of action and target organs for
silymarin require further verification and investigation, high-risk individuals may benefit from
supplementation with this herbal medicine.
© 2018 Society of Chemical Industry.
KEYWORDS:
diabetes; dyslipidemia; hypertension; metabolic syndrome; milk thistle; silymarin
The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of

type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial.
Huseini HF, et al. Phytother Res. 2006 Dec;20(12):1036-9.
Abstract
Oxidative stresses are increasingly implicated in the pathogenesis of diabetic complications which may
either cause direct pancreatic beta-cell damage or lead to metabolic abnormalities that can induce or
aggravate diabetes. The valuable effect of antioxidant nutrients on the glycemic control of diabetic
patients has been reported in experimental and clinical studies. The present study was designed to
investigate the effects of the herbal medicine, Silybum marianum seed extract (silymarin), which is
known to have antioxidant properties on the glycemic profile in diabetic patients. A 4-month
randomized double-blind clinical trial was conducted in 51 type II diabetic patients in two well-matched
groups. The first group (n = 25) received a silymarin (200 mg) tablet 3 times a day plus conventional
therapy. The second group (n = 26) received the same therapy but a placebo tablet instead of silymarin.
The patients were visited monthly and glycosylated hemoglobin (HbA(1)c), fasting blood glucose (FBS),
insulin, total cholesterol, LDL and HDL, triglyceride, SGOT and SGPT levels were determined at the
beginning and the end of the study. The results showed a significant decrease in HbA(1)c, FBS, total
cholesterol, LDL, triglyceride SGOT and SGPT levels in silymarin treated patients compared with placebo
as well as with values at the beginning of the study in each group. In conclusion, silymarin treatment in
type II diabetic patients for 4 months has a beneficial effect on improving the glycemic profile.
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Milk thistle (Silybum marianum): A concise overview on its chemistry,

pharmacological, and nutraceutical uses in liver diseases.
Abenavoli L, et al. Phytother Res. 2018 Nov;32(11):2202-2213. doi:
10.1002/ptr.6171. Epub 2018 Aug 6.
Abstract
Milk thistle (MT; Silybum marianum), a member of the Asteraceae family, is a therapeutic herb with a
2,000-year history of use. MT fruits contain a mixture of flavonolignans collectively known as silymarin,
being silybin (also named silibinin) the main component. This article reviews the chemistry of MT, the
pharmacokinetics and bioavailability, the pharmacologically relevant actions for liver diseases (e.g., anti-
inflammatory, immunomodulating, antifibrotic, antioxidant, and liver-regenerating properties) as well as
the clinical potential in patients with alcoholic liver disease, nonalcoholic fatty liver disease, viral
hepatitis, drug-induced liver injury, and mushroom poisoning. Overall, literature data suggest that,
despite encouraging preclinical data, further well-designed randomized clinical trials are needed to fully
substantiate the real value of MT preparations in liver diseases.
© 2018 John Wiley & Sons, Ltd.
KEYWORDS:
liver fibrosis; oxidative stress; silybin; silymarin
Flavonolignans: One Step Further in the Broad-Spectrum Approach of Cancer.

Antal DS, et al. Anticancer Agents Med Chem. 2020 Jan 23. doi:
Abstract
BACKGROUND:
The small chemical class of flavonolignans encompasses unique hybrid molecules with versatile
biological activities. Their anticancer effects have received considerable attention, and a large body of
supporting evidence has accumulated. Moreover, their ability to interact with proteins involved in drug
308
resistance, and to enhance the effects of conventional chemotherapeutics in decreasing cell viability
make them influential partners in addressing cancer.
OBJECTIVE:
The review provides an outline of the various ways in which flavonolignans advance the combat against
cancer. While the main focus falls on flavonolignans from milk thistle, attention is drawn to the yet
underexplored potential of less known flavonolignan subgroups derived from isoflavonoids and aurones.
METHODS:
Proceeding from the presentation of natural flavonolignan subtypes and their occurrence, the present
work reviews these compounds with regard to their molecular targets in cancer, anti-angiogenetic
effects, synergistic efficacy in conjunction with anticancer agents, reversal of drug resistance, and
importance in overcoming the side effects of anticancer therapy. Recent advances in the endeavor to
improve flavonolignan bioavailability in cancer are also presented.
CONCLUSIONS:
Significant progress has been achieved in detailing the molecular mechanisms of silybin and its
congeners in experimental models of cancer. The availability of novel formulations with improved
bioavailability, and data from phase I clinical trials in cancer patients provide an encouraging basis for
more extensive trials aimed at evaluating the benefits of Silybum flavonolignans in cancer management.
On the other hand, further research on the antitumor efficacy of isoflavonolignans and other subtypes
of flavonolignans should be pursued.
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
KEYWORDS:
Anti-angiogenetic; Chemical structure; Isoflavonolignans; Nanoformulation; Pro-apoptotic; Silybum

flavonolignans
309
The effect of milk thistle (Silybum marianum) and its main flavonolignans on
CYP2C8 enzyme activity in human liver microsomes.
Albassam AA, Frye RF, Markowitz JS. Chem Biol Interact. 2017 Jun 1;271:24-29.
doi: 10.1016/j.cbi.2017.04.025. Epub 2017 Apr 27.
Abstract
Milk thistle is a widely-consumed botanical used for an array of purported health benefits. The primary
extract of milk thistle is termed silymarin, a complex mixture that contains a number of structurally-
related flavonolignans, the flavonoid, taxifolin, and a number of other constituents. The major
flavonolignans present in most extracts are silybin A, silybin B, isosilybin A and isosilybin B, silydianin,
silychristin and isosilychristin. Silymarin itself has been reported to inhibit CYP2C8 activity in vitro, but
the effect of the individual flavonolignans on this enzyme has not been studied. To investigate the
effects of milk thistle extract and its main flavonolignans (silybin A, silybin B, isosilybin A and isosilybin B)
on CYP2C8 activity at relevant concentrations, the effect of milk thistle extract and the flavonolignans on
CYP2C8 enzyme activity was studied in vitro using human liver microsomes (HLM) incorporating an
enzyme-selective substrate for CYP2C8, amodiaquine. Metabolite formation was analyzed using liquid
chromatography-tandem mass spectrometry (LC/MS-MS). The concentration causing 50% inhibition of
enzyme activity (IC50) was used to express the degree of inhibition. Isosilibinin, a mixture of the
diastereoisomers isosilybin A and isosilybin B, was found to be the most potent inhibitor, followed by
isosilybin B with IC50 values (mean ± SE) of 1.64 ± 0.66 μg/mL and 2.67 ± 1.18 μg/mL, respectively. The
rank order of observed inhibitory potency after isosilibinin was silibinin > isosilybin A > silybin A > milk
thistle extract > and silybin B. These in vitro results suggest a potentially significant inhibitory effect of
isosilibinin and isosilybin B on CYP2C8 activity. However, the observed IC50 values are unlikely to be
achieved in humans supplemented with orally administered milk thistle extracts due to the poor
bioavailability of flavonolignans documented with most commercially available formulations.
KEYWORDS:
Cytochrome P450; Drug metabolism; Enzyme inhibition; Isosilybin; Milk thistle; Silybin; Silymarin
310
Molecular Hydrogen
Molecular Hydrogen as a Neuroprotective Agent.
Iketani M, Ohsawa I. Curr Neuropharmacol. 2017;15(2):324-331.
Abstract
Oxidative stress and neuroinflammation cause many neurological disorders. Recently, it has been
reported that molecular hydrogen (H2) functions as an antioxidant and anti-inflammatory agent. The
routes of H2 administration in animal model and human clinical studies are roughly classified into three
types, inhalation of H2 gas, drinking H2-dissolved water, and injection of H2-dissolved saline. This review
discusses some of the remarkable progress that has been made in the research of H2 use for
neurological disorders, such as cerebrovascular diseases, neurodegenerative disorders, and neonatal
brain disorders. Although most neurological disorders are currently incurable, these studies suggest the
clinical potential of H2 administration for their prevention, treatment, and mitigation. Several of the
potential effectors of H2 will also be discussed, including cell signaling molecules and hormones that are
responsible for preventing oxidative stress and inflammation. Nevertheless, further investigation will be
required to determine the direct target molecule of H2.
Molecular hydrogen as a novel antioxidant: overview of the advantages of

hydrogen for medical applications.
Ohta S. Methods Enzymol. 2015;555:289-317. doi: 10.1016/bs.mie.2014.11.038.
Epub 2015 Jan 21.
Abstract
Molecular hydrogen (H2) was believed to be inert and nonfunctional in mammalian cells. We overturned
this concept by demonstrating that H2 reacts with highly reactive oxidants such as hydroxyl radical
((•)OH) and peroxynitrite (ONOO(-)) inside cells. H2 has several advantages exhibiting marked effects for
medical applications: it is mild enough neither to disturb metabolic redox reactions nor to affect
311
signaling by reactive oxygen species. Therefore, it should have no or little adverse effects. H2 can be
monitored with an H2-specific electrode or by gas chromatography. H2 rapidly diffuses into tissues and
cells to exhibit efficient effects. Thus, we proposed the potential of H2 for preventive and therapeutic
applications. There are several methods to ingest or consume H2: inhaling H2 gas, drinking H2-dissolved
water (H2-water), injecting H2-dissolved saline (H2-saline), taking an H2 bath, or dropping H2-saline
onto the eyes. Recent publications revealed that, in addition to the direct neutralization of highly
reactive oxidants, H2 indirectly reduces oxidative stress by regulating the expression of various genes.
Moreover, by regulating gene expression, H2 functions as an anti-inflammatory, antiallergic, and
antiapoptotic molecule, and stimulates energy metabolism. In addition to growing evidence obtained by
model animal experiments, extensive clinical examinations were performed or are under way. Since
most drugs specifically act on their specific targets, H2 seems to differ from conventional
pharmaceutical drugs. Owing to its great efficacy and lack of adverse effects, H2 has potential for clinical
applications for many diseases.
© 2015 Elsevier Inc. All rights reserved.
KEYWORDS:
Clinical examination; Hydroxyl radical; Inert gas; No adverse effect; Peroxynitrite; Rapid diffusion;
Selective reduction
Molecular hydrogen as a preventive and therapeutic medical gas: initiation,

development and potential of hydrogen medicine.
Ohta S. Pharmacol Ther. 2014 Oct;144(1):1-11. doi:
10.1016/j.pharmthera.2014.04.006. Epub 2014 Apr 24.
Abstract
Molecular hydrogen (H2) has been accepted to be an inert and nonfunctional molecule in our body. We
have turned this concept by demonstrating that H2 reacts with strong oxidants such as hydroxyl radical
in cells, and proposed its potential for preventive and therapeutic applications. H2 has a number of
advantages exhibiting extensive effects: H2 rapidly diffuses into tissues and cells, and it is mild enough
neither to disturb metabolic redox reactions nor to affect signaling reactive oxygen species; therefore,
there should be no or little adverse effects of H2. There are several methods to ingest or consume H2;
inhaling H2 gas, drinking H2-dissolved water (H2-water), injecting H2-dissolved saline (H2-saline), taking
an H2 bath, or dropping H2-saline into the eyes. The numerous publications on its biological and medical
benefits revealed that H2 reduces oxidative stress not only by direct reactions with strong oxidants, but
312
also indirectly by regulating various gene expressions. Moreover, by regulating the gene expressions, H2
functions as an anti-inflammatory and anti-apoptotic, and stimulates energy metabolism. In addition to
growing evidence obtained by model animal experiments, extensive clinical examinations were
performed or are under investigation. Since most drugs specifically act to their targets, H2 seems to
differ from conventional pharmaceutical drugs. Owing to its great efficacy and lack of adverse effects,
H2 has promising potential for clinical use against many diseases.
KEYWORDS:
Anti-inflammation; Antioxidant; Clinical examination; No adverse effect; Oxidative stress; Reactive

oxygen species
Effects of Molecular Hydrogen Assessed by an Animal Model and a

Randomized Clinical Study on Mild Cognitive Impairment.
Nishimaki K, et al. Curr Alzheimer Res. 2018 Mar 14;15(5):482-492. doi:
10.2174/1567205014666171106145017.
Abstract
BACKGROUND:
Oxidative stress is one of the causative factors in the pathogenesis of neurodegenerative diseases
including mild cognitive impairment (MCI) and dementia. We previously reported that molecular
hydrogen (H2) acts as a therapeutic and preventive antioxidant.
OBJECTIVE:
We assess the effects of drinking H2-water (water infused with H2) on oxidative stress model mice and
subjects with MCI.
METHODS:
313
Transgenic mice expressing a dominant-negative form of aldehyde dehydrogenase 2 were used as a

dementia model. The mice with enhanced oxidative stress were allowed to drink H2-water. For a
randomized double-blind placebo-controlled clinical study, 73 subjects with MCI drank ~300 mL of H2-
water (H2-group) or placebo water (control group) per day, and the Alzheimer's Disease Assessment
Scale-cognitive subscale (ADAS-cog) scores were determined after 1 year.
RESULTS:
In mice, drinking H2-water decreased oxidative stress markers and suppressed the decline of memory
impairment and neurodegeneration. Moreover, the mean lifespan in the H2-water group was longer
than that of the control group. In MCI subjects, although there was no significant difference between
the H2- and control groups in ADAS-cog score after 1 year, carriers of the apolipoprotein E4 (APOE4)
genotype in the H2-group were improved significantly on total ADAS-cog score and word recall task
score (one of the sub-scores in the ADAS-cog score).
CONCLUSION:
H2-water may have a potential for suppressing dementia in an oxidative stress model and in the APOE4
carriers with MCI.
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
KEYWORDS:
ADAS-cog score; ApoE4; aldehyde dehydrogenase 2; hydrogen; hydrogen water; mild cognitive
impairment; oxidative stress; randomized clinical study
Hydrogen ameliorates chronic intermittent hypoxia-induced neurocognitive

impairment via inhibiting oxidative stress.
Li W, et al. Brain Res Bull. 2018 Oct;143:225-233. doi:
10.1016/j.brainresbull.2018.09.012. Epub 2018 Sep 20.
Abstract
314
Obstructive sleep apnea (OSA) is a very common breathing and sleep disorder characterized by
intermittent hypoxia (IH), which is often associated with behavioral and neurocognitive functions
impairment. Hydrogen (H2), as a novel and effective antioxidant, is reported to be a potential
neuroprotective agent. The aim of this study is to investigate whether H2 could improve CIH-induced
neurocognitive impairment and the related mechanism. Rats were exposed to IH for 5 weeks (8 h/day)
and/or inhalation of H2 gas 2 h/day. Morris Water Maze test was used to appraise the spatial reference
and working memory. The oxidative stress was evaluated through the level of MDA and SOD and
apoptosis of hippocampal neurons was assayed with Bcl-2/Bax ratio and TUNEL staining. Our results
showed that H2 treatment improved the CIH-induced spatial learning and memory impairments.
Moreover, inhalation of H2 gas reduced the level of MDA and increased in the activity of SOD, indicating
suppressed CIH-induced oxidative stress. In addition, H2 could increase expression of Bcl-2/Bax ratio and
inhibited neurons apoptosis in hippocampus. In conclusion, these results suggest that inhalation of H2
could attenuate the CIH-induced neurocognitive functions impairment via anti-oxidant and anti-
apoptosis effect. Additional, our findings may provide a potential therapeutic for neurocognitive
diseases in patients with OSA.
KEYWORDS:
Apoptosis; Chronic intermittent hypoxia; Hydrogen; Neurocognitive impairment; Oxidative stress
Hydrogen protects against chronic intermittent hypoxia induced renal

dysfunction by promoting autophagy and alleviating apoptosis.
Guan P, et al. Life Sci. 2019 May 15;225:46-54. doi: 10.1016/j.lfs.2019.04.005.
Epub 2019 Apr 2.
Abstract
AIMS:
Hydrogen gas (H2) has a diversity of effects such as anti-apoptotic, anti-inflammatory and anti-oxidative
properties. However, molecular mechanism underlying the potential effect of H2 on chronic
intermittent hypoxia (CIH) induced renal injury remains obscure.

315
In the present study, adult male Sprague-Dawley rats were randomly allocated into four groups: control
(CON) group, CIH group, CIH with H2 treatment (CIH + H2) group, and control with H2 treatment
(CON + H2) group. Oxidative stress, autophagy and endoplasmic reticulum (ER) stress were detected to
determine how H2 affected the renal function of CIH exposed rats.
KEY FINDINGS:
We demonstrated that rats who inhale hydrogen gas showed improved renal function, alleviated
pathological damage, oxidative stress and apoptosis in CIH rats. Meanwhile, CIH-induced endoplasmic
reticulum stress was decreased by H2 as the expressions of CHOP, caspase-12, and GRP78 were down-
regulated. Furthermore, relative higher levels of LC3-II/I ratio and Beclin-1, with decreased expression of
p62, were found after H2 administrated. Inhibition of mTOR may be involved in the upregulation of
autophagy by H2. Finally, increased phosphorylation of p38 and JNK was involved in the CIH-induced
pathological process. H2 could inhibit the activation of p38 and JNK, suggesting H2 played an active part
in resisting renal injury via MAPK.
SIGNIFICANCE:
Taken together, our study reveals that H2 can ameliorate CIH-induced kidney injury by decreasing
endoplasmic reticulum stress and activating autophagy through inhibiting oxidative stress-dependent
p38 and JNK MAPK activation.
KEYWORDS:
Autophagy; Chronic intermittent hypoxia; ER stress; Hydrogen; Kidney
The preventive and therapeutic effects of molecular hydrogen in ocular

diseases and injuries where oxidative stress is involved.
Cejka C, Kubinova S, Cejkova J. Free Radic Res. 2019 Mar;53(3):237-247. doi:
10.1080/10715762.2019.1582770. Epub 2019 Mar 19.
Abstract
316
Oxidative stress initiates, accompanies and contributes to the development of several human diseases
and injuries, including ocular diseases. Reactive oxygen species (ROS) can generate oxidative stress via
excessive ROS production and/or decreased physiologically occurring antioxidants. To replace these
weakened antioxidants, substances with effective antioxidant properties are needed in order to
suppress oxidative stress and enable healing. Molecular hydrogen (H2) is very suitable for this purpose
due to its unique properties. H2 is the only antioxidant that crosses the blood-brain and blood-ocular
barriers. It quickly penetrates through tissue due to its small molecular size and effectively removes ROS,
mainly hydroxyl radicals and peroxynitrite. Apart from its antioxidant effects, H2 also displays anti-
inflammatory, antiapoptotic, cytoprotective and mitohormetic properties. A significant advantage of H2
is its nontoxicity, even when applied at high concentrations. In this review, we present the results of
studies utilising H2 in the treatment of ocular diseases involving oxidative stress. These results, obtained
in experimental animals as well as in human clinical studies, show that the suppression of oxidative
stress by H2 treatment leads to the prevention or improvement of ocular diseases. In severe
degenerative diseases, H2 slows disease progression.
KEYWORDS:
Molecular hydrogen; ocular diseases and injuries; reactive oxygen species
MSM
Methylsulfonylmethane: Applications and Safety of a Novel Dietary
Supplement.
Butawan M, Benjamin RL, Bloomer RJ. Nutrients. 2017 Mar 16;9(3). pii: E290. doi:
10.3390/nu9030290.
Abstract
Methylsulfonylmethane (MSM) has become a popular dietary supplement used for a variety of
purposes, including its most common use as an anti-inflammatory agent. It has been well-investigated in
animal models, as well as in human clinical trials and experiments. A variety of health-specific outcome
measures are improved with MSM supplementation, including inflammation, joint/muscle pain,
oxidative stress, and antioxidant capacity. Initial evidence is available regarding the dose of MSM
needed to provide benefit, although additional work is underway to determine the precise dose and
time course of treatment needed to provide optimal benefits. As a Generally Recognized As Safe (GRAS)
approved substance, MSM is well-tolerated by most individuals at dosages of up to four grams daily,
317
with few known and mild side effects. This review provides an overview of MSM, with details regarding
its common uses and applications as a dietary supplement, as well as its safety for consumption.
KEYWORDS:
MSM; dimethyl sulfone; inflammation; joint pain; methylsulfonylmethane
A randomized controlled trial evaluating methylsulfonylmethane versus

placebo to prevent knee pain in military initial entry trainees.
Tennent DJ, Hylden CM, Kocher BK, Aden JK, Johnson AE. US Army Med Dep J. 2017
Oct-Dec;(3-17):21-25.
Abstract
BACKGROUND:
Methylsulfonylmethane (MSM) is a naturally occurring sulfur containing substance that has been shown
to have anti-inflammatory and antioxidative properties. Previous studies using MSM as an oral
supplement to improve pain in those patients with knee osteoarthritis have shown superiority
compared to placebo. However, these studies are not translatable to active individuals performing high
impact activities and have not evaluated MSM as a preventative measure.
METHODS:
A total of 180 subjects ranging in age from 18 to 40 years were enrolled. Subjects were randomized into
2 groups receiving either 3 grams OptiMSM methylsulfonylmethane (Bergstrom Nutrition, Vancouver,
WA) or a placebo for 8 weeks. Outcomes measured were the Knee Osteoarthritis Outcome Score (KOOS)
and the Profile of Moods States (POMS).
RESULTS:
Three grams of MSM administered daily did not provide significant improvements in the 5 KOOS
subscales or the 6 POMS subscales at 30 days or 60 days.
CONSLUSION:
Although 3 grams of MSM daily can be used safely, there does not appear to be a significant
improvement in KOOS or POMS.
318
Dimethyl Sulfoxide (DMSO) and Methylsulfonylmethane (MSM) for

Osteoarthritis
National Center for Complementary and Integrative Health (NCCIH).
NCIH.nih.gov. September 24, 2017
https://nccih.nih.gov/health/supplements/dmso-msm
Dimethyl sulfoxide (DMSO) and methylsulfonylmethane (MSM) are two chemically related substances
that have been studied for osteoarthritis. DMSO is used topically (applied to the skin). MSM is sold as a
dietary supplement, either alone or in combination with other ingredients such as glucosamine.
Bottom Line
Only a small amount of research has been conducted on DMSO or MSM for osteoarthritis. No
conclusions can be reached about whether either of these substances is helpful.
Safety
The safety of DMSO and MSM is uncertain because little research has been done on this topic. Side
effects of DMSO include digestive upset, skin irritation, and a garlic-like taste, breath, and body odor.
Side effects of MSM include allergic reactions, digestive upsets, and skin rashes.
If you’re using or considering DMSO or MSM for osteoarthritis, consult your health care provider.
8 Science-Backed Benefits of MSM Supplements

Written by Jillian Kubala, MS, RD on May 21, 2018. Healthline.com
https://www.healthline.com/nutrition/msm-supplements
Methylsulfonylmethane, more commonly known as MSM, is a popular dietary supplement used to treat
a wide array of symptoms and conditions.
It’s a sulfur-containing compound found naturally in plants, animals and humans. It can also be
produced in a lab to create dietary supplements in powder or capsule form.
MSM is widely used in the alternative medicine field and by people looking for a natural way to relieve
joint pain, reduce inflammation and boost immunity.
In addition, research supports its use in treating a number of conditions from arthritis to rosacea.
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Assessment of safety and efficacy of methylsulfonylmethane on bone and knee

joints in osteoarthritis animal model.
Ezaki J, Hashimoto M, Hosokawa Y, Ishimi Y. J Bone Miner Metab. 2013
Jan;31(1):16-25. doi: 10.1007/s00774-012-0378-9. Epub 2012 Aug 10.
https://www.ncbi.nlm.nih.gov/pubmed/23011466/
Abstract
Methylsulfonylmethane (MSM), which is one of the popular ingredients of so-called health foods in
Japan, is expected to relieve inflammation in arthritis and allergies. However, there is no scientific
evidence to confirm the efficacy and safety of MSM in detail. In this study, we examined the effects of
MSM on cartilage formation in growing rats (G) and cartilage degradation in STR/Ort mice (A), an
accepted human osteoarthritis (OA) model. For cartilage formation study, 6-week-old growing male
Wister rats were assigned to four groups to receive a control or MSM-containing diet. To examine the
efficacy of MSM on the cartilage of OA model mouse, 10-week-old male STR/OrtCrlj mice were assigned
to three groups to receive a control or MSM-containing diet. The dosages used were amounts equal to
the recommended supplements for humans [0.06 g/kg body weight (BW)/day: MSM1G and MSM1A], 10
fold higher (0.6 g/kg BW/day: MSM10G and MSM10A), and 100 fold higher (6 g/kg BW/day: MSM100G).
Intake of MSM for 4 weeks did not affect cartilage formation in the knee joint in growing rats. Body,
liver, and spleen weight in the MSM100G group were significantly lower than those in the control group.
Intake of MSM for 13 weeks decreased degeneration of the cartilage at the joint surface in the knee
joints in STR/Ort mice in a dose-dependent manner. These results suggest that appropriate intake of
MSM is possibly effective in OA model mice; however, intake of large amounts of MSM induced atrophy
of several organs.
Efficacy of methylsulfonylmethane supplementation on osteoarthritis of the

knee: a randomized controlled study.
Debbi EM1, et al. BMC Complement Altern Med. 2011 Jun 27;11:50. doi:
10.1186/1472-6882-11-50.
Abstract
BACKGROUND:
Patients with osteoarthritis (OA) take a variety of health supplements in an attempt to reduce pain and
improve function. The aim of this study was to determine the efficacy of methylsulfonylmethane (MSM)
in treating patients with knee OA.
METHODS:
320
This study was a prospective, randomized, double-blind, controlled clinical trial. Forty nine men and
women 45-90 (mean 68 ± SD 7.3) years of age with knee OA according to the American College of
Rheumatology clinical criteria for OA of the knee and with radiographic confirmed knee OA were
enrolled in the study and randomly assigned into 2 groups: One received MSM in doses of 1.125 grams 3
times daily for 12 weeks and the other received a placebo in the same dosing frequency. The primary
outcomes were the WOMAC Osteoarthritis Index for pain, stiffness and physical function, the
Aggregated Locomotor Function (ALF) test that evaluates each patient's physical function, the SF-36
quality of life health survey and the visual-analogue-scale (VAS) for pain. The secondary outcomes were
Knee Society Clinical Rating System for Knee Score (KSKS) and Function Score (KSFS). Patients were
assessed at baseline, 6 weeks and 12 weeks. All continuous variables were tested by the Kolmogorov-
Smirnov test for Normal distribution. Changes within the groups and differences between the groups
were calculated by repeated measures of analysis (ANOVA) with one nested variable.
RESULTS:
There were significant differences between treatment groups over time in WOMAC physical function
(14.6 mm [CI: 4.3, 25.0]; p = 0.04) and in WOMAC total score (15.0 mm [CI: 5.1, 24.9]; p = 0.03).
Treatment groups did not differ significantly in WOMAC pain (12.4 mm [CI: 0.0, 24.8]); p = 0.08) or
WOMAC stiffness (27.2 mm [CI: 8.2, 46.2]; p = 0.08). There was a non-significant difference in SF-36 total
score between treatment groups (11.6 [CI: 1.0, 22.1]; p = 0.54). A significant difference was found
between groups in VAS for pain (0.7 s [CI: -0.9, 2.4]; p = 0.05). Secondary outcomes showed non-
significant differences between the two groups.
CONCLUSIONS:
Patients with OA of the knee taking MSM for 12 weeks showed an improvement in pain and physical
function. These improvements, however, are small and it is yet to be determined if they are of clinical
significance.

Indones. 2017 Apr;49(2):105-111.
Abstract
BACKGROUND:

321
METHODS:
a double blind, randomized controlled clinical trial was conducted on 147 patients with knee OA
treatment.
RESULTS:
on statistical analysis it was found that at the 12th week, there are significant difference between three
(p<0.001).
CONCLUSION:
combination of glucosamine-chondroitinsulfate-methylsulfonylmethane showed clinical benefit for

KEYWORDS:

10.1177/0394632015622215. Epub 2015 Dec 18.
322
Abstract
KEYWORDS:
Systematic review of the nutritional supplements dimethyl sulfoxide (DMSO)

and methylsulfonylmethane (MSM) in the treatment of osteoarthritis.
Brien S, Prescott P, Bashir N, Lewith H, Lewith G. Osteoarthritis Cartilage. 2008
Nov;16(11):1277-88. doi: 10.1016/j.joca.2008.03.002. Epub 2008 Apr 15.
Abstract
OBJECTIVE:
323
Conventional treatment of osteoarthritis (OA) with non-steroidal anti-inflammatory drugs is associated

with serious gastrointestinal side effects and in view of the recent withdrawal of some cyclo-oxygenase-
2 inhibitors, identifying safer alternative treatment options is needed. The objective of this systematic
review is to evaluate the existing evidence from randomised controlled trials of two chemically related
nutritional supplements, dimethyl sulfoxide (DMSO) and methylsulfonylmethane (MSM) in the
treatment of OA to determine their efficacy and safety profile.
METHODS:
The electronic databases [Cochrane Library, Medline, Embase, Amed, Cinahl and NeLH (1950 to
November 2007)] were searched. The search strategy combined terms: osteoarthritis, degenerative
joint disorder, dimethyl sulfoxide, DMSO, methylsulfonylmethane, MSM, clinical trial; double-blind,
single blind, RCT, placebo, randomized, comparative study, evaluation study, control. Inclusion and
exclusion criteria were applied. Data were extracted and quality was assessed using the JADAD scale.
RESULTS:
Six studies were included [evaluating a total of 681 patients with OA of the knee for DMSO (N=297 on
active treatment); 168 patients for MSM (N=52 on active treatment)]. Two of the four DMSO trials, and
both MSM trials reported significant improvement in pain outcomes in the treatment group compared
to comparator treatments, however, methodological issues and concerns over optimal dosage and
treatment period, were highlighted.
CONCLUSION:
No definitive conclusion can currently be drawn for either supplement. The findings from all the DMSO
studies need to be viewed with caution because of poor methodology including; possible unblinding,
and questionable treatment duration and dose. The data from the more rigorous MSM trials provide
positive but not definitive evidence that MSM is superior to placebo in the treatment of mild to
moderate OA of the knee. Further studies are now required to identify both the optimum dosage and
longer-term safety of MSM and DMSO, and definitive efficacy trials.
Evaluation of the Effect of Mega MSM on Improving Joint Function in

Populations Experiencing Joint Degeneration
Gang Xu, et al. Int J Biomed Sci. 2015 Jun; 11(2): 54–60.
Abstract
Joint degeneration has become a commonplace problem in aging populations. The main clinical
manifestations include joint pain, joint stiffness and joint swelling with functional disorder. Mega MSM
324
is a nutritional supplement that may provide potential relief for joint problems associated with joint
degeneration. The current experiment performed was a 12-week, randomized, double-blind, controlled
study conducted on populations in China experiencing joint degeneration. The objective of the study
was to determine whether the daily use of Mega MSM capsules could improve joint function, relieve
symptoms of joint degeneration and improve the quality of life in aging populations. A total of 100 male
and female participants over 50 years old who had at least one of the related symptoms of joint
degeneration (joint pain, joint stiffness, joint swelling, difficulty walking, difficulty getting up from bed
and difficulty going down stairs) were recruited and their symptoms of joint degeneration before and
after the intervention were recorded. In this study, Mega MSM shows positive effects in improving joint
function, relieving symptoms associated with joint degeneration and improving the quality of life in
aging populations.
Keywords: Joint degeneration, joint pain, joint stiffness, joint swelling, Mega MSM, quality of life

Abstract
BACKGROUND:
METHODS:
325
RESULTS:
interaction effect P = 0.027; ssffness score, ↓30% versus ↓12%, respecsvely, interaction effect
CONCLUSIONS:
Open-label, randomized, controlled pilot study of the effects of a glucosamine

complex on Low back pain
Laure Tant, MD,* Bruno Gillard, MD, and Thierry Appelboom, MD, PhD. Curr Ther
Res Clin Exp. 2005 Nov; 66(6): 511–521. doi: 10.1016/j.curtheres.2005.12.009
Abstract
Background:
A series of studies has suggested some efficacy of glucosamine in arthrosis of the knee, but virtually no
documentation exists regarding its effects on low back pain.
Objectives:
The primary objective of this study was to examine whether a 12-week course of a glucosamine complex
(GC) could benefit patients having low back pain despite a course of noninvasive physical therapy. In
addition, we sought to delineate the subgroup of responders.
Methods:
This open-label, randomized, controlled study was conducted at the Division of Rheumatology and
Physical Medicine, Erasme University Hospital, Brussels, Belgium. Male and female outpatients aged 40
to 80 years with low back pain (duration, ≥ 12 weeks; pain score on 10-cm visual analog scale [VAS] [0 =
326
none to 10 = worst imaginable], ≥3 cm) despite noninvasive physical therapy (massage, stretching, heat
application, and analgesics for ≥4 weeks) were included. Patients were randomly assigned to receive, in
addition to conventional treatment (CT) (physical therapy plus analgesics/antiinflammatories), a GC
(enriched with sulfonyl methane, silicon, and a botanical extract of Ribes nigrum) or CT alone (control)
for 12 weeks. Pain at rest and on movement (effort) and early morning lumbar stiffness were measured
every 4 weeks using the VAS. The primary end point was improvement in VAS score for pain at rest at 12
weeks. Two validated questionnaires were used to assess improvements in quality of life (QOL)
(Oswestry Disability Questionnaire [ODQ] [10 items; scale: 0 = no disability to 60 = maximal disability]
and Roland-Morris Disability Questionnaire [RMDQ] [24 items; scale: 0 = no disability to 24 = severe
disability]). Responders were defined as patients who positively assessed the efficacy of the GC. At each
visit, patients were also asked about possible adverse events.
Results:
Of 36 enrolled patients, 32 completed the study (18 men, 14 women; mean [SE] age, 64 [2] years; 17 in
the GC group and 15 in the control group). Four patients were lost to follow-up. At week 4, changes
from baseline VAS scores for pain at rest and lumbar stiffness were significantly greater in the GC group
compared with the control group (P < 0.001 and P = 0.011, respectively). At week 4, QOL was found to
be improved, as measured using the ODQ, in the GC group compared with the control group (P = 0.028),
but the between-group difference as measured using the RMDQ was not significant. The improvements
from baseline on the questionnaires were sustained over the 12-week period in the GC group (all, P <
0.001). Gastrointestinal adverse effects were reported by 1 GC-treated patient and 1 patient in the
control group, but neither patient withdrew from the study. Of the 17 GC-treated patients, 9 considered
themselves responders, but the profile of a responder could not be delineated.
Conclusions:
In this study in patients with low back pain, analgesic effect and improvement in QOL were found with
the use of GC. GC was well tolerated.
Key words: arthrosis, back pain, glucosamine, methylsulfonylmethane, silicon, Ribes nigrurn
Mushrooms
327
The effects of dietary supplementation with Agaricales mushrooms and other

medicinal fungi on breast cancer: Evidence-based medicine
Maria Rita Carvalho Garbi Novaes, Fabiana Valadares, Mariana Campos Reis,
Daniella Rodrigues Gonçalves, and Marilia da Cunha Menezes. Clinics (Sao Paulo).
2011 Dec; 66(12): 2133–2139. doi: 10.1590/S1807-59322011001200021
Abstract
Breast cancer is the most prevalent cancer in women. The most frequent therapeutic approaches for the
treatment of this disease are chemotherapy, radiotherapy, hormone therapy, and surgery. Conventional
pharmacological treatments cause many harmful side effects in patients. To improve the quality of life
of breast cancer patients, researchers have sought alternative adjuvant treatment strategies. To assess
the effects of fungi and other basidiomycetes Agaricales on the co-adjuvant treatment of breast cancer,
we conducted a literary review of the available scientific evidence. We selected articles published in
refereed journals from 1990 to 2011 in Medline, Lilacs, CAPES, Scielo, and Pubmed. Articles written in
English, Spanish, and Portuguese were reviewed. We used the following descriptors: Agaricales,
medicinal mushroom/fungus, breast cancer, dietary supplementation, synonyms, and related terms. The
pharmacological effects of nutritional and medicinal mushrooms have been reported in several
experimental clinical studies and have shown promising results in the adjuvant treatment of breast
cancer. Adjuvant treatment with mushrooms is associated with improvements in the immunological and
hematologic parameters of breast cancer, as well as in the quality of life of these patients. Randomized
clinical studies are needed to elucidate the possible mechanisms of action and clinical benefits of these
fungi with respect to survival time, disease progression, and metastasis in breast cancer.
Keywords: Nutritional supplement, Agaricus sylvaticus, Medicinal mushroom, Adjuvant treatment,

Basidiomycetes
Impact of Agaricus bisporus Mushroom Consumption on Gut Health Markers

in Healthy Adults
Julie Hess, Qi Wang, Trevor Gould, and Joanne Slavin. Nutrients. 2018 Oct; 10(10):
1402. Published online 2018 Oct 2. doi: 10.3390/nu10101402
Abstract
328
Eating Agaricus bisporus mushrooms may impact gut health, because they contain known prebiotics.
This study assessed mushroom consumption compared to meat on gastrointestinal tolerance, short
chain fatty acid (SCFA) production, laxation, and fecal microbiota. A randomized open-label crossover
study was conducted in healthy adults (n = 32) consuming protein-matched amounts of mushrooms or
meat twice daily for ten days. Breath hydrogen measures were taken on day one, and gastrointestinal
tolerance was evaluated throughout treatments. Fecal sample collection was completed days 6–10, and
samples were assessed for bacterial composition, SCFA concentrations, weight, pH, and consistency.
There were no differences in breath hydrogen, stool frequency, consistency, fecal pH, or SCFA
concentrations between the two diets. The mushroom diet led to greater overall gastrointestinal
symptoms than the meat diet on days one and two. The mushroom-rich diet resulted in higher average
stool weight (p = 0.002) and a different fecal microbiota composition compared to the meat diet, with
greater abundance of Bacteroidetes (p = 0.0002) and lower abundance of Firmicutes (p = 0.0009). The
increase in stool weight and presence of undigested mushrooms in stool suggests that mushroom
consumption may impact laxation in healthy adults. Additional research is needed to interpret the
health implications of fecal microbiota shifts with mushroom feeding.
Keywords: mushrooms, gut health, laxation, prebiotic, fiber, microbiota
Antioxidant Versus Pro-Apoptotic Effects of Mushroom-Enriched Diets on

Mitochondria in Liver Disease
Adriana Fontes et al. Int J Mol Sci. 2019 Aug; 20(16): 3987. Published online 2019
Aug 16. doi: 10.3390/ijms20163987
Abstract
Mitochondria play a central role in non-alcoholic fatty liver disease (NAFLD) progression and in the
control of cell death signalling during the progression to hepatocellular carcinoma (HCC). Associated
with the metabolic syndrome, NAFLD is mostly driven by insulin-resistant white adipose tissue lipolysis
that results in an increased hepatic fatty acid influx and the ectopic accumulation of fat in the liver.
Upregulation of beta-oxidation as one compensatory mechanism leads to an increase in mitochondrial
tricarboxylic acid cycle flux and ATP generation. The progression of NAFLD is associated with alterations
in the mitochondrial molecular composition and respiratory capacity, which increases their vulnerability
to different stressors, including calcium and pro-inflammatory molecules, which result in an increased
generation of reactive oxygen species (ROS) that, altogether, may ultimately lead to mitochondrial
dysfunction. This may activate further pro-inflammatory pathways involved in the progression from
steatosis to steatohepatitis (NASH). Mushroom-enriched diets, or the administration of their isolated
bioactive compounds, have been shown to display beneficial effects on insulin resistance, hepatic
steatosis, oxidative stress, and inflammation by regulating nutrient uptake and lipid metabolism as well
as modulating the antioxidant activity of the cell. In addition, the gut microbiota has also been described
329
to be modulated by mushroom bioactive molecules, with implications in reducing liver inflammation

during NAFLD progression. Dietary mushroom extracts have been reported to have anti-tumorigenic
properties and to induce cell-death via the mitochondrial apoptosis pathway. This calls for particular
attention to the potential therapeutic properties of these natural compounds which may push the
development of novel pharmacological options to treat NASH and HCC. We here review the diverse
effects of mushroom-enriched diets in liver disease, emphasizing those effects that are dependent on
mitochondria.
Keywords: mitochondria, non-alcoholic fatty liver disease, fungi, mushrooms, truffles, antioxidants,
oxidative stress, lipid metabolism, apoptosis, NASH, HCC
Traditional knowledge and use of wild mushrooms by Mixtecs or Ñuu savi, the
people of the rain, from Southeastern Mexico
Faustino Hernández Santiago, et al. J Ethnobiol Ethnomed. 2016; 12(1): 35.
Published online 2016 Sep 5. doi: 10.1186/s13002-016-0108-9
Abstract
Background
Mexico is an important global reservoir of biological and cultural richness and traditional knowledge of
wild mushrooms. However, there is a high risk of loss of this knowledge due to the erosion of traditional
human cultures which is related with the rapid acculturation linked to high migration of rural
populations to cities and the U.S.A., and the loss of natural ecosystems. The Mixtec people, the third
largest native group in Mexico only after the Nahua and the Maya, maintain ancient traditions in the use
and knowledge of wild mushrooms. Paradoxically, there are few studies of the Mixtec ethnomycology.
This study shows our ethnomycological research, mainly focused on knowledge and use of wild
mushrooms in communities of the Mixteca Alta, in southeastern Mexico. We hypothesized that among
the studied communities those with a combination of higher vegetation cover of natural pine and oak
forests, lower soil erosion and higher economic margination had a greater richness and knowledge of
wild mushrooms. Our study therefore aimed to record traditional knowledge, use, nomenclature and
classification of wild mushrooms in four Mixtec communities and to analyze how these aspects vary
according to environmental and cultural conditions among the studied communities.
Methods
330
In order to analyze the cultural significance of wild mushrooms for the Mixtec people, 116 non-
structured and semi-structured interviews were performed from 2009 to 2014. Information about the
identified species, particularly the regional nomenclature and classification, their edibility, toxicity and
ludic uses, the habitat of useful mushrooms, traditional recipes and criteria to differentiate between
toxic and edible species, and mechanisms of knowledge transmission were studied. The research had
the important particularity that the first author is Mixtec, native of the study area. A comparative
qualitative analysis between the richness of fungal species used locally and the official information of
the natural vegetation cover, soil erosion and economic marginalization in each of the studied
communities was conducted.
Results
A total of 106 species of mushrooms were identified growing in pine and oak forest, deciduous tropical
forest and grassland; among the identified mushrooms we recorded 26 species locally consumed, 18
considered toxic, 6 having ludic uses and the remaining 56 species not being used in the studied areas
but some of them having potential as food (56 species) or medicine (28 species). We recorded that 80,
22 and 4 species are ectomycorrhizal, saprotrophic and parasites, respectively. Our study shows that a
complex and accurate knowledge related with the use, nomenclature, classification, ecology,
gastronomy of wild mushrooms has been developed by Mixtecs; and that there is a relation between
natural vegetation cover, lower soil erosion and higher economic marginalization and richness,
knowledge and use of mushrooms in the studied communites.
Conclusion
Our study showed that conservation and adaptation of ancestral mycological knowledge survives mainly
through oral transmition, maintenance of cultural identity, forest protection, preservation native
language and also paradoxically through the current socieconomical marginality among the Mixtec
people. We also found that those studied communities with a combination of higher vegetation cover of
natural pine and oak forests, lower soil erosion and higher economic marginalization showed a greater
richness and knowledge of wild mushrooms. Use and sustainable management of wild mushrooms can
be an alternative for local integrated development, but local knowledge and traditional worldview
should be included into the regional programs of Mixtec biocultural conservation.
Keywords: Ethnomycology, Edible wild mushrooms, Oaxaca, Biocultural importance, Mycological

resources, Oral tradition
331
An Inulin-Specific Lectin with Anti-HIV-1 Reverse Transcriptase,

Antiproliferative, and Mitogenic Activities from the Edible Mushroom
Agaricus bitorquis
Guo-Qing Zhang, et al. Biomed Res Int. 2019; 2019: 1341370. Published online
2019 Mar 19. doi: 10.1155/2019/1341370
Abstract
A novel lectin (ABL) was purified from the dried fruiting bodies of Agaricus bitorquis. An efficient 3-step
purification protocol involved two consecutive steps of ion exchange chromatography on Q-Sepharose
and SP-Sepharose and gel filtration by FPLC on Superdex 75. ABL is a monomeric protein with the
molecular mass of 27.6 kDa, which is different from other lectins from genus Agaricus. Its N-terminal
amino acid sequence is EYTISIRVYQTNPKGFNRPV which is unique and sharing considerably high
similarity of other mushroom lectins. The hemagglutinating activity of the lectin was inhibited by inulin.
Based on hemagglutination tests, ABL prefers rabbit, human type A, and AB erythrocytes to human type
B and O erythrocytes. The lectin inhibits the activity of HIV-1 reverse transcriptase and the proliferation
of leukemia cell (L1210) with an IC50 value of 4.69 and 4.97 μM, respectively. Furthermore, ABL
demonstrates the highest mitogenic activity with a response of 24177.7 ± 940.6 [3H-methyl] thymidine
counts per minute (CPM) at a concentration of 0.91 μM.
Mushroom Lectins as Promising Anticancer Substances.

Singh RS, Kaur HP, Kanwar JR. Curr Protein Pept Sci. 2016;17(8):797-807.
Abstract
Lectins are proteins/glycoproteins of non-immune origin, which are widely distributed in nature. They
have at least one non-catalytic domain, which binds reversibly to specific monosaccharides or
oligosaccharides. Lectins recognizing sugar moieties in cell walls or cell membranes alter the membrane
physiology and trigger biochemical changes in the cell. Thus, various applications of lectins have been
described, for example as tools to identify aberrant glycans expressed by neoplastic cells and as
antitumor agents by inducing apoptosis by various mechanisms. In order to widen applications of anti-
tumor lectins, a detailed investigation of their action mechanism is required. Mushrooms are a valuable
source of novel lectins with unique specificities and potentials for biotechnological and biomedical
applications. This article reviews information on anti-proliferative activity of mushroom lectins obtained
in-vitro and in-vivo. The possible role of lectins as cancer therapeutics is discussed together with the
mechanisms underlying the anti-proliferative activity, which may help to exploit these biomolecules as
potential novel antitumor drugs in near future.
332
Medicinal mushroom modulators of molecular targets as cancer therapeutics.

Zaidman BZ, Yassin M, Mahajna J, Wasser SP. Appl Microbiol Biotechnol. 2005
Jun;67(4):453-68. Epub 2005 Feb 23.
Abstract
Empirical approaches to discover anticancer drugs and cancer treatments have made limited progress in
the past several decades in finding a cure for cancer. The expanded knowledge of the molecular basis of
tumorigenesis and metastasis, together with the inherently vast structural diversity of natural
compounds found in mushrooms, provided unique opportunities for discovering new drugs that
rationally target the abnormal molecular and biochemical signals leading to cancer. This review focuses
on mushroom low-molecular-weight secondary metabolites targeting processes such as apoptosis,
angiogenesis, metastasis, cell cycle regulation, and signal transduction cascades. Also discussed in this
review are high-molecular-weight polysaccharides or polysaccharide-protein complexes from
mushrooms that appear to enhance innate and cell-mediated immune responses, exhibit antitumor
activities in animals and humans, and demonstrate the anticancer properties of selenium compounds
accumulated in mushrooms.
Nettle (Urtica)
Abstract
333
PARTICIPANTS:

Med. 2013;20(4):800-2.
Abstract
INTRODUCTION:
334
population.
AIM:
rheumatic diseases.
RESULTS:
CONCLUSION:
Antinociceptive and anti-inflammatory properties of the hydroalcoholic

extract of stems from Equisetum arvense L. in mice.
Do Monte FH, et al. Pharmacol Res. 2004 Mar;49(3):239-43.
Abstract
In this study, antinociceptive and anti-inflammatory effects of hydroalcoholic extract of stem from
Equisetum arvense in mice were evaluated. The extract (10, 25, 50 and 100mgkg(-1), i.p.), reduced the
writhing induced by acetic acid in 49, 57, 93 and 98%, respectively. In the formalin test, 50 and
100mgkg(-1) (i.p.) extract, reduced in 80 and 95% the licking activity in the first phase, but in the second
phase only the latter dose diminished the licking time (35%). In both phases, naloxone failed to revert
the analgesic effect of the extract. In the hot-plate test, the extract at 100 and 200mgkg(-1) does not
change the latency to licking or jumping. In the carrageenan-induced paw oedema, the extract at
335
50mgkg(-1), reduced the paw oedema 2h (25%) and 4h (30%) after carrageenan administration. The
dose of 100mgkg(-1) caused reduction of the paw oedema (29%) only 4h after carrageenan
administration. These results indicate that this extract exhibits an antinociceptive effect in chemical
models of nociception which is not related to the opioid system, as well as anti-inflammatory properties.
6 Evidence-Based Benefits of Stinging Nettle

Written by Ryan Raman, MS, RD on November 21, 2018. Healthline.com
https://www.healthline.com/nutrition/stinging-nettle
Stinging nettle (Urtica dioica) has been a staple in herbal medicine since ancient times.
Ancient Egyptians used stinging nettle to treat arthritis and lower back pain, while Roman troops rubbed
it on themselves to help stay warm .
Its scientific name, Urtica dioica, comes from the Latin word uro, which means “to burn,” because its
leaves can cause a temporary burning sensation upon contact.
The leaves have hair-like structures that sting and also produce itching, redness and swelling. However,
once it is processed into a supplement, dried, freeze-dried or cooked, stinging nettle can be safely
consumed. Studies link it to a number of potential health benefits.
Randomized controlled trial of nettle sting for treatment of base-of-thumb

pain.
Randall C, Randall H, Dobbs F, Hutton C, Sanders H. J R Soc Med. 2000
Jun;93(6):305-9.
Author information
Abstract
There are numerous published references to use of nettle sting for arthritis pain but no randomized
controlled trials have been reported. We conducted a randomized controlled double-blind crossover
study in 27 patients with osteoarthritic pain at the base of the thumb or index finger. Patients applied
stinging nettle leaf (Urtica dioica) daily for one week to the painful area. The effect of this treatment was
compared with that of placebo, white deadnettle leaf (Lamium album), for one week after a five-week
washout period. Observations of pain and disability were recorded for the twelve weeks of the study.
After one week's treatment with nettle sting, score reductions on both visual analogue scale (pain) and
health assessment questionnaire (disability) were significantly greater than with placebo (P = 0.026 and
P = 0.0027).
336
Nettle sting of Urtica dioica for joint pain--an exploratory study of this
complementary therapy.
Randall C1, Meethan K, Randall H, Dobbs F. Complement Ther Med. 1999
Sep;7(3):126-31.
Abstract
This exploratory study aims to explore the present use of the common stinging nettle to treat joint pain.
Eighteen self-selected patients using the nettle sting of Urtica dioica were interviewed. Information
regarding patients' use of nettle therapy was elicited, in particular mode of application, dosage and
effects. All except one respondent were sure that netles had been very helpful and several considered
themselves cured. No observed side effects were reported, except a transient urticarial rash. This
exploratory study suggests nettle sting is a useful, safe and cheap therapy which needs further study. A
randomized controlled trial is planned in collaboration with a rheumatology specialist.
Nettle sting for chronic knee pain: a randomised controlled pilot study.
Randall C, Dickens A, White A, Sanders H, Fox M, Campbell J. Complement Ther
Med. 2008 Apr;16(2):66-72. doi: 10.1016/j.ctim.2007.01.012. Epub 2007 Apr 17.
Abstract
BACKGROUND:
Non-pharmacological interventions for chronic knee pain are increasingly requested by patients and are
recommended in current treatment guidelines. An intervention that has been used for many years for
pain relief is nettle sting.
OBJECTIVES:
To explore the feasibility of a definitive RCT of nettle sting for chronic knee pain, in particular the
acceptability of the research to GPs and patients, and the optimal methods for recruitment and
outcome measurement.
METHODS:
Patient blinded pilot RCT, set in two inner city primary care practices in Plymouth, UK. Potential
participants were identified from practice computerised databases using three different approaches:
age and analgesic use, age and appropriate Read code, or age alone. Patients had to be aged between
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55 and 80 years with knee pain and a presumptive clinical diagnosis of OA knee, with a baseline WOMAC
pain subscale score of more than 4. They were randomised to receive either treatment with Urtica
dioica, or placebo intervention with Urtica galeopsifolia daily for 1 week. The main outcome measure for
the treatment effect was the WOMAC pain subscale; other outcomes included quantitative and
qualitative data to inform the design of a future study.
RESULTS:
Out of 45 patients who were eligible, 42 were recruited. Invitations targeted at patients who were both
currently receiving repeat prescriptions for non-steroidal or analgesic drugs and had relevant Read
codes proved most efficient for recruitment. Mean baseline WOMAC pain subscale scores were 9.2 (S.D.
3.4) and 7.9 (2.3) in the two groups. The mean reduction in pain score at the end of treatment in the
nettles group was 1.7 (95% confidence interval 0.6, 2.9) and in the controls 1.6 (CI 0.5, 2.7). All GP
practices, and all patients approached, were willing to be involved in the research. Patients liked the
treatment mostly because it was 'natural'. The sting was acceptable and viewed as a minor irritation.
CONCLUSION:
Research into nettle sting is acceptable to patients and GPs, and patients do not find the treatment
more than a minor irritation. Larger rigorous studies are justified to determine the effectiveness of this
ancient therapy.
Phytalgic, a food supplement, vs placebo in patients with osteoarthritis of the

knee or hip: a randomised double-blind placebo-controlled clinical trial.
Jacquet A, et al. Arthritis Res Ther. 2009;11(6):R192. doi: 10.1186/ar2891. Epub
2009 Dec 16.
Abstract
INTRODUCTION:
The medicinal treatment of osteoarthritis (OA) is mostly symptomatic to relieve pain and incapacity with
analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), drugs with well-known risks.
Complementary medicines might reduce the symptoms of OA and decrease the need for NSAIDs. This
study tested the effects of a food supplement, Phytalgic, on pain and function in patients with
osteoarthritis and their use of analgesic and NSAIDs.
METHODS:
A randomized double-blind parallel-groups clinical trial compared Phytalgic (fish-oil, vitamin E, Urtica
dioica) to a placebo for three months, in 81 patients with OA of the knee or hip using NSAIDs and/or
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analgesics regularly. The main outcome measures were use of NSAIDs (in Defined Daily Doses per day -
DDD/day) or analgesics (in 500 mg paracetamol-equivalent tablets per week (PET/week) measured each
month, and Western Ontario-McMaster University Osteo-Arthritis Index (WOMAC) function scales.
RESULTS:
After three months of treatment, the mean use of analgesics in the active arm (6.5 PET/week) vs. the
placebo arm (16.5) was significantly different (P < 0.001) with a group mean difference of -10.0 (95% CI:
-4.9 to -15.1). That of NSAIDs in the active arm (0.4 DDD/day) vs the placebo arm (1.0 DDD/day) was
significantly different (P = 0.02) with a group mean difference of - 0.7 DDD/day (95% CI: -0.2 to -1.2).
Mean WOMAC scores for pain, stiffness and function in the active arm (respectively 86.5, 41.4 and
301.6) vs the placebo arm (resp. 235.3, 96.3 and 746.5) were significantly different (P < 0.001) with
group mean differences respectively of -148.8 (95% CI: -97.7 to -199.9), -54.9 (95% CI: -27.9 to -81.9)
and -444.8 (95% CI: -269.1 to -620.4).
CONCLUSIONS:
The food supplement tested appeared to decrease the need for analgesics and NSAIDs and improve the
symptoms of osteoarthritis.
Evaluation of Antioxidant, Antidiabetic and Antiobesity Potential of Selected

Traditional Medicinal Plants.
Sekhon-Loodu S, Rupasinghe HPV. Front Nutr. 2019 Apr 25;6:53. doi:
10.3389/fnut.2019.00053. eCollection 2019.
Abstract
This study evaluated potential antidiabetic and antiobesity properties in vitro of selected medicinal
plants. The hot water (WE) and ethanol extracts (EE) of sweet gale (Myrica gale L.), roseroot (Rhodiola
rosea L.), sheep sorrel (Rumex acetosa L.), stinging nettles (Utrica dioica L.) and dandelion (Taraxacum
officinale L.) were tested for total antioxidant capacity using ferric reducing antioxidant power (FRAP)
and DPPH• scavenging capacity assays, followed by α-amylase, α-glucosidase and formation of
advanced glycation end products (AGE) inhibition assays in vitro. Myrica gale EE had the highest total
phenolic content (12.4 mmol GAE/L), FRAP value (17.4 mmol TE/L) and DPPH• scavenging activity (IC50
= 3.28 mg/L). Similarly, Myrica gale also exhibited significantly lower IC50 values for the percentage
inhibition of α-amylase (IC50 = 62.65 mg/L) and α-glucosidase (IC50 = 27.20 mg/L) compared to
acarbose (IC50 = 91.71 mg/L; IC50 = 89.50 mg/L, respectively) (p ≤ 0.05). The 3T3-L1 preadipocyte study
also revealed that Myrica gale EE (54.8%) and stinging nettles (62.2% EE; 63.2% WE) significantly
inhibited the adipogenesis in adipocytes in vitro (p ≤ 0.05). Polyphenols present in these medicinal
plants have the potential to use in managing type 2 diabetes and obesity.
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KEYWORDS:
amylase; antioxidants; diabetes; glucosidase; obesity; phytochemicals; polyphenols
Nootropics
Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors.
Froestl W, Muhs A, Pfeifer A. J Alzheimers Dis. 2012;32(4):793-887. doi:
10.3233/JAD-2012-121186.
Abstract
Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from
Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition
refers to a capacity for information processing, applying knowledge, and changing preferences. It
involves memory, attention, executive functions, perception, language, and psychomotor functions. The
term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in
clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical
experiments. To classify the compounds, a concept is proposed assigning drugs to 18 categories
according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion
channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease-
modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with
amyloid-β and tau. For drugs, whose mechanism of action is not known, they are either classified
according to structure, e.g., peptides, or their origin, e.g., natural products. The review covers the
evolution of research in this field over the last 25 years.
Pharmacokinetic and pharmacodynamic of the cognitive enhancer modafinil:

Relevant clinical and forensic aspects.
Sousa A, Dinis-Oliveira RJ. Subst Abus. 2020 Jan 17:1-19. doi:
340
Abstract
Modafinil is a nonamphetamine nootropic drug with an increasingly therapeutic interest due to its
different sites of action and behavioral effects in comparison to cocaine or amphetamine. A review of
modafinil (and of its prodrug adrafinil and its R-enantiomer armodafinil) chemical, pharmacokinetic,
pharmacodynamic, toxicological, clinical and forensic aspects was performed, aiming to better
understand possible health problems associated to its unconscious and unruled use. Modafinil is a
racemate metabolized mainly in the liver into its inactive acid and sulfone metabolites, which undergo
primarily renal excretion. Although not fully clarified, major effects seem to be associated to inhibition
of dopamine reuptake and modulation of several other neurochemical pathways, namely noradrenergic,
serotoninergic, orexinergic, histaminergic, glutamatergic and GABAergic. Due its wake-promoting
effects, modafinil is used for the treatment of daily sleepiness associated to narcolepsy, obstructive
sleep apnea and shift work sleep disorder. Its psychotropic and cognitive effects are also attractive in
several other pathologies and conditions that affect sleep structure, induce fatigue and lethargy, and
impair cognitive abilities. Additionally, in health subjects, including students, modafinil is being used off-
label to overcome sleepiness, increase concentration and improve cognitive potential. The most
common adverse effects associated to modafinil intake are headache, insomnia, anxiety, diarrhea, dry
mouth and raise in blood pressure and heart rate. Infrequently, severe dermatologic effects in children,
including maculopapular and morbilliform rash, erythema multiforme and Stevens-Johnson Syndrome
have been reported. Intoxication and dependence associated to modafinil are uncommon. Further
research on effects and health implications of modafinil and its analogs is steel needed to create
evidence-based policies.
KEYWORDS:
Nootropics; abuse and dependence; adrafinil; adverse effects; armodafinil; cognitive enhancement;
modafinil; pharmacodynamics; pharmacokinetics
Brain Ageing, Cognition and Diet: A Review of the Emerging Roles of Food-
Based Nootropics in Mitigating Age-related Memory Decline.
Onaolapo AY, Obelawo AY, Onaolapo OJ. Curr Aging Sci. 2019;12(1):2-14. doi:
10.2174/1874609812666190311160754.
Abstract
BACKGROUND:
Age-related cognitive decline has been suggested to result from an increase in the brain neuron loss,
which is attributable to continued derangement of the brain's oxidant/ antioxidant balance. Increased
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oxidative stress and a concomitant decrease in the brain's antioxidant defense system have been
associated with functional senescence and organismal ageing. However, nature has configured certain
foods to be rich sources of nootropic agents, with research showing that increased consumption of such
foods or food ingredients may be protective against ageing-related memory decline. This knowledge is
becoming increasingly valuable in an era when the boundary that separates food from medicine is
becoming blurred. In this review, we examine extant literature dealing with the impact of ageing on
brain structure and function, with an emphasis on the roles of oxidative stress. Secondly, we review the
benefits of food-based antioxidants with nootropic effects and/or food-based nootropic agents in
mitigating memory decline; with a view to improving our understanding of likely mechanisms. We also
highlight some of the limitations to the use of food-based nootropics and suggest ways in which they
can be better employed in the clinical management of age-related cognitive decline.
CONCLUSION:
While it is known that the human brain endures diverse insults in the process of ageing, food-based
nootropics are likely to go a long way in mitigating the impacts of these insults. Further research is
needed before we reach a point where food-based nootropics are routinely prescribed.
KEYWORDS:
Ageing; antioxidants; dementia; nootropic; nutraceuticals; nutrition.
Neuroprotection with Natural Antioxidants and Nutraceuticals in the Context

of Brain Cell Degeneration: The Epigenetic Connection.
Carrera I, Martínez O, Cacabelos R. Curr Top Med Chem. 2019;19(32):2999-3011.
doi: 10.2174/1568026619666191202155738.
Abstract
Bioactive antioxidant agents present in selected plants are known to provide the first line of biological
defense against oxidative stress. In particular, soluble vitamin C, E, carotenoids and phenolic compounds
have demonstrated crucial biological effects in cells against oxidative damage, preventing prevalent
chronic diseases, such as diabetes, cancer and cardiovascular disease. The reported wide range of
effects that included anti-aging, anti-atherosclerosis, anti-inflammatory and anticancer activity were
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studied against degenerative pathologies of the brain. Vitamins and different phytochemicals are
important epigenetic modifiers that prevent neurodegeneration. In order to explore the potential
antioxidant sources in functional foods and nutraceuticals against neurodegeneration, the present paper
aims to show a comprehensive assessment of antioxidant activity at chemical and cellular levels. The
effects of the different bioactive compounds available and their antioxidant activity through an
epigenetic point of view are also discussed.
Nootropics are the Brain Boosters Everyone Will Be Taking in 2018

Jennifer Chesak. Medically reviewed by Debra Rose Wilson, PhD, MSN, RN, IBCLC,
AHN-BC, CHT. Healthline. October 11, 2017.
https://www.healthline.com/health/nootropics-what-is-it-and-list-of-supplements
Nootropics are a wide range of supplements and compounds that work to boost your mental function or
moods. One nootropic might reportedly juice creativity, while another might give you a mega
motivational kick in the booty. Yet another might tell your anxiety it’s time to go into hibernation.
The mechanisms behind each nootropic is different, and research is still in the works for many of them.
One of the most popular forms is in your morning cup of joe: caffeine.
We like caffeine for the way it wakes us up and makes us feel mentally alert and focused, but we rarely
think about the science behind it. Caffeine has this stimulating effect because it inhibits certain
receptors that slow down brain activity. As an added bonus, a recent study shows that regular caffeine
consumption could also have long-term effects, like decreasing your risk of dementia or Alzheimer’s
disease.
Piracetam, the first compound to be labeled a nootropic, has been shown to help improve cognitive
function in children with learning disorders such as dyslexia and ADHD. Another supplement called
pyritinol, which is semi-synthetic, is two vitamin B-6 molecules attached to each other. It’s been
associated with improved memory and reaction time.
What are nootropics (smart drugs)?

Jennifer Berry. Medically reviewed by Alan Carter, Pharm.D. Medical News Today.
September 18, 2019
343
Nootropics, or "smart drugs," are a class of substances that can boost brain performance. They are
sometimes called cognition enhancers or memory enhancing substances.
Prescription nootropics are medications that have stimulant effects. They can counteract the symptoms
of medical conditions such as attention deficit hyperactivity disorder (ADHD), narcolepsy, or Alzheimer's
disease.
Nonprescription substances that can enhance brain performance or focus — such as caffeine and
creatine — are also considered nootropics. They do not treat diseases but may have some effects on
thinking, memory, or other mental functions.
Oat Straw (Avena Sativa)

Avena sativa (Oat), a potential neutraceutical and therapeutic agent: an
overview.
Singh R, De S, Belkheir A. Crit Rev Food Sci Nutr. 2013;53(2):126-44. doi:
10.1080/10408398.2010.526725.
Abstract
The aim of the present review article is to summarize the available information related to the
availability, production, chemical composition, pharmacological activity, and traditional uses of Avena
sativa to highlight its potential to contribute to human health. Oats are now cultivated worldwide and
form an important dietary staple for the people in number of countries. Several varieties of oats are
available. It is a rich source of protein, contains a number of important minerals, lipids, β-glucan, a
mixed-linkage polysaccharide, which forms an important part of oat dietary fiber, and also contains
various other phytoconstituents like avenanthramides, an indole alkaloid-gramine, flavonoids,
flavonolignans, triterpenoid saponins, sterols, and tocols. Traditionally oats have been in use since long
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and are considered as stimulant, antispasmodic, antitumor, diuretic, and neurotonic. Oat possesses
different pharmacological activities like antioxidant, anti-inflammatory, wound healing,
immunomodulatory, antidiabetic, anticholesterolaemic, etc. A wide spectrum of biological activities
indicates that oat is a potential therapeutic agent.
Oats
EMedicineHealth.com. Updated 9/11/19.
https://www.emedicinehealth.com/oats/vitamins-supplements.htm
People use oats for joint pain (rheumatism), fatigue, a fatigue-related condition called neurasthenia
syndrome, withdrawal from nicotine and narcotics, and lowering high uric acid levels that can cause
gout. Oats are also used for anxiety, excitation and stress; as well as for weak bladder and kidney
ailments. Other uses include connective tissue disorders, skin diseases, fat redistribution syndrome
associated with HIV treatment, and as a tonic.
Oat straw is used for the flu, swine (H1N1) flu, coughs, bladder disorders, joint pain, eye ailments,
frostbite, gout, and a skin infection called impetigo.
Whole grain oats, more than just a fiber: Role of unique phytochemicals.
Sang S, Chu Y. Mol Nutr Food Res. 2017 Jul;61(7). doi: 10.1002/mnfr.201600715.
Epub 2017 Feb 22.
Abstract
Oats are a good source of soluble dietary fiber, especially β-glucan, which has outstanding functional
and nutritional properties. β-Glucan is considered to be the major active component of oats because of
its cholesterol-lowering and antidiabetic effects. However, the nutritional benefits of oats appear to go
beyond fiber to bioactive phytochemicals with strong antioxidant and anti-inflammatory effects. In this
review, we summarize current knowledge on the chemistry, stability, bioavailability, and health effects
of two unique phytochemicals in oats, avenanthramides, and avenacosides A and B. We conclude that
studies on the beneficial effects of avenanthramides and avenacosides A and B are still in their infancy,
and additional health benefits of these unique oat components may yet be identified.
KEYWORDS:
Avenacosides; Avenanthramides Health effect; Oats; Phytochemicals

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An extract from wild green oat improves rat behaviour.

Schellekens C, Perrinjaquet-Moccetti T, Wullschleger C, Heyne A. Phytother Res.
2009 Oct;23(10):1371-7. doi: 10.1002/ptr.2751.
Abstract
An extract of wild green oat (Avena sativa L.), was tested in vivo in rats for its behavioural effects after
chronic oral administration via extract-admixed food. Thirty six male Sprague-Dawley rats received (A)
standard diet (controls), (B) 10 g/kg extract-admixed food or (C) 100 g/kg extract-admixed food. The
following behavioural tests were performed: elevated plus maze, forced swimming, conditioned
avoidance response and tetradic encounter. Body weight, food and fluid consumption were measured
and apparent physical appearance was determined twice a week. Apart from a slightly decreased food
and fluid intake in the high dose group there were no side effects observed during the treatment. The
low dose led to an improvement of active stress response, an enhancement of shock avoidance learning
and an increased synchrony in social behaviour. It may be concluded that the wild green oat extract is
suitable to improve behavioural initiative in different situations.
Avenanthramide C from germinated oats exhibits anti-allergic inflammatory

effects in mast cells.
Dhakal H, et al. Sci Rep. 2019 May 3;9(1):6884. doi: 10.1038/s41598-019-43412-
2.
Abstract
Mast cells play a crucial role in allergic diseases via the release of inflammatory mediators, particularly
histamine and pro-inflammatory cytokines. Avenanthramide (Avn) C, a polyphenol found mainly in oats,
is known to exhibit various biological properties. In this study, we aimed to evaluate the effectiveness of
Avn C from germinated oats against mast cell-mediated allergic inflammation. For the in vitro study,
RBL-2H3, mouse bone marrow-derived mast cells and rat peritoneal mast cells were used. Avn C (1-
100 nM) inhibited the immunoglobulin (Ig)E-stimulated mast cells degranulation by suppressing
phosphorylation of phosphoinositide 3-kinase and phospholipase Cγ1 and decreasing intracellular
calcium levels. It inhibited IgE-stimulated secretion of inflammatory cytokines via suppression of FcεRI-
mediated signaling proteins Lyn, Syk, Akt, and nuclear factor-κB. To verify the effects of Avn C in vivo,
ovalbumin-induced active systemic anaphylaxis (ASA) and IgE-mediated passive cutaneous anaphylaxis
(PCA) models were used. Oral administration of Avn C dose-dependently attenuated the ASA reactions,
as evidenced by the inhibition of hypothermia and reduction of elevated serum histamine, IgE, and
interleukin-4 levels. Avn C also inhibited the PCA reactions, such as ear swelling and plasma
346
extravasation. Our results suggested that Avn C from germinated oats might be a possible therapeutic
candidate for mast cell-mediated allergic inflammation.
Avenanthramides, polyphenols from oats, exhibit anti-inflammatory and anti-

itch activity.
Sur R, Nigam A, Grote D, Liebel F, Southall MD. Arch Dermatol Res. 2008
Nov;300(10):569-74. doi: 10.1007/s00403-008-0858-x. Epub 2008 May 7.
Abstract
Oatmeal has been used for centuries as a soothing agent to relieve itch and irritation associated with
various xerotic dermatoses; however few studies have sought to identify the active phytochemical(s) in
oat that mediate this anti-inflammatory activity. Avenanthramides are phenolic compounds present in
oats at approximately 300 parts per million (ppm) and have been reported to exhibit anti-oxidant
activity in various cell-types. In the current study we investigated whether these compounds exert anti-
inflammatory activity in the skin. We found that avenanthramides at concentrations as low as 1 parts
per billion inhibited the degradation of inhibitor of nuclear factor kappa B-alpha (IkappaB-alpha) in
keratinocytes which correlated with decreased phosphorylation of p65 subunit of nuclear factor kappa B
(NF-kappaB). Furthermore, cells treated with avenanthramides showed a significant inhibition of tumor
necrosis factor-alpha (TNF-alpha) induced NF-kappaB luciferase activity and subsequent reduction of
interleukin-8 (IL-8) release. Additionally, topical application of 1-3 ppm avenanthramides mitigated
inflammation in murine models of contact hypersensitivity and neurogenic inflammation and reduced
pruritogen-induced scratching in a murine itch model. Taken together these results demonstrate that
avenanthramides are potent anti-inflammatory agents that appear to mediate the anti-irritant effects of
oats.
Potential health benefits of avenanthramides of oats.

Meydani M. Nutr Rev. 2009 Dec;67(12):731-5. doi: 10.1111/j.1753-
4887.2009.00256.x.
Abstract
Oats are known to be a healthy food for the heart due mainly to their high beta-glucan content. In
addition, they contain more than 20 unique polyphenols, avenanthramides, which have shown strong
antioxidant activity in vitro and in vivo. The polyphenols of oats have also recently been shown to exhibit
anti-inflammatory, antiproliferative, and anti-itching activity, which may provide additional protection
against coronary heart disease, colon cancer, and skin irritation.
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Avenanthramides are bioavailable and have antioxidant activity in humans

after acute consumption of an enriched mixture from oats.
Chen CY, Milbury PE, Collins FW, Blumberg JB. J Nutr. 2007 Jun;137(6):1375-82.
Abstract
The consumption of polyphenols is associated with a decreased risk of cardiovascular disease.

Avenanthramides (AV), alkaloids occurring only in oats, may have anti-atherosclerotic activity, but there
is no information concerning their bioavailability and bioactivity in humans. We characterized the
pharmacokinetics and antioxidant action of avenanthramide A, B, and C in healthy older adults in a
randomized, placebo-controlled, 3-way crossover trial with 1-wk washout periods. Six free-living
subjects (3 mol/L, 3 F; 60.8 +/- 3.6 y) consumed 360 mL skim milk alone (placebo) or containing 0.5 or 1
g avenanthramide-enriched mixture (AEM) extracted from oats. Plasma samples were collected over a
10-h period. Concentrations of AV-A, AV-B, and AV-C in the AEM were 154, 109, and 111 micromol/g,
respectively. Maximum plasma concentrations of AV (free + conjugated) after consumption of 0.5 and 1
g AEM were 112.9 and 374.6 nmol/L for AV-A, 13.2 and 96.0 nmol/L for AV-B, and 41.4 and 89.0 nmol/L
for AV-C, respectively. Times to reach the C(max) for both doses were 2.30, 1.75, and 2.15 h for AV-A,
AV-B, and AV-C and half times for elimination were 1.75, 3.75, and 3.00 h, respectively. The elimination
kinetics of plasma AV appeared to follow first-order kinetics. The bioavailability of AV-A was 4-fold larger
than that of AV-B at the 0.5 g AEM dose. After consumption of 1 g AEM, plasma reduced glutathione
was elevated by 21% at 15 min (P < or = 0.005) and by 14% at 10 h (P < or = 0.05). Thus, oat AV are
bioavailable and increase antioxidant capacity in healthy older adults.
Can Oat Straw Extract Improve Your Health?

Healthline.com. Written by Kelli McGrane, MS, RD on August 28, 2019
https://www.healthline.com/nutrition/oat-straw-extract
Oat straw comes from the unripened Avena sativa plant, which is commonly grown in Northern Europe
and North America.
As an extract, oat straw is often sold as a tincture but can also be found in powder and capsule form.
It’s believed to offer numerous health benefits, such as reduced inflammation and improved brain
function and mood.
This article reviews oat straw extract and its potential benefits.
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Oregano Oil (Carvacrol)

Bactericidal Property of Oregano Oil Against Multidrug-Resistant Clinical
Isolates.
Lu M, Dai T, Murray CK, Wu MX. Front Microbiol. 2018 Oct 5;9:2329. doi:
10.3389/fmicb.2018.02329. eCollection 2018.
Abstract
Development of non-antibiotic alternatives to treat infections caused by multidrug-resistant (MDR)

microbes represents one of the top priorities in healthcare and community settings, especially in the
care of combat trauma-associated wound infections. Here, we investigate efficacy of oregano oil against
pathogenic bacteria including MDR isolates from the combat casualties in vitro and in a mouse burn
model. Oregano oil showed a significant anti-bacterial activity against 11 MDR clinical isolates including
four Acinetobacter baumannii, three Pseudomonas aeruginosa, and four methicillin-resistant
Staphylococcus aureus (MRSA) obtained from combat casualties and two luminescent strains of PA01
and MRSA USA300, with a MIC ranging from 0.08 mg/ml to 0.64 mg/ml. Oregano oil also effectively
eradicated biofilms formed by each of the 13 pathogens above at similar MICs. Transmission electron
microscopy (TEM) and scanning electron microscopy (SEM) revealed that oregano oil damaged bacterial
cells and altered the morphology of their biofilms. While efficiently inactivating bacteria, there was no
evidence of resistance development after up to 20 consecutive passages of representative bacterial
strains in the presence of sublethal doses of oregano oil. In vivo study using the third-degree burn
wounds infected with PA01 or USA300 demonstrated that oregano oil, topically applied 24 h after
bacterial inoculation, sufficiently reduced the bacterial load in the wounds by 3 log10 in 1 h, as
measured by drastic reduction of bacterial bioluminescence. This bactericidal activity of oregano oil
concurred with no significant side effect on the skin histologically or genotoxicity after three topical
applications of oregano oil at 10 mg/ml for three consecutive days. The investigation suggests potentials
of oregano oil as an alternative to antibiotics for the treatment of wound-associated infections
regardless of antibiotic susceptibility.
Oregano
Vitamins & Supplements. WebMD.2018
https://www.webmd.com/vitamins/ai/ingredientmono-644/oregano
349
Oregano is a plant. The leaf is used to make medicine.
Oregano is used for respiratory tract disorders such as coughs, asthma, croup, and bronchitis. It is also
used for gastrointestinal (GI) disorders such as heartburn and bloating. Other uses include treating
menstrual cramps, rheumatoid arthritis, urinary tract disorders including urinary tract infections (UTIs),
headaches, and heart conditions.
The oil of oregano is taken by mouth for intestinal parasites, allergies, sinus pain, arthritis, cold and flu,
swine flu, earaches, and fatigue. It is applied to the skin for skin conditions including acne, athlete's foot,
oily skin, dandruff, canker sores, warts, ringworm, rosacea, and psoriasis; as well as for insect and spider
bites, gum disease, toothaches, muscle pain, and varicose veins. Oregano oil is also used topically as an
insect repellent.
In foods and beverages, oregano is used as a culinary spice and a food preservative.
How does it work?
Oregano contains chemicals that might help reduce cough and spasms. Oregano also might help
digestion by increasing bile flow and fighting against some bacteria, viruses, fungi, intestinal worms, and
other parasites.
In vitro activities of non-traditional antimicrobials alone or in combination

against multidrug-resistant strains of Pseudomonas aeruginosa and
Acinetobacter baumannii isolated from intensive care units.
Timurkaynak F, et al. Int J Antimicrob Agents. 2006 Mar;27(3):224-8. Epub 2006
Feb 7.
Abstract
The aim of this study was to assess the in vitro activity of a number of non-traditional antibiotics
(colistin, azithromycin, doxycycline and rifampicin) against multidrug-resistant (MDR) strains of
Pseudomonas aeruginosa and Acinetobacter baumannii isolated from Intensive Care Units (ICUs). We
also used the checkerboard method to determine whether combinations of colistin with another non-
traditional antibiotic or meropenem act synergistically against these strains. Thirty-five P. aeruginosa
and 25 A. baumannii strains that were found to be MDR were included the study. Isolates were collected
from the specimens of patients in ICUs from 2001 to 2003. All isolates were identified by standard
methods and stored at -20 degrees C until use. Antibiotic powders of azithromycin, doxycycline,
rifampicin, meropenem and colistin were obtained from their manufacturers. Minimum inhibitory
concentrations (MICs) were determined by the agar dilution method on Mueller-Hinton agar. Five
strains of A. baumannii and five strains of P. aeruginosa, all of which had different MIC values for
colistin, were selected for the synergy study using the checkerboard titration method. The susceptibility
350
results for doxycycline and meropenem were interpreted according to National Committee for Clinical
Laboratory Standards guidelines. The susceptibility breakpoints for colistin and rifampicin were
established as 4 mg/L and 2 mg/L, respectively, based on previous studies. Pseudomonas aeruginosa
ATCC 27853 and Escherichia coli ATCC 25922 were used as control strains. Testing against the P.
aeruginosa strains revealed high MIC50 values for all the drugs except colistin. Doxycycline and colistin
were both effective against the A. baumannii strains, with high susceptibility rates of 92% and 100%,
respectively. Azithromycin had a high MIC50 value against these strains, whilst rifampicin had a
moderate effect (susceptibility rate 64%). The combination of colistin and rifampicin was fully synergistic
against four A. baumannii and two P. aeruginosa strains. Combinations of colistin with meropenem and
of colistin with azithromycin each showed synergistic activity against three A. baumannii isolates, whilst
the same combinations resulted in generally additive or indifferent effects against P. aeruginosa strains.
The colistin and doxycycline combination was generally partially synergistic or additive against all the
isolates. MDR strains of P. aeruginosa and A. baumannii, which cause nosocomial infections with an
increasing ratio in recent years, have limited treatment options. According to our in vitro study results,
non-traditional antibiotics such as doxycycline and colistin can be an alternative for the treatment of
infections caused by these strains. Combinations of colistin with non-traditional antibiotics or
meropenem could be promising alternatives for the treatment of infections due to MDR strains of A.
baumannii and P. aeruginosa.
Oregano.
Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National
Library of Medicine (US); 2006-.
Excerpt
Oregano (Origanum vulgare) leaves and oil contain carvacrol, thymol, eugenol and rosmarinic acid.
Oregano has been used in medicinal doses for respiratory and gastrointesinal disorders and as an
antimicrobial. Oregano oil has been advocated as a treatment for lactation-related Candida infection of
the nipples;[1] however, no clinical studies have confirmed the safety or efficacy of this use. No data
exist on the excretion of any components of oregano into breastmilk or on the safety and efficacy of
oregano in nursing mothers or infants. Oregano and oregano oil are "generally recognized as safe"
(GRAS) as food ingredients by the U.S. Food and Drug Administration. Oregano is generally well
tolerated, but gastrointestinal upset and allergic skin reactions have been reported rarely. Because of a
lack of data, oregano in amounts higher than those found in foods as a flavoring should probably be
avoided during breastfeeding. Dietary supplements do not require extensive pre-marketing approval
from the U.S. Food and Drug Administration. Manufacturers are responsible to ensure the safety, but do
not need to prove the safety and effectiveness of dietary supplements before they are marketed.
Dietary supplements may contain multiple ingredients, and differences are often found between labeled
and actual ingredients or their amounts. A manufacturer may contract with an independent
351
organization to verify the quality of a product or its ingredients, but that does not certify the safety or
effectiveness of a product. Because of the above issues, clinical testing results on one product may not
be applicable to other products. More detailed information about dietary supplements is available
elsewhere on the LactMed Web site.
Biological and pharmacological activities of carvacrol and carvacrol bearing

essential oils.
Baser KH. Curr Pharm Des. 2008;14(29):3106-19.
Abstract
Oregano essential oils obtained from the genera Origanum, Thymus, Coridothymus, Thymbra, Satureja
and Lippia are rich in carvacrol, a monoterpenic phenol isomeric with thymol. Turkey is the biggest
exporter of oregano herb and oil to the world markets. Oregano is mainly used in food, spice and
pharmaceutical industries. Carvacrol is responsible for the biological activities of oregano. Many diverse
activities of carvacrol such as antimicrobial, antitumor, antimutagenic, antigenotoxic, analgesic,
antispasmodic, antiinflammatory, angiogenic, antiparasitic, antiplatelet, AChe inhibitory, antielastase,
insecticidal, antihepatotoxic and hepatoprotective activities and uses such as feed additive, in honeybee
breeding and in gastrointestinal ailments have been shown. This paper highlights these activities and
attempts to explain the possible in vivo mechanism of action of carvacrol.
Acaricidal activity of oregano oil and its major component, carvacrol, thymol
and p-cymene against Psoroptes cuniculi in vitro and in vivo.
Shang X, et al. Vet Parasitol. 2016 Aug 15;226:93-6. doi:
10.1016/j.vetpar.2016.07.001. Epub 2016 Jul 2.
Abstract
Oregano oil possesses marked antioxidant and antimicrobial activity and is widely applied in animal
husbandry. In the present study, we aimed to investigate the acaricidal activities of oregano oil and its
major component, carvacrol, thymol and p-cymene against Psoroptes cuniculi in vitro and in vivo. The
results revealed that oregano oil exhibited significant acaricidal effects against P. cuniculi that were
dose- and time-dependent response. In in vitro test, concentrations of 0.05% and 0.02% (v/v) killed all of
the mites within 1h and 6h, respectively. Moreover, 0.1mg/ml (w/v) carvacrol, 0.2mg/ml (w/v) thymol
and 1% p-cymene (v/v) also possessed marked acaricidal activities, and compared with the control
group, elicited mean mortalities of 84.00%, 96.00% and 66% at 24h, respectively. The median lethal
352
times (LT50) against P. cuniculi of the concentrations of 0.02%, 0.01% and 0.005% (v/v) of oregano oil,
thymol, carvacrol and p-cymene were 2.171h, 11.396h, 26.102h, and 4.424h, 8.957h and 15.201h,
respectively. Meanwhile, twenty naturaly infested rabbits were used to four homogeneity groups:
negative control (without treatment), positive control (treated with ivermectin), group treated with 1%
of oregano oil and other group with 5% of oregano oil. All the treatments were topically. After the
treatment of 1% and 5% oregano oil, the P. cuniculi were completely eliminated in the rabbits, and at
the end of the test (day 20), the rabbits of all treatment groups exhibited favorable mental and physical
statuses. These results indicated that oregano oil could be widely applied as a potential acaricidal agent
in the treatment of animal acariasis in the future.
Biological Activities of Asteraceae (Achillea millefolium and Calendula

officinalis) and Lamiaceae (Melissa officinalis and Origanum majorana) Plant
Extracts.
García-Risco MR, et al. Plant Foods Hum Nutr. 2017 Mar;72(1):96-102. doi:
10.1007/s11130-016-0596-8.
Abstract
Asteraceae (Achillea millefolium and Calendula officinalis) and Lamiaceae (Melissa officinalis and
Origanum majorana) extracts were obtained by applying two sequential extraction processes:
supercritical fluid extraction with carbon dioxide, followed by ultrasonic assisted extraction using green
solvents (ethanol and ethanol:water 50:50). The extracts were analyzed in terms of the total content of
phenolic compounds and the content of flavonoids; the volatile oil composition of supercritical extracts
was analyzed by gas chromatography and the antioxidant capacity and cell toxicity was determined.
Lamiaceae plant extracts presented higher content of phenolics (and flavonoids) than Asteraceae
extracts. Regardless of the species studied, the supercritical extracts presented the lowest antioxidant
activity and the ethanol:water extracts offered the largest, following the order Origanum majorana >
Melissa officinalis ≈ Achillea millefolium > Calendula officinalis. However, concerning the effect on cell
toxicity, Asteraceae (especially Achillea millefolium) supercritical extracts were significantly more
efficient despite being the less active as an antioxidant agent. These results indicate that the effect on
cell viability is not related to the antioxidant activity of the extracts.
6 Science-Based Health Benefits of Oregano

Written by Rachael Link, MS, RD on October 27, 2017. Healthline.com
https://www.healthline.com/nutrition/6-oregano-benefits
Oregano is considered a staple herb in many cuisines around the world.

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It has a strong flavor and brings warmth to dishes, along with a hint of subtle sweetness.
It can be found fresh, dried or as an oil, and all are said to have significant health benefits.
Though typically used in small amounts, oregano packs in some important nutrients. Just one teaspoon
of dried oregano can fulfill about 8% of your daily vitamin K needs .
From helping fight bacteria to reducing inflammation, studies have unearthed some of its impressive
potential benefits.
Anti-inflammatory and anti-ulcer activities of carvacrol, a monoterpene

present in the essential oil of oregano.
Silva FV, et al. J Med Food. 2012 Nov;15(11):984-91. doi: 10.1089/jmf.2012.0102.
Epub 2012 Aug 14.
Abstract
This study reports a pharmacological evaluation of anti-inflammatory and anti-ulcer activities of

carvacrol, a phenolic monoterpene constituent of essential oils produced by oregano and other several
aromatic plants and spices, in experimental models of edema induced by different phlogistic agents and
gastric lesions induced by acetic acid. In models of paw edema induced by dextran or histamine,
carvacrol was effective at 50 mg/kg (46% and 35%, respectively); in these models, cyproheptadine
reduced edema formation (61% and 43%, respectively). In edema induced by substance P, carvacrol
(100 mg/kg) and ruthenium red (3 mg/kg) also decreased the edema formation (46% and 40%,
respectively). Carvacrol significantly reduced the ear edema induced by 12-O-tetradecanoylphorbol
acetate and arachidonic acid at 0.1 mg per ear (43% and 33%, respectively), similar to indomethacin at
0.5 mg per ear or 2.0 mg per ear (55% and 57%, respectively). Carvacrol (at doses of 25, 50, and
100 mg/kg) showed a healing capacity on gastric lesions induced by acid acetic (60%, 91%, and 81%,
respectively) after 14 days of treatment. These results suggest that carvacrol acts on different
pharmacological targets, probably interfering in release and/or synthesis of inflammatory mediators,
such as the prostanoids, and thus favoring the healing process for gastric ulcers.
Anti-inflammatory effects of carvacrol: evidence for a key role of interleukin-

10.
Lima Mda S, et al. Eur J Pharmacol. 2013 Jan 15;699(1-3):112-7. doi:
10.1016/j.ejphar.2012.11.040. Epub 2012 Dec 3.
354
Abstract
Carvacrol, a phenolic monoterpene, has been reported to possess anti-inflammatory properties.

However, the mechanisms involved in its pharmacological properties are currently not well understood.
In the present study, the contribution of cytokine modulation to the anti-inflammatory effects of
carvacrol was investigated in a classical inflammation model: the complete Freund's adjuvant (CFA)-
induced paw inflammation in mice. The paw edema was measured using a plesthismometer. Paw tissue
was removed 2h after the inflammatory stimulus to determine the levels of prostaglandin E(2) (PGE(2))
by enzyme immunoassay, the levels of interleukin-1 β (IL-1β), tumor necrosis factor-α (TNF-α), and
interleukin-10 (IL-10) by ELISA or the mRNA expression of cyclooxygenase-2 (COX-2), IL-1β, TNF-α, and
IL-10 by real-time PCR. Administration of carvacrol produced anti-inflammatory effects against CFA-
induced inflammation in mice. Treatment of mice with carvacrol at 50 and 100mg/kg attenuated the
paw edema and reduced the IL-1β and PGE(2), but not TNF-α, local levels. Similarly, carvacrol
(100mg/kg) reduced the COX-2 and IL-1β mRNA expression. The levels of IL-10, an anti-inflammatory
cytokine, and the IL-10 mRNA expression in the inflamed paw were enhanced by carvacrol. In addition,
the treatment with carvacrol did not reduce the CFA-induced paw edema in IL-10 knockout mice. The
present results suggest that carvacrol causes anti-inflammatory effects by reducing the production of
inflammatory mediators, such as IL-1β and prostanoids, possibly through the induction of IL-10 release.
What are the health benefits of oregano?

Joseph Nordqvist . Reviewed by Natalie Butler, RD, LD . Medical News Today. Last
updated Mon 11 December 2017
Oregano oil contains an essential compound called carvacrol, which has antimicrobial properties.
The herb has shown antimicrobial activity in a number of studies. One group of researchers found that
Origanum vulgare essential oils were effective against 41 strains of the food pathogen Listeria
monocytogenes.
Another team from India and the United Kingdom (U.K.) reported that the essential oil of Himalayan
oregano has strong antibacterial properties that may protect against the hospital superbug, MRSA.
"We have done a few preliminary tests and have found that the essential oil from the oregano kills
MRSA at a dilution 1 to 1,000. The tests show that the oil kills MRSA both as a liquid and as a vapor and
its antimicrobial activity is not diminished by heating in boiling water." - Prof. Vyv Salisbury, the
University of the West of England, Bristol. The project won an award from the United Nations in 2008.
Scientists from Germany and Switzerland identified an active ingredient in oregano, known as beta-
caryophyllin (E-BCP), which may help treat disorders such as osteoporosis and arteriosclerosis. E-BCP is a
dietary cannabinoid.
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Probiotics
Using probiotics in clinical practice: Where are we now? A review of existing
meta-analyses
Rondanelli, M, et al. Gut Microbes. 2017; 8(6): 521–543. Published online 2017 Jul
21. doi: 10.1080/19490976.2017.1345414
ABSTRACT
The scientific literature has demonstrated that probiotics have a broad spectrum of activity, although
often the results are contradictory. This study provides a critical overview of the current meta-analyses
that have evaluated the efficacy of probiotics in physiologic and pathological conditions, such as
metabolic disease, antibiotic-associated and Clostridium difficile-associated diarrhea, IBS, constipation,
IBD, chemotherapy-associated diarrhea, respiratory tract infection, ventilator-associated pneumonia,
NAFLD, liver encephalopathy, periodontitis, depression, vaginosis, urinary tract infections, pancreatitis,
incidence of ventilator-associated pneumonia, hospital infection and stay in ICU, mortality of post-
trauma patients, necrotising enterocolitis in premature infants.
Only for antibiotic- and Clostridium difficile-associated diarrhea, and respiratory tract infections the
effects of probiotics are considered “evidence-based.” Concerning other fields, meta-analyses lacks to
define type and biologic effect of probiotic strains, as well as the outcome in a disease state. Therefore,
the results presented should be a stimulus for further studies which will provide clinical
recommendations.
KEYWORDS: cardiovascular disease, diabetes, gastrointestinal disease, infections, obesity, probiotics
Introduction
The scientific literature related to the favorable effects of probiotics on human health has continued to
accumulate in recent years,1 and meta-analyses that have collectively evaluated the effects of probiotics
in specific physiologic and pathological conditions are now numerous.
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The fields of study in which meta-analysis and systematic reviews have been published concerning the
assessment of effectiveness of taking probiotics are given in Table 1, and cover certain categories of
patients (premature infants and trauma patients) and specific diseases, such as metabolic disorders
(diabetes, dyslipidemia, hypertension, obesity), gastrointestinal disorders (inflammatory bowel disease,
constipation, antibiotic-associated diarrhea, diarrhea secondary to treatment of eradication Clostridium
difficile, Helicobacter Pylori, diarrhea secondary to chemotherapy), atopic diseases (atopic syndrome
and food hypersensitivity, allergic rhinitis), liver disease (cirrhosis, non-alcoholic fatty liver disease,
hepatic encephalopathy), pancreatic disorders (acute pancreatitis), infections of the respiratory tract,
urinary tract infections, bacterial vaginosis, periodontitis, and depressive disorder.
Probiotics for the prevention of pediatric antibiotic-associated diarrhea.

Goldenberg, JZ. Cochrane Database Syst Rev. 2015 Dec 22;(12):CD004827. doi:
10.1002/14651858.CD004827.pub4.
Probiotics for the prevention of pediatric antibiotic-associated diarrhea. [Cochrane Database Syst Rev.
2019]
Abstract
BACKGROUND:
Antibiotics are frequently prescribed in children. They alter the microbial balance within the
gastrointestinal tract, commonly resulting in antibiotic-associated diarrhea (AAD). Probiotics may
prevent AAD via restoration of the gut microflora.
OBJECTIVES:
The primary objectives were to assess the efficacy and safety of probiotics (any specified strain or dose)
used for the prevention of AAD in children.
SEARCH METHODS:
MEDLINE, EMBASE, CENTRAL, CINAHL, AMED, and the Web of Science (inception to November 2014)
were searched along with specialized registers including the Cochrane IBD/FBD review group, CISCOM
(Centralized Information Service for Complementary Medicine), NHS Evidence, the International
Bibliographic Information on Dietary Supplements as well as trial registries. Letters were sent to authors
357
of included trials, nutraceutical and pharmaceutical companies, and experts in the field requesting
additional information on ongoing or unpublished trials. Conference proceedings, dissertation abstracts,
and reference lists from included and relevant articles were also searched.
SELECTION CRITERIA:
Randomized, parallel, controlled trials in children (0 to 18 years) receiving antibiotics, that compare
probiotics to placebo, active alternative prophylaxis, or no treatment and measure the incidence of
diarrhea secondary to antibiotic use were considered for inclusion.
Study selection, data extraction as well as methodological quality assessment using the risk of bias
instrument was conducted independently and in duplicate by two authors. Dichotomous data (incidence
of diarrhea, adverse events) were combined using a pooled risk ratio (RR) or risk difference (RD), and
continuous data (mean duration of diarrhea, mean daily stool frequency) as mean difference (MD),
along with their corresponding 95% confidence interval (95% CI). For overall pooled results on the
incidence of diarrhea, sensitivity analyses included available case versus extreme-plausible analyses and
random- versus fixed-effect models. To explore possible explanations for heterogeneity, a priori
subgroup analysis were conducted on probiotic strain, dose, definition of antibiotic-associated diarrhea,
as well as risk of bias. We also conducted post hoc subgroup analyses by patient diagnosis, single versus
multi-strain, industry sponsorship, and inpatient status. The overall quality of the evidence supporting
the outcomes was evaluated using the GRADE criteria.
MAIN RESULTS:
Twenty-three studies (3938 participants) met the inclusion criteria. Trials included treatment with either
Bacillus spp., Bifidobacterium spp., Clostridium butyricum, Lactobacilli spp., Lactococcus spp.,
Leuconostoc cremoris, Saccharomyces spp., orStreptococcus spp., alone or in combination. Eleven
studies used a single strain probiotic, four combined two probiotic strains, three combined three
probiotic strains, one combined four probiotic strains, two combined seven probiotic strains, one
included ten probiotic strains, and one study included two probiotic arms that used three and two
strains respectively. The risk of bias was determined to be high or unclear in 13 studies and low in 10
studies. Available case (patients who did not complete the studies were not included in the analysis)
results from 22/23 trials reporting on the incidence of diarrhea show a precise benefit from probiotics
compared to active, placebo or no treatment control. The incidence of AAD in the probiotic group was
8% (163/1992) compared to 19% (364/1906) in the control group (RR 0.46, 95% CI 0.35 to 0.61; I(2) =
55%, 3898 participants). A GRADE analysis indicated that the overall quality of the evidence for this
outcome was moderate. This benefit remained statistically significant in an extreme plausible (60% of
358
children loss to follow-up in probiotic group and 20% loss to follow-up in the control group had diarrhea)
sensitivity analysis, where the incidence of AAD in the probiotic group was 14% (330/2294) compared to
19% (426/2235) in the control group (RR 0.69; 95% CI 0.54 to 0.89; I(2) = 63%, 4529 participants). None
of the 16 trials (n = 2455) that reported on adverse events documented any serious adverse events
attributable to probiotics. Meta-analysis excluded all but an extremely small non-significant difference in
adverse events between treatment and control (RD 0.00; 95% CI -0.01 to 0.01). The majority of adverse
events were in placebo, standard care or no treatment group. Adverse events reported in the studies
include rash, nausea, gas, flatulence, abdominal bloating, abdominal pain, vomiting, increased phlegm,
chest pain, constipation, taste disturbance, and low appetite.
Moderate quality evidence suggests a protective effect of probiotics in preventing AAD. Our pooled
estimate suggests a precise (RR 0.46; 95% CI 0.35 to 0.61) probiotic effect with a NNT of 10. Among the
various probiotics evaluated, Lactobacillus rhamnosus or Saccharomyces boulardii at 5 to 40 billion
colony forming units/day may be appropriate given the modest NNT and the likelihood that adverse
events are very rare. It is premature to draw conclusions about the efficacy and safety of other probiotic
agents for pediatric AAD. Although no serious adverse events were observed among otherwise healthy
children, serious adverse events have been observed in severely debilitated or immuno-compromised
children with underlying risk factors including central venous catheter use and disorders associated with
bacterial/fungal translocation. Until further research has been conducted, probiotic use should be
avoided in pediatric populations at risk for adverse events. Future trials would benefit from a standard
and valid outcomes to measure AAD.
The Clinical and Economic Impact of Probiotics Consumption on Respiratory

Tract Infections: Projections for Canada
Irene Lenoir-Wijnkoop, Laetitia Gerlier, Denis Roy, and Gregor Reid. Ana Paula
Arez, Editor. PLoS One. 2016; 11(11): e0166232. Published online 2016 Nov 10.
doi: 10.1371/journal.pone.0166232
Abstract
Introduction
There is accumulating evidence supporting the use of probiotics, which are defined as “live micro-
organisms which, when administered in adequate amounts, confer a health benefit on the host”, as a
preventive measure against respiratory tract infections (RTI). Two recent meta-analyses showed
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probiotic consumption (daily intake of 107 to 1010 CFU in any form for up to 3 months) significantly
reduced RTI duration, frequency, antibiotic use and work absenteeism.
Objectives
The aim of this study was to assess the impact of probiotic use in terms of number of RTI episodes and
days averted, and the number of antibiotic prescriptions and missed workdays averted, in the general
population of Canada. In addition, the corresponding economic impact from both a healthcare payer
and a productivity perspective was estimated.
Methods
A microsimulation model was developed to reproduce the Canadian population (sample rate of 1/1000
= 35 540 individuals) employing age and gender. RTI incidence was taken from FluWatch consultation
rates for influenza-like illness (2013–14) and StatCan all-cause consultations statistics. The model was
calibrated on a 2.1% RTI annual incidence in the general population (5.2 million RTI days) and included
known risk factors (smoking status, shared living conditions and vaccination status). RTI-related
antibiotic prescriptions and work absenteeism were obtained from the literature.
Results
The results indicate that probiotic use saved 573 000–2.3 million RTI-days, according to the YHEC–
Cochrane scenarios respectively. These reductions were associated with an avoidance of 52 000–84 000
antibiotic courses and 330 000–500 000 sick-leave days. A projection of corresponding costs reductions
amounted to Can$1.3–8.9 million from the healthcare payer perspective and Can$61.2–99.7 million
when adding productivity losses.
Conclusion
The analysis shows that the potential of probiotics to reduce RTI-related events may have a substantial
clinical and economic impact in Canada.
Go to:
Introduction
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Respiratory tract infections (RTI) are highly contagious infections of the sinus, throat, or airways.
Typically viral, these self-limiting infections can last up to 2 weeks and vary in severity [1]. Influenza-like-
illness (ILI) and influenza are common RTIs, and are defined as acute onset of respiratory symptoms (i.e.
cough, sore throat or shortness of breath), accompanied by fever, headache and/or myalgia [1–3]. Cases
of laboratory-confirmed influenza virus are termed ‘influenza’ [1].
Due to their high incidence, RTIs carry a heavy burden on society and the healthcare systems.
Approximately 5–20% of the population will have at least one RTI annually, resulting in 31.4 million
outpatient visits, 3.1 million hospitalized days, and 41 000 deaths each year in the USA [4]. ILI and
influenza are estimated to result in 3–5 million illnesses and 250 000–500 000 deaths annually, around
the world [5]. In Canada, 14 000–17 000 hospitalizations (8–10% of all hospital admissions) [6] and 3 500
deaths are attributed to influenza each year [7]. The estimated total annual economic burden of RTIs in
Canada in 2008, was Can$5.4 billion, representing 2.9% of all healthcare costs [2, 8].
Treatment of RTIs relies mainly on symptom control, however, despite being most commonly of viral
etiology, they often lead to the prescription of antibiotics [9, 10]. The use of antiviral agents within 48
hours of illness onset reduces the duration of symptoms by about 1 day; however their effectiveness
might be limited by side effects and resistance [11–14]. In the absence of satisfactory treatments,
prevention is the cornerstone of influenza management [1, 14]. In addition to limiting contact and
frequent hand washing [15], the mainstay of prevention against influenza infection is vaccination [1, 14].
Although influenza is considered to be a vaccine preventable disease, vaccine effectiveness can be
limited by mismatches with the circulating viral strains [14] and low uptake in the population [16].
Probiotics, defined as “live micro-organisms which, when administered in adequate amounts, confer a
health benefit on the host” [17], are being consumed with increasing frequency over the past ten years.
There is accumulating evidence supporting the use of probiotics, both in food products and nutritional
supplements, as a preventive measure against RTIs [18–24]. Two recent meta-analyses by the York
Health Economics Consortium (YHEC) and the Cochrane Collaboration [18, 20], showed that probiotic
consumption reduced RTI duration by 0.8 days [20] and 1.9 days [18] respectively. Moreover, they
reduced the incidence of RTIs by 47% [18], the antibiotic prescription rate by 35% [18] and absenteeism
by 17% [20]. We hypothesize that there are potential benefits to the Canadian healthcare system
associated with these reductions in RTI incidence and duration, which may contribute in lightening the
burden of an increasing scarcity of resources.
Objective
The primary objective of this study was to assess the clinical impact of probiotics use projected to
Canada: number of RTI episodes and RTI days averted, number of RTI-related antibiotics prescriptions
361
and missed work days averted. Our secondary objective was to estimate the related economic impact
from a healthcare payer perspective and a productivity perspective.
Results
A sampling rate of 1/1000, or 35 540 simulated individuals, reproduced the Canadian population
structure in terms of age and gender, with an error rate less than 5% between expected population size
and modeled population size.
Under the YHEC scenario, which focused on the probiotic effect on RTI duration, projected to the
Canadian population over a one year period (Sept 2013 –Aug 2014), probiotic consumption would avert
572 629 days of RTI illness (10.4% reduction), 51 526 antibiotic prescriptions for RTI (26.4% reduction)
and 329 977 days of missed work (35.9% reduction), compared to no probiotic consumption (Fig 3).
Under the Cochrane scenario, which focused on the effect of probiotics on reducing both RTI incidence
and duration, over the same time period and projected to the Canadian population, probiotics
consumption would avert 2 329 800 RTI days (35.3% reduction), 180 000 RTI episodes (23.9% reduction),
almost 84 272 antibiotics prescriptions for RTI (42.8% reduction) and 500 228 missed work days (51.3%
reduction), compared to no probiotic consumption.
In terms of economic impact, the cost reduction associated with the averted RTI events amount to
Can$1.29 million from the HCP perspective and Can$61.22 million when taking productivity losses into
account (-30.6%), based on YHEC scenario.
In the Cochrane scenario, the economic impact of averted RTI events was estimated at Can$8.89 million
from the HCP perspective and Can$99.77 million when productivity losses are included (Fig 4).
A higher relative benefit of probiotic consumption on the reduction of RTI duration was observed among
children < 10 years old, on individuals living in a community setting and on those who were not
vaccinated against influenza. Children < 10 years old represented 10.5% of the population (N = 3 721
000) but accounted for 19.5% of the potentially averted RTI days (-111 650 days), thus, this young age
group shows a higher incremental benefit than other age groups. Individuals working or living in a
community setting accounted for 50.7% (N = 18 000 000) of the total population but accounted for
56.8% (-325 459 days) of the total RTI-days saved with probiotics consumption. Non-vaccinated
individuals represented 69.4% of the total Canadian population in 2014, these individuals accounted for
74.5% of the total RTI-days potentially averted in the general population under the YHEC scenario,
meaning that even vaccinated individuals can have some benefits of probiotics.
The results of the sensitivity analyses showed that the model results are robust against varying RTI rates
from the preceding (2012–13) and following (2014–15) seasons, and the lower and upper 95%
confidence limits of RTI duration and RTI incidence.
362
The impact of probiotic consumption on RTI days based on 2012–13 and 2014–15 seasons did not differ
substantially from the base case results. Averted RTI days ranged from 465 080 to 582 890 in the YHEC
scenario (corresponding HCP costs of averted RTI events Can$1.07–1.33 million and Can$50.63–63.76
million when including productivity losses), and from 1.62 to 2.42 million days in the Cochrane scenario
(corresponding HCP costs of averted RTI events Can$ 5.87–8.99 million and Can$70.44–103.17 with
productivity losses).
Applying the lower and upper 95% confidence limits of the reduction of RTI duration from the YHEC
meta-analysis (-0.04 to -1.50 days per episode), the potentially averted RTI days in the probiotics arm
varied between 29 720 and 1.12 million days; from the Cochrane meta-analysis (-2.03 to -1.75 days per
episode), the potentially averted RTI days in the probiotics arm varied between 2.27 and 2.38 million.
When testing the 95% CI around the reduction of RTI incidence from the Cochrane meta-analysis (RR
from 0.50 to 0.84), the averted RTI days in the probiotics arm varied between 1.67 and 2.92 million days.
Discussion
The microsimulation described here estimates the potential clinical and economic benefits of probiotic
consumption on RTIs in Canada, under two distinct scenarios derived from two recent meta-analyses
[18, 20]. The model was anchored on the Canadian population structure and RTI incidence data were
applied. Projecting the clinical benefits onto the Canadian population demonstrates that probiotic
consumption has the potential to save 180 000 RTI episodes and 500 000–2.3 million RTI-days with an
associated avoidance of 50 000–85 000 antibiotic courses and 300 000–500 000 work absenteeism days.
These averted RTI events, when translated into averted costs for the HCP, would represent Can$1.3–8.9
million and up to Can$61.2–99.7 million when including the averted costs of productivity losses.
Our findings are consistent with a similar analysis conducted on the French population, which showed
that population level probiotic consumption in France would potentially save 2.4–6.6 million RTI sick
days, 291 000–473 000 antibiotic courses and 581 000–1.5 million work absenteeism days. The
economic impact of preventive probiotic use was estimated to be €14.6 - €37.7 million to the French
National Health Care System [25]. The main reason for a higher probiotic impact in the French analysis is
that the RTI definition was encompassing not only ILI but also common colds.
Data on common colds were indeed not available for the Canadian population, therefore only ILIs were
included in the model, resulting in a more restrictive inclusion. As well, unlike the French model, the
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impact of confounding due to vaccination against influenza was decreased in the Canadian model by
including the vaccination status of the population. Both of these factors led to a more conservative
model.
As in the French model, the Canadian model shows a higher incremental benefit of probiotic
consumption among children < 10 years old and individuals living in a community setting. This is likely
due to a higher incidence of ILIs among children [48] and the ease of transmission among individuals
who go to school and work in close proximity to others [42, 43]. The Canadian model also shows higher
benefit among people not vaccinated against influenza.
In both French and Canadian analyses, the acquisition cost of probiotics was not included since
probiotics are purchased on a voluntary basis by the families without any subsidy or reimbursement,
independent of their health status. As such, the cost of probiotics is not part of the HCP perspective
adopted in our study. The particularity of probiotics, and healthy/functional food in general, compared
to a standard health intervention is that individuals can decide to acquire probiotics for several reasons
(taste/preference over non-fermented dairy products, healthier diet purpose,…) and the potential RTI
prevention properties might only be part of it. From the large Canadian survey on healthy food [32], the
average household budget for such products in heavy vs light users is Can$175 vs. Can$128 per week i.e.
an incremental weekly expense of Can$47 for heavy users. This might represent the willingness to pay
(WTP) of Canadian households for healthy food including probiotics. In comparison, the cost of
probiotics in France per household was estimated between Can$182 and Can$484 for a period of 7
months i.e. Can$7–17 per week. This suggests that the acquisition cost of probiotics is largely inferior to
the WTP for healthy food, and this without any incentives (aside private advertising). Other out-of-
pockets expenses that were not included in this model due to lack of data were over-the-counter (OTC)
medication and costs related to informal care for a sick parent or child. The above mentioned costs
would be part of a so-called ‘society’ perspective, along with any Government expenses on campaigns or
advertisements to, for example, encourage healthy lifestyle choices in the population. However, this fell
beyond the scope of our analysis.
Importantly, the current incidence data were representative of individuals consulting a GP for their RTI.
They represent only a very small proportion of RTI sufferers, and therefore, the real savings may be
higher than reported.
The role of functional foods is increasingly being recognized as important, by not only public health
departments, but also by payers and policymakers [49]. Epidemiological studies have established the
clinical benefits of nutrition and functional foods on disease, including the use of probiotics to prevent
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diseases [50]. Several meta-analyses of randomized controlled trials have shown a benefit of probiotic
interventions in various therapeutic areas including neonatology [51], gastroenterology [52],
cardiovascular risk factors [53], urinary [54] and respiratory tract [18, 20]. Along with the clinical
benefits, functional foods have the potential to impact healthcare costs. In the current context of
competing healthcare dollars, with the challenge of allocating limited funds to an extensive list of needs,
functional food–including probiotics- offers an attractive population based strategy for improving
health. The emerging discipline of nutrition economics [55], to which this study contributes, will help
decision makers to evaluate the relevance of assessing the economic impact of nutrition [49].
This analysis shows that increasing probiotic consumption is likely to have substantial positive
consequences, not only on the healthcare system, but also on work absenteeism of sick employees per
se as well as those absent because of their children with respiratory illness. This is meaningful, as
approximately one third of employees working in an open office plan confirm their working
environment puts them at increased risk of illness due to the close and open contact with colleagues
[56]. The impact of RTI on work presenteeism (reduced on-the-job productivity due to RTI symptoms)
could be another field of research to cover.
Efficacy of Using Probiotics with Antagonistic Activity against Pathogens of

Wound Infections: An Integrative Review of Literature
Fijan, S, et al. Biomed Res Int. 2019; 2019: 7585486. Published online 2019 Dec
12. doi: 10.1155/2019/7585486
Abstract
The skin and its microbiota serve as physical barriers to prevent invasion of pathogens. Skin damage can
be a consequence of illness, surgery, and burns. The most effective wound management strategy is to
prevent infections, promote healing, and prevent excess scarring. It is well established that probiotics
can aid in skin healing by stimulating the production of immune cells, and they also exhibit antagonistic
effects against pathogens via competitive exclusion of pathogens. Our aim was to conduct a review of
recent literature on the efficacy of using probiotics against pathogens that cause wound infections. In
this integrative review, we searched through the literature published in the international following
databases: PubMed, ScienceDirect, Web of Science, and Scopus using the search terms “probiotic” AND
“wound infection.” During a comprehensive review and critique of the selected research, fourteen in
vitro studies, 8 animal studies, and 19 clinical studies were found. Two of these in vitro studies also
included animal studies, yielding a total of 39 articles for inclusion in the review. The most commonly
used probiotics for all studies were well-known strains of the species Lactobacillus plantarum,
Lactobacillus casei, Lactobacillus acidophilus, and Lactobacillus rhamnosus. All in vitro studies showed
successful inhibition of chosen skin or wound pathogens by the selected probiotics. Within the animal
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studies on mice, rats, and rabbits, probiotics showed strong opportunities for counteracting wound
infections. Most clinical studies showed slight or statistically significant lower incidence of surgical site
infections, foot ulcer infection, or burn infections for patients using probiotics. Several of these studies
also indicated a statistically significant wound healing effect for the probiotic groups. This review
indicates that exogenous and oral application of probiotics has shown reduction in wound infections,
especially when used as an adjuvant to antibiotic therapy, and therefore the potential use of probiotics
in this field remains worthy of further studies, perhaps focused more on typical skin inhabitants as next-
generation probiotics with high potential.
5. Conclusion
Although this review is directed at the antimicrobial role of probiotics in combating wound infections
and has shown promising results as possible alternatives or adjuvant therapies, the problem is still more
complex. In order to achieve optimal wound healing, it is necessary to address in parallel additional
factors regarding the patient's general health or the wound's physical environment and the body's
immune response [23, 151]. Despite the fact that it is known that wound healing is impaired by wound
infection, the exact role of probiotics in delayed wound healing remains controversial due to
discrepancy in clinical results [14, 64, 152]. However, an impressive number of studies as noted in this
review have shown that exogenous and oral application of probiotics together with antibiotics before
and after surgery has shown reduction in wound site infections and shorter duration of antibiotic
therapy. In addition, topical application of probiotics for burn infections and chronic ulcers decreased
the pathogen load. Therefore, the potential use of probiotics for wound infections remains worthy of
some more intense future study [153]. Further studies could also be warranted for topical application of
probiotics, perhaps focused more on typical skin inhabitants as topical probiotics with high potential.
Stress matters: Randomized controlled trial on the effect of probiotics on

neurocognition
S. Papalini, et al. Neurobiol Stress. 2019 Feb; 10: 100141. Published online 2018
Dec 10. doi: 10.1016/j.ynstr.2018.100141
Abstract
Probiotics are microorganisms that provide health benefits when consumed. In animals, probiotics
reverse gut microbiome-related alterations in depression-like symptoms, in cognition, and in hormonal
stress response. However, in humans, a causal understanding of the gut-brain link in emotion and
cognition is lacking. Additionally, whether the effects of probiotics on neurocognition are visible only in
presence of stress, remains unclear. We investigated the effects of a multispecies probiotic
(Ecologic®Barrier) on specific neurocognitive measures of emotion reactivity, emotion regulation, and
cognitive control using fMRI. Critically, we also tested whether probiotics can buffer against the
detrimental effects of acute stress on working memory. In a double blind, randomized, placebo-
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controlled, between-subjects intervention study, 58 healthy participants were tested once before and
once after a 28-day intervention.
Without stress induction, probiotics did not affect brain, behavioral, or related self-report measures.
However, relative to placebo, the probiotics group did show a significant stress-related increase in
working memory performance after supplementation. This change was associated with intervention-
related neural changes in frontal cortex during cognitive control exclusively in the probiotics group.
Overall, our results show neurocognitive effects of a multispecies probiotic in healthy women only under
challenging situations, buffering against the detrimental effects of stress on cognition.
Keywords: Probiotic, Neuroimaging, Cognitive control, Emotion, Stress, Working memory
6. Conclusions
We showed that 4-weeks of supplementation with probiotics positively affected cognition under
challenging situations induced by acute stress, which was associated with changes in frontal brain
regions during cognitive control. However, on neurocognitive tasks administered in relative neutral
situations we did not observe effects of probiotics across the group. Our findings of stress-dependent
beneficial effects of probiotics on cognition can be of clinical importance for stress-related psychiatric
and gastro-intestinal disorders.
Probiotics in Disease Prevention and Treatment

Yuying Liu, PhD, Dat Q. Tran, MD, and J. Marc Rhoads, MD. J Clin Pharmacol. J Clin
Pharmacol. 2018 Oct; 58(Suppl 10): S164–S179.doi: 10.1002/jcph.1121
Abstract
Few treatments for human diseases have received as much investigation in the past 20 years as
probiotics. In 2017, English-language meta-analyses totaling 52 studies determined the effect of
probiotics on conditions ranging from necrotizing enterocolitis and colic in infants to constipation,
irritable bowel syndrome, and hepatic encephalopathy in adults. The strongest evidence in favor of
probiotics lies in the prevention or treatment of 5 disorders: necrotizing enterocolitis, acute infectious
diarrhea, acute respiratory tract infections, antibiotic-associated diarrhea, and infant colic. Probiotic
mechanisms of action include the inhibition of bacterial adhesion; enhanced mucosal barrier function;
modulation of the innate and adaptive immune systems (including induction of tolerogenic dendritic
cells and regulatory T cells); secretion of bioactive metabolites; and regulation of the enteric and central
nervous systems. Future research is needed to identify the optimal probiotic and dose for specific
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diseases, to address whether the addition of prebiotics (to form synbiotics) would enhance activity, and
to determine if defined microbial communities would provide benefit exceeding that of single-species
probiotics.
Keywords: allergy, diarrhea, immunology, lactobacillus, microbiome, regulatory T cells
Probiotics have been defined as “live organisms that when administered in adequate doses confer a
health benefit to the host”1 (FAO/WHO 2002) and are included in a number of fermentable foods, pills,
powders, and liquid drops. Common probiotics are available in pharmacies, groceries, and online in the
United States. They include but are not limited to Lactobacillus rhamnosus GG, Lactobacillus reuteri,
Lactobacillus casei, Lactobacillus paracasei, Bacillus coagulans, Bacillus clausii, Bifidobacterium infantis,
Bifidobacterium longum, Bifidobacterium infantis, Streptococcus thermophilus, Escherichia coli strain
Nissle 1917, and yeasts, including Saccharomyces boulardii and Saccharomyces cerevisiae. Many
probiotics contain mixtures of 2 or more individual species. Prebiotics are defined as metabolic
substrates that promote the growth and/or activity of beneficial microorganisms, usually in the
gastrointestinal tract.2 Although their definition has been debated and modified, the general consensus
is that prebiotics are nondigestible by human gastrointestinal cells. Prebiotics include oligosaccharides,
resistant starch, and soluble or insoluble fibers. Synbiotics are defined as mixtures of probiotics and
prebiotics that beneficially affect the host by impacting the microbiome within the gastrointestinal
tract.3
Each of the above definitions is loosely applied in most countries by the various food and
pharmaceutical industries that produce these products, as they attempt to take advantage of the
protean health advantages being documented by probiotic research. For example, many probiotic
yogurts are marketed to promote human health. Live cultures are present in cheese, kimchee,
kombucha tea, and miso soup. There are even probiotics designed to be administered to domestic pets.
Prebiotics are added to formulas, cheese, and even juices. However, an improvement in health as a
result of the selective stimulation of the growth of a defined population of intestinal bacteria—which is
implied in the definition of prebiotics—is difficult to verify and is rarely done. Finally, prebiotics (typically
fructooligosaccharides or inulin) are often added to probiotic foods at a low concentration to minimize
gastrointestinal symptoms. Because of these low concentrations (<10%), there is most often no
evidence to support an additive, synergistic, or even measurable effect of the product.3 Strong
legislation is needed in order to authorize health claims for only selected strains with health-proven
benefits.
The human microbiome refers to our commensal microbiota (bacteria, fungi, archaea, viruses, and
protozoans), their genes, and gene products. The microbiome is of great interest to all researchers in
medicine, affecting each major organ system, including even the cardiovascular system and the central
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nervous system (the latter leading to the term psychobiome). Humans harbor 1014 microbes, compared
to 1013 of our own cells, and there are 1000 to 1500 unique species that colonize the human colon, of
which the average person has approximately 160 species, contributing to about 3% of the human body
mass.4 It seems ridiculous that one could consume a single probiotic at doses of 108 to 1010 colony-
forming units (CFU) daily and expect that it could produce an effect on a health outcome. Evidence,
however, is provided herein that shows that, indeed, probiotics at these doses do have proven health
benefits in humans, and we will provide the evidence and potential mechanisms.
Go to:
Evidence From Human Trials: Absent, Evolving, or Conclusive?
Few treatments for human diseases have received as much investigation in the past 20 years as
probiotics. In the past single year, PubMed records 792 clinical trials of probiotics for human conditions.
In examining the evidence for treatment efficacy, we are reminded that the strength of evidence (from
weakest to strongest) is: case series → case control studies → cohort studies → randomized controlled
trials (RCTs) → systemasc reviews, and → (finally) meta-analysis. In 2017, English-language meta-
analyses totaling 52 studies determined the effect of probiotics on conditions ranging from necrotizing
enterocolitis and colic in infants to constipation, irritable bowel syndrome, and hepatic encephalopathy
in adults (Table 1). Other studies focused on serum lipid levels, late-onset sepsis in preterm infants,
blood glucose and hemoglobin A1C levels in people with type 2 diabetes, and disease activity in
ulcerative colitis. Each of the above studies demonstrated efficacy of the probiotic for the condition
studied. Importantly, there were also a few negative meta-analyses. Probiotic efficacy was not
demonstrated in studies investigating the prevention of urinary tract infection, reducing the risk of
developing bronchopulmonary dysplasia or retinopathy of prematurity, or in helping to eradicate
bacterial vaginosis.
Upper Respiratory Infections
All probiotics induce an immune response, and probiotics increase immunoglobulin A (IgA)-secreting
cells in respiratory and gastrointestinal mucosae.14 Day care center studies showed that consuming a
daily probiotic by healthy children resulted in an approximately 25% reduction in the number of days of
school missed.15 Systematic reviews of probiotics have shown that there is a reduction of the severity
of symptoms associated with probiotics and a shorter duration of respiratory tract infection by
approximately 1 day.16
Antibiotic-Associated Diarrhea (AAD)
Antibiotics are the most often prescribed medicines for children, with more than 50% of all children <18
years old receiving at least 1 course.17 The most widely prescribed antibiotics are amoxicillin,
azithromycin, and amoxicillin/clavulanate. AAD is a very frequent side effect of antibiotic therapy,
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affecting approximately 11% of all children who receive antibiotics and 18% of those <2 years old.17
Initially, a meta-analysis of AAD by Hempel et al included 63 RCTs and 11811 subjects. The majority used
Lactobacillus as the study product. Results showed that the relative risk of developing AAD when taking
a probiotic was 0.58 (95%CI, 0.50-0.68; P < .001). However, there was heterogeneity in the pooled
results. They concluded that probiotics are associated with a reduction in AAD; however, more research
is needed to determine the best probiotic.
A more recent meta-analysis, extracted from 30 trials in China involving more than 7000 participants
included 21 trials that focused on children. The probiotic always included Bifidobacilli, often in
combination with other probiotic(s). Results confirmed the efficacy of probiotic prophylaxis, with an
odds ratio of developing AAD of 0.34 (95%CI 0.23-0.43, P < 0.01) in the children receiving a
Bifidobacillus-containing preparation—a powerful impact.
Irritable Bowel Syndrome (IBS)
Abdominal pain and IBS, collectively called functional bowel disorders, are the most common conditions
leading to consultation by the pediatric gastroenterologist, and they affect about 10% of all school-aged
children, similar to the prevalence in adults. There may be some regional variability; for example, IBS has
been identified in 13% of children in China, 10% in the United States, and 6% in Sri Lanka.18 In adults,
the prevalence of IBS is 18% in Latin America, 8% to 10% in North America and Asia, and 6% in Africa and
the Middle East.19 IBS is defined by the Rome Criteria: recurrent abdominal pain at least 1 day weekly
for >3 months that is (1) related to defecation, (2) a change in stool form, and/or (3) a change in stool
frequency.
The etiology of IBS is multifactorial and includes a genetic predisposition, a reaction to life stresses,
and/or the presence of an environmental trigger (such as infectious diarrhea). Several groups have
identified an altered microbial community, as an additional and potentially central factor, in the feces of
patients with IBS. The most notable patient population was those individuals with IBS characterized by
diarrhea20,21 (Figure 2). These patients clearly have a distinct microbial population, characterized by
reduced microbial diversity, reduced butyrate-producing organisms (a metabolite that enhances gut
barrier function), and reduced methane producers (which dispose of gas).21 These observations make
IBS a notable disease for targeted microbial manipulation.
Probiotics Enhance Intestinal Barrier Function
A hyperpermeable epithelial barrier in the gastrointestinal tract is proposed to be a major cause of

chronic inflammation. Probiotics enhance the structure and function of intestinal epithelial barriers,
including increasing mucin production, enhancing tight junctions, and modulating signaling pathways
that affect cell proliferation and survival.62,63 Under normal physiological conditions, goblet cells
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continually produce mucins to replenish and maintain the mucus barrier; however, goblet cell function
can be disrupted by various factors (such as microbes, microbial toxins, and cytokines) that can affect
the integrity of the mucus barrier. This occurs in various pathological conditions such as chronic
inflammatory diseases.64
L. plantarum (strain 299v) has the capacity to enhance the production and secretion of mucins (MUC2
and MUC3) from human intestinal (HT-29) epithelial cells.65 Probiotic mixtures also increase MUC2 gene
expression and mucin protein secretion in rat colon.66 L. rhamnosus GG–derived soluble proteins (p40
and p70) ameliorate intestinal injury and inflammation by inhibiting epithelial cell apoptosis67 and
increasing mucin production through transactivation of the epidermal growth factor receptor.68 Some
probiotics have been demonstrated to protect tight junctions by changes in tight junction–related
proteins, such as zonulin-1, occludins, and claudins, and by enhancing the electrical resistance of tight
junctions contained in the apical junction complexes between adjacent polarized epithelia.69 Feeding
Lactobacillus rhamnosus GG early in life to newborn mice enhanced epithelial cell proliferation,
differentiation, tight junction formation, and mucosal IgA production.70 Other cellular and molecular
mechanisms such as the release of metabolites and bioactive molecules, suppression of oxidative stress,
interference with inflammatory pathways, and augmention of the levels of mucosal IgA help protect and
repair epithelial barriers.
Probiotics have an enduring effect on symptoms via long-term colonization.
In most trials, the administered probiotic cannot be detected in the stool weeks after discontinuing the
probiotic. In some trials, it was difficult to isolate the probiotic even while it is being consumed! In our
safety trial of L. reuteri in adult volunteers, for example, only low levels of the probiotic could be
detected in stool by PCR during treatment, and at 1 and 4 months after treatment, there was no more
detectable L. reuteri.112 In a study in which we investigated a formula with or without L. rhamnosus GG,
we could detect an increase in L. rhamnosus in the stool with a median value of 4% of total bacterial
sequences after 2 weeks of consumption of L. rhamnosus GG (using 16S ribosomal DNA sequencing).
However, while the infants were continuing to drink the formula, at 42 and 90 days, the population of L.
rhamnosus decreased to <1%. We suspect that in both studies the probiotics were colonizing the small
intestine and/or being outcompeted in the colon. Similarly, with minimal evidence of fecal excretion,
daily oral L. reuteri evoked observable effects on fecal calprotectin,112 and in infants L. reuteri had
potentially beneficial effects on the low neutrophil counts in peripheral blood that were seen in
approximately 50% of the infants with colic.113 There may be probiotics that are able to establish long-
term colonization under optimal conditions. For example, Panigrahi et al114 showed that in term infants
in India, supplementation with L. plantarum and fructooligosaccharides daily for 7 days resulted in 100%
colonization by 2 months, but fewer of these infants (32%) remained colonized by 6 months. It is unclear
if these infants remained colonized later in life.
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Perhaps a useful analogy for how a small number of probiotics could affect the microbiome of a host is
one that gardeners would appreciate. A probiotic is not like a rapidly spreading, colorful, perennial
flower, such as Impatiens walleriana. Probiotics are more like simple garden clover (Trifolium). Clover
prevents weeds from forming, retains moisture for the other flowers, fixes nitrogen into the soil, and
improves soil tilth (softness).
In summary, evidence-based, mechanistic research on probiotics reveals that cultured microorganisms,

when given in adequate quantities for sufficient periods of time, are beneficial in many human disease
conditions and safer than most pharmaceuticals. These conditions include infantile colic, acute
infectious diarrhea, and IBS. Probiotics also can prevent antibiotic-associated diarrhea and NEC. Much
more research is needed, and clearly probiotics do have potential risks that need to be monitored.
Future investigations are needed to identify the optimal probiotic and dose for specific diseases, first in
animal models comparing various strains, and second in RCTs. Animal trials should use multiple “omics”
to investigate not only the organisms but their effects on the global fecal community and their key
metabolites, establishing mechanism of action. Their impact on the immune system is key to the
understanding of how to therapeutically approach the globally increasing incidence of autoimmune
diseases, including arthritis and other rheumatologic disorders, IBD, eosinophilic diseases, and multiple
sclerosis.
These studies must also address whether the addition of a prebiotic would enhance the therapeutic
effect of a probiotic and to determine if the administration of human-derived or synthetic “defined
microbial communities” (as opposed to single organism probiotics) would provide additional benefit.
Safety considerations will almost certainly favor a probiotic approach over the administration of fecal
transplantation, because of lower risks to the host, greater ease of administration, and lower cost of
production.
Cutting Edge: Probiotics and Fecal Microbiota Transplantation in

Immunomodulation
Wenjie Zeng, et al. J Immunol Res. 2019; 2019: 1603758. Published online 2019
Apr 16. doi: 10.1155/2019/1603758
Abstract
Probiotics are commensal or nonpathogenic microbes that confer beneficial effects on the host through
several mechanisms such as competitive exclusion, antibacterial effects, and modulation of immune
responses. Some probiotics have been found to regulate immune responses via immune regulatory
mechanisms. T regulatory (Treg) cells, T helper cell balances, dendritic cells, macrophages, B cells, and
natural killer (NK) cells can be considered as the most determinant dysregulated mediators in
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immunomodulatory status. Recently, fecal microbiota transplantation (FMT) has been defined as the
transfer of distal gut microbial communities from a healthy individual to a patient's intestinal tract to
cure some immune disorders (mainly inflammatory bowel diseases). The aim of this review was followed
through the recent literature survey on immunomodulatory effects and mechanisms of probiotics and
FMT and also efficacy and safety of probiotics and FMT in clinical trials and applications.
1. Introduction
Probiotics were defined in 2002 by experts from the Food and Agriculture Organization of the United
Nations and the World Health Organization, and the definition was updated by the International
Scientific Association in 2013 [1]. The definition states that probiotics are “live strains of strictly selected
microorganisms which, when administered in adequate amounts, confer a health benefit on the host.”
Probiotic products are commonly known to be microecological preparations and are used to improve
the structure of intestinal flora, inhibit the growth of harmful microorganisms, and enhance the
immunity of the human body. To be considered microecologics, probiotics must satisfy the following
conditions [2]: be live microorganisms; stay alive and stable before use after culture, production, and
storage; be resistant to gastric acid, bile, and trypsin, and remain alive to colonize and proliferate in the
intestinal tract; be scientifically proven to be beneficial to the host; and be proven to be safe and
reliable or an member of the original intestinal microflora. Currently, the extensively studied and
developed probiotics include the related bacteria of Lactobacillus, Bifidobacteria, Escherichia coli (E.
coli), and Enterococcus and some yeasts [3].
Currently, as a means of intestinal microecological regulation in addition to microecological

preparations, fecal microbiota transplantation (FMT) has become popular in recent years. FMT refers to
the transplantation of functional bacteria in the feces of healthy donors into the gastrointestinal tract of
the patient to restore the balance of the intestinal microecology, which subsequently treats diseases
associated with disorders of intestinal microorganisms. As far back as traditional medical treatments in
the fourth century of China, there have been relevant records of FMT treatment [4]. In the era of
modern medicine, the earliest report of FMT was in 1958. Eiseman et al. successfully used FMT to treat a
case with pseudomembranes [5]. The first report of FMT application in the treatment of Clostridium
difficile (C. difficile) infection (CDI) was in 1983 [6]. In 2010, the United States recommended FMT as a
treatment plan for CDI in their clinical guidelines [7]. FMT has now been deemed the primary therapy for
refractory and relapsed CDI. In recent years, FMT has become a research focus on biomedicine and
clinical medicine. FMT has also been clinically applied to inflammatory bowel disease (IBD), irritable
bowel syndrome, chronic functional constipation, intestinal cancer, foodborne allergic
gastroenteropathy, and so on [8], and researchers have achieved a certain clinical efficacy. Recently,
some studies have shown that there is a very strong potential application for FMT in the field of
nongastrointestinal diseases, such as treating arteriosclerosis, metabolic syndrome, diabetes, hepatic
encephalopathy, neurodegenerative diseases, among others [9].
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2. Probiotics and the Immune System
Relevant studies on the mechanism of probiotics mainly focus on the intestinal tract. However, the
effect of probiotics is not confined to the initial infection site, and probiotics can work throughout the
entire body via the immune system. In gut-associated lymphoid tissues (GALT), probiotic and antigen
substances from its metabolites are phagocytized or internalized by M cells to form endosomes.
Antigens in M cells are rapidly released and taken in by dendritic cells (DCs), which can transport the
antigens to local lymph nodes and then activate naive T and B cells to differentiate into different
effector subpopulations, initiating the release of the corresponding cytokines and displaying different
immune functions.
A number of studies show that the mechanisms of probiotics include (1) enhancement of the chemical
and biological barriers in the intestinal tract as well as regulation of the balance of intestinal flora.
Through a space-occupying effect, competition, or antagonism [10–14], and by secreting antibacterial or
bactericidal substances (e.g., bacteriocin), increasing digestive enzyme activity, producing organic acid,
and so on [15], probiotics can exert an antibacterial effect, maintain the function of intestinal epithelial
cells, prevent pathogenic bacteria adhesion, and inhibit the growth of pathogenic bacteria. (2) Through
increasing the synthesis of tight junction proteins between epithelial cells [16, 17], probiotics stimulate
and promote the expression and secretion of mucous glycoproteins [18], enhance the integrity of
intestinal epithelial cells, strengthen the mechanical barrier function of the intestinal tract, and prevent
the displacement of intestinal bacteria and endotoxins. (3) Probiotics regulate innate and adaptive
immunity, including promoting the development and maturation of the immune system [19], enhancing
the viability of macrophages and natural killer (NK) cells [20], stimulating the secretion of secretory
immunoglobulin A (sIgA) [21], activating related immune responses mediated by Toll-like receptor (TLR)
and nucleotide-binding oligomerization domain-containing protein- (NOD-) like receptors (NLR),
regulating the T helper cell (Th)1/Th2 immune response, increasing the number of regulatory T cells
(Treg) that secrete interleukin- (IL-) 10 and transforming growth factor (TGF)-β, and strengthening their
function as well as reducing the level of allergen-specific IgE [22].
The role of probiotics in the immune system is complex. The immune stimulations induced by probiotics
are manifested as an increase in the generation of immunoglobulins, enhanced activity of macrophages
and lymphocytes, and stimulation of interferon- (IFN-) γ. Probiotics that inhibit the immune system are
mainly embodied in their anti-inflammatory action. Figure 1 summarizes the dual function of probiotics
in the immune system in in vitro and animal experiments.
Conclusions and Future Perspectives
Probiotics have a large spectrum and have been used in main diseases, such as IBD, necrotizing
enterocolitis (NEC), irritable bowel syndrome IBS, diarrhea, and other gastrointestinal diseases, in vivo
and in vitro. Due to their ability to regulate systemic immune function, probiotics have recently
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attracted attention in the development of new treatments for obesity, insulin resistance syndrome, type
2 diabetes mellitus and nonalcoholic liver steatosis, hepatic encephalopathy, autism and chronic kidney
disease, allergic asthma, atopic dermatitis (AD), acne, rheumatoid arthritis, prevention of dental caries,
preventive treatment of an infection, and other fields. In addition, the use of probiotic strains as carriers
of antigen delivery is a viable alternative strategy to overcome the shortcomings of vaccines. However,
despite their active role in various tumor diseases, probiotics also have side effects associated with
anticancer therapies.
The immunomodulation induced by probiotics is a complex interaction between different hosts and
microorganisms, so the immunomodulatory characteristics of specific probiotics cannot be generalized.
Presently, the composition, dosage, course of treatment, specific mechanism of action, and efficacy of
probiotics used in clinical treatment have not been standardized. Overall, probiotics are generally
considered safe, but there is growing evidence of widespread concern about the safety of probiotics. In
2002, a joint report by the World Health Organization and the United Nations Food and Agriculture
Organization showed that probiotics can cause four side effects, namely, systemic infection, harmful
metabolic activity, excessive immune stimulation, and gene transfer in susceptible individuals. Recently,
two reports in September 2018 also noted the unknown aspects of the safety of probiotics at this stage
and raised concerns in the scientific community about studying adverse reactions to probiotics. Zmora
et al. [129] emphasize that the colonization of probiotics is highly personalized and that different
individuals have different sensitivity to different probiotic colonization. The host microbiome influences
probiotic colonization through competitive rejection of the same species and specific immune
mechanisms. The intake of probiotics did not significantly affect the composition of the symbiotic
community but instead stimulated the response of the host immune system. Therefore, we suggest that
it is necessary to develop personalized probiotics from the perspective of the specificity of the intestinal
flora and host physiology. When a clinical application of probiotics is selected, it should gradually
transform from empirical treatment to evidence-based treatment, and suitable individualized treatment
plans should be developed for patients using evidence-based treatments.
Suez et al. [130] reported that in mice and mixed probiotic intervention in healthy subjects and fecal
bacteria autograft (aFMT) of antibiotics might improve the recovery of the intestinal flora after
disturbance; the study illustrated that compared with spontaneous recovery, probiotic preparations
significantly delayed the host's feces and the reconstruction of the intestinal mucosa flora and host the
transcriptome of recovery. Moreover, this study showed that it is difficult to be fully recovered; this is
mainly because of the soluble factors that secreted probiotic bacteria inhibition, and probiotics in the
potential beneficial effects of antibiotic therapy possibly will be offset by intestinal mucosa recovery
effect. It is important to note that microbiome transplantation enables rapid and nearly complete
recovery of host-microbiome and transcriptome within a few days. This suggests that, compared with
probiotics or prebiotics, fecal bacteria transplantation as the most direct method of intestinal flora
intervention may be more effective and feasible.
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Since 2013, when it was included in the FDA's official treatment guidelines for relapsing C. difficile, fecal
transplants have seen more comprehensive development worldwide. Compared to the standard use of
probiotics, FMT can be explored faster and further in this area. At present, the standardization of donor
screening, microflora separation and preparation, transplantation, and other aspects involved in the
FMT process has begun to take shape. Recently, a large number of studies [131–135] have proposed the
step-up treatment strategy of FMT: when the single FMT and multiple FMTs (greater than or equal to 2)
are not effective, FMT can be combined with conventional drug therapy (such as glucocorticoid,
cyclosporine, anti-TNF-beta antibody, and whole intestinal nutrition). The efficacy of each step can be
improved in the next step. This FMT stepwise treatment strategy is suitable for refractory IBD, immune-
related diseases [135], and severe or complex CDI [131], especially for patients who are not responsive
to conventional therapeutic drugs. At the same time, severe adverse events caused by FMT can be
caused by infectious microorganisms in donor feces, which is because many infectious diseases in the
donor are still difficult to be excluded. Therefore, FMT-related adverse events in specific populations
should be prevented, especially those with low immunity. During FMT treatment through the digestive
tract, improper fecal bacteria infusion technology and process may also lead to nausea, vomiting,
aspiration, and other adverse events. In order to prevent FMT transmission diseases, strict donor
screening should be carried out, and FMT treatment decisions, methods, short-term and long-term
follow-up safety evaluation, and supervision will be the focus of future research.
To sum up, personalized probiotics intervention and standardized fecal bacteria transplantation should
be challenges and prospects for future research on the intervention model of intestinal flora.
Furthermore, increasing evidence shows that the microbiome has potential effects outside the intestinal
tract, such as vagina and sinus tract [136], urethra, [137] and skin [138]. Therefore, future research
should focus on a specific use of microbiome in different organs.
Implications of Probiotics on the Maternal-Neonatal Interface: Gut Microbiota,

Immunomodulation, and Autoimmunity
Brianna Swartwout and Xin M. Luo. Front Immunol. 2018; 9: 2840. Published
online 2018 Dec 3. doi: 10.3389/fimmu.2018.02840
Abstract
Probiotics are being investigated for the treatment of autoimmune disease by re-balancing dysbiosis
induced changes in the immune system. Pregnancy is a health concern surrounding autoimmune
disease, both for the mother and her child. Probiotics for maternity are emerging on the market and
have gained significant momentum in the literature. Thus far, evidence supports that probiotics alter the
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structure of the normal microbiota and the microbiota changes significantly during pregnancy. The
interaction between probiotics-induced changes and normal changes during pregnancy is poorly
understood. Furthermore, there is emerging evidence that the maternal gut microbiota influences the
microbiota of offspring, leading to questions on how maternal probiotics may influence the health of
neonates. Underpinning the development and balance of the immune system, the microbiota, especially
that of the gut, is significantly important, and dysbiosis is an agent of immune dysregulation and
autoimmunity. However, few studies exist on the implications of maternal probiotics for the outcome of
pregnancy in autoimmune disease. Is it helpful or harmful for mother with autoimmune disease to take
probiotics, and would this be protective or pathogenic for her child? Controversy surrounds whether
probiotics administered maternally or during infancy are healthful for allergic disease, and their use for
autoimmunity is relatively unexplored. This review aims to discuss the use of maternal probiotics in
health and autoimmune disease and to investigate their immunomodulatory properties.
Keywords: probiotics, gut microbiota, maternal, neonatal, autoimmunity
Conclusions
Significant grounds have been covered in establishing the link between dysbiosis and autoimmune
disease marked by the presence of a leaky gut and systemic inflammation. From what we can study of
the complex ecosystem that is the gut microbiota, probiotics induce significant changes to the normal
microbiota and enhance anti-inflammatory immune reactions. Through their immunological modulatory
capacity, probiotics can therefore alleviate autoimmune disease severity.
The normal gut microenvironment undergoes specific changes during maternity including an increase in
gut barrier permeability. Furthermore, specific changes in the immune system occur to support and
tolerate the developing fetus. Maternally administered probiotics may impact the health of a child by
altering the bacteria that initially colonize the developing infant. Maternal probiotics thus have the
potential to influence neonatal immune development since the initial programming of the immune
system is dependent on the gut microbiota.
As the influence of the maternal-neonatal interface on the gut microbiota in autoimmune disease is a
poorly understood, further research is required regarding the impact of maternal probiotics on the
development of the fetus and the implications in autoimmune disease. A number of gaps exist in the
literature regarding maternal probiotics for autoimmune diseases in both mothers and their children.
Designing studies aimed at understanding how probiotics act in an immunomodulatory capacity to
ameliorate or exacerbate autoimmune diseases in pregnancy and infancy is, without excuse, a requisite
edge for cutting into the issues surrounding autoimmunity and pregnancy.
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Systematic review: probiotics in the management of lower gastrointestinal

symptoms – an updated evidence-based international consensus
A. P. S. Hungin, et al. Aliment Pharmacol Ther. 2018 Apr; 47(8): 1054–1070.
Published online 2018 Feb 20. doi: 10.1111/apt.14539
Summary
Background
In 2013, a systematic review and Delphi consensus reported that specific probiotics can benefit adult
patients with irritable bowel syndrome (IBS) and other gastrointestinal (GI) problems.
Aim
To update the consensus with new evidence.
Methods
A systematic review identified randomised, placebo-controlled trials published between January 2012
and June 2017. Evidence was graded, previously developed statements were reassessed by an 8-expert
panel, and agreement was reached via Delphi consensus.
Results
A total of 70 studies were included (IBS, 34; diarrhoea associated with antibiotics, 13; diarrhoea
associated with Helicobacter pylori eradication therapy, 7; other conditions, 16). Of 15 studies that
examined global IBS symptoms as a primary endpoint, 8 reported significant benefits of probiotics vs
placebo. Consensus statements with 100% agreement and “high” evidence level indicated that specific
probiotics help reduce overall symptom burden and abdominal pain in some patients with IBS and
duration/intensity of diarrhoea in patients prescribed antibiotics or H. pylori eradication therapy, and
have favourable safety. Statements with 70%-100% agreement and “moderate” evidence indicated that,
in some patients with IBS, specific probiotics help reduce bloating/distension and improve bowel
movement frequency/consistency.
Conclusions
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This updated review indicates that specific probiotics are beneficial in certain lower GI problems,
although many of the new publications did not report benefits of probiotics, possibly due to inclusion of
new, less efficacious preparations. Specific probiotics can relieve lower GI symptoms in IBS, prevent
diarrhoea associated with antibiotics and H. pylori eradication therapy, and show favourable safety. This
study will help clinicians recommend/prescribe probiotics for specific symptoms.
Salvia/Sage
Natural products and their (semi-)synthetic forms in treatment of migraine:
History and current status.
Tauchen J. Curr Med Chem. 2019 Jan 25. doi:
Abstract
BACKGROUND:
Migraine may be described as a headache with moderate to extreme pain that is often accompanied by
incapacitating neurological symptoms. It is estimated that 12% of the world population suffers from
migraine. Although a number of drugs have been used for treatment of migraine, most of these are not
effective for every patient and may have undesirable side-effects. Thus there is an enormous unmet
need in current migraine therapy for discovering safer and more effective agents.
METHODS:
The information summarized in this review was obtained through extensive literature review and search
of relevant books and articles with the use of Web of Knowledge and SciVerse Scopus databases.
RESULTS:
Greater understanding of the molecular mechanisms underlying the etiopathogenesis of migraine is

helpful in identifying novel targets for antimigraine drugs such as cannabinoid, histamine, and melatonin
receptors. In the past, natural product-derived constituents have served as an invaluable source of
numerous medicinally useful antimigraine agents and it may be expected that further promising drug
candidates from natural products will be discovered for antimigraine pharmacotherapy with better
efficacy and fewer adverse-effects.
CONCLUSIONS:
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The discovery of novel targets in migraine therapy has opened new horizons for compounds that have
not been clinically tested or that previously failed in clinical trials as potential antimigraine drugs.
Ginkgolide B, melatonin, histamine, oxytocin, various ribosomal peptide toxins, kavalactones, devil's
claw-derived compounds, salvinorin A and petasin are among those agents that show considerable
promise as novel drugs in migraine prevention and treatment. It is necessary to conduct more research
to better understand their antimigraine action, to confirm their effectiveness and safety, and to
introduce them into clinical practice.
KEYWORDS:
headache; migraine disorders natural compounds; nociception; novel targets; pain

doi: 10.22038/IJBMS.2018.24026.6021.
Abstract
KEYWORDS:

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12 Health Benefits and Uses of Sage

Written by Ryan Raman, MS, RD on December 14, 2018. Healthline.com
https://www.healthline.com/nutrition/sage
Sage is a staple herb in various cuisines around the world.
Its other names include common sage, garden sage and Salvia officinalis. It belongs to the mint family,
alongside other herbs like oregano, rosemary, basil and thyme.
Sage has a strong aroma and earthy flavor, which is why it’s typically used in small amounts. Even so, it’s
packed with a variety of important nutrients and compounds.
Polyphenolics of Salvia--a review.

Lu Y, Foo LY. Phytochemistry. 2002 Jan;59(2):117-40.
Abstract
Salvia is an important genus widely cultivated and used in flavouring and folk medicines. The genus has
attracted great interest so much so that it has been the subject of numerous chemical studies. It is a rich
source of polyphenols, with an excess of 160 polyphenols having been identified, some of which are
unique to the genus. A large number of these polyphenolic compounds are apparently constructed from
the caffeic acid building block via a variety of condensation reactions. The nature of these polyphenols
which have been reported is compiled in this report together with some bioactivity data in an effort to
show the rapid development in the phytochemistry and the therapeutic applications of the Salvia
species.
In vitro antioxidant and antiproliferative activities of nine Salvia species.

Loizzo MR, et al. Nat Prod Res. 2014;28(24):2278-85. doi:
10.1080/14786419.2014.939086. Epub 2014 Jul 21.
Abstract
Supported by a growing increase of scientific research attesting the health properties of salvia species,
we have decided to investigate nine Salvia namely Salvia sclarea, Salvia atropatana, Salvia sahendica,
Salvia hydrangea, Salvia xanthocheila, Salvia macrosiphon, Salvia glutinosa, Salvia chloroleuca and Salvia
ceratophylla species for their antioxidant and antiproliferative activities. In order to correlate the
bioactivity with their phytochemical content, the total phenol and total flavonoid contents were also
381
determined. S. ceratophylla exhibited the strongest activity against C32 cells with an IC50 value of 20.8
μg mL(- 1), while S. glutinosa exhibited an IC50 value of 29.5 μg mL(- 1) against ACHN cell line.
Interestingly, S. glutinosa displayed also the highest DPPH radical-scavenging activity with an IC50 of 3.2
μg mL(- 1). These species are characterised by the highest total phenol and flavonoid contents. The
obtained results suggest that Salvia species are healthy plant foods.
Sage tea drinking improves lipid profile and antioxidant defences in humans.
Sá CM, et al. Int J Mol Sci. 2009 Sep 9;10(9):3937-50. doi: 10.3390/ijms10093937.
Abstract
Salvia officinalis (common sage) is a plant with antidiabetic properties. A pilot trial (non-randomized
crossover trial) with six healthy female volunteers (aged 40-50) was designed to evaluate the beneficial
properties of sage tea consumption on blood glucose regulation, lipid profile and transaminase activity
in humans. Effects of sage consumption on erythrocytes' SOD and CAT activities and on Hsp70
expression in lymphocytes were also evaluated. Four weeks sage tea treatment had no effects on
plasma glucose. An improvement in lipid profile was observed with lower plasma LDL cholesterol and
total cholesterol levels as well as higher plasma HDL cholesterol levels during and two weeks after
treatment. Sage tea also increased lymphocyte Hsp70 expression and erythrocyte SOD and CAT
activities. No hepatotoxic effects or other adverse effects were observed.
Metformin-like effect of Salvia officinalis (common sage): is it useful in

diabetes prevention?
Lima CF, Azevedo MF, Araujo R, Fernandes-Ferreira M, Pereira-Wilson C. Br J
Nutr. 2006 Aug;96(2):326-33.
Abstract
Common sage (Salvia officinalis L.) is among the plants that are claimed to be beneficial to diabetic
patients, and previous studies have suggested that some of its extracts have hypoglycaemic effects in
normal and diabetic animals. In the present study, we aimed to verify the antidiabetic effects of an
infusion (tea) of common sage, which is the most common form of this plant consumed. Replacing water
with sage tea for 14 d lowered the fasting plasma glucose level in normal mice but had no effect on
glucose clearance in response to an intraperitoneal glucose tolerance test. This indicated effects on
gluconeogenesis at the level of the liver. Primary cultures of hepatocytes from healthy, sage-tea-
drinking rats showed, after stimulation, a high glucose uptake capacity and decreased gluconeogenesis
in response to glucagon. Essential oil from sage further increased hepatocyte sensitivity to insulin and
inhibited gluconeogenesis. Overall, these effects resemble those of the pharmaceutical drug metformin,
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a known inhibitor of gluconeogenesis used in the treatment and prevention of type 2 diabetes mellitus.
In primary cultures of rat hepatocytes isolated from streptozotocin (STZ)-induced diabetic rats, none of
these activities was observed. The present results seem to indicate that sage tea does not possess
antidiabetic effects at this level. However, its effects on fasting glucose levels in normal animals and its
metformin-like effects on rat hepatocytes suggest that sage may be useful as a food supplement in the
prevention of type 2 diabetes mellitus by lowering the plasma glucose of individuals at risk.
Salvia officinalis, Rosmarinic and Caffeic Acids Attenuate Neuropathic Pain

and Improve Function Recovery after Sciatic Nerve Chronic Constriction in
Mice.
El Gabbas Z, et al. Evid Based Complement Alternat Med. 2019 Jun
24;2019:1702378. doi: 10.1155/2019/1702378. eCollection 2019.
Abstract
The leaves of Salvia officinalis L. have a traditional reputation for the management of pain in Morocco.
This study was conducted to investigate the curative effects of Salvia officinalis (SO) and its major
constituents Rosmarinic (ROS) and Caffeic acids (CAF) on peripheral neuropathic pain in mice. Chronic
constriction injury (CCI) was induced in mice, and neuropathic pain behaviors tests were evaluated by
mechanical, chemical, thermal sensation tests and functional recovery of the sciatic nerve at different
time intervals, i.e., (day 0, 1, 7, 14, and 21). Ethanolic extract of SO (100 and 200 mg/kg, p.o.), ROS (10
and 20 mg/kg, i.p.), CAF (30 and 40 mg/kg, i.p.), and CLOM (5 mg/kg, i.p., a positive control) was given
for 21 days after surgery. Hematological and biochemical parameters were also measured as well as
histopathological analysis. CCI produced significant development in mechanical and thermal
hyperalgesia, cold allodynia, and rise in the sciatic functional index in mice. Chronic treatments with SO
extract, ROS, CAF, and CLOM for 3 weeks significantly increased mechanical sensibility, cold, and
thermal withdrawal latency and enhanced functional recovery of the injured nerve. The same
treatments remarkably ameliorated hematological parameters and did not alter biochemical levels. The
histopathological findings had revealed the protective effect of SO, ROS, and CAF against the CCI-
induced damage. Our data support the use of SO in folk medicine to alleviate pain. Their main phenolic
constituents could be promising antineuropathic compounds, which may be attributed to their
biological activities including anti-inflammatory, antioxidant, and neuroprotective effects. SO leaves may
be a good candidate to treat neuropathic pain.
383
Comparison of benzydamine hydrochloride and Salvia officinalis as an

adjuvant local treatment to systemic nonsteroidal anti-inflammatory drug in
controlling pain after tonsillectomy, adenoidectomy, or both: an open-label,
single-blind, randomized clinical trial.
Lalićević S, Djordjević I. Curr Ther Res Clin Exp. 2004 Jul;65(4):360-72. doi:
10.1016/j.curtheres.2004.07.002.
Abstract
BACKGROUND:
Benzydamine hydrochloride (BNZD) is a nonsteroidal anti-inflammatory drug (NSAID) used in an oral

rinse formulation as an adjuvant to other NSAIDs in controlling postoperative pain after tonsillectomy,
adenoidectomy, or both. Salvia officinalis (SO) is a topically applied herbal preparation frequently used
for the same indication. Pain, bleeding, and infection are the most common postoperative complications
of tonsillectomy.
OBJECTIVE:
The aim of this study was to compare the efficacy and tolerability of BNDZ with those of SO as adjuvant
treatments in controlling postoperative pain.
METHODS:
This open-label, single-blind, randomized clinical trial was conducted at the Department of
Otorhinolaryngology, Clinical Hospital Center "Dr. Dragiša Mišović-Dedinje" (Belgrade, Serbia and
Montenegro). Pediatric and adult patients undergoing tonsillectomy, adenoidectomy, or both were
enrolled. Patients were randomized to receive BNZD or SO, in addition to ibuprofen 20 mg/kg·d
(children) or diclofenac 100 mg/d (adults). The primary end point was the proportion of patients with
mild or no pain on postoperative days 1, 2, 4, and 7. Secondary end points were the incidences of
infection, hemorrhage, and other adverse events.
RESULTS:
A total of 420 patients were enrolled (217 females, 203 males; 278 children, 142 adults; mean [SD] age,
6.2 [2.1] years [children] and 24.1 [9.8] years [adults] [range, 3-45 years]). One hundred thirty-eight
children received BNZD; 140 received SO (both in addition to ibuprofen 20 mg/kg·d). Seventy-two adults
received BNZD; 70 received SO (both in addition to diclofenac 100 mg/d). A significantly lower
proportion of children treated with adjuvant BNZD experienced moderate or severe pain than those
treated with SO at each time point (P < 0.01 at days 1 and 4; P < 0.001 at days 2 and 7). In children, the
risk for postoperative infection was similar between BNZD and SO (absolute risk reduction [ARR], 6.9%;
384
95% CI, 6.4%-7.6%); however, the risk was reduced in adults (ARR, 19.0%; 95% CI, 16.5%-21.9%; P =
0.008).
CONCLUSIONS:
In this clinical trial of children and adults who underwent tonsillectomy, adenoidectomy, or both, BNZD,
as an adjuvant to an NSAID, was more effective than SO in controlling postoperative pain and infection.
The pain-reducing effect of BNZD was of quick onset and persisted for 1 week after surgery. The safety
profile of BNZD was comparable to that of SO, with the exception of postoperative infection in adults,
for which BNZD was more efficacious. In particular, the use of BNZD was not associated with a high risk
for early postoperative hemorrhage.
KEYWORDS:
Salvia officinalis; benzydamine hydrochloride; clinical trial; efficacy; safety; tonsillectomy
Salvia divinorum: from recreational hallucinogenic use to analgesic and anti-

inflammatory action.
Coffeen U, Pellicer F. J Pain Res. 2019 Mar 22;12:1069-1076. doi:
10.2147/JPR.S188619. eCollection 2019.
Abstract
Salvia divinorum is a herbal plant native to the southwest region of Mexico. Traditional preparations of
this plant have been used in illness treatments that converge with inflammatory conditions and pain.
Currently, S. divinorum extracts have become popular in several countries as a recreational drug due to
its hallucinogenic effects. Its main active component is a diterpene named salvinorin A (SA), a potent
naturally occurring hallucinogen with a great affinity to the κ opioid receptors and with allosteric
modulation of cannabinoid type 1 receptors. Recent biochemical research has revealed the mechanism
of action of the anti-inflammatory and analgesic effect of SA at the cellular and molecular level.
Nevertheless, because of their short-lasting and hallucinogenic effect, the research has focused on
discovering a new analogue of SA that is able to induce analgesia and reduce inflammation with a long-
lasting effect but without the hallucinatory component. In this review, we explore the role of S.
divinorum, SA and its analogues. We focus mainly on their analgesic and anti-inflammatory roles but
also mention their psychoactive properties.
KEYWORDS:
Salvia divinorum; inflammation; pain; psychoactivity; salvinorin A

385
Salvia mellifera-How Does It Alleviate Chronic Pain?

Adams JD, Guhr S, Villaseñor E. Medicines (Basel). 2019 Jan 24;6(1). pii: E18. doi:
10.3390/medicines6010018.
Abstract
Black sage, Salvia mellifera, can be made into a sun tea that is used as a foot soak to treat pain patients.
The monoterpenoids and diterpenoids in the preparation penetrate the skin of the feet and stop the
pain chemokine cycle, which may be the basis of chronic pain. Several chronic pain patients have
reported long-term improvements in their pain after treatment with the preparation.
KEYWORDS:
Salvia mellifera; black sage; chronic pain; pain chemokine cycle
SAM-e (Ademetionine)
Sam-E
Diet & Weight Management. WebMD. 2018.
https://www.webmd.com/diet/qa/what-is-same
SAM-e is a compound that's made naturally in the body and plays an important role in normal bodily
function. Its scientific name is S-adenosylmethionine. SAM-e is also known as ademetionine and SAMe.
There's evidence that SAM-e can be a treatment for osteoarthritis pain. Some studies have found that
oral SAM-e works as well as NSAID painkillers, such as ibuprofen. SAM-e takes longer to act than drugs,
but it also has fewer side effects.
SAM-e has also been used to treat depression for many years. Some studies have found that SAM-e
might work as well as tricyclic antidepressant, but many of these studies were flawed or too small to be
conclusive.
Ademetionine
Medically reviewed by Michael Charles, MD on June 7, 2016 — Written by Anna
Zernone Giorgi. Healthline.com
386
https://www.healthline.com/health/ademetionine
Ademetionine is a form of the amino acid methionine. It also is called S-adenosylmethionine, or SAMe.
Typically, a human body makes all the ademetionine it needs for good health. However, low levels of
methionine, folate, or vitamin B-12 can cause a drop in ademetionine levels. Since this chemical doesn’t
exist in foods, a synthetic version is sometimes used to normalize levels in the body.
Ademetionine is sold as a dietary supplement in the United States. In Europe, it is used as a prescription
drug.
What does ademetionine do?
SAMe plays a role in the immune system, maintains cell membranes, and helps produce and break down
brain chemicals, such as serotonin, melatonin, and dopamine.
Additional but inconclusive research suggests that it also may be useful for treating symptoms of:
• depression
• cirrhosis of the liver
• chronic viral hepatitis
• jaundice in pregnancy
• Gilbert’s syndrome
• fibromyalgia
• nerve problems related to AIDS
• cholestasis (blocked bile flow from the liver to the gall bladder)
Evidence-Based Evaluation of Complementary Health Approaches for Pain

Management in the United States.
Nahin RL, Boineau R, Khalsa PS, Stussman BJ, Weber WJ. Mayo Clin Proc. 2016
Sep;91(9):1292-306. doi: 10.1016/j.mayocp.2016.06.007.
Abstract
Although most pain is acute and resolves within a few days or weeks, millions of Americans have
persistent or recurring pain that may become chronic and debilitating. Medications may provide only
partial relief from this chronic pain and can be associated with unwanted effects. As a result, many
individuals turn to complementary health approaches as part of their pain management strategy. This
article examines the clinical trial evidence for the efficacy and safety of several specific approaches-
acupuncture, manipulation, massage therapy, relaxation techniques including meditation, selected
natural product supplements (chondroitin, glucosamine, methylsulfonylmethane, S-
387
adenosylmethionine), tai chi, and yoga-as used to manage chronic pain and related disability associated
with back pain, fibromyalgia, osteoarthritis, neck pain, and severe headaches or migraines.
Chondroprotection and the prevention of osteoarthritis progression of the

knee: a systematic review of treatment agents.
Gallagher B, et al. Am J Sports Med. 2015 Mar;43(3):734-44. doi:
10.1177/0363546514533777. Epub 2014 May 27.
Abstract
BACKGROUND:
Structure-modifying medications or nutraceuticals may be an effective treatment for osteoarthritis. This

study identified 12 treatments that may possess chondroprotective properties: oral glucosamine;
chondroitin; nonsteroidal anti-inflammatory drugs (NSAIDs); polyunsaturated fatty acids; S-
adenosylmethionine; avocado and soybean unsaponifiable fractions; methylsulfonylmethane; vitamins
C, D, and E; intra-articular injections of hyaluronic acid; and platelet-rich plasma (PRP).
PURPOSE:
To perform a systematic review of randomized controlled trials for the effectiveness of each agent in
preserving articular cartilage of the knee and delaying the progression of osteoarthritis.
STUDY DESIGN:
Systematic review; Level of evidence, 2.
METHODS:
A literature search was performed using PubMed, EMBASE, and the Cochrane Central Register of
Controlled Trials. Searches were performed using "treatment," "osteoarthritis," and "knee" as keywords.
Selection criteria included randomized controlled trials of ≥12 months, with a placebo control,
measuring radiographic changes in joint space width, cartilage volume, or radiographic progression of
osteoarthritis. The primary outcome was changes in joint integrity measures.
RESULTS:
A total of 3514 studies were identified from the initial search, 13 of which met inclusion criteria.
Treatment with chondroitin sulfate showed a significant reduction in cartilage loss in 3 of 4 studies
identified compared with placebo. Two of 3 trials identified for glucosamine also reported significant
structural effects relative to placebo. Intra-articular hyaluronic acid was effective in lowering the rate of
cartilage loss in only 1 of 3 studies identified versus placebo. Of the 6 studies identified for NSAIDs,
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vitamin E, and vitamin D, none showed any structural effect compared with placebo. No studies were
found that met the inclusion criteria for polyunsaturated fatty acids, S-adenosylmethionine, avocado
and soybean unsaponifiable fractions, methylsulfonylmethane, vitamin C, or PRP.
CONCLUSION:
For patients with or at risk for osteoarthritis, the use of glucosamine and chondroitin sulfate may serve
as a nonoperative means to protect joint cartilage and delay osteoarthritis progression. Hyaluronic acid
injections showed variable efficacy, while NSAIDs and vitamins E and D showed no effect on
osteoarthritis progression. The other agents evaluated had no evidence in the literature to support or
refute their use for chondroprotection.
Therapeutic benefits of the methyl donor S-adenosylmethionine on nerve

injury-induced mechanical hypersensitivity and cognitive impairment in mice.
Grégoire S, et al. Pain. 2017 May;158(5):802-810. doi:
10.1097/j.pain.0000000000000811.
Abstract
Despite considerable advances in understanding mechanisms involved in chronic pain, effective

treatment remains elusive. Comorbid conditions including anxiety, depression, and cognitive
impairment further impact quality of life. Chronic pain is associated with reversible changes in brain
anatomy and function and with long-term changes in gene expression. Epigenetic mechanisms, including
DNA methylation, contribute to wide-spread and long-lasting reprogramming of gene expression. We
previously reported decreases in global DNA methylation in the mouse frontal cortex 6 months after
induction of neuropathic pain using the spared nerve injury (SNI) model. Here, we examined the
therapeutic effect of increasing DNA methylation using the methyl donor S-adenosylmethionine (SAM).
S-adenosylmethionine is marketed as a nutritional supplement for a range of conditions including liver
disease, depression, osteoarthritis, fibromyalgia, and dementia. Three months after SNI or sham
surgery, animals were treated with SAM (20 mg/kg, 3×/week) or saline orally for 4 months, and the
impact on sensory, motor, motivational, and cognitive indices was measured. S-adenosylmethionine
attenuated SNI-induced mechanical hypersensitivity and reduced active avoidance of mechanical stimuli
but had no effect on cold sensitivity or motor capacity. S-adenosylmethionine completely blocked nerve
injury-induced cognitive impairment and attenuated SNI-induced decreases in global DNA methylation
in the frontal cortex. In summary, chronic oral administration of the methyl donor, SAM, attenuated
sensory and cognitive symptoms associated with nerve injury in mice. These effects may be mediated, in
part, through modulation of DNA methylation in the central nervous system by systemic administration
of the methyl donor SAM.
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A pilot study of S-adenosylmethionine in treatment of functional abdominal

pain in children.
Choi LJ, Huang JS. Altern Ther Health Med. 2013 Sep-Oct;19(5):61-4.
Abstract
CONTEXT:
Functional abdominal pain (FAP) is one of the most common functional gastrointestinal disorders
(FGIDs) in children. Currently, medical practitioners widely use tricyclic antidepressants to treat FAP.
Those antidepressants, however, have been associated with an increased risk of suicidal ideation, and
the accompanying side effects often limit the benefits. S-adenosylmethionine (SAM-e) is a dietary
supplement that has efficacy as an antidepressant and as a treatment for chronic pain.
OBJECTIVE:
The research team hypothesized that during SAM-e exposure (1) participants' pain reports would
significantly improve over time, (2) participants' reported quality of life would significantly improve over
time, and (3) toxicity measures (liver-function tests and mania and depression scales) would not change
significantly.
DESIGN:
The research team performed an open-label, doseescalation trial of oral SAM-e among children with
FAP. Participants came to the research facility for measurements at baseline and after 2 wk, 1 mo, and 2
mo. The research team monitored participants for potential toxicities (liver toxicity, mania, and
depression) throughout the trial.
SETTING:
The trial was conducted at the University of California, San Diego.
PARTICIPANTS:
The research team recruited children and adolescents with FAP via advertisement at several community
general pediatric clinics and at the research team's subspecialty pediatric gastrointestinal clinic at a
tertiary care center. The eight resulting participants were children with a median and mean age of 14 y.
INTERVENTION:
To treat persistent abdominal pain, all participants received SAM-e at an initial dose of 200 mg/d, with
escalation to a maximum dose of 1400 mg/d over the period of 2 mo.
OUTCOME MEASURES:
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The primary outcomes were the participants' self-reports of pain and quality of life. The research team
used the multidimensional measure for recurrent abdominal pain (MM-RAP), Wong-Baker FACES Pain
Rating Scale, and the PedsQL for those measurements. The team used repeated measures analyses to
analyze the data.
RESULTS:
Six participants completed the study. The research team demonstrated an improvement in self-pain
reports over the 2-mo follow-up period (P = .004). The median dose of SAM-e that participants took at
the 2-mo follow-up period was 1400 mg (interquartile range: 950-1400 mg) daily. Liver function tests
and assessments for mania and depression did not change over the study period.
CONCLUSIONS:
Oral SAM-e demonstrates promise in reducing abdominal pain among children with FAP, with minimal
toxicity. The research team needs to conduct larger, placebo-controlled trials to support its initial
findings.
[S-adenosyl L-methionine in CNS diseases].

Krzystanek M, et al. Psychiatr Pol. 2011 Nov-Dec;45(6):923-31. [Article in Polish]
Abstract
S-adenosyl L-methionine (SAMe) is the natural, universal methyl group donor, participating in
transmethylation reactions, known and commonly used as a dietary supplement since 1952. It plays an
important role in the synthesis of neuromediators and melatonin and mechanisms of epigenetic
regulation. The aim of this article is to review the literature about possibilities of SAMe application in the
therapy of CNS diseases: depression, dementia syndromes, schizophrenia and somatic disorders. SAMe
is the promising dietary supplement, which may be successfully used as a substance increasing
effectiveness of the treatment of depression, with antidepressants in monotherapy in mild depressive
states or depressive symptoms. SAMe addition to antipsychotic drug, may lead to the improvement of
the quality of life and reduction of aggressiveness of patients. SAMe may be an effective substance in
the therapy and prophylaxis of mild cognitive impairments and mild dementia syndrome. SAMe
possesses some hepatoprotective action, so it may decrease the risk of the development of neoplasm,
alcohol-induced liver disease (ALD) and cirrhosis. SAMe improves the functions of joints and decreases
the experience of pain in rheumatoid arthritis (RA).
391
One-Carbon Metabolism Supports S-Adenosylmethionine and Histone

Methylation to Drive Inflammatory Macrophages.
Yu W, et al. Mol Cell. 2019 Jul 23. pii: S1097-2765(19)30496-4. doi:
10.1016/j.molcel.2019.06.039. [Epub ahead of print]
Abstract
Activated macrophages adapt their metabolic pathways to drive the pro-inflammatory phenotype, but
little is known about the biochemical underpinnings of this process. Here, we find that
lipopolysaccharide (LPS) activates the pentose phosphate pathway, the serine synthesis pathway, and
one-carbon metabolism, the synergism of which drives epigenetic reprogramming for interleukin-1β (IL-
1β) expression. Glucose-derived ribose and one-carbon units fed by both glucose and serine metabolism
are synergistically integrated into the methionine cycle through de novo ATP synthesis and fuel the
generation of S-adenosylmethionine (SAM) during LPS-induced inflammation. Impairment of these
metabolic pathways that feed SAM generation lead to anti-inflammatory outcomes, implicating SAM as
an essential metabolite for inflammatory macrophages. Mechanistically, SAM generation maintains a
relatively high SAM:S-adenosylhomocysteine ratio to support histone H3 lysine 36 trimethylation for IL-
1β production. We therefore identify a synergistic effect of glucose and amino acid metabolism on
orchestrating SAM availability that is intimately linked to the chromatin state for inflammation.
Skullcap (Scutellaria)
Cartilage Protection and Analgesic Activity of a Botanical Composition
Comprised of Morus alba, Scutellaria baicalensis, and Acacia catechu.
Yimam M, et al. Evid Based Complement Alternat Med. 2017;2017:7059068. doi:
10.1155/2017/7059068. Epub 2017 Aug 20.
Abstract
Although there have been augmented advances in drug discovery, current OA management is
inadequate due to the lack of successful therapies proven to be effective in modifying disease
progression. For some, the risk outweighs the benefit. As a result, there is a desperate need for safe and
efficacious natural alternatives. Here we evaluated a composition from Morus alba, Scutellaria
baicalensis, and Acacia catechu in maintaining joint structural integrity and alleviating OA associated
392
symptoms in monoiodoacetate- (MIA-) induced rat OA disease model. Study lasted for 6 weeks. 59.6%,
64.6%, 70.7%, 69.9%, and 70.3% reductions in pain sensitivity were observed for rats treated with the
composition from week 1 to week 5, respectively. Statistically significant improvements in articular
cartilage matrix integrity (maintained at 57.1% versus MIA + vehicle treated rats) were shown from the
modified total Mankin score for animals treated with the composition. The composition showed a
statistically significant reduction in uCTX-II level (54.1% reductions). The merit of combining these
botanicals was also demonstrated in their synergistic analgesic activity. Therefore, the standardized
blend of Morus alba, Scutellaria baicalensis, and Acacia catechu could potentially be considered as an
alternative remedy from natural sources for the management of OA and/or its associated symptoms.
A combination of Scutellaria baicalensis and Acacia catechu extracts for short-

term symptomatic relief of joint discomfort associated with osteoarthritis of
the knee.
Arjmandi BH, et al. J Med Food. 2014 Jun;17(6):707-13. doi:
10.1089/jmf.2013.0010. Epub 2014 Mar 10.
Abstract
The extracts of Scutellaria baicalensis and Acacia catechu have been shown in previous studies to
alleviate joint discomfort, reduce stiffness, and improve mobility by reducing the production of
proinflammatory molecules over long periods of supplementation. The acute effects of intake of these
extracts have not yet been investigated. Thus, we carried out a 1 week clinical trial to examine the
extent to which UP446-a natural proprietary blend of S. baicalensis and A. catechu (UP446)-decreases
knee joint pain, mobility, and biomarkers of inflammation in comparison to naproxen. Seventy-nine men
and women (40-90 years old) diagnosed as having mild to moderate osteoarthritis (OA) consumed either
500 mg/day of the UP446 supplement or 440 mg/day of naproxen for 1 week in a double-blind
randomized control trial. Pain, knee range of motion (ROM), and overall physical activity were evaluated
at the start and at the end of treatment. Fasting blood was collected to determine serum interleukins 1β
and 6, tumor necrosis factor-α, C-reactive protein, and hyaluronic acid. The UP446 group experienced a
significant decrease in perceived pain (P=.009) time dependently. Stiffness was significantly reduced by
both treatments (P=.002 UP446, P=.008 naproxen). Significant increases in mean ROM over time (P=.04)
were found in the UP446 group. These findings suggest that UP446 is effective in reducing the physical
symptoms associated with knee OA.
UP446, analgesic and anti-inflammatory botanical composition.

Yimam M1 Brownell L, Pantier M, Jia Q. Pharmacognosy Res. 2013 Jul;5(3):139-
45. doi: 10.4103/0974-8490.112406.
393
Abstract
BACKGROUND:
Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease. Long-term use of
currently available therapies for RA produces adverse effects that limit dosage and duration; hence
there is a need for safe and effective alternatives suitable for long term chronic use. UP446, a
composition consisting primarily of baicalin from Scutellaria baicalensis Georgi (Family: Lamiaceae) and
(+)-catechin from the heartwoods of Acacia catechu (Family: Mimosaceae), has been previously shown
to reduce production of eicosanoids and leukotrienes through dual inhibition of cyclooxygenase (COX)
and lipoxygenase (LOX) enzymes and to decreased mRNA and protein levels of the proinflammatory
cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α.
AIM:
To evaluate the likelihood of UP446 in moderating arthritis and its associated symptoms in an
experimental animal model of RA.
A RA rat model was induced by injecting Freund's complete adjuvant into left and right hind paw and
base of the tail. Animals were administered UP446 (50 mg/kg), ibuprofen (150 mg/kg mg/kg) or vehicle
by oral gavage 30 min prior to arthritis induction and each day thereafter for 14 days.
RESULT:
Animals treated with UP446 showed 23.7, 31.9, 33.4, 29.3, and 33.1% reduction in pain sensitivity; 46.0,
36.7, 33.7, 34.8, and 33.4% reduction in ankle diameter on days 3, 5, 7, 9, and 13; respectively;
compared to vehicle. Similarly paw edema was significantly reduced with an average of 30% for the first
inflammatory reaction period (day 1-8) followed by 37.1 and 33.6% reduction on day 9 and 13.
CONCLUSION:
These data indicate potential benefit of UP446 in alleviating symptoms of RA and support human clinical
evaluation of this botanical composition in patients with RA.
KEYWORDS:
Acacia catechu; Scutellaria baicalensis Georgi; inflammation; pain; rheumatoid arthritis

394
Analgesic effects of a standardized bioflavonoid composition from Scutellaria

baicalensis and Acacia catechu.
Yimam M, Brownell L, Hodges M, Jia Q. J Diet Suppl. 2012 Sep;9(3):155-65. doi:
10.3109/19390211.2012.708713. Epub 2012 Aug 10.
Abstract
Anti-inflammatory properties of both baicalin and catechins have been widely reported. However, the
reports of analgesic effects of baicalin and catechins are limited. Three commonly used pain-related
animal models were employed to evaluate the analgesic activity of UP446, a standardized bioflavonoid
composition of baicalin and catechins. Carrageenan-induced paw edema, formalin test, and abdominal
constriction assays were used to evaluate antinociceptive activity of 150 mg/kg or 100 mg/kg oral doses
of UP446. Ibuprofen was used as a reference compound in each test. Pretreatment of carrageenan-
induced hyperalgesic animals with UP446 at 150 mg/kg oral dosage reduced the hypersensitivity of pain
by 39.5%. Similarly, a single dose of UP446, given orally at 100 mg/kg, exhibited 58% and 71.9%
inhibition in pain sensitivity compared to vehicle-treated control in writhing and formalin tests,
respectively. These findings suggest that the standardized anti-inflammatory bioflavonoid composition,
UP446, could also be employed to inhibit nociception.
Elucidation of the Anti-Inflammatory Mechanisms of Bupleuri and Scutellariae

Radix Using System Pharmacological Analyses.
Shen X, et al. Mediators Inflamm. 2017;2017:3709874. doi:
10.1155/2017/3709874. Epub 2017 Jan 16.
https://www.ncbi.nlm.nih.gov/pubmed?term=elucidation%20of%20the%20anti-
inflammatory%20mechanisms%20of%20bupleurum%20and%20scutellariae&cmd=correctspelling
Abstract
Objective. This study was aimed at elucidating the molecular mechanisms underlying the anti-
inflammatory effect of the combined application of Bupleuri Radix and Scutellariae Radix and explored
the potential therapeutic efficacy of these two drugs on inflammation-related diseases. Methods. After
searching the databases, we collected the active ingredients of Bupleuri Radix and Scutellariae Radix and
calculated their oral bioavailability (OB) and drug-likeness (DL) based on the absorption-distribution-
metabolism-elimination (ADME) model. In addition, we predicted the drug targets of the selected active
components based on weighted ensemble similarity (WES) and used them to construct a drug-target
network. Gene ontology (GO) analysis and KEGG mapper tools were performed on these predicted
target genes. Results. We obtained 30 compounds from Bupleuri Radix and Scutellariae Radix of good
quality as indicated by ADME assays, which possess potential pharmacological activity. These 30
ingredients have a total of 121 potential target genes, which are involved in 24 biological processes
395
related to inflammation. Conclusions. Combined application of Bupleuri Radix and Scutellariae Radix was
found not only to directly inhibit the synthesis and release of inflammatory cytokines, but also to have
potential therapeutic effects against inflammation-induced pain. In addition, a combination therapy of
these two drugs exhibited systemic treatment efficacy and provided a theoretical basis for the
development of drugs against inflammatory diseases.
GABA-modulating phytomedicines for anxiety: A systematic review of

preclinical and clinical evidence.
Savage K, Firth J, Stough C, Sarris J. Phytother Res. 2018 Jan;32(1):3-18. doi:
10.1002/ptr.5940. Epub 2017 Nov 23.
Abstract
Anxiety disorders are chronic and functionally disabling conditions with high psychological stress,
characterised by cognitive symptoms of excessive worry and focus difficulties and physiological
symptoms such as muscle tension and insomnia. Gamma-aminobutyric acid (GABA) is an inhibitory
neurotransmitter within the central nervous system and is a key target of pharmacotherapies in the
treatment of anxiety. Although current pharmaceutical treatments are often efficacious, they may cause
undesirable side effects including cognitive decrements and withdrawal symptoms. Plant-based
"phytomedicines" may provide novel treatment options, to act as an adjunctive or alternative to existing
anxiolytic medications. As such, we conducted a systematic review to assess the current body of
literature on anxiolytic phytomedicines and/or phytoconstituents. An open-ended search to 5 July 2017
was conducted using MEDLINE (PubMed), Scopus, and Cochrane library online databases and performed
in a stepped format from preclinical to clinical investigations. Eligible studies must have had (a) in vitro
evidence of GABA-modulating activity, (b) animal studies using anxiety models to test an anxiolytic
effect, and (c) human clinical trials. Ten phytomedicines were identified as having preclinical
investigations showing interaction with the GABA system, in addition to human clinical trials: kava,
valerian, pennywort, hops, chamomile, Ginkgo biloba, passionflower, ashwagandha, skullcap, and lemon
balm. Collectively, the literature reveals preclinical and clinical evidence for various phytomedicines
modulating GABA-pathways, with comparative anxiolytic effect to the current array of pharmaceuticals,
along with good safety and tolerability profiles.
KEYWORDS:
GABA; anxiety; anxiolytic; herbal; phytomedicine; phytotherapy

396
Skullcap (Scutellaria Baicalensis) Hexane Fraction Inhibits the Permeation of

Ovalbumin and Regulates Th1/2 Immune Responses.
Jung SY, et al. Nutrients. 2017 Oct 28;9(11). pii: E1184. doi: 10.3390/nu9111184.
Abstract
Skullcap (Scutellaria baicalensis) is well known for its anti-inflammatory and anti-allergic effects. In our
previous study, we found that skullcap could inhibit allergen permeation and regulate Th1/2 immune
balance. To reveal the key fractions and components of skullcap, we fractionated skullcap extract into
five fractions: hexane, chloroform, ethyl acetate, butanol, and water fraction. Among these fractions,
the hexane fraction significantly suppressed the production of Th2-mediated cytokines (Interleukin (IL)-
4, 5, 10 and 13) and increased Th1-mediated cytokines (Interferon (IFN)-γ and IL-12). Furthermore, the
hexane fraction inhibited the permeation of ovalbumin (OVA), used as an allergen, across the intestinal
epithelial cell monolayer. To confirm the active compounds in the hexane fraction, fatty acids were
analyzed. Linoleic acid (LA, C18:2 (>59.7%)) was identified as the most important fatty acid in the
skullcap hexane fraction. LA significantly suppressed IL-4 production and increased IFN-γ secretion, as
well as inhibiting OVA permeation. Thus, LA significantly diminished the permeation of allergen by
enhancing intestinal barrier function and regulated allergic responses to maintain Th1/Th2 immune
balance.
KEYWORDS:
Scutellaria baicalensis; Th1/2 immune response; Th1/Th2 balance; linoleic acid; ovalbumin permeation;
skullcap
Baicalin Attenuates Joint Pain and Muscle Dysfunction by Inhibiting Muscular

Oxidative Stress in an Experimental Osteoarthritis Rat Model.
Chen DS, et al. Arch Immunol Ther Exp (Warsz). 2018 Dec;66(6):453-461. doi:
10.1007/s00005-018-0518-6. Epub 2018 Aug 3.
Abstract
Osteoarthritis (OA) is the most common degenerative joint disease, and causes major pain and disability
in adults. It has been reported that muscle weakness and inflammation contribute to osteoarthritis
development and progression. Oxidative stress plays important roles in muscle dysfunction and
inflammation in osteomyelitis. Baicalin, the major active constituent of the isolated root of
Scutellarialateriflora Georgi, has been shown to have anti-oxidative and anti-inflammatory effects. In
this study, we evaluated the potential effects of baicalin on osteoarthritis. We established experimental
397
osteoarthritis rat model, applied baicalin to the rats, and then explored the potential protective effect of
baicalin on osteoarthritis severity, muscle dysfunction, and oxidative stress. Baicalin alleviated severity
of OA in rats. Baicalin application attenuated muscle dysfunction in OA rats by increasing citrate
synthase activity, myosin heavy chain IIa expression, and decreasing interleukin 6 production. Baicalin
decreased muscular reactive oxygen species generation in OA rats. Baicalin inhibited nuclear factor
erythroid-derived 2-like 2 expression in OA rats. Baicalin attenuated osteoarthritis in rat by inhibiting
oxidative stress.
KEYWORDS:
Baicalin; Joint pain; Muscle; Osteoarthritis; Oxidative stress
Oxidative stress, aging, and diseases

Ilaria Liguor, et al. Clin Interv Aging. 2018; 13: 757–772. Published online 2018
Apr 26. doi: 10.2147/CIA.S158513
Abstract
Reactive oxygen and nitrogen species (RONS) are produced by several endogenous and exogenous
processes, and their negative effects are neutralized by antioxidant defenses. Oxidative stress occurs
from the imbalance between RONS production and these antioxidant defenses. Aging is a process
characterized by the progressive loss of tissue and organ function. The oxidative stress theory of aging is
based on the hypothesis that age-associated functional losses are due to the accumulation of RONS-
induced damages. At the same time, oxidative stress is involved in several age-related conditions (ie,
cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease,
neurodegenerative diseases, and cancer), including sarcopenia and frailty. Different types of oxidative
stress biomarkers have been identified and may provide important information about the efficacy of the
treatment, guiding the selection of the most effective drugs/dose regimens for patients and, if
particularly relevant from a pathophysiological point of view, acting on a specific therapeutic target.
Given the important role of oxidative stress in the pathogenesis of many clinical conditions and aging,
antioxidant therapy could positively affect the natural history of several diseases, but further
investigation is needed to evaluate the real efficacy of these therapeutic interventions. The purpose of
this paper is to provide a review of literature on this complex topic of ever increasing interest.
Keywords: elderly, reactive oxygen species, reactive nitrogen species, antioxidants

398
Skullcap: Benefits, Side Effects, and Dosage

Written by Jillian Kubala, MS, RD on April 30, 2019. Healthline.com
https://www.healthline.com/nutrition/skullcap
Skullcap (sometimes spelled scullcap) is the common name for Scutellaria, a genus of flowering plants in
the mint family.
The name is derived from the Latin word scutella, which means “little dish,” as the small flowers of
these plants have a dish- or helmet-like shape. Skullcap is not to be confused with death caps, which are
a highly poisonous mushroom .
Various parts of skullcaps, such as their roots and leaves, have been used in traditional Chinese and
Native American medicine to treat a variety of ailments, ranging from diarrhea to chronic pain.
Today, this plant is widely available in supplement form and purported to provide an array of health
benefits, from boosting heart health to relieving anxiety.
Turmeric (Curcuma)
evidence.
10.1515/revneuro-2018-0097.
Abstract
399
KEYWORDS:
Review of Anti-Inflammatory Herbal Medicines.

Ghasemian M, Owlia S, Owlia MB. Adv Pharmacol Sci. 2016;2016:9130979. doi:
10.1155/2016/9130979. Epub 2016 May 10.
Abstract
Medicinal plants and their secondary metabolites are progressively used in the treatment of diseases as
a complementary medicine. Inflammation is a pathologic condition that includes a wide range of
diseases such as rheumatic and immune-mediated conditions, diabetes, cardiovascular accident, and
etcetera. We introduce some herbs which their anti-inflammatory effects have been evaluated in clinical
and experimental studies. Curcuma longa, Zingiber officinale, Rosmarinus officinalis, Borago officinalis,
evening primrose, and Devil's claw are some of the introduced medicinal herbs in this review. Since the
treatment of inflammation is not a one-dimensional remedy, this review tries to reach a
multidimensional therapeutic approach to inflammation with the help of herbal medicine and
modification in lifestyle.

Current Knowledge.
10.2174/1389200218666170710190249.
Abstract
400
BACKGROUND:
METHOD:
CONCLUSION:
KEYWORDS:
Does diet play a role in reducing nociception related to inflammation and

chronic pain?
Bjørklund G, et al. Nutrition. 2019 Oct;66:153-165. doi:
10.1016/j.nut.2019.04.007. Epub 2019 Apr 26.
Abstract
401
Dietary habits are fundamental issues to assess when modulating health and well-being; however,
different nutritional panels may help individuals prevent acute and chronic pain. Many substances,
known to be active antioxidants and anti-inflammatory compounds, should serve this fundamental task.
Antinociceptive and analgesic natural compounds include flavonoids, terumbone from ginger root,
curcuminoids, ω-3 polyunsaturated fatty acids, and taurine. Furthermore, correct intake of trace
elements and minerals is strategic to reduce inflammation-related pain. This review addresses these
items in an effort to suggest new criteria for proper dietary supplementation to prevent pain.

Abstract
OBJECTIVE:
METHODS:
RESULTS:
402
CONCLUSIONS:
KEYWORDS:

doi: 10.22038/IJBMS.2018.24026.6021.
Abstract
KEYWORDS:

403

Abstract
BACKGROUND:
METHODS:
RESULTS:
interaction effect P = 0.027; ssffness score, ↓30% versus ↓12%, respecsvely, interacson effect
CONCLUSIONS:
404
Abstract
PARTICIPANTS:
405
10 Proven Health Benefits of Turmeric and Curcumin

Written by Kris Gunnars, BSc on July 13, 2018. Healthline.com
https://www.healthline.com/nutrition/top-10-evidence-based-health-benefits-of-turmeric
Turmeric may be the most effective nutritional supplement in existence.
Many high-quality studies show that it has major benefits for your body and brain.
Turmeric is the spice that gives curry its yellow color.
It has been used in India for thousands of years as a spice and medicinal herb.
Recently, science has started to back up what Indians have known for a long time — it really does
contain compounds with medicinal properties.
These compounds are called curcuminoids, the most important of which is curcumin.
Curcumin is the main active ingredient in turmeric. It has powerful anti-inflammatory effects and is a
very strong antioxidant.
Anti-inflammatory properties of curcumin, a major constituent of Curcuma

longa: a review of preclinical and clinical research.
Jurenka JS. Altern Med Rev. 2009 Jun;14(2):141-53.
Abstract
Curcuma longa (turmeric) has a long history of use in Ayurvedic medicine as a treatment for
inflammatory conditions. Turmeric constituents include the three curcuminoids: curcumin
(diferuloylmethane; the primary constituent and the one responsible for its vibrant yellow color),
demethoxycurcumin, and bisdemethoxycurcumin, as well as volatile oils (tumerone, atlantone, and
zingiberone), sugars, proteins, and resins. While numerous pharmacological activities, including
antioxidant and antimicrobial properties, have been attributed to curcumin, this article focuses on
curcumin's anti-inflammatory properties and its use for inflammatory conditions. Curcumin's effect on
cancer (from an anti-inflammatory perspective) will also be discussed; however, an exhaustive review of
its many anticancer mechanisms is outside the scope of this article. Research has shown curcumin to be
406
a highly pleiotropic molecule capable of interacting with numerous molecular targets involved in
inflammation. Based on early cell culture and animal research, clinical trials indicate curcumin may have
potential as a therapeutic agent in diseases such as inflammatory bowel disease, pancreatitis, arthritis,
and chronic anterior uveitis, as well as certain types of cancer. Because of curcumin's rapid plasma
clearance and conjugation, its therapeutic usefulness has been somewhat limited, leading researchers to
investigate the benefits of complexing curcumin with other substances to increase systemic
bioavailability. Numerous in-progress clinical trials should provide an even deeper understanding of the
mechanisms and therapeutic potential of curcumin.
Potential therapeutic effects of curcumin, the anti-inflammatory agent, against

neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and
neoplastic diseases.
Aggarwal BB1, Harikumar KB. Int J Biochem Cell Biol. 2009 Jan;41(1):40-59. doi:
10.1016/j.biocel.2008.06.010. Epub 2008 Jul 9.
Abstract
Although safe in most cases, ancient treatments are ignored because neither their active component nor
their molecular targets are well defined. This is not the case, however, with curcumin, a yellow-pigment
substance and component of turmeric (Curcuma longa), which was identified more than a century ago.
For centuries it has been known that turmeric exhibits anti-inflammatory activity, but extensive research
performed within the past two decades has shown that this activity of turmeric is due to curcumin
(diferuloylmethane). This agent has been shown to regulate numerous transcription factors, cytokines,
protein kinases, adhesion molecules, redox status and enzymes that have been linked to inflammation.
The process of inflammation has been shown to play a major role in most chronic illnesses, including
neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. In the
current review, we provide evidence for the potential role of curcumin in the prevention and treatment
of various proinflammatory chronic diseases. These features, combined with the pharmacological safety
and negligible cost, render curcumin an attractive agent to explore further.
Pharmacological basis for the role of curcumin in chronic diseases: an age-old

spice with modern targets.
Aggarwal BB, Sung B. Trends Pharmacol Sci. 2009 Feb;30(2):85-94. doi:
10.1016/j.tips.2008.11.002. Epub 2008 Dec 26.
Abstract
407
Curcumin (diferuloylmethane), a yellow pigment in the spice turmeric (also called curry powder), has
been used for centuries as a treatment for inflammatory diseases. Extensive research within the past
two decades has shown that curcumin mediates its anti-inflammatory effects through the
downregulation of inflammatory transcription factors (such as nuclear factor kappaB), enzymes (such as
cyclooxygenase 2 and 5 lipoxygenase) and cytokines (such as tumor necrosis factor, interleukin 1 and
interleukin 6). Because of the crucial role of inflammation in most chronic diseases, the potential of
curcumin has been examined in neoplastic, neurological, cardiovascular, pulmonary and metabolic
diseases. The pharmacodynamics and pharmacokinetics of curcumin have been examined in animals
and in humans. Various pharmacological aspects of curcumin in vitro and in vivo are discussed in detail
here.
Role of curcumin in health and disease.

Pari L1, Tewas D, Eckel J. Arch Physiol Biochem. 2008 Apr;114(2):127-49. doi:
10.1080/13813450802033958
Abstract
Curcumin (diferuloylmethane) is an orange-yellow component of turmeric (Curcuma longa), a spice

often found in curry powder. In recent years, considerable interest has been focused on curcumin due to
its use to treat a wide variety of disorders without any side effects. It is one of the major curcuminoids
of turmeric, which impart its characteristic yellow colour. It was used in ancient times on the Indian
subcontinent to treat various illnesses such as rheumatism, body ache, skin diseases, intestinal worms,
diarrhoea, intermittent fevers, hepatic disorders, biliousness, urinary discharges, dyspepsia,
inflammations, constipation, leukoderma, amenorrhea, and colic. Curcumin has the potential to treat a
wide variety of inflammatory diseases including cancer, diabetes, cardiovascular diseases, arthritis,
Alzheimer's disease, psoriasis, etc, through modulation of numerous molecular targets. This article
reviews the use of curcumin for the chemoprevention and treatment of various diseases.
Curcumin as "Curecumin": from kitchen to clinic.

Goel A, Kunnumakkara AB, Aggarwal BB. Biochem Pharmacol. 2008 Feb
15;75(4):787-809. Epub 2007 Aug 19.
Abstract
408
Although turmeric (Curcuma longa; an Indian spice) has been described in Ayurveda, as a treatment for
inflammatory diseases and is referred by different names in different cultures, the active principle called
curcumin or diferuloylmethane, a yellow pigment present in turmeric (curry powder) has been shown to
exhibit numerous activities. Extensive research over the last half century has revealed several important
functions of curcumin. It binds to a variety of proteins and inhibits the activity of various kinases. By
modulating the activation of various transcription factors, curcumin regulates the expression of
inflammatory enzymes, cytokines, adhesion molecules, and cell survival proteins. Curcumin also
downregulates cyclin D1, cyclin E and MDM2; and upregulates p21, p27, and p53. Various preclinical cell
culture and animal studies suggest that curcumin has potential as an antiproliferative, anti-invasive, and
antiangiogenic agent; as a mediator of chemoresistance and radioresistance; as a chemopreventive
agent; and as a therapeutic agent in wound healing, diabetes, Alzheimer disease, Parkinson disease,
cardiovascular disease, pulmonary disease, and arthritis. Pilot phase I clinical trials have shown curcumin
to be safe even when consumed at a daily dose of 12g for 3 months. Other clinical trials suggest a
potential therapeutic role for curcumin in diseases such as familial adenomatous polyposis,
inflammatory bowel disease, ulcerative colitis, colon cancer, pancreatic cancer, hypercholesteremia,
atherosclerosis, pancreatitis, psoriasis, chronic anterior uveitis and arthritis. Thus, curcumin, a spice
once relegated to the kitchen shelf, has moved into the clinic and may prove to be "Curecumin".
Curcumin: the Indian solid gold.

Aggarwal BB, Sundaram C, Malani N, Ichikawa H. Adv Exp Med Biol. 2007;595:1-
75.
Abstract
Turmeric, derived from the plant Curcuma longa, is a gold-colored spice commonly used in the Indian
subcontinent, not only for health care but also for the preservation of food and as a yellow dye for
textiles. Curcumin, which gives the yellow color to turmeric, was first isolated almost two centuries ago,
and its structure as diferuloylmethane was determined in 1910. Since the time of Ayurveda (1900 Bc)
numerous therapeutic activities have been assigned to turmeric for a wide variety of diseases and
conditions, including those of the skin, pulmonary, and gastrointestinal systems, aches, pains, wounds,
sprains, and liver disorders. Extensive research within the last half century has proven that most of these
activities, once associated with turmeric, are due to curcumin. Curcumin has been shown to exhibit
antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has
a potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimer's disease, and
other chronic illnesses. These effects are mediated through the regulation of various transcription
factors, growth factors, inflammatory cytokines, protein kinases, and other enzymes. Curcumin exhibits
activities similar to recently discovered tumor necrosis factor blockers (e.g., HUMIRA, REMICADE, and
ENBREL), a vascular endothelial cell growth factor blocker (e.g., AVASTIN), human epidermal growth
factor receptor blockers (e.g., ERBITUX, ERLOTINIB, and GEFTINIB), and a HER2 blocker (e.g.,
409
HERCEPTIN). Considering the recent scientific bandwagon that multitargeted therapy is better than
monotargeted therapy for most diseases, curcumin can be considered an ideal "Spice for Life".
The targets of curcumin.

Zhou H, Beevers CS, Huang S. Curr Drug Targets. 2011 Mar 1;12(3):332-47.
Abstract
Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a

polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries,
curcumin has been used in some medicinal preparation or used as a food-coloring agent. In recent years,
extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-
amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are
diverse and appear to involve the regulation of various molecular targets, including transcription factors
(such as nuclear factor-kB), growth factors (such as vascular endothelial cell growth factor),
inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases
(such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other
enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of
multiple targets, as well as its safety for human use, curcumin has received considerable interest as a
potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis,
allergies, Alzheimer's disease, and other inflammatory illnesses. This review summarizes various in vitro
and in vivo pharmacological aspects of curcumin as well as the underlying action mechanisms. The
recently identified molecular targets and signaling pathways modulated by curcumin are also discussed
here.
Curcumin in inflammatory diseases.

Shehzad A, Rehman G, Lee YS. Biofactors. 2013 Jan-Feb;39(1):69-77. doi:
10.1002/biof.1066. Epub 2012 Dec 22.
Abstract
Curcumin (diferuloylmethane), a yellow coloring agent extracted from turmeric is also used as a remedy
for the treatment and prevention of inflammatory diseases. Acute and chronic inflammation is a major
factor in the progression of obesity, type II diabetes, arthritis, pancreatitis, cardiovascular,
neurodegenerative and metabolic diseases, as well as certain types of cancer. Turmeric has a long
history of use in Ayurvedic medicine for the treatment of inflammatory disorders. Recent studies on the
efficacy and therapeutic applicability of turmeric have suggested that the active ingredient of tumeric is
410
curcumin. Further, compelling evidence has shown that curcumin has the ability to inhibit inflammatory
cell proliferation, invasion, and angiogenesis through multiple molecular targets and mechanisms of
action. Curcumin is safe, non-toxic, and mediates its anti-inflammatory effects through the down-
regulation of inflammatory transcription factors, cytokines, redox status, protein kinases, and enzymes
that all promote inflammation. In addition, curcumin induces apoptosis through mitochondrial and
receptor-mediated pathways, as well as activation of caspase cascades. In the current study, the anti-
inflammatory effects of curcumin were evaluated relative to various chronic inflammatory diseases.
Based on the available pharmacological data obtained from in vitro and in vivo research, as well as
clinical trials, an opportunity exists to translate curcumin into clinics for the prevention of inflammatory
diseases in the near future.
Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-

kappaB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1,
and abrogation of tumor cell proliferation.
Takada Y, Bhardwaj A, Potdar P, Aggarwal BB. Oncogene. 2004 Dec
9;23(57):9247-58.
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin have been shown to suppress
transcription factor NF-kappaB, which controls the expression of genes such as cyclooxygenase (COX)-2
and cyclin D1, leading to inhibition of proliferation of tumor cells. There is no systematic study as to how
these drugs differ in their ability to suppress NF-kappaB activation and NF-kappaB-regulated gene
expression or cell proliferation. In the present study, we investigated the effect of almost a dozen
different commonly used NSAIDs on tumor necrosis factor (TNF)-induced NF-kappaB activation and NF-
kappaB-regulated gene products, and on cell proliferation. Dexamethasone, an anti-inflammatory
steroid, was included for comparison with NSAIDs. As indicated by DNA binding, none of the drugs alone
activated NF-kappaB. All compounds inhibited TNF-induced NF-kappaB activation, but with highly
variable efficacy. The 50% inhibitory concentration required was 5.67, 3.49, 3.03, 1.25, 0.94, 0.60, 0.38,
0.084, 0.043, 0.027, 0.024, and 0.010 mM for aspirin, ibuprofen, sulindac, phenylbutazone, naproxen,
indomethacin, diclofenac, resveratrol, curcumin, dexamethasone, celecoxib, and tamoxifen,
respectively. All drugs inhibited IkappaBalpha kinase and suppressed IkappaBalpha degradation and NF-
kappaB-regulated reporter gene expression. They also suppressed NF-kappaB-regulated COX-2 and
cyclin D1 protein expression in a dose-dependent manner. All compounds inhibited the proliferation of
tumor cells, with 50% inhibitory concentrations of 6.09, 1.12, 0.65, 0.49, 1.01, 0.19, 0.36, 0.012, 0.016,
0.047, 0.013, and 0.008 mM for aspirin, ibuprofen, sulindac, phenylbutazone, naproxen, indomethacin,
diclofenac, resveratrol, curcumin, dexamethasone, celecoxib, and tamoxifen, respectively. Overall these
results indicate that aspirin and ibuprofen are least potent, while resveratrol, curcumin, celecoxib, and
tamoxifen are the most potent anti-inflammatory and antiproliferative agents of those we studied.
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Antioxidant and anti-inflammatory properties of curcumin.

Menon VP, Sudheer AR. Adv Exp Med Biol. 2007;595:105-25.
Abstract
Curcumin, a yellow pigment from Curcuma longa, is a major component of turmeric and is commonly
used as a spice and food-coloring agent. It is also used as a cosmetic and in some medical preparations.
The desirable preventive or putative therapeutic properties of curcumin have also been considered to
be associated with its antioxidant and anti-inflammatory properties. Because free-radical-mediated
peroxidation of membrane lipids and oxidative damage of DNA and proteins are believed to be
associated with a variety of chronic pathological complications such as cancer, atherosclerosis, and
neurodegenerative diseases, curcumin is thought to play a vital role against these pathological
conditions. The anti-inflammatory effect of curcumin is most likely mediated through its ability to inhibit
cyclooxygenase-2 (COX-2), lipoxygenase (LOX), and inducible nitric oxide synthase (iNOS). COX-2, LOX,
and iNOS are important enzymes that mediate inflammatory processes. Improper upregulation of COX-2
and/or iNOS has been associated with the pathophysiology of certain types of human cancer as well as
inflammatory disorders. Because inflammation is closely linked to tumor promotion, curcumin with its
potent anti-inflammatory property is anticipated to exert chemopreventive effects on carcinogenesis.
Hence, the past few decades have witnessed intense research devoted to the antioxidant and anti-
inflammatory properties of curcumin. In this review, we describe both antioxidant and anti-
inflammatory properties of curcumin, the mode of action of curcumin, and its therapeutic usage against
different pathological conditions.
Safety and anti-inflammatory activity of curcumin: a component of tumeric

(Curcuma longa).
Chainani-Wu N. J Altern Complement Med. 2003 Feb;9(1):161-8.
Abstract
INTRODUCTION:
Tumeric is a spice that comes from the root Curcuma longa, a member of the ginger family,
Zingaberaceae. In Ayurveda (Indian traditional medicine), tumeric has been used for its medicinal
properties for various indications and through different routes of administration, including topically,
orally, and by inhalation. Curcuminoids are components of tumeric, which include mainly curcumin
(diferuloyl methane), demethoxycurcumin, and bisdemethoxycurcmin.
412
OBJECTIVES:
The goal of this systematic review of the literature was to summarize the literature on the safety and
anti-inflammatory activity of curcumin.
METHODS:
A search of the computerized database MEDLINE (1966 to January 2002), a manual search of
bibliographies of papers identified through MEDLINE, and an Internet search using multiple search
engines for references on this topic was conducted. The PDR for Herbal Medicines, and four textbooks
on herbal medicine and their bibliographies were also searched.
RESULTS:
A large number of studies on curcumin were identified. These included studies on the antioxidant, anti-
inflammatory, antiviral, and antifungal properties of curcuminoids. Studies on the toxicity and anti-
inflammatory properties of curcumin have included in vitro, animal, and human studies. A phase 1
human trial with 25 subjects using up to 8000 mg of curcumin per day for 3 months found no toxicity
from curcumin. Five other human trials using 1125-2500 mg of curcumin per day have also found it to be
safe. These human studies have found some evidence of anti-inflammatory activity of curcumin. The
laboratory studies have identified a number of different molecules involved in inflammation that are
inhibited by curcumin including phospholipase, lipooxygenase, cyclooxygenase 2, leukotrienes,
thromboxane, prostaglandins, nitric oxide, collagenase, elastase, hyaluronidase, monocyte
chemoattractant protein-1 (MCP-1), interferon-inducible protein, tumor necrosis factor (TNF), and
interleukin-12 (IL-12).
CONCLUSIONS:
Curcumin has been demonstrated to be safe in six human trials and has demonstrated anti-
inflammatory activity. It may exert its anti-inflammatory activity by inhibition of a number of different
molecules that play a role in inflammation.
Turmeric with Black Pepper

Why Turmeric and Black Pepper Is a Powerful Combination
Written by Amy Goodson, MS, RD, CSSD, LD on July 4, 2018. Healthline.com
413
https://www.healthline.com/nutrition/turmeric-and-black-pepper
Turmeric, also known as the golden spice, is a tall plant that grows in Asia and Central America.
It gives curry its yellow color and has been used in traditional Indian medicine for thousands of years to
treat various health conditions.
Studies support its use and show that it can benefit your health.
But coupling turmeric with black pepper may enhance its effects.
Both turmeric and black pepper have key active ingredients that contribute to their anti-inflammatory,
antioxidant and disease-fighting qualities.
Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials

Subash C. Gupta, Sridevi Patchva, and Bharat B. Aggarwal corresponding author.
AAPS J. 2013 Jan; 15(1): 195–218.Published online 2012 Nov 10. doi:
10.1208/s12248-012-9432-8
Abstract
Extensive research over the past half century has shown that curcumin (diferuloylmethane), a
component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling
pathways. Extensive clinical trials over the past quarter century have addressed the pharmacokinetics,
safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects
have been observed in patients with various pro-inflammatory diseases including cancer, cardiovascular
disease, arthritis, uveitis, ulcerative proctitis, Crohn’s disease, ulcerative colitis, irritable bowel disease,
tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen
planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes,
diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired
immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis,
and chronic bacterial prostatitis. Curcumin has also shown protection against hepatic conditions, chronic
arsenic exposure, and alcohol intoxication. Dose-escalating studies have indicated the safety of
curcumin at doses as high as 12 g/day over 3 months. Curcumin’s pleiotropic activities emanate from its
ability to modulate numerous signaling molecules such as pro-inflammatory cytokines, apoptotic
proteins, NF–κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E2, prostate-specific
antigen, adhesion molecules, phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1,
creatinine, HO-1, AST, and ALT in human participants. In clinical trials, curcumin has been used either
alone or in combination with other agents. Various formulations of curcumin, including nanoparticles,
liposomal encapsulation, emulsions, capsules, tablets, and powder, have been examined. In this review,
we discuss in detail the various human diseases in which the effect of curcumin has been investigated.
414
Key words: clinical trial, curcumin, human diseases, inflammation, safety
Curcumin: A Review of Its’ Effects on Human Health

Susan J. Hewlings and Douglas S. Kalman. Foods. 2017 Oct; 6(10): 92.Published
online 2017 Oct 22. doi: 10.3390/foods6100092
Abstract
Turmeric, a spice that has long been recognized for its medicinal properties, has received interest from
both the medical/scientific world and from culinary enthusiasts, as it is the major source of the
polyphenol curcumin. It aids in the management of oxidative and inflammatory conditions, metabolic
syndrome, arthritis, anxiety, and hyperlipidemia. It may also help in the management of exercise-
induced inflammation and muscle soreness, thus enhancing recovery and performance in active people.
In addition, a relatively low dose of the complex can provide health benefits for people that do not have
diagnosed health conditions. Most of these benefits can be attributed to its antioxidant and anti-
inflammatory effects. Ingesting curcumin by itself does not lead to the associated health benefits due to
its poor bioavailability, which appears to be primarily due to poor absorption, rapid metabolism, and
rapid elimination. There are several components that can increase bioavailability. For example, piperine
is the major active component of black pepper and, when combined in a complex with curcumin, has
been shown to increase bioavailability by 2000%. Curcumin combined with enhancing agents provides
multiple health benefits. The purpose of this review is to provide a brief overview of the plethora of
research regarding the health benefits of curcumin.
Keywords: curcumin, turmeric, antioxidant, anti-inflammatory, polyphenol
Influence of piperine on the pharmacokinetics of curcumin in animals and

human volunteers.
Shoba G, et al. Planta Med. 1998 May;64(4):353-6.
Abstract
The medicinal properties of curcumin obtained from Curcuma longa L. cannot be utilised because of
poor bioavailability due to its rapid metabolism in the liver and intestinal wall. In this study, the effect of
combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, was evaluated on the
bioavailability of curcumin in rats and healthy human volunteers. When curcumin was given alone, in
the dose 2 g/kg to rats, moderate serum concentrations were achieved over a period of 4 h.
Concomitant administration of piperine 20 mg/kg increased the serum concentration of curcumin for a
415
short period of 1-2 h post drug. Time to maximum was significantly increased (P < 0.02) while
elimination half life and clearance significantly decreased (P < 0.02), and the bioavailability was
increased by 154%. On the other hand in humans after a dose of 2 g curcumin alone, serum levels were
either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher
concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in
bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum
concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no
adverse effects.
Studies on the in vitro absorption of spice principles--curcumin, capsaicin and

piperine in rat intestines.
Suresh D, Srinivasan K. Food Chem Toxicol. 2007 Aug;45(8):1437-42. Epub 2007
Feb 12.
Abstract
A comparative evaluation of the absorbability of three structurally similar and physiologically active
spice principles in an in vitro system consisting of everted rat intestinal sacs was made. When everted
sacs of rat intestines were incubated with 50-1000 microg of curcumin in 10 ml incubation medium,
absorption of the spice principle was maximum at 100 microg concentration. The amount of absorbed
curcumin present in the serosal fluid was negligible. This and the comparatively lower recovery of the
original compound suggested that curcumin to some extent undergoes a modification during
absorption. For similar concentrations of added piperine, about 44-63% of piperine disappeared from
the mucosal side. Absorption of piperine which was maximum at 800 microg per 10 ml was about 63%.
The absolute amounts of piperine absorbed in this in vitro system exceeded the amounts of curcumin.
The absorbed piperine could be traced in both the serosal fluid and in the intestinal tissue, indicating
that piperine did not undergo any metabolic change during the process of absorption. 7-12% of the
absorbed piperine was found in the serosal fluid. When everted sacs of rat intestines were incubated
with 10-500 microg of capsaicin, a maximum of 82-88% absorption could be seen in the lower
concentrations, and the amount of absorbed capsaicin did not proportionately increase at higher
concentrations. A relatively higher percentage of the absorbed capsaicin could be seen in the serosal
fluid as compared to curcumin or piperine. When these spice active principles were associated with
mixed micelles, their in vitro intestinal absorption was relatively higher. Curcumin absorption in everted
intestinal sac increased from 48.7% to 56.1% when the same was present in micelles. In the case of
capsaicin and piperine, increase in absorption was 27.8-44.4% and 43.4-57.4%, respectively, when they
were present in micelles as compared to its native form.
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Ubiquinol
Ubiquinol is superior to ubiquinone to enhance Coenzyme Q10 status in older
men.
Zhang Y , Liu J , Chen XQ , Oliver Chen CY . Food Funct. 2018 Nov 14;9(11):5653-
5659. doi: 10.1039/c8fo00971f.
Abstract
Coenzyme Q10 (CoQ10) exerts its functions in the body through the ability of its benzoquinone head
group to accept and donate electrons. The primary functions are to relay electrons for ATP production in
the electron transport chain and to act as an important lipophilic antioxidant. Ubiquinone, the oxidized
form of CoQ10, is commonly formulated in commercial supplements, and it must be reduced to
ubiquinol to exert CoQ10's functions after consumption. Thus, we aimed to examine whether as
compared to ubiquinone, ubiquinol would be more effective to enhance the CoQ10 status in older men.
We conducted a double-blind, randomized, crossover trial with two 2-week intervention phases and a 2-
week washout between crossovers. Ten eligible older men were randomized to consume either the
ubiquinol or ubiquinone supplement at a dose of 200 mg d-1 with one of the main meals. A total of 4
blood samples were collected after an overnight fast for the determination of ubiquinone and ubiquinol
in plasma and PBMC and the assessment of FRAP, total thiol, and malondialdehyde (MDA) in plasma and
ATP in PBMC. After 2 weeks of the supplementation, the ubiquinol supplement significantly increased
plasma ubiquinone 1.7 fold from 0.2 to 0.6 μmol L-1 and total CoQ10 (the sum of 2 forms) 1.5 fold from
1.3 to 3.4 μmol L-1 (p < 0.05) and tended to increase the plasma ubiquinol status 1.5 fold from 1.1 to 2.8
μmol L-1, but did not alter the ratio of ubiquinol to total CoQ10. The ubiquinone supplement
insignificantly increases plasma ubiquinol, ubiquinone, and total CoQ10 and did not affect the ratio. Of
10 subjects, six were more responsive to the ubiquinol supplement and 2 were more so to the
ubiquinone. The supplementation of both CoQ10 forms did not alter the CoQ10 status in PBMC. FRAP,
total thiol, and MDA in plasma and ATP in PBMC were not changed during the intervention. The
significant increase in plasma CoQ10 status observed after the 2-week supplementation suggested that
ubiquinol appeared to be a better supplemental form to enhance the CoQ10 status than ubiquinone in
older men. Neither ubiquinol nor ubiquinone supplement affected the measured biomarkers of
oxidative stress.
417
Effect of ubiquinol supplementation on biochemical and oxidative stress

indexes after intense exercise in young athletes.
Orlando P, et al. Redox Rep. 2018 Dec;23(1):136-145. doi:
10.1080/13510002.2018.1472924.
Abstract
OBJECTIVES:
Physical exercise significantly impacts the biochemistry of the organism. Ubiquinone is a key component
of the mitochondrial respiratory chain and ubiquinol, its reduced and active form, is an emerging
molecule in sport nutrition. The aim of this study was to evaluate the effect of ubiquinol
supplementation on biochemical and oxidative stress indexes after an intense bout of exercise.
METHODS:
21 male young athletes (26 + 5 years of age) were randomized in two groups according to a double blind
cross-over study, either supplemented with ubiquinol (200 mg/day) or placebo for 1 month. Blood was
withdrawn before and after a single bout of intense exercise (40 min run at 85% maxHR). Physical
performance, hematochemical parameters, ubiquinone/ubiquinol plasma content, intracellular reactive
oxygen species (ROS) level, mitochondrial membrane depolarization, paraoxonase activity and oxidative
DNA damage were analyzed.
RESULTS:
A single bout of intense exercise produced a significant increase in most hematochemical indexes, in
particular CK and Mb while, on the contrary, normalized coenzyme Q10 plasma content decreased
significantly in all subjects. Ubiquinol supplementation prevented exercise-induced CoQ deprivation and
decrease in paraoxonase activity. Moreover at a cellular level, in peripheral blood mononuclear cells,
ubiquinol supplementation was associated with a significant decrease in cytosolic ROS while
mitochondrial membrane potential and oxidative DNA damage remained unchanged.
DISCUSSION:
Data highlights a very rapid dynamic of CoQ depletion following intense exercise underlying an
increased demand by the organism. Ubiquinol supplementation minimized exercise-induced depletion
and enhanced plasma and cellular antioxidant levels but it was not able to improve physical
performance indexes or markers of muscular damage.
418
KEYWORDS:
Intense exercise; mitochondrial function; oxidative stress; paraoxonase activity; peripheral blood
mononuclear cells; physical performance; reactive oxygen species; ubiquinol
A sensitive mass spectrometric assay for mitochondrial CoQ pool redox state
in vivo.
Burger N, et al. Free Radic Biol Med. 2020 Feb 1;147:37-47. doi:
10.1016/j.freeradbiomed.2019.11.028. Epub 2019 Dec 5.
Abstract
Coenzyme Q (CoQ) is an essential cofactor, primarily found in the mitochondrial inner membrane where
it functions as an electron carrier in the respiratory chain, and as a lipophilic antioxidant. The redox state
of the CoQ pool is the ratio of its oxidised (ubiquinone) and reduced (ubiquinol) forms, and is a key
indicator of mitochondrial bioenergetic and antioxidant status. However, the role of CoQ redox state in
vivo is poorly understood, because determining its value is technically challenging due to redox changes
during isolation, extraction and analysis. To address these problems, we have developed a sensitive
liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay that enables us to extract and
analyse both the CoQ redox state and the magnitude of the CoQ pool with negligible changes to redox
state from small amounts of tissue. This will enable the physiological and pathophysiological roles of the
CoQ redox state to be investigated in vivo.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
KEYWORDS:
CoQ(10); CoQ(9); Coenzyme Q; Mass spectrometry; Mitochondria; Oxidative stress; Redox state
Ubiquinol Improves Endothelial Function in Patients with Heart Failure with

Reduced Ejection Fraction: A Single-Center, Randomized Double-Blind
Placebo-Controlled Crossover Pilot Study.
Kawashima C, et al. Am J Cardiovasc Drugs. 2019 Nov 12. doi: 10.1007/s40256-
019-00384-y. [Epub ahead of print]
419
Abstract
BACKGROUND:
Endothelial dysfunction is reportedly associated with worse outcomes in patients with chronic heart
failure. Ubiquinol is a reduced form of coenzyme Q10 (CoQ10) that may improve endothelial function.
OBJECTIVE:
We assessed the hypothesis that ubiquinol improves peripheral endothelial function in patients with
heart failure with reduced ejection fraction (HFrEF).
METHODS:
In this randomized, double-blind, placebo-controlled, crossover pilot study, 14 patients with stable
HFrEF were randomly and blindly allocated to ubiquinol 400 mg/day or placebo for 3 months. After a 1-
month washout period, patients were crossed over to the alternative treatment. Before and after each
treatment, we assessed peripheral endothelial function using the reactive hyperemia index (RHI) and
analyzed it using the natural logarithm of RHI (LnRHI).
RESULTS:
Peripheral endothelial function as assessed by LnRHI tended to improve with ubiquinol 400 mg/day for 3
months (p = 0.076). Original RHI values were also compared, and RHI significantly improved with
ubiquinol treatment (pre-RHI 1.57 [interquartile range (IQR) 1.39-1.80], post-RHI 1.74 [IQR 1.63-2.02],
p = 0.026), but not with placebo (pre-RHI 1.67 [IQR 1.53-1.85], post-RHI 1.51 [IQR 1.39-2.11], p = 0.198).
CONCLUSIONS:
Ubiquinol 400 mg/day for 3 months led to significant improvement in peripheral endothelial function in
patients with HFrEF. Ubiquinol may be a therapeutic option for individuals with HFrEF. Large-scale
randomized controlled trials of CoQ10 supplementation in patients with HFrEF are needed.
420
Ubiquinol (reduced Coenzyme Q10) in patients with severe sepsis or septic

shock: a randomized, double-blind, placebo-controlled, pilot trial.
Donnino MW, et al. Crit Care. 2015 Jul 1;19:275. doi: 10.1186/s13054-015-0989-
3.
Abstract
INTRODUCTION:
We previously found decreased levels of Coenzyme Q10 (CoQ10) in patients with septic shock. The
objective of the current study was to assess whether the provision of exogenous ubiquinol (the reduced
form of CoQ10) could increase plasma CoQ10 levels and improve mitochondrial function.
METHODS:
We performed a randomized, double-blind, pilot trial at a single, tertiary care hospital. Adults (age ≥18
years) with severe sepsis or septic shock between November 2012 and January 2014 were included.
Patients received 200 mg enteral ubiquinol or placebo twice a day for up to seven days. Blood draws
were obtained at baseline (0 h), 12, 24, 48, and 72 h. The primary outcome of the study was change in
plasma CoQ10 parameters (total CoQ10 levels, CoQ10 levels relative to cholesterol levels, and levels of
oxidized and reduced CoQ10). Secondary outcomes included assessment of: 1) vascular endothelial
biomarkers, 2) inflammatory biomarkers, 3) biomarkers related to mitochondrial injury including
cytochrome c levels, and 4) clinical outcomes. CoQ10 levels and biomarkers were compared between
groups using repeated measures models.
RESULTS:
We enrolled 38 patients: 19 in the CoQ10 group and 19 in the placebo group. The mean patient age was
62 ± 16 years and 47% were female. Baseline characteristics and CoQ10 levels were similar for both
groups. There was a significant increase in total CoQ10 levels, CoQ10 levels relative to cholesterol levels,
and levels of oxidized and reduced CoQ10 in the ubiquinol group compared to the placebo group. We
found no difference between the two groups in any of the secondary outcomes.
CONCLUSIONS:
In this pilot trial we showed that plasma CoQ10 levels could be increased in patients with severe sepsis
or septic shock, with the administration of oral ubiquinol. Further research is needed to address
whether ubiquinol administration can result in improved clinical outcomes in this patient population.
421
Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme

Q10 for Parkinson's disease.
Yoritaka A, et al. Parkinsonism Relat Disord. 2015 Aug;21(8):911-6. doi:
10.1016/j.parkreldis.2015.05.022. Epub 2015 May 29.
Abstract
INTRODUCTION:
Mitochondrial complex I deficiencies have been found in post-mortem brains of patients with
Parkinson's disease (PD). Coenzyme Q10 (CoQ10) is the electron acceptor found in complexes I and II,
and is a potent antioxidant. A recent trial of the oxidized form of CoQ10 for PD failed to show benefits;
however, the reduced form of CoQ10 (ubiquinol-10) has shown better neuroprotective effects in animal
models.
METHODS:
Randomized, double-blind, placebo-controlled, parallel-group pilot trials were conducted to assess the
efficacy of ubiquinol-10 in Japanese patients with PD. Participants were divided into two groups: PD
experiencing wearing off (Group A), and early PD, without levodopa (with or without a dopamine
agonist) (Group B). Participants took 300 mg of ubiquinol-10 or placebo per day for 48 weeks (Group A)
or 96 weeks (Group B).
RESULTS:
In Group A, total Unified Parkinson's Disease Rating Scale (UPDRS) scores decreased in the ubiquinol-10
group (n = 14; mean ± SD [-4.2 ± 8.2]), indicating improvement in symptoms. There was a statistically
significant difference (p < 0.05) compared with the placebo group (n = 12; 2.9 ± 8.9). In Group B, UPDRS
increased in the ubiquinol-10 group (n = 14; 3.9 ± 8.0), as well as in the placebo group (n = 8; 5.1 ± 10.3).
CONCLUSIONS:
This is the first report showing that ubiquinol-10 may significantly improve PD with wearing off, as
judged by total UPDRS scores, and that ubiquinol-10 is safe and well tolerated.
422
Myocardial energetics and ubiquinol in diastolic heart failure.

Bates A, Shen Q, Hiebert JB, Thimmesch A, Pierce JD. Nurs Health Sci. 2014
Dec;16(4):428-33. doi: 10.1111/nhs.12168. Epub 2014 Sep 28.
Abstract
Diastolic heart failure, or heart failure with preserved ejection fraction, is a leading cause of morbidity
and mortality. There are no current therapies effective in improving outcomes for these patients. The
aim of this article is to review the literature and examine the role of coenzyme Q10 in heart failure with
preserved ejection fraction related to mitochondrial synthesis of adenosine triphosphate and reactive
oxygen species production. The study results reflect that myocardial energetics alters in diastolic heart
failure and that there is defective energy metabolism and increased oxidative stress. Studies are
emerging to evaluate coenzyme Q10 , particularly ubiquinol, as a supplemental treatment for heart-
failure patients. In diastolic heart-failure patients, clinicians are beginning to use supplemental therapies
to improve patient outcomes, and one promising complementary treatment to improve left ventricular
diastolic function is ubiquinol. Additional studies are needed using large-scale randomized models to
confirm if ubiquinol would be beneficial. Since ubiquinol is an antioxidant and is required for adenosine
triphosphate production, clinicians and health scientists should be aware of the potential role of this
supplement in the treatment of diastolic heart failure.
© 2014 Wiley Publishing Asia Pty Ltd.
KEYWORDS:
ATP; HFpEF; coronary artery disease; heart disease; myocardial energetics; ubiquinol
Combining Ubiquinol With a Statin May Benefit Hypercholesterolaemic

Patients With Chronic Heart Failure.
Kloer HU, Belardinelli R, Ruchong O, Rosenfeldt F. Heart Lung Circ. 2020
Feb;29(2):188-195. doi: 10.1016/j.hlc.2019.08.017. Epub 2019 Sep 20.
Abstract
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Heart failure (HF) is one of the most common causes of death in Western society. Recent results
underscore the utility of coenzyme Q10 (CoQ10) addition to standard medications in order to reduce
mortality and to improve quality of life and functional capacity in chronic heart failure (CHF). The
rationale for CoQ10 supplementation in CHF is two-fold. One is the well-known role of CoQ10 in
myocardial bioenergetics, and the second is its antioxidant property. Redox balance is also improved by
oral supplementation of CoQ10, and this effect contributes to enhanced endothelium-dependent
relaxation. Previous reports have shown that CoQ10 concentration is decreased in myocardial tissue in
CHF and by statin therapy, and the greater the CoQ10 deficiency the more severe is the
cardiocirculatory impairment. In patients with CHF and hypercholesterolaemia being treated with
statins, the combination of CoQ10 with a statin may be useful for two reasons: decreasing skeletal
muscle injury and improving myocardial function. Ubiquinol, the active reduced form of CoQ10,
presents higher bioavailability than the oxidised form ubiquinone, and should be the preferred form to
be added to a statin. The combination ezetimibe/simvastatin may have advantages over single statins.
Since ezetimibe reduces absorption of cholesterol and does not affect CoQ10 synthesis in the liver, the
impact of this combination on CoQ10 tissue levels will be much less than that of high dose statin
monotherapy at any target low density lipoprotein-cholesterol (LDL-C) level to be reached. This
consideration makes the ezetimibe/statin combination the ideal LDL-lowering agent to be combined
with ubiquinol in CHF patients. However, particular caution is advisable with the use of strategies of
extreme lowering of cholesterol that may negatively impact on myocardial function. All in all there is a
strong case for considering co-administration of ubiquinol with statin therapy in patients with depressed
or borderline myocardial function.
Copyright © 2019. Published by Elsevier B.V.
KEYWORDS:
Cholesterol; Coenzyme Q(10); Heart failure; Statin
Vitamin D3
Dietary vitamin D3 deficiency alters intestinal mucosal defense and increases
susceptibility to Citrobacter rodentium-induced colitis
Natasha R. Ryz, et al. Am J Physiol Gastrointest Liver Physiol. 2015 Nov 1; 309(9):
G730–G742. Published online 2015 Sep 3. doi: 10.1152/ajpgi.00006.2015
424
Abstract
Vitamin D deficiency affects more that 1 billion people worldwide. Although thought to increase risk of
bacterial infections, the importance of vitamin D on host defense against intestinal bacterial pathogens
is currently unclear since injection of the active form of vitamin D, 1,25(OH)2D3, increased susceptibility
to the enteric bacterial pathogen Citrobacter rodentium by suppressing key immune/inflammatory
factors. To further characterize the role of vitamin D during bacteria-induced colitis, we fed weanling
mice either vitamin D3-deficient or vitamin D3-sufficient diets for 5 wk and then challenged them with
C. rodentium. Vitamin D3-deficient mice lost significantly more body weight, carried higher C. rodentium
burdens, and developed worsened histological damage. Vitamin D3-deficient mice also suffered greater
bacterial translocation to extra-intestinal tissues, including mesenteric lymph nodes, spleen, and liver.
Intestinal tissues of infected vitamin D3-deficient mice displayed increased inflammatory cell infiltrates
as well as significantly higher gene transcript levels of inflammatory mediators TNF-α, IL-1β, IL-6, TGF-β,
IL-17A, and IL-17F as well as the antimicrobial peptide REG3γ. Notably, these exaggerated inflammatory
responses accelerated the loss of commensal microbes and were associated with an impaired ability to
detoxify bacterial lipopolysaccharide. Overall, these studies show that dietary-induced vitamin D
deficiency exacerbates intestinal inflammatory responses to infection, also impairing host defense.
Keywords: vitamin D, Citrobacter rodentium, inflammation, colitis, segmented filamentous bacteria
RESULTS
Vitamin D3-deficient mice are more susceptible to C. rodentium infection, carrying higher cecal and
extraintestinal pathogen burdens.
To determine the role of vitamin D3 during enteric infection, we first fed weanling mice either a vitamin
D3-deficient (0 IU) or vitamin D3-sufficient (1,000 IU) diets for 5 wk. There was no difference in food
intake or body weight between the two groups during the 5-wk feeding trial (data not shown). Dietary
vitamin D3 is converted in the liver into 25(OH)D3, which is the major circulating form of vitamin D in
the body and used to assess vitamin D status. After 5 wk, vitamin D3-deficient mice had significantly
lower levels of serum 25(OH)D3, compared with vitamin D3-sufficient mice (Fig. 1A), in agreement with
previous studies (3, 35). Vitamin D also plays an important role in regulating calcium metabolism in the
body, and supplemental dietary calcium has previously been shown to protect against C. rodentium
infection (40, 50), but we found no difference in serum calcium between the diet groups (Fig. 1B),
similar to findings by Lagishetty et al. (35), whose feeding protocol (including diet manufacturer) we
replicated.
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Investigating Transdermal Delivery of Vitamin D3

Ahmed Alsaqr, Mohammed Rasoully, and Florin Marcel Musteat. AAPS
PharmSciTech. 2015 Aug; 16(4): 963–972. Published online 2015 Jan 22. doi:
10.1208/s12249-015-0291-3
Abstract
Transdermal delivery of therapeutic amounts of vitamin D3 is proposed to overcome its variable oral
bioavailability, especially for people who suffer from fat malabsorption. The main challenge for this
delivery route is to overcome the barrier properties of skin, especially for very lipophilic compounds
such as vitamin D3. In this study, the effect of different penetration enhancers, such as oleic acid,
dodecylamine, ethanol, oleic acid in propylene glycol, isopropyl myristate, octyldodecanol, and oleyl
alcohol in propylene glycol were evaluated in vitro for their effectiveness in delivering vitamin D3
through polyamide filter, polydimethylsiloxane membrane, and porcine skin. A diffusion cell was used to
study the transdermal permeability of vitamin D3. Ointment formulations of vitamin D3 were prepared
containing the most widely used penetration enhancers, oleic acid, and dodecylamine. The ointment
containing oleic acid as chemical penetration enhancer did not improve delivery compared to control.
On the other hand, the formulation containing dodecylamine as a penetration enhancer did improve the
transdermal delivery of vitamin D3. However, statistical significance and an amount high enough for
nutritional supplementation purposes were reached only when the skin was pretreated with 50%
ethanol. In these conditions, the ointment delivered an amount of 760-ng vitamin D3 per cm2 of skin.
The research shows promise that transdermal delivery could be an effective administration route for
vitamin D3 when ethanol and dodecylamine are used as penetration enhancers.
KEY WORDS: dodecylamine, ethanol, penetration enhancer, transdermal delivery, vitamin D3
CONCLUSIONS
This study sought to investigate transdermal delivery of vitamin D3 by using different chemical
penetration enhancers. To our best knowledge, this is the first report investigating quantitatively the
transdermal delivery of vitamin D3, which opens the prospect for further research regarding this
delivery route for vitamin D3. Combining dodecylamine and ethanol as penetration enhancers
significantly improved the transdermal delivery of vitamin D3 when compared to the control
formulation. Based on the recommended daily dose of vitamin D3 (400 IU or 10 μg) and the results of
this study, delivery of the recommended daily dose could potentially be achieved by covering a surface
of skin of 3.6 ×3.6 cm with vitamin D3 ointment containing both ethanol and dodecylamine. Although
these results have only been demonstrated for porcine skin, it is possible that similar results will be
obtained in vivo in humans since porcine skin is known to be the best alternative to human skin for in
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vitro testing of transdermal delivery. This research suggests that transdermal delivery could be an
effective way for humans to receive the recommended daily dose of vitamin D3. Transdermal delivery of
vitamin D3 could be especially helpful for people who suffer from fat malabsorption.
UVB Exposure of Farm Animals: Study on a Food-Based Strategy to Bridge the

Gap between Current Vitamin D Intakes and Dietary Targets
Alexandra Schutkowsk, et al. PLoS One. 2013; 8(7): e69418. Published online 2013
Jul 24. doi: 10.1371/journal.pone.0069418
Abstract
Vitamin D deficiency is a global health problem. This study aimed to investigate the efficacy of
ultraviolet (UV) B radiation for improving vitamin D3 content of eggs and meat. In a two-factorial design
hens that received diets with 0 (-D3) or 3,000 IU (+D3) vitamin D3/kg were non-exposed (-UVB) or
exposed to UVB radiation (+UVB) for 3 h daily over 4 weeks. Data show that UVB radiation was very
effective in raising the vitamin D3 content of egg yolk and meat. Egg yolk from +UVB/−D3 hens had a
higher vitamin D3 content (17.5±7.2 µg/100 g dry matter (DM)) than those from the –UVB/+D3 group
(5.2±2.4 µg/100 g DM, p<0.01). Vitamin D3 content in egg yolk of vitamin D3-supplemented hens could
be further increased by UVB radiation (32.4±10.9 µg/100 g DM). The content of 25-hydroxyvitamin D3
(25(OH)D3) in the egg yolk also increased in response to UVB, although less pronounced than vitamin
D3. Meat revealed about 4-fold higher vitamin D3 contents in response to UVB than to dietary vitamin
D3 (p<0.001). In conclusion, exposure of hens to UVB is an efficient approach to provide consumers with
vitamin D3-enriched foods from animal sources.
Conclusions
In conclusion, the current study shows that UVB exposure of chickens that ensures irradiation of the
whole body, including legs, is highly effective in increasing the vitamin D concentration in eggs, and also
meat. We therefore consider UVB treatment of farmed animals as an effective and novel approach for
“bio-addition” of foods with vitamin D. Considering the option that free-ranged chickens are still
exposed to natural sun light, free-range husbandry could become a cheap alternative to the artificial
UVB irradiation to produce vitamin D3 fortified eggs.
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Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on

Progression-Free Survival Among Patients With Advanced or Metastatic
Colorectal Cancer
The SUNSHINE Randomized Clinical Trial

Kimmie Ng, MD, MPH, et al. JAMA. 2019 Apr 9; 321(14): 1370–1379. Published
online 2019 Apr 9. doi: 10.1001/jama.2019.2402
Key Points
Question
Does high-dose vitamin D3 supplementation prolong progression-free survival when added to standard
chemotherapy in patients with advanced or metastatic colorectal cancer?
Findings
In this phase 2 randomized clinical trial that included 139 patients with advanced or metastatic
colorectal cancer, treatment with chemotherapy plus high-dose vitamin D3 supplementation vs
chemotherapy plus standard-dose vitamin D3 resulted in a median progression-free survival of 13
months vs 11 months, respectively, that was not statistically significant, but a multivariable hazard ratio
of 0.64 for progression-free survival or death that was statistically significant.
Meaning
These findings regarding a potential role for high-dose vitamin D3 supplementation in the treatment of
patients with advanced or metastatic colorectal cancer warrant further evaluation in a larger
multicenter randomized clinical trial.
Abstract
Importance
In observational studies, higher plasma 25-hydroxyvitamin D (25[OH]D) levels have been associated with
improved survival in metastatic colorectal cancer (CRC).
Objective
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To determine if high-dose vitamin D3 added to standard chemotherapy improves outcomes in patients

with metastatic CRC.
Design, Setting, and Participants
Double-blind phase 2 randomized clinical trial of 139 patients with advanced or metastatic CRC
conducted at 11 US academic and community cancer centers from March 2012 through November 2016
(database lock: September 2018).
Interventions
mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D3 (n = 69) or
standard-dose vitamin D3 (n = 70) daily until disease progression, intolerable toxicity, or withdrawal of
consent.
Main Outcomes and Measures
The primary end point was progression-free survival (PFS) assessed by the log-rank test and a supportive
Cox proportional hazards model. Testing was 1-sided. Secondary end points included tumor objective
response rate (ORR), overall survival (OS), and change in plasma 25(OH)D level.
Results
Among 139 patients (mean age, 56 years; 60 [43%] women) who completed or discontinued
chemotherapy and vitamin D3 (median follow-up, 22.9 months), the median PFS for high-dose vitamin
D3 was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS
events) for standard-dose vitamin D3 (log-rank P = .07); multivariable hazard ratio for PFS or death was
0.64 (1-sided 95% CI, 0 to 0.90; P = .02). There were no significant differences between high-dose and
standard-dose vitamin D3 for tumor ORR (58% vs 63%, respectively; difference, −5% [95% CI, −20% to
100%], P = .27) or OS (median, 24.3 months vs 24.3 months; log-rank P = .43). The median 25(OH)D level
at baseline for high-dose vitamin D3 was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D3
(difference, −2.6 ng/mL [95% CI, −6.6 to 1.4], P = .30); at first restaging, 32.0 ng/mL vs 18.7 ng/mL
(difference, 12.8 ng/mL [95% CI, 9.0 to 16.6], P < .001); at second restaging, 35.2 ng/mL vs 18.5 ng/mL
(difference, 16.7 ng/mL [95% CI, 10.9 to 22.5], P < .001); and at treatment discontinuation, 34.8 ng/mL
vs 18.7 ng/mL (difference, 16.2 ng/mL [95% CI, 9.9 to 22.4], P < .001). The most common grade 3 and
higher adverse events for chemotherapy plus high-dose vs standard-dose vitamin D3 were neutropenia
(n = 24 [35%] vs n = 21 [31%], respectively) and hypertension (n = 9 [13%] vs n = 11 [16%]).
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Conclusions and Relevance
Among patients with metastatic CRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to
standard chemotherapy resulted in a difference in median PFS that was not statistically significant, but
with a significantly improved supportive hazard ratio. These findings warrant further evaluation in a
larger multicenter randomized clinical trial.
Effect of calcium phosphate and vitamin D3 supplementation on bone

remodelling and metabolism of calcium, phosphorus, magnesium and iron
Ulrike Trautvetter, et al. Nutr J. 2014; 13: 6. Published online 2014 Jan 17. doi:
10.1186/1475-2891-13-6
Abstract
Background
The aim of the present study was to determine the effect of calcium phosphate and/or vitamin D3 on
bone and mineral metabolism.
Methods
Sixty omnivorous healthy subjects participated in the double-blind, placebo-controlled parallel designed
study. Supplements were tricalcium phosphate (CaP) and cholecalciferol (vitamin D3). At the beginning
of the study (baseline), all subjects documented their normal nutritional habits in a dietary record for
three successive days. After baseline, subjects were allocated to three intervention groups: CaP
(additional 1 g calcium/d), vitamin D3 (additional 10 μg/d) and CaP + vitamin D3. In the first two weeks,
all groups consumed placebo bread, and afterwards, for eight weeks, the test bread according to the
intervention group. In the last week of each study period (baseline, placebo, after four and eight weeks
of intervention), a faecal (three days) and a urine (24 h) collection and a fasting blood sampling took
place. Calcium, phosphorus, magnesium and iron were determined in faeces, urine and blood. Bone
formation and resorption markers were analysed in blood and urine.
Results
After four and eight weeks, CaP and CaP + vitamin D3 supplementations increased faecal excretion of
calcium and phosphorus significantly compared to placebo. Due to the vitamin D3 supplementations
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(vitamin D3, CaP + vitamin D3), the plasma 25-(OH)D concentration significantly increased after eight
weeks compared to placebo. The additional application of CaP led to a significant increase of the 25-
(OH)D concentration already after four weeks. Bone resorption and bone formation markers were not
influenced by any intervention.
Conclusions
Supplementation with daily 10 μg vitamin D3 significantly increases plasma 25-(OH)D concentration. The
combination with daily 1 g calcium (as CaP) has a further increasing effect on the 25-(OH)D
concentration. Both CaP alone and in combination with vitamin D3 have no beneficial effect on bone
remodelling markers and on the metabolism of calcium, phosphorus, magnesium and iron.
Cholecalciferol (Vitamin D3) Improves Myelination and Recovery after Nerve

Injury
Jean-Francois Chabas, et al. PLoS One. 2013; 8(5): e65034.Published online 2013
May 31. doi: 10.1371/journal.pone.0065034
Abstract
Previously, we demonstrated i) that ergocalciferol (vitamin D2) increases axon diameter and potentiates
nerve regeneration in a rat model of transected peripheral nerve and ii) that cholecalciferol (vitamin D3)
improves breathing and hyper-reflexia in a rat model of paraplegia. However, before bringing this
molecule to the clinic, it was of prime importance i) to assess which form – ergocalciferol versus
cholecalciferol – and which dose were the most efficient and ii) to identify the molecular pathways
activated by this pleiotropic molecule. The rat left peroneal nerve was cut out on a length of 10 mm and
autografted in an inverted position. Animals were treated with either cholecalciferol or ergocalciferol, at
the dose of 100 or 500 IU/kg/day, or excipient (Vehicle), and compared to unlesioned rats (Control).
Functional recovery of hindlimb was measured weekly, during 12 weeks, using the peroneal functional
index. Ventilatory, motor and sensitive responses of the regenerated axons were recorded and
histological analysis was performed. In parallel, to identify the genes regulated by vitamin D in dorsal
root ganglia and/or Schwann cells, we performed an in vitro transcriptome study. We observed that
cholecalciferol is more efficient than ergocalciferol and, when delivered at a high dose (500 IU/kg/day),
cholecalciferol induces a significant locomotor and electrophysiological recovery. We also demonstrated
that cholecalciferol increases i) the number of preserved or newly formed axons in the proximal end, ii)
the mean axon diameter in the distal end, and iii) neurite myelination in both distal and proximal ends.
Finally, we found a modified expression of several genes involved in axogenesis and myelination, after
24 hours of vitamin supplementation. Our study is the first to demonstrate that vitamin D acts on
431
myelination via the activation of several myelin-associated genes. It paves the way for future
randomised controlled clinical trials for peripheral nerve or spinal cord repair.
Conclusion
In a previous study, we demonstrated that ergocalciferol potentiates axon regeneration. We show here
that cholecalciferol is more efficient than ergocalciferol, inducing a functional recovery reaching control-
like values, and, even at a high dose, is non-toxic for the treated rats. We also unveil calcitriol-regulated
genes that play a role in axogenesis and myelination. Altogether, our data pave the way for a
randomised controlled trial in patients with a peripheral nerve injury.
Efficacy of vitamin D3 supplementation in reducing incidence of pulmonary

tuberculosis and mortality among HIV-infected Tanzanian adults initiating
antiretroviral therapy: study protocol for a randomized controlled trial
Christopher R. Sudfeld, et al. Trials. 2017; 18: 66. Published online 2017 Feb 10.
doi: 10.1186/s13063-017-1819-5
Abstract
Background
HIV-infected adults initiating antiretroviral therapy (ART) in sub-Saharan Africa continue to experience
high rates of morbidity and mortality during the initial months of treatment. Observational studies in
high-income and resource-limited settings indicate that HIV-infected adults with low vitamin D levels
may be at increased risk of mortality, HIV disease progression, and incidence of pulmonary tuberculosis
(TB). As a result, vitamin D3 supplementation may improve survival and treatment outcomes for HIV-
infected adults initiating ART.
Methods/Design
The Trial of Vitamins-4 (ToV4) is an individually randomized, double-blind, placebo-controlled trial of

vitamin D3 (cholecalciferol) supplementation conducted among 4000 HIV-infected adults with low
vitamin D levels [25-hydroxyvitamin D (25(OH)D) <30 ng/mL] initiating ART in Dar es Salaam, Tanzania.
The two primary aims of the trial are to determine the effect of a vitamin D3 supplementation regimen
on incidence of (1) mortality and (2) pulmonary TB as compared to a matching placebo regimen. The
primary safety outcome of the study is incident hypercalcemia. The investigational vitamin D3 regimen
consists of oral supplements containing 50,000 IU vitamin D3 taken under direct observation at
randomization and once a week for 3 weeks (four doses) followed by daily oral supplements containing
2000 IU vitamin D3 taken at home from the fourth week until trial discharge at 1 year post ART
432
initiation. Trial participants are followed up at weekly clinic visits during the first month of ART and at
monthly clinic visits thereafter until trial discharge at 1 year post ART initiation. Secondary aims of the
trial are to examine the effect of the vitamin D3 regimen on CD4 T cell reconstitution, incidence of non-
TB comorbidities, body mass index (BMI), depression and anxiety, physical activity, bone health, and
immunologic biomarkers.
Discussion
The ToV4 will provide causal evidence on the effect of vitamin D3 supplementation on incidence of
pulmonary TB and mortality among HIV-infected Tanzanian adults initiating ART. The trial will also give
insight to whether vitamin D3 supplementation trials for the prevention of pulmonary TB should be
pursued in HIV-uninfected populations.
Vitamin K2
Effect of vitamin K2 on type 2 diabetes mellitus: A review.
Li Y, Chen JP, Duan L, Li S. Diabetes Res Clin Pract. 2018 Feb;136:39-51. doi:
10.1016/j.diabres.2017.11.020. Epub 2017 Dec 2.
Abstract
Type 2 diabetes mellitus (T2DM) continue to be a major public health problem around the world that
frequently presents with microvascular and macrovascular complications. Individuals with T2DM are not
only suffering from significant emotional and physical misery, but also at increased risk of dying from
severe complications. In recent years, evidence from prospective observational studies and clinical trials
has shown T2DM risk reduction with vitamin K2 supplementation. We thus did an overview of currently
available studies to assess the effect of vitamin K2 supplementation on insulin sensitivity, glycaemic
control and reviewed the underlying mechanisms. We proposed that vitamin K2 improved insulin
sensitivity through involvement of vitamin K-dependent-protein osteocalcin, anti-inflammatory
properties, and lipid-lowering effects. Vitamin K2 had a better effect than vitamin K1 on T2DM. The
interpretation of this review will increase comprehension of the development of a therapeutic strategy
to prevent and treat T2DM.
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KEYWORDS:
Adiponectin; Diabetes mellitus, type 2; Inflammation; Insulin resistance; Osteocalcin; Vitamin K2
Regulation of bone remodeling by vitamin K2.

Myneni VD, Mezey E. Oral Dis. 2017 Nov;23(8):1021-1028. doi:
10.1111/odi.12624. Epub 2017 Apr 5.
Abstract
All living tissues require essential nutrients such as amino acids, fatty acids, carbohydrates, minerals,
vitamins, and water. The skeleton requires nutrients for development, maintaining bone mass and
density. If the skeletal nutritional requirements are not met, the consequences can be quite severe. In
recent years, there has been growing interest in promotion of bone health and inhibition of vascular
calcification by vitamin K2. This vitamin regulates bone remodeling, an important process necessary to
maintain adult bone. Bone remodeling involves removal of old or damaged bone by osteoclasts and its
replacement by new bone formed by osteoblasts. The remodeling process is tightly regulated, when the
balance between bone resorption and bone formation shifts to a net bone loss results in the
development of osteoporosis in both men and women. In this review, we focus on our current
understanding of the effects of vitamin K2 on bone cells and its role in prevention and treatment of
osteoporosis.
Published 2016. This article is a U.S. Government work and is in the public domain in the USA.
KEYWORDS:
bone remodeling; osteocalcin; osteoporosis; vitamin K2
Vitamin K2 in bone metabolism and osteoporosis.

Plaza SM, Lamson DW. Altern Med Rev. 2005 Mar;10(1):24-35.
434
Abstract
This article covers in vitro, in vivo, and human data on the positive effect of vitamin K2 on osteoporosis.
Data is available on vitamin K2 for osteoporosis caused by a number of conditions, including
postmenopausal osteoporosis, Parkinson's disease, biliary cirrhosis, stroke, and drug-induced
osteoporosis. The activity of vitamin K2 involves both an increase in the bone-building process and a
separate decrease in the bone-loss process. Vitamin K2 exerts a more powerful influence on bone than
vitamin K1, and should be considered for prevention or treatment in those conditions known to
contribute to osteoporosis.
Vitamin K2 Status and Arterial Stiffness Among Untreated Migraine Patients: A

Case-Control Study.
Mansour AG, et al. Headache. 2019 Nov 25. doi: 10.1111/head.13715. [Epub
ahead of print]
Abstract
OBJECTIVE:
We aimed to examine arterial stiffness and vitamin K2 status in migraine subjects by comparison to
controls.
BACKGROUND:
Migraine is a primary headache disorder that has been associated with an increased risk of
cardiovascular events. Mechanisms underlying this increased risk, however, remain unclear. Vitamin K2
deficiency emerged as a cardiovascular risk factor, but vitamin K2 status has never been explored in
migraine subjects.
DESIGN AND METHODS:
This is a case-control, single-center, observational study that includes a cohort of subjects with migraine
and their age- and sex-matched controls. Arterial stiffness was measured using carotid-femoral pulse
wave velocity (cfPWV). Dephosphorylated-uncarboxylated matrix-Gla-protein (dp-ucMGP) was used as a
marker for vitamin K2 status. A propensity-matched scoring method was used.
RESULTS:
435
A total of 146 patients (73 matched pairs) were included in this study, of whom 89% were women with a
mean age of 31.9 ± 8.4 years. Compared with controls, migraine patients had statistically significantly
higher mean cfPWV (7.2 ± 1.1 vs 6.4 ± 0.8 m/s, 95% confidence interval (CI) of mean difference [0.45,
1.08], P < .001), as well as higher dp-ucMGP (454.3 ± 116.7 pmol/L vs 379.8 ± 126.6 pmol/L, 95% CI of
mean difference [34.63, 114.31], P < .001). Higher cfPWV was associated with higher dp-ucMGP
concentrations only in the migraine with aura (MWA) group. Moreover, migraine subjects had a higher
frequency of vitamin K2 deficiency (dp-ucMGP ≥ 500 pmol/L) compared to controls, but this association
was not statistically significant (23/73 [31.5%] vs 16/73 [21.9%], P = .193).
CONCLUSIONS:
Individuals with migraine have worse indices of arterial stiffness as compared with their age- and sex-
matched control subjects. This increase in arterial stiffness is associated with an increase in markers of
vitamin K2 deficiency in the MWA group.
© 2019 American Headache Society.
KEYWORDS:
arterial stiffness; matrix Gla protein; migraine; migraine with aura; pulse wave velocity; vitamin K2
Therapeutic effects of systemic vitamin k2 and vitamin d3 on gingival

inflammation and alveolar bone in rats with experimentally induced
periodontitis.
Aral K, et al. J Periodontol. 2015 May;86(5):666-73. doi:
10.1902/jop.2015.140467. Epub 2015 Jan 8.
Abstract
BACKGROUND:
The synergistic effects of vitamin D3 and vitamin K2 on bone loss prevention have been reported. This
study evaluates the effects of vitamin D3 and vitamin K2 supplementation in conjunction with
conventional periodontal therapy (scaling and root planing [SRP]) on gingival interleukin (IL)-1β and IL-
10, serum bone alkaline phosphatase (B-ALP) and tartrate-resistant acid phosphatase 5b (TRAP-5b), and
calcium and alveolar bone levels in rats with experimentally induced periodontitis.
436
METHODS:
Seventy-two rats were divided into the following groups: 1) healthy; 2) periodontitis; 3) SRP; 4) SRP +
vitamin D3; 5) SRP + vitamin K2; and 6) SRP + vitamins K2 and D3. Periodontitis was induced by ligature
placement for 7 days, and vitamin K2 (30 mg/kg) and/or vitamin D3 (2 μg/kg) were administered for 10
days in the SRP + vitamin D3, SRP + vitamin K2, and SRP + vitamins K2 and D3 groups by oral gavage. On
day 18, the animals were sacrificed, serum B-ALP, TRAP-5b, and calcium levels were measured, gingiva
specimens were extracted for IL-1β and IL-10 analysis, and distances between the cemento-enamel
junction and alveolar bone crest were evaluated.
RESULTS:
Alveolar bone levels in the periodontitis group were significantly greater than those in the other five
groups. No significant differences were found in gingival IL-1β and IL-10, serum B-ALP and TRAP-5b, and
calcium and alveolar bone levels between the groups receiving SRP and vitamins and the group receiving
SRP alone.
CONCLUSION:
Within the limitations of this study, vitamin D3 and K2 alone or in combination did not affect gingival IL-
1β and IL-10, serum B-ALP and TRAP-5b levels, or alveolar bone compared with conventional
periodontal therapy alone.
KEYWORDS:
Biological markers; cholecalciferol; cytokines; periodontitis; vitamin K 2.
Treatment with vitamin D3 and/or vitamin K2 for postmenopausal

osteoporosis.
Iwamoto J, Takeda T, Ichimura S. Keio J Med. 2003 Sep;52(3):147-50.
Abstract
It is established in Japan that treatment with 1alpha-hydroxyvitamin D3 (alfacalcidol) slightly reduces

bone turnover, sustains lumbar bone mineral density (BMD), and prevents osteoporotic vertebral
437
fractures in postmenopausal women with osteoporosis, while vitamin K2 (menatetrenone) enhances

gamma-carboxylation of bone glutamic acid residues and secretion of osteocalcin, sustains lumbar BMD,
and prevents osteoporotic fractures in patients with osteoporosis. Available evidence suggests that the
effect of vitamin K2 on mineralization by human periosteal osteoblasts is enhanced in the presence of
1,25 dihydroxyvitamin D3 in vitro. The effect of vitamin K2 on BMD in ovariectomized rats is affected by
the plasma 25-hydroxyvitamin D3 level in vivo, and is significant only when rats are fed a diet containing
vitamin D3. Based on this line of evidence, combined treatment with alfacalcidol and menatetrenone for
osteoporosis is surmised to be more effective than treatment with menatetrenone alone, and may have
anabolic effects on osteoporotic bone. This combined treatment may increase bone formation as well as
bone resorption over the mild anti-resorptive effect of alfacalcidol itself, and shows the greatest effect
on lumbar BMD or the incidence of vertebral fractures in studies in which the mean age and years since
menopause of subjects were low and the degree of osteoporosis was mild. It may be effective for mild
postmenopausal osteoporosis in which age-related deterioration of trabecular bone properties remains
below the threshold for vertebral fractures, even if bone resorption is increased and trabecular bone has
deteriorated.
White Willow Bark

Natural or Plant Products for the Treatment of Neurological Disorders: Current
Knowledge.
10.2174/1389200218666170710190249.
Abstract
BACKGROUND:
METHOD:
438

CONCLUSION:
KEYWORDS:

10.1097/BRS.0000000000001310.
Abstract
STUDY DESIGN:
OBJECTIVES:
439
METHODS:
RESULTS:
CONCLUSIONS:
A commercialized dietary supplement alleviates joint pain in community adults: a

double-blind, placebo-controlled community trial.
Abstract
BACKGROUND:
METHODS:
440
RESULTS:
interaction effect P = 0.027; ssffness score, ↓30% versus ↓12%, respecsvely, interacson effect
CONCLUSIONS:

Med. 2013;20(4):800-2.
Abstract
INTRODUCTION:
441
population.
AIM:
rheumatic diseases.
RESULTS:
CONCLUSION:
Willow Bark: Nature’s Aspirin

January 9, 2017 — Written by Rena Goldman and Kathryn Watson.
Healthline.com.
https://www.healthline.com/health/willow-bark-natures-aspirin
Willow bark, the bark of several varieties of willow tree, has been used for centuries as a pain reliever.
The active ingredient in the medicine made from willow bark is called salicin.
Some people use willow bark as an alternative to aspirin, particularly those that experience chronic
headaches or back pain. Willow bark is also used in some products to aid weight loss.
442
It comes from the branches of 2- to 3-year-old willow trees. Willow trees and shrubs grow all over the
world, except for Australia and Antarctica. The white willow and black willow are two of the most
common willows that are used medicinally.
Bioaccessibility in vitro of nutraceuticals from bark of selected Salix species.

Gawlik-Dziki U, Sugier D, Dziki D, Sugier P. ScientificWorldJournal. 2014 Feb
17;2014:782763. doi: 10.1155/2014/782763. eCollection 2014.
Abstract
The aim of this study was to investigate and to compare the extractability, bioaccessibility, and
bioavailability in vitro of antioxidative compounds from bark of selected Salix species: S. alba (SA), S.
daphnoides (SD), S. purpurea (SP), and S. daphnoides x purpurea (SDP) hybrid willow clones originating
from their natural habitats and cultivated on the sandy soil. The highest amount of phenolic glycosides
was found in the bark of SDP and SD. The best source of phenolics was bark of SDP. The highest content
of flavonoids were found in SD bark samples, whereas the highest concentration of bioaccessible and
bioavailable phenolic acids was determined in SDP bark. Bark of all tested Salix species showed
significant antiradical activity. This properties are strongly dependent on extraction system and genetic
factors. Regardless of Salix genotypes, the lowest chelating power was found for chemically-extractable
compounds. Bark of all Salix species contained ethanol-extractable compounds with reducing ability.
Besides this, high bioaccessibility and bioavailability in vitro of Salix bark phytochemicals were found.
Obtained results indicate that extracts from bark tested Salix genotypes can provide health promoting
benefits to the consumers; however, this problem requires further study.
Efficacy and Safety of White Willow Bark (Salix alba) Extracts.

Shara M, Stohs SJ. Phytother Res. 2015 Aug;29(8):1112-6. doi: 10.1002/ptr.5377.
Epub 2015 May 22.
Abstract
Willow bark extract has been used for thousands of years as an anti-inflammatory, antipyretic, and
analgesic. In spite of its long history of use, relatively few human and animal studies have been
published that confirm anecdotal observations. A small number of clinical studies have been conducted
that support the use of willow bark extracts in chronic lower back and joint pain and osteoarthritis.
Willow bark extracts also are widely used in sports performance and weight loss products presumably
because of anti-inflammatory and analgesic activities, although no human studies have been published
that specifically and directly document beneficial effects. In recent years, various in vitro and animal
443
studies have demonstrated that the anti-inflammatory activity of willow bark extract is associated with
down regulation of the inflammatory mediators tumor necrosis factor-α and nuclear factor-kappa B.
Although willow bark extracts are generally standardized to salicin, other ingredients in the extracts
including other salicylates as well as polyphenols, and flavonoids may also play prominent roles in the
therapeutic actions. Adverse effects appear to be minimal as compared to non-steroidal anti-
inflammatory drugs including aspirin. The primary cause for concern may relate to allergic reactions in
salicylate-sensitive individuals.
A systematic review on the effectiveness of willow bark for musculoskeletal pain.

Vlachojannis JE, Cameron M, Chrubasik S. Phytother Res. 2009 Jul;23(7):897-900.
doi: 10.1002/ptr.2747.
Abstract
Since ancient times preparations from Salix species have been used to alleviate pain. The aim of this
study was to update the evidence of the effectiveness of willow bark products in the treatment of
musculoskeletal pain. OVID(MEDLINE), PUBMED, Silverplatter, and CENTRAL and manual searches were
used to identify clinical trials investigating Salix preparations. Authors SC and JEV extracted the data
independently and discussed disagreements. Seven manuscripts were identified, reporting four trials
with confirmatory and four with exploratory study designs. Three manuscripts presented the same trial
data: repetitious reports were excluded. One confirmatory and two exploratory studies indicate a dose-
dependent analgesic effect not inferior to rofecoxib in patients with low back pain. In one exploratory
and one confirmatory study conflicting results were achieved in participants with osteoarthritis. No
significant effect was seen in a confirmatory study in patients with rheumatoid arthritis, but this study
was grossly underpowered. All studies investigated ethanolic extracts with daily doses up to 240 mg
salicin over periods of up to six weeks. Minor adverse events occurred during treatment. The review
provides moderate evidence of effectiveness for the use of ethanolic willow bark extract in low back
pain. Further studies are required to find out if treatment of osteoarthritis and rheumatoid arthritis
requires extract with higher doses than 240 mg salicin per day.
Willow bark extract: the contribution of polyphenols to the overall effect.

Nahrstedt A, Schmidt M, Jäggi R, Metz J, Khayyal MT. Wien Med Wochenschr.
2007;157(13-14):348-51.
Abstract
444
The efficacy of willow bark extract in the treatment of painful mobility disorders, such as back pain and
arthritis, has been attributed to the content of salicin and its derivatives as pro-drugs of salicylates.
However, based on clinical experience and the evidence of experimental pharmacological studies, the
fraction of total salicin cannot satisfactorily explain the clinical efficacy of willow bark. In addition,
salicins and their metabolites lack the acetylating potential of ASA and must therefore possess a
different mechanism of action. A detailed pharmacological screening of the aqueous willow bark extract
STW 33-I addressed the question of the identification of fractions contributing to the overall effect. All in
vivo and in vitro models studied pointed to relevant contributions of the fraction of polyphenols and
flavonoids. The single compounds or their combinations responsible for the effect remain to be
elucidated.
In vitro anti-proliferative effects of the willow bark extract STW 33-I.

Bonaterra GA, Kelber O, Weiser D, Metz J, Kinscherf R. Arzneimittelforschung.
2010;60(6):330-5. doi: 10.1055/s-0031-1296296.
https://www.ncbi.nlm.nih.gov/pubmed/?term=In+vitro+anti-
proliferative+effects+of+the+willow+bark+extract+STW+33-I.
Abstract
The well-known anti-inflammatory and analgesic effects of the phytopharmacon willow bark extract
have been attributed to the content of salicin; however, pharmacological studies have shown that salicin
alone, despite being involved in its therapeutic action, cannot fully explain its clinical efficacy. In addition
to reducing inflammation and pain, acetylsalicylic acid (ASA, CAS 50-78-2), like other synthetic non-
steroidal anti-inflammatory drugs (NSAIDs), has been shown to exert anti-proliferative effects and to
induce apoptosis in a variety of cell lines, e.g., colon, stomach, and prostate cancer cells. To investigate
the mechanism of action and possible anti-proliferative and proapoptotic effects of willow bark, a water
extract (STW 33-I) and a polyphenol rich fraction (fraction E) have been tested by using the colon-
carcinoma cell line HT-29. Both, STW 33-I and its fraction E showed significant anti-proliferative and (1)
Introduction The most well-known component of willow bark extract is salicin, which is metabolized in
vivo to salicylic acid. The standardized aqueous willow bark extract STW 33-I, which is an effective
analgesic and anti-inflammatory drug, contains 23-26% total salicin derivatives and additionally
flavonoids, condensed tannins and polyphenols. Typical representatives of the flavonoids are glycosides
of naringenin, isosalipurpuroside or eriodictyol. In vitro experiments have demonstrated for pro-
apoptotic effects on HT-29 cancer cells. Related to the salicin content of the willow bark extract, a higher
dosage of ASA was needed. Furthermore, compared to ASA and to diclofenac (Diclo, CAS 15307-79-6),
the COX-1 and COX-2 mRNA expressions were influenced differently by STW 33-I and fraction E. ASA and
Diclo inhibited both the COX-1 and COX-2 mRNA expressions, whereas STW 33-I and its fraction E
increased the COX-1 mRNA expression. In addition to the already well-known anti-inflammatory and
analgesic effects, willow bark extract has been found to possess anti-proliferative and pro-apoptotic
effects similar to NSAIDs. The different influence of willow bark on the COX-1 and COX-2 mRNA
445
expressions in comparison to NSAIDs might be relevant, e.g., for prevention of undesirable side effects
such as gastric erosions.
Anti-inflammatory effects of the willow bark extract STW 33-I (Proaktiv(®)) in LPS-
activated human monocytes and differentiated macrophages.
Bonaterra GA, et al. Phytomedicine. 2010 Dec 1;17(14):1106-13. doi:
10.1016/j.phymed.2010.03.022. Epub 2010 May 31.
Abstract
INTRODUCTION:
Willow bark extract is frequently used in the treatment of painful rheumatological diseases, such as
arthritis and back pain. Its effect has been attributed to its main component salicin, but pharmacological
studies have shown that the clinical efficacy of the willow bark extract cannot be explained by its salicin
content alone. Therefore different modes of action have been suggested for the anti-inflammatory
effect of willow bark extract. Here, we report in vitro data revelling the effect and mode of action of the
aqueous willow bark extract STW 33-I as well as a water-soluble fraction (fraction E [Fr E]) in comparison
with well-known non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin (ASA) and diclofenac (Diclo)
on pro-inflammatorily activated human monocytes and differentiated macrophages.
RESULTS:
STW 33-I and the water-soluble Fr E showed concentration-dependent and significant anti-inflammatory
effects in lipopolysaccharide-activated monocytes. Both inhibited the intracellular protein expression of
tumour necrosis factor-alpha (TNFα) as well as the mRNA expression of TNFα and cyclooxygenase 2
(COX-2), and the release of nitric oxide (NO). In addition, apoptosis of pro-inflammatorily activated
monocytes was induced. Furthermore, treatment of activated macrophages with STW 33-I inhibited the
nuclear translocation of the p65 subunit of the nuclear transcription factor-kappa B (NF-κB p65).
CONCLUSIONS:
The present in vitro investigations suggest a significant anti-inflammatory activity of willow bark water
extract STW 33-1 and of its water-soluble fraction by inhibiting pro-inflammatory cytokines (TNFα), COX-
2 and nuclear translocation of the transcription factor NF-κB in pro-inflammatorily activated monocytes.
Our results provide further evidence for the therapeutic use of STW 33-I in inflammation-related
disorders.
446
Salicin-7-sulfate: A new salicinoid from willow and implications for herbal medicine.
Noleto-Dias C, Ward JL, Bellisai A, Lomax C, Beale MH. Fitoterapia. 2018
Jun;127:166-172. doi: 10.1016/j.fitote.2018.02.009. Epub 2018 Feb 12.
Abstract
Willow (Salix sp.) is a historically well-known herbal medicine that provided the lead compound (salicin)
for the discovery of aspirin, one of the most successful plant derived drugs in human medicine. During a
metabolomics screen of 86 Salix species contained in the UK National Willow Collection, we have
discovered, isolated and fully characterised a new natural salicinoid - salicin-7-sulfate. This molecule
may have important human pharmacological actions that need to be considered in determining the
efficacy and safety of willow herbal medicines.
KEYWORDS:
Salicin; Salicin-7-sulfate; Salix; Willow

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Supplements Revealed

A-to-Z Research Guide

PART ONE: THE EXPERTS

PART TWO: THE RESEARCH

Links to companies and supplements mentioned in this

2019-2020 REVEALED FILMS, INC. ALL RIGHTS RESERVED

Dr. Ann Shippy

She likes nicotinamide diribacide for brain health.

Ann’s Recommended Supplement Brands:

Dr. Anna Cabeca

Sleep is also key - “Anti-aging at its finest.”

Ann’s Recommended Supplement Brands:

Kion, Thorne, and TianChi.

Bryan’s Recommendations/Recommended brands:

Kavaplex is Cameron’s proprietary blend.

Ageless Energy Health

He also studied environmental toxicology, especially involving mercury. He shifted to developing

Quicksilver Scientific products.

Dr. Edward Group

Global Healing Center proprietary supplements.

Dr. Eric and Sabrina Zielinski

Meet Eric and Sabrina:

Eric and Sabrina’s Recommendations:

Anti-inflammatory oils: citrus, chamomile, lavender, and peppermint.

For allergies: peppermint, lavender, lemon, tea tree.

For pain: clary sage

For weight loss: grapefruit and inhaling lime weight loss

For anxiety and depression: citrus related: bergamot, neruli

Eric and Sabrina’s Website: www.naturallivingfamily.com

Specialty Nutrition Consulting brand.

Harris B. Williams Jr.

New research includes bamboo, “Which really helps increasing circulation.”

Jason is a Chiropractor at Core Therapies who makes use of supplementation. He had a

“I look at oxygen now as that missing nutrient.”

He recommends “nutravore dieting” with a focus on micronutrients. He educates consumers on picking

Nitric oxide, turmeric, astaxanthin, arginine, beet, kale, and citrulline.

Organixx and Primal Life Organics products.

Dr. Kellyann Petrucci

This healthy foundation gives you timeless beauty.

Bone broth, organic and free-range. Mineralized salts are best.

Megaspore Biotic brand of Probiotic

Patrick Sullivan Jr.

Mega Food - a line of organic whole food-based supplements.

GundryMD proprietary products.

He considers some staples to be a protein supplement, a probiotic, digestive enzymes, magnesium,

Primal Life Organics brand.

Hydrogen gas as a supplement.

Molecular Hydrogen Institute

Cytodotox company - heavy metal and toxin detox.

Will is the Chief Scientific Officer at MitoQ Limited. He is a pharmacologist by training.

Ubiquinol form of CoQ10 for energy, heart health, and antioxidant.

A Case for Alpha-Lipoic Acid as an Alternative Treatment for Diabetic Polyneuropathy....................... 38

Herbal Medicine for Low Back Pain: A Cochrane Review. ...................................................................... 56

In vivo activity assessment of a "honey-bee pollen mix" formulation. .................................................. 72

A commercialized dietary supplement alleviates joint pain in community adults: a double-blind,

The pharmacology of topical analgesics. .............................................................................................. 107

13 Benefits of Taking Fish Oil ................................................................................................................ 177

Cannabidiol: promise and pitfalls. ........................................................................................................ 211

Maca ........................................................................................................................................................................................ 243

Methylsulfonylmethane: Applications and Safety of a Novel Dietary Supplement. ............................ 273

Oregano Oil (Carvacrol) ............................................................................................................................................... 305

Medicinal herbs in the treatment of neuropathic pain: a review. ....................................................... 336

Curcumin in inflammatory diseases...................................................................................................... 366