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The Journal of cannabis in clinical Practice

“Is this the best way we can grow our big orchards?” —Woody Guthrie


autumn 2011

Ethan Russo reviews the evidence

Terpenoids, ‘minor’ cannabinoids contribute to ‘entourage effect’ of cannabis-based medicines
by fred Gardner The chemical structure of tetrahyrdocannabinol (THC) was determined in 1964 by Raphael Mechoulam and Yechiel Gaoni. For more than three decades thereafter, the blatant psychoactivity of THC induced scientists to define it as the active ingredient in the plant. Experienced marijuana smokers who tried the drug Marinol (pure, synthetic THC) when it became prescribable in the mid-1980s reported that the effects were dissimilar. But it wasn’t until the late 1990s that the research establishment acknowledged that another compound, cannabidiol (CBD), also exerted effects when present in significant amounts. In 1999 a British start-up, GW Pharmaceuticals, began clinical trials of a whole-plant extract containing roughly equal amounts of THC and CBD. Multiple Sclerosis patients found the combination extract —dubbed “Sativex”— more effective in reducing pain and spasticity than a high-THC extract devoid of CBD, and less psychoactive. Sativex has now been approved for use by MS patients in England, Canada, New Zealand, and a growing list of European countries. CBD is no longer referred to as a “minor cannabinoid” at scientific conferences and in the literature. Several cannabinoids still considered “minor” —tetrahydrocannabavarin (THCV), cannabigerol (CBG) and cannabichromene (CBC)— also show therapeutic promise, according to recent studies. Plants with high levels of each have been grown out in GW Pharmaceuticals’ glasshouses for research purposes. Wake up and smell the terpenes! Scientists are now formally acknowledging something else that Cannabis consumers have long taken for granted: aroma is associated with effect. predominate. They tend to be volatile molecules that readily evaporate, and they’re very potent —all it takes is a few reaching the nose to announce their presence. Evidence that “phytocannabinoid-terpenoid interactions” enhance the therapeutic effects of cannabis was presented by Ethan Russo, MD, at a conference in Israel last fall and published in the August 2011 British Journal of Pharmacology. Russo, a neurologist and ethnobotanist, is senior medical adviser at GW Pharmaceuticals.

Project CBD Update—
starts on page 7 • CBD-Rich Strains Abound Some 35 strains containing more than 4% Cannabidiol have been identified by labs serving the medical cannabis industry in the U.S. • SCC Launches Survey The Society of Cannabis Clinicians has begun collecting patients’ responses to CBD-rich products. • How CBD Works Martin A. Lee lays out what scientists have learned about the mechanism of action by which CBD exerts its effects. • “Sour Tsunami” Stabilized Lawrence Ringo (below) has bred plants that produce seeds with a one-in-four chance of containing 10-11% CBD (and 6-7% THC)!

Hergenrather expects Russo’s talk to “generate great interest in terpenes among medical cannabis users as well as physicians.”
Both terpenoids and cannabinoids are secreted inside the Cannabis plant’s glandular trichomes, and they have a parent compound in common (geranyl pyrophosphate). More than 200 terpenoids have been identified in Cannabis. The most common and most studied include limonene, myrcene, alpha-pinene, linalool, beta-caryophyllene, caryophyllene oxide, nerolidol and phytol. Anecdotal evidence suggests that pinene is alerting, limonene “sunshine-y,” and myrcene sedating. The fact that most terpenoid compounds are common components of the human diet and “generally recognized as safe” by the Food and Drug Administration has made research possible, and scientists employed by flavor and fragrances manufacturers have investigated their properties over the years. But the terpenoids “remain understudied” in terms of therapeutic potential, according to Russo. His paper mustered all the evidence —proof in some cases, hints in others— that cannabinoids and terpenoids

The aroma of a given plant depends on which terpenoids predominate.
Plant cannabinoids —21-carbon molecules found only in Cannabis— are odorless. It’s the terpenoids —components of the plant’s “essential oils”— that create the fragrance. Terpenoids contain repeating units of a 5-carbon molecule called isoprene and are prevalent in smelly herbs such as mints and sage, citrus peel, some flowers, aromatic barks and woods. The aroma of a given plant depends on which terpenoids

• Harlequin, Omrita Rx3 Clones Released To expedite patient access to CBD-rich medicine, the developers of two remarkable strains have chosen to make clones available (rather than provide only flowers) to dispensaries participating in Project CBD. • ICRS 2011: CBD Research Accelerates “CBD was the star of the show on opening day here at ICRS, demonstrating potent anti-cancer effects in a variety of cancer types.” —Jahan Marcu, on the International Cannabinoid Research Society meeting in early July.

glandular triChomeS (globules atop stalks) contain specialized cells that secrete both cannabinoids and terpenoids.

can work in concert to abate symptoms of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA, which kills more Americans nowadays than AIDS) and other illnesses. Jeffrey Hergenrather, MD, president of the Society of Cannabis Clinicians, who heard Russo’s presentation in Israel, expects its publication to “generate great interest in terpenes among medical cannabis users as well as physicians.” The SCC recently began collecting data on patients’ responses to CBD-rich Cannabis. Future surveys will seek to document which other cannabinoids and which terpenoids are associated with which effects.
continued on page 19

ethan ruSSo, raphael meChoulam, and yeChiel gaoni

at the “cannabinoids in biology and Medicine” workshop held at hebrew University in Jerusalem last november. The event honored Mechoulam on his 80th birthday. his many accomplishments include helping to discover the structure of cbd (with shvo in 1963), Thc (with Gaoni in 1964), and anandamide, the neurotransmitter that Thc mimics (with devane in 1992). a 1998 paper by shimon ben-shabatt, co-authored by Mechoulam, proposed that endocannabinoids (made in the body) act in concert with other compounds to exert an “entourage effect.” russo, a senior medical advisor with GW Pharmaceuticals, applied the entourage concept to phytocannabinoids (made by the plant). photo by lumir hanuS

trichome production.

braCtS on CannabiS flowerS are sites of most abundant

aleSSia ligreSti’S iCrS talK described “Mechanisms of the anti-cancer effects of cannabidiol and other nonpsychotropic cannabinoids on human prostate carcinoma.” her team studied 12 cannabinoids in pure form and in “relative enriched extracts” (in each of which a different cannabinoid was predominant). They observed, “Generally, among all pure compounds tested, CBD was the most efficacious at reducing cell viability... and in many cases the [extracts] were more potent than pure compounds.” cbc and cbG were also found to be effective, but “to a lesser extent.” Prostate cancer cells are killed, Ligresti reported, “through several concurring molecular mechanisms.” an entourage effect!

—19— O’Shaughnessy’s • Autumn 2011

Entourage Effect from page 1
The “Entourage Effect” The conference at which Russo presented his paper was held at Hebrew University, Jerusalem, where Raphael Mechoulam directs a lab, in honor of Mechoulam’s 80th birthday. In 1999 Mechoulam co-authored a paper with Shimon Ben-Shabat suggesting that cannabinoids made in the body work by means of an “entourage effect.” They had found that the endocannabinoid 2-AG (2-arachidonoylglycerol), when administered with two related compounds, would bind more readily at the cannabinoid receptors and exert more pronounced behavioral effect on mice. To pharmacologists who customarily designed experiments aimed at finding the active ingredient, this had heavy implications. Mechoulam spelled them out: “Biochemically active natural products, from either plant or animal origin, are in many instances accompanied by chemically related though biologically inactive

“Very seldom is the biological activity of the active constituent assayed together with inactive ‘entourage’ compounds.” —Raphael Mechoulam
constituents. Very seldom is the biological activity of the active constituent assayed together with inactive ‘entourage’ compounds. Investigations of the effect of the active component in the presence of its ‘entourage’ compounds may lead to results that differ from those observed with the active component only.” In 2001 John McPartland and Russo published a paper in the Journal of Cannabis Therapeutics applying the “entourage” concept to the plant itself. “Good evidence shows that secondary compounds in cannabis may enhance the beneficial effects of THC... and reduce THC-induced anxiety, cholinergic deficits, and immunosuppresion,” they wrote. “Cannabis terpenoids

and flavonoids may also increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens, and provide antiinflammatory activity.” A decade later, Russo is substantiating the molecular-teamwork hypothesis and expanding on it. His BJP paper, “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects,” contains 304 citations. Although the paper takes the form of a review of the literature, Russo’s perspective is forward-looking and practical. The paper can be read as a strategic guide for breeding and/or blending Cannabis so as to maximize specific medical effects. Its structure is straightforward: 1. Russo cites studies documenting the beneficial effects of THC, CBD, CBC, THCV, CBDV, CBG and CBN (noting the adverse effects attributed to THC). 2. He cites studies documenting the beneficial effects of Limonene, α-Pinene, Myrcene, Linalool, β-Caryophyllene,

Caryophyllene Oxide, Nerolidol, and Phytol. 3. He notes which cannabinoid effects would be augmented by which terpenoids, and which terpenoid effects would be augmented by which cannabinoids. There is a huge body of information to convey, and Russo’s style is compressed —documented fact after documented fact after documented fact, with insights positioned fittingly. The slides he showed in Israel have been integrated into two fullpage tables for the BJP paper, listing the relevant studies and the cannabinoid-terpenoid combinations likely to produce a desired effect. The paper, online at http//, is well worth reading. Our summary and the disjointed highlights that follow cannot do justice to Russo’s carefully constructed thesis.
continued on next page

Phytocannabinoid Effects
Δ9-tetrahydroCannabinol (thC) Cannabigerol (Cbg) • Anti-hypertensive • Next most effective phytocannabinoid vs. breast cancer after CBD • Inhibits keratinocyte proliferation (anti-psoriasis?) • Powerful activity against MRSA • Analgesic? • Inhibits anandamide reuptake. • TRPM8 antagonist (application in prostate cancer?) tetrahydroCannabivarin (thCv)

• Analgesic via CB1, CB2 • Antipruritic • Neuroprotective/Antioxidant • 20 times the anti-inflammatory effect of aspirin • Twice the anti-inflammatory effect of hydrocortisone • Not a Cox-1 or Cox-2 inhibitor • Reduces amyloid plaque build-up Cannabidiol (Cbd)

• GABA uptake inhibitor (more potent than THC or CBD) • Modest antifungal activity • Antidepressant CannabiChromene (CbC)

• Anti-inflammatory • Analgesic (less than THC) • Antibiotic/antifungal • Cancer cytotoxic agent • CBC extract antidepressant in rodents • Anandamide reuptake inhibitor

• CB1 antagonist at low doses, but CB1 agonist at higher doses. • Produces weight loss, decreased body fat, increased energy expenditure in obese mice. • Anticonvulsant in rodent cerebellum and pyriform cortex. Cannabidivarin (Cbdv)

• Neuroprotective antioxidant, strongly inhibits glutamate excitotoxicity; more potent antioxidant than Vitamins C, E • Inhibits uptake of anandamide, weakly inhibits its breakdown • Alerting vs. THC • Anticonvulsant • Anti-anxiety • Cytotoxic in breast cancer and many other cancer cell lines; cytopreservative for normal cells • Antagonist at GPR55 and GPR18 • Antagonizes tumor necrosis factor alpha in rodent rheumatoid arthritis. • Not Cox-1 or Cox-2 inhibitor • Agonist at serotonin receptor (why it may counter anxiety) • Reduces nausea • Improved cognition in hepatatic encephalopathy • Enhances adenosine receptor A2A signaling via inhibition of an adenosine transporter, suggesting anti-inflammatory and analgesic role • Prevents prion accumulation and neuronal toxicity • Powerful activity against MRSA

• Anticonvulsant in hippocampal slices

Cannabinol (Cbn)

• Sedative • Anticonvulsant • Anti-inflammatory • Antibiotic, potent against MRSA • TRPV2 agonist of interest in burns • Inhibits keratinocyte proliferation (utility in psoriasis?) • Stimulates recruitment of quiescent mesenchymal stem cells in marrow, promoting bone formation Inhibited breast cancer resistance protein. Megadoses might help treat breast tumors.

PhyTocannabinoids and ThEir EffEcTs were reviewed by Ethan russo, Md, at the international Workshop on the cannabinoids in biology and Medicine, held in Jerusalem, november 2010. Phytocannabinoids are odorless, 21-carbon molecules found only in the cannabis plant and nowhere else in nature. russo’s slides, excerpted above, cited the studies by which each cannabinoid effect was determined. The relevant studies are also cited in russo’s paper in the august 2011 British Journal of Pharmacology,

“Taming Thc: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects” —online at abstract. GW Pharmaceuticals has developed cannabis cultivars in which cbc and ThcV are predominant —and one in which the entire cannabinoid content is cbG. GW Pharmaceuticals’ plant-breeding program is described on their website and in a fourpart series by Etienne de Meijer and co-workers in the journal Euphytica.

—20— O’Shaughnessy’s • Autumn 2011

Entourage Effect from

previous page

The cannabinoids formerly Known as Minor (cfKMs) The extensive breeding program directed by GW Pharmaceuticals’ Etienne de Meijer has yielded plants rich in CBD, CBC, CBG, and THCV. Cannabichromene (CBC) is produced early in the plant’s life cycle according to a paper published by de Meijer in 2009. Citing de Meijer’s co-worker David Potter, Russo notes that “An innovative technique employing cold water extraction of immature leaf matter from selectively bred

cannabis chemotypes yields a high-CBC ‘enriched trichrome preparation.’” Cannabigerolic acid (CBGA), the precursor of THC, CBD, and CBC in their acid forms, is usually found at low concentrations. “But recent breeding work has yielded cannabis chemotypes lacking in downstream enzymes that express 100% of their phytocannabinoid content as CBG,” according to Russo. (More details are provided on GW Pharmaceuticals’ very informative website.) Tetrahydrocannabivarin (THCV) blocks

Every compound the plant produces has or had an evolutionary purpose.
the CB1 receptor at low doses, and activates it at high doses. GW Pharmaceuticals hopes that a THCV-rich extract will be an effective appetite suppressant and will counter the symptoms of metabolic syndrome. THCV is present in cannabis chemotypes from southern Africa —from which

plants that are “highly predominant” in THCV have been bred. Terpene factoids Whereas plant cannabinoids are found nowhere else in nature, terpenoids are produced by countless plant species. Some 20,000 terpenoids have been identified by chemists; they constitute the largest group of plant chemicals. More than 200 have been found in cannabis. “Essential oil composition is much more genetically than environmentally detercontinued on next page

Terpenoid Effects and Synergistic Cannabinoids
limonene (also found in lemon) α-pinene (also found in pine needles)

• Antidepressant and immune stimulator in humans —CBD • Anti-anxiety, antidepressant in mice via serotonin receptor. CBD • Apoptosis of breast cancer cells —CBD, CBG • Effective against dermatophytes —CBG • Gastro-esophageal reflux —THC myrCene (also found in hops)

• Anti-inflammatory via prostaglandin E-1 mechanism —CBD • Bronchodilatory in humans —THC • Acetylcholinesterase inhibitor, aiding memory —THC?, CBD • Anti-MRSA et al —CBD, CBG, CBN • Wide-spectrum antibiotic linalool (also found in lavender) • Anti-anxiety —CBD, CBG? • Sedative on inhalation in mice —THC • Local anesthetic equal to procaine, menthol —THC •Anticonvulsant/anti-glutamate —CBD, THCV, CBDV • Analgesic in mice • May achieve these effects by modulating glutamate and GABA neurotransmission.

• Blocks inflammation via prostaglandin E2 —CBD • Analgesic in mice, antagonized by naloxone —CBD, THC • Sedating; muscle relaxant; potentiated sleep time —THC • Blocks hepatic carcinogenesis by aflatoxin —CBD, CBG beta-Caryophyllene (also found in Echinacea)

phytol (also found in green tea)

nerolidol (also found in orange)

• Counters mutagenic effect of Vitamin A • Blocks breakdown of GABA —CBG • Sedative —THC, CBN • Skin penetrant —? • Inhibits fungal growth —CBC • Utility in contact dermatitis?

• Anti-inflammatory via PGE-1 —CBD • Gastric cytoprotective —THC • Selective CB2 full agonist (anti-inflammatory, analgesic) —THC • Treatment of pruritus? —THC • Treatment of addiction? —CBD Caryophyllene oxide (also found in lemon balm)

• Antifungal in onychomycosis — CBC, CBG • Insecticidal —THCA, CBGA

TErPEnoids coMMon in cannabis, their effects, and synergistic cannabinoids as listed by russo. aromatic terpenes abound in smelly herbs such as mints and sage, citrus peel, some flowers, barks and woods. In Cannabis, terpenoids and cannabinoids are produced by secretory cells in the glandular trichomes. Terpenes contain repeating units of isoprene, a 5-carbon molecule. Terpenoid naming is based on 10-carbon units: monoterpenes contain 10 carbons, sesquiterpenes 15, diterpenes 20, etc. Monoterpenes are lightest and evaporate most readily. Thus cannabis extracts tend to lose myrcene, pinene, and limonene (all monoterpenes) in proportion to beta-caryophyllene (a sesqui-

terpene). Some 200 terpenoids have been identified in Cannabis, but only those shown here and a few others occur frequently in significant amounts. Russo specified which cannabinoids are likely to augment medically useful terpenoid effects and vice versa. GW Pharmaceuticals has developed a cannabinoid-free cannabis cultivar, which should facilitate investigation of terpenoid effects. see and Meijer EPM

de, hammond KM, sutton a. 2009, “The inheritance of chemical phenotype in cannabis sativa L. (iV): cannabinoid-free plants,” Euphytica 168: 95-112.

—21— O’Shaughnessy’s • Autumn 2011

Entourage Effect from previous page

mined,” Russo states. Every compound the plant produces has or had an evolutionary purpose. The bitter 15-carbon terpenoids in the fan leaves repel grazing animals, while the predominantly monoterpene mix in the flowers is unappealing to insects — and, thanks to its stickiness, can also entrap them. Alpha-pinene is the most common terpenoid in the plant world; limonene is second. Named for their strong presence in pine needles and lemons, respectively, they are monoterpenes, also prevalent in cannabis. Terpenoids may account for only 1% of the weight when cannabis is tested but 10% of the weight within the trichome. Monoterpenes evaporate more readily than the di- and sesquiterpenes during drying, storage, and production of extracts, which results in a relatively higher proportion of caryophyllene. Beneficial Effects How do terpenoids exert effects within the body? Citing the relevant studies, Russo explains that they are “lipophilic, interact with cell membranes, neuronal and muscle ion channels, neurotransmitter receptors, G-protein coupled (odorant) receptors, second messenger systems and enzymes.”

Limonene, inhaled, is an immunostimulant. In lab experiments it has killed breast cancer cells and acne bacteria. It is a potential treatment for gastro-esophageal reflux. Alpha-pinene —as anyone who has walked into piney woods and breathed deeply can sense— is a bronchodilator. It also has anti-bacterial and antibiotic properties. α-Pinene inhibits the enzyme that breaks down acetylcholine, a neurotransmitter involved in memory. “This feature could counteract short-term memory deficits induced by THC intoxication,” Russo notes.

Cannabis designer extracts are likely to yield safe, effective new treatments for a wide range of conditions
act synergistically. • They can work on separate targets. For example, if CBD were combined with limonene as an acne treatment, the cannabinoid could penetrate the skin and induce the cells that produce sebum to selfdestruct, while the terpenoid could inhibit production of the key pathogen, Propionbacterium acnes. (Linalool and alpha-pinene also suppress P. acnes.) • They can interact to overcome bacterial resistance. For example, CBD and CBG “powerfully inhibit MRSA,” according to one study cited by Russo, while in another study, an essential oil rich in pinene proved “as effective against MRSA and other antibiotic resistant bacterial strains as vancomycin.” • They can have an antagonistic effect, as in the case of CBD countering THC’s ability to promote an accelerated heartbeat, the munchies, drowsiness, and anxiety. Key role for cbd CBD will play a key role in extracts designed for medical use. Although deemed “non-psychoactive,” CBD reduces anxiety by affecting the serotonin receptors. It also reduces cravings —for heroin, cocaine, food, nicotine and other addictive substances. Russo describes a recent study that “demonstrated the fascinating result” that stroke patients who had suffered damage to a part of the brain called the insula “were able to quit tobacco smoking without relapse or urges.” “In a provocative parallel,” he adds, functional MRIs of patients given CBD (600 mg p.o.) dramatically reduced activity observed within the left insula “suggesting the possibility that CBD could act as a pharmaceutical surrogate for insular damage in exerting an anti-addiction therapeutic benefit.” Which terpenoid(s) would be complementary? Citing a study in which inhaledvapor from an essential oil of black pepper reduced craving for cigarettes, Russo writes: “the terpene profile of black pepper suggests possible candidates: myrcene via sedation, pinene via increased alertness, or especially caryophyllene via CB2 agonism.”

Myrcene, combined with THC, may produce the ‘couch-lock’ phenomenon of certain chemotypes.
Myrcene, another monoterpene common in cannabis, is also abundant in the flowers of humulus lupulus —hops— the only other member of the Cannabinacae family. In addition to its anti-inflammatory effect, Russo writes, “Myrcene is a recognized sedative as part of hops preparations, employed to aid sleep in Germany... Myrcene acted as a muscle relaxant in mice, and potentiated barbiturate sleep time at high doses. “Together, these data would support the hypothesis that myrcene is a prominent sedative terpenoid in cannabis, and combined with THC, may produce the ‘couchlock’ phenomenon of certain chemotypes that is alternatively decried or appreciated by recreational cannabis consumers.”

Russo’s BJP paper contains an assertion, tangential to his theme, that seems like a big story in and of itself: “Government-approved cannabis supplied to patients in national programs in the Netherlands and Canada is gammairradiated to sterilize coliform bacteria, but the safety of this technique for a smoked and inhaled product has never been specifically tested.” (Emphasis added by O’Shaughnessy’s.) Russo cites studies showing that “Gamma-irradiation significantly reduced linalool titres in fresh cilantro, and myrcene and linalool in orange juice.” In other words, getting zapped withgamma rays may not only make plants unsafe to inhale, it can reduce their nutritional value. The research agenda Cannabis designer extracts are likely to yield safe, effective new treatments for a wide range of conditions, and —in due course, it is hoped— to regulatory approval and sales. GW Pharmaceuticals has already bred cannabis chemotypes with very high fractions of myrcene and limonene, and we assume they’re working on plants high in pinene, linalool and other terpenoids with therapeutic potential. As Russo puts it in his BJP paper, “Selective cross-breeding of high-terpenoid- and high-phytocannabinoid-specific chemotypes has... become a rational target.” Meanwhile back in California, researchminded doctors, cannabis cultivators, dispensary and lab owners, have been thinking along similar lines. (The idea that cannabis can be bred to maximize production of more than one compound is as obvious as the association between aroma and effect.) We don’t have the resources to do high throughput pharmacological screening or animal studies involving radioactive labeling, but we do have access to labs that can identify the compounds in a cannabis bud, and we have our own senses to evaluate effects. As O’Shaughnessy’s goes to press in late August, we know of two labs in California that have begun testing for terpenes and others are maing plans to do so. (See story on next page.) and will carry updates on what we, collectively, are about to learn.

is irradiation safe?

Limonene has been shown to decrease anxiety in mice via the serotonin receptors.
The beneficial effects are wide-ranging and, in many cases, well established. Limonene, for example, has been shown to decrease anxiety in mice via the serotonin receptors. “Compelling confirmatory evidence in humans,” Russo writes, was provided by a Japanese study of severely depressed hospital patients whose moods improved when exposed to citrus fragrance. (Nine of 12 were able to get off antidepressants.)

Linalool has sedative and anticonvulsant properties.
Linalool, which is abundant in lavender, affects serotonin neurotransmission and counters anxiety, according to a study cited by Russo. Linalool has sedative and anti-convulant properties, and is also “the likely suspect in the remarkable therapeutic capabilities of lavender essential oil to alleviate skin burns without scarring.” Beta-caryophyllene, which is found in black pepper, Echinacea, and marigolds, “is frequently the predominant terpenoid in cannabis extracts, particularly if they have been processed under heat.” β-caryophyllene is anti-inflammatory and, unlike other anti-inflammatories, protective of the stomach lining. In 2008 Swiss investigators led by Jurg Gertsch showed that β-caryophyllene activates the CB2 receptor —making it “the first proven phytocannabinoid beyond the cannabis genus,” Russo proclaims. “Given the lack of psychoactivity attributed to CB2 agonists, caryophyllene offers great promise as a therapeutic compound, whether systemically or in dermatological applications.” Other terpenoids with therapeutic potential mentioned by Russo in his BJP paper are nerolidol (found in citrus, it may have sedative and anti-fungal effects); caryophyllene oxide (found in the herb lemon balm, it repels insects); and phytol (a breakdown product of chlorophyll with relaxant properties that may be the reason that green tea, despite its caffeine content, doesn’t jangle the nerves). In their landmark 2001 paper in the Journal of Cannabinoid Therapeutics, Russo and lead author John McPartland touched on the beneficial effects of eucalypytol, pulegone, alpha-terpineol and other possibly efficacious terpenoids. These compounds were not discussed in Russo’s 2011 BJP paper. designer Extracts Russo describes several mechanisms by which terpenoids and/or cannabinoids can

Essential resource

The handbook of Essential oils: science, Technology and applications by K. Husnu Can Baser and Gerhard Buchbuaer, is a 975-page compendium published in 2010 By CRC Press, Boca Raton, FL. Ethan Russo must have made good use of this book. Reviewing it in Herbalgram, he wrote, “The antimicrobial activities of the terpenoids are handled with an introduction in which the activity of thymol (an ingredient in Listerine) is stated as 10-fold stronger than phenol. This is followed by an astounding 177 pages of tables documenting previous experimental work examining the effects of various agents.” A chapter on aromatherapy points out the difficulty of conducting randomized clinical trials (RCTs) with substances that have such obviously distinct smells. No RCTs, no “scientific validity.”

raPhaEL MEchoULaM in the fall of 2010, addressing scientists assembled in his honor. Ethan russo paid homage to a 1999 paper in which Mechoulam used the term “entourage effect” to describe how compounds act in concert to activate receptors in the body. Mechoulam commented in that paper, “This type of synergism may play a role in the widely held (but not experimentally based) view that in some cases plants are better drugs than the natural products isolated from them.” photo by ZaCh Klein

—22— O’Shaughnessy’s • Autumn 2011

Labs Begin Testing for Terpenes
Two labs have begun testing cannabis samples for terpenes. The Werc Shop began doing so in June and now has a validated method of identifying “about 30 different terpenes,” says owner Jeff Raber.

Jackie Robinsons of Analytical Chemistry

“This is definitely where the variability in strains comes from,” says Raber.
“This is definitely where the variability in strains comes from,” says Raber, although he has gotten very little feedback from patients linking specific compounds to specific effects. “The ones containing pinene are uplifting, fairly consistently.” Raber has identified terpineol as “a unique terpene in ‘Jack Herer’ and some of the ‘Jack’ crosses like J-1. “That’s the only one that jumps out at me, so far,” he said in late August. “We haven’t had many people wanting to do the test for it.” Terpineol is commonly found in pines and other conifers that produce turpentine, and in Eucalyptus sap. Cannabis strains other than Jack Herer will be found to contain terpineol, we can say with certainty, because it was one of the beneficial terpenes described in MacPartland and Russo’s landmark 2001 paper in the Journal of Cannabis Therapeutics. They wrote: “α-Terpineol, terpinen-4-ol, and 4-terpineol are three closely related monoterpenoids. Inhalation of α-terpineol reduced mouse motility 45% (Buchbauer et al 1993). Burits and Bucar (2000) demonstrated that 4-terpineol exhibits “respectable” radical scavenging and antioxidant properties. Terpinen-4-ol, α-terpineol, and α-pinene demonstrated dose-dependent antibiotic properties against Staphylococcus aureus, S. epidermidis and Propionibacterium acnes (Raman et al 1995). Similar studies have demonstrated antimicrobial

activity against a wide range of pathogenic organisms, excluding Pseudomonas (Carson and Riley 1995). Campbell et al (1997) have demonstrated a moderate antimalarial effect against two strains of Plasmodium falciparum by an essential oil with major α-terpineol and α-caryophyllene components.” Raber uses a mass spectrometer (MS) to detect the presence of terpenes and a gas chromatograph with a flame ionization detector (GC-FID) to measure quantity. Whereas THC levels exceeding 10% are common in California cannabis nowadays, Raber says that it is not common for many terpenes to exceeded one percent. “But there are so many, that when you add up all those fractions of a percent, they might account for as much as four percent of the weight, creating a profound physiological impact.” Donald Land of Halent Labs in Davis, who uses liquid-chromatography-mass spectrometry to test for terpenes, informs us that “Cannabinoids are, in fact, a subclass of terpenes, though they are seldom referred to as such. Since these particular terpenes are only produced in cannabis and all derive from the parent compound, cannabigerol acid (CBGA), they are most often referred to by their more specific moniker, ‘cannabinoids.’” Land teaches analytical chemistry at UC Davis. He says that THC and CBD account for about 75% of a cannabis plant’s essential oil. The so-called “minor cannabinoids” account for another 5-6%. And the compounds Land defines as “additional terpenoids” (that are not unique to the cannabis plant) make up another 5-6%. Halent also tests for a number of “minor” cannabinoids. Out-of-the-ordinary strains identified to date include ones containing THCVA (5.5%), THCV (3%), CBDA (14%), and CBCA (1%), and CBLA (cannabicyclol, 2%).

PHARM CHEM IN MENLO PARK was the first private-sector analytic lab to test marijuana —back in the 1970s. Marijuana smokers were concerned that herb imported from Mexico might contain paraquat, an herbicide known to cause lung damage if inhaled. The U.s. government had orchestrated an aerial eradication program that the Mexican army carried out with the help of dEa advisors. some 10,000 acres of marijuana were sprayed in 1975, mainly around sinaloa. but the campesinos would harvest the plants immediately after the helicopters flew off, before the herbicide took effect and destroyed the buds. The dried herb wound up being sold and smoked. by the mid-1980s, many fortune 500 companies were using Pharm chem to test employees’ urine for illicit drug metabolites, and the company was grossing millions. The chemist who founded the lab had a crisis of conscience, sold out, and moved to oregon, where he devoted himself to fly fishing.

scc Presentations in Jerusalem
Willits-based William Courtney, MD, and his partner Kristen Peskuski each presented posters at the conference in Israel. Hers described a study involving eight subjects to determine whether ingesting fresh Cannabis buds has a psychoactive effect. (In the plant THC exists in its acid form, THCA. After harvest, heat changes it to the psychoactive neutral form.) “Five volunteers were heavy users, two were accustomed to only leaf, and one was naive to cannabis,” Peskuski reported. “Raw flowers were eaten for a two-week period; only psychoactive effects were examined. None of the patients felt euphoria or dysphoria from fresh cannabis flower consumption.” Courtney’s poster, “Conditionally Essential and Essential Cannabinoid Acids,” advocated consuming cannabinoid acids in large quantity to bolster the immune system. Having monitored consumption of juiced raw bud and leaf by thousands of patients, Courtney concluded that it results in “improved relief, and dramatic reduction in NSAIDs and analgesic use.” Jeffrey Hergenrather, MD, of Sebastopol presented a poster co-authored by Stacey Kerr, MD, of Santa Rosa, “Clinical Improvement and Reduction of ImmunoSuppressive Drug Therapy in CannabisTreated Patients With Inflammatory Bowel Disease.” The study involved a chart review of 38 patients with inflammatory bowel disease who used Cannabis for symptom relief. “All patients studied had an independent diagnosis of Crohn’s disease or ulcerative colitis. Inclusion criteria included the completion of a questionnaire designed to elicit details of the clinical course and use of all medications, includ-

david lampaCh,

Co-founder of Steep hill, the first lab to serve the medical cannabis industry, announces another first: technology that will enable dispensaries to evaluate cannabis onsite. sensors at the dispensary, controlled by servers at the lab, measure Thc, cbd, Thca, and moisture content. “Test data is processed offsite via the internet and results are returned in less than 80 seconds,” says Lampach.

William courtney, Md (right) with israeli researcher Zvi Vogel. ing Cannabis. “Results indicate that these patients found statistically significant improvement of their clinical course and a marked reduction or discontinuation of conventional pharmaceutical therapy associated with the regular use of Cannabis. Cannabis serves as an effective immunomodulator, antispasmodic and appetite stimulant with a wide margin of safety and freedom of undesirable adverse effects compared with conventional pharmacotherapy.” Hergenrather continues to add new patients to the study and data from ongoing patients. He has been invited to present his most recent findings at the International Association of Cannabinoid Medicine meeting in Bonn in September.

ULTra-fasT LiQUid chroMaToGraPhy sysTEM from Shimadzu Scientific Instruments is used by The Werc Shop, the first lab to test Cannabis in Southern California (and the first in California to test for terpenes). Components at right are a photo-diode-array detector on top of a column (in housing) through which molecules pass selectively based on a selected solvent. as each chemical leaves the column and reaches the detector, a signal is received by the computer (at left) and translated by software into weight percentages of the sample. Third from left are a control box on top of an autosampler which is responsible for repeatable and accurate injection of sample onto the column. second from left: bottles containing different solvents are used in constantly changing ratios to create a gradient designed to selectively remove molecules from the column based on their chemical properties. below the solvent bottles are the two pumps used to move the solvents through the system in ratios that will create the desired gradient mixture.

—23— O’Shaughnessy’s • Autumn 2011

Learning from patients from page 4
suffer needlessly.

It is ironic that cannabis use — which enables patients to reduce their use of narcotics— is a reason some doctors cite in cutting patients off from previously prescribed opioids.
It is ironic that cannabis use —which enables patients to reduce their use of narcotics— is a reason some doctors cite in cutting patients off from previously prescribed opioids. The law itself implies that cannabis should be used only in desperate and/or terminal cases. It is far from an enthusiastic embrace of the healing power and potential of cannabis. I have now monitored cannabis use by

who have been treated brusquely, or even verbally assaulted, when they wanted to talk about cannabis. Patients frequently report accusations of drug-seeking and addiction. I hear of doctors who vehemently denounce cannabis and those who use it, who become irate and abusive, or who walk out of the room and break off the relationship because a patient had brought up the topic. A patient who has been investigating medical cannabis, or who has started experimenting with it, takes a real risk in sharing what they’ve learned with their regular doctor. The response is often a misinformation diatribe. The patient quickly realizes that the physician knows less about cannabis than he or she does.
martha: “i have had headaches since i was eight years old.”

lives dictated by it.

Problems arise when the patient returns to the doctor who has been managing the pain medications and describes his improved mood and ability to function thanks to cannabis — and the doctor acts suspicious and disapproving.
Then, to his further gratification, the patient discovers that he can begin to reduce his use of the hated narcotics, by anywhere from 40 to 100 percent. Antidepressants and anxiety meds are similarly reduced once patients progress into successful use of medical cannabis. These patients are often ecstatic about finally being able to reduce their need for drugs, or leave them behind entirely. Their stories are among the most moving and dramatic that I hear. In the population I see, there is rarely a downside to cannabis use. Problems arise when the patient returns to the doctor who has been managing the pain medications and describes his improved mood and ability to function thanks to cannabis —and the doctor acts suspicious and disapproving. Pain clinic patients may be subject to random urine testing, which serves two functions: It confirms that the patient is taking a narcotic as prescribed, rather than diverting it, and also serves as a screen for other drugs the patient may be using. The patient may have signed a contract agreeing not to use medications other than those prescribed by the clinic or physician. If the patient has signed a contract, and/ or knows that the clinic or physician has a negative attitude about cannabis, he may choose to hide his use, and hope not to get tested until he can wean off of narcotics completely. Or he may decide to level with the doctor, and hope that the progress he has made in getting off opioids and other medications will be looked upon favorably. Granted, this patient is in violation of a contract. However it can be argued that the enactment of medical cannabis laws in Michigan and other states changed the legal context, giving patients the right to experiment with a newly available treatment. The physician has made it clear that he will not be facilitating this experiment, by demanding that a contract be signed, or even with a notice on the wall (“Don’t even ask about medical marijuana!”) I have seen more than a hundred patients in this difficult situation. Their lives have been greatly improved with cannabis self-treatment, which allows narcotic reduction. Yet they frequently continue to need a certain amount of pain medication, whether daily or for occasional pain flares. Sooner or later, the narcotics prescriber discovers the cannabis use and, all too often, drops the patient from further treatment. This leads me to wonder: what kind of physician reflexively ignores these desired milestones of patient progress with pain, anxiety, depression, and reduction in use of toxic medications? What kind of mind-set dismisses the evidence of scientific research, as well as the testimony of the patient, and finds her not deserving of further efforts at treatment? And what kind of rigidity insists on maintaining the fiction that cannabis is the equivalent of cocaine, heroin or methamphetamine? Obviously, the categorization of cannabis on Schedule I with truly harmful and addictive drugs is the underlying issue. This classification is disingenuous, given that the government has recognized the medical effectiveness of cannabis and supplied it to patients, and the DEA has been
continued on next page

Martha: Migraine headache

Graphic by Damian King

more than 4,000 patients at the THCF office.
(I’ve worked there for 18 months, averaging two days weekly and seeing about 30 to 35 patients per day.) I typically see one or two migraine patients a day. Many tell me that inhaled cannabis quickly makes a headache remarkably less painful, or knocks it out completely. Some, like Martha, 20, report a preventive effect, i.e., less frequent headaches as a result of regular use. Martha is representative of dozens of patients in their late teens or early 20s who report good to outstanding results with cannabis treatment of migraine.

Martha: I have had headaches since I was eight years old. They can last anywhere from eight to 48 or even 72 hours. They can be five times a week or seven times a week. They can get so bad in intensity that I have to just go lock myself in my room, with no light, no sound. I have gone thorough 10 medications trying to find something that works, and nothing helped. But once I tried the medical marijuana, it completely took the migraines away. Dr. M: And you shared your success with cannabis? Martha: Yes, with my grandmother. She had migraines all her life too, and this has been the only thing that has helped her. Now she’s hooked! (Laughs.) Dr. M: Is there a downside to marijuana? Do you have any problems from it?

lateral shoulder pain, and back pain with radiation down his left leg, and numbness to his foot. He was taking large doses of oxycodone multiple times daily to keep it under control. In addition to his orthopedic problems, Gus has had two strokes and a heart attack, with coronary stent placement. He’s bipolar, on two psychiatric meds. He has pulmonary hypertension, and requires oxygen by nasal canula. Considering his formidable problem and medication lists, Gus didn’t look too bad. He made it around without a cane, by leaning on the handle of his oxygen tank caddy. By coincidence, I saw Gus again at my urgent care workplace, two weeks after I had certified him at my solo practice office. I picked up his chart, which said “Seeking to establish primary care,” and walked in to the exam room. Dr. M: I thought you had a primary care doctor? Gus: Well, I did, but he fired me. Dr. M: But I thought he was okay with your getting certified by me, and even had something good to say about me? Gus: That’s what he said first. But when I want back again, he gave me a urine test, and I was positive for marijuana. So he canned me. Dr. M: Any explanation? Gus: No, and when I asked for one, the office manager said he wouldn’t talk to me. Gus was running out of pain meds. I asked if he was getting good results from the weed. He said it helped reduce the pain when he used it with his Percocet, but he hadn’t tried cutting back on the prescription drug yet. He was a little dubious, having been on high doses for a long time. I told him that I had seen plenty of people do it, and that any reduction would be a victory.

Most troubling are stories of patients cut off from their medications when their use of cannabis is revealed.
If the patient has already been getting relief from cannabis, the claims of ineffectiveness reveal the physician’s separation from reality. Some doctors insist that any perceived benefit from cannabis could only be a placebo effect. This is related with a straight face, to patients who have tried numerous medications over the years without getting truly satisfactory results — until they tried cannabis. The patient now has to deal with an attitude issue once the doctor’s buttons are pushed by mention of marijuana. The previously rational, knowledgeable, and compassionate physician has abruptly revealed that he has a streak of arrogance, and seems opinionated and even uncaring. Most troubling are stories of patients cut off from their medications when their use of cannabis is revealed. This generally involves a specialist, often in the pain management field, but primary care physicians can act this way, too. Typically, the patient has had a chronic pain condition for many years. Pain has been managed with one or more opioid analgesics and combination drugs. Maybe she is taking only one Vicodin (hydroxycodone with acetominophen), two or three times daily (a relatively low dose of an entry-level opioid). Or perhaps the patient suffers from severe pain of long standing, with complications of depression and anxiety. These patients can be on high doses of oxycodone combinations (the next step in narcotic strength) or even morphine, methadone, or fentanyl by transdermal patch. The mood problems may be treated with one or more antidepressants from different families, as well as one or more anxiety medications. Most patients at or nearing this level of drug treatment will be experiencing one or more side effects —lethargy, fatigue and mental sluggishness are common, as well as constipation and other GI disturbances. Damage to the kidneys and liver can be ongoing, but undetected. These patients are taking medication because of severe pain and/or dependence. Most would like to be taking less, and many are actively pursuing optimization of cannabis treatment to reduce opioid use. In my experience, cannabis users are, as a group, highly knowledgeable about narcotic analgesic toxicity, and motivated to reduce their dosages. Here’s a common scenario: a patient is introduced to cannabis, or reintroduced after a gap of years since high school or college, and finds that it works. He is better able to cope with his chronic pain, often dramatically so. Patients don’t always say that cannabis takes their pain away. Most will say that cannabis makes the pain less of a problem, or lets them direct their attention away from it, instead of having their

Treximet actually made me feel like I was having a heart attack.
Martha: No I don’t —unlike all the other medications I tried. One, Treximet actually made me feel like I was having a heart attack. But medical marijuana just completely takes the migraines away with no side effects. Dr. M: How are your studies going? Martha: Great; my GPA is 3.7.

Gus: chronic pain —and dropped by his Md for cannabis use.
I certified Gus in my office this spring as a holistic consult. He already had a primary care physician, and I didn’t take his Medicaid insurance. He told me that his doctor would not sign a cannabis certification, but had been supportive of his decision to try it by getting signed up elsewhere. Gus had little experience with cannabis, but wanted to try it, with the hope of alleviating pain, and reducing his use of opioid painkillers. Gus is 65, with a list of chronic problems. He had rotator cuff surgery years ago to repair an injured shoulder. The experience left him extremely reluctant to submit to the further surgeries his doctors were recommending: the other shoulder, and his lumbar spine. So Gus has been living with severe pain for over a decade: bi-

dealing with fellow phySiCianS
I occasionally hear from patients seeking certification that their doctors are open to their use of cannabis. These physicians will oblige by readily supplying record copies, or creating statements expressly for our clinic that list diagnoses and verify ongoing treatment. They cannot issue certifications, however, because the hospital or group practice for whom they work has a policy that forbids it. Unfortunately, for every patient with a supportive doctor, I see a dozen or more