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Nervous System and herbal medicine

Nervous System and herbal medicine

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Lecture notes on nervous system; [part 1
Lecture notes on nervous system; [part 1

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Nervous system Part 1

Brain chemistry
Blood-brain barrier
 tight junctions between endothelial cells forming the wall of the
capillaries in the brain and fatty astrocytes that wrap around
 In peripheral tissues the endothelial junctions contain gaps.
 Penetration of substances across the blood-brain barrier;
determined by the molecular size, lipid-solubility, and presence of
endothelial carrier transport.
 chemical messengers; released when an action potential
reaches the synaptic terminals.
 The neurotransmitters contained in the esicles spill into the
synapse and passiely diffuse across.
 ! synaptic neurotransmitter may become inactiated by seeral
" passiely diffuse
" undergo enzymatic brea#down, or conersion
" ta#en up into cell through a selectie reupta#e
" intracellularly ta#en bac# into a esicle for future release
 !cetylcholine-sensitie or cholinergic receptors
" nicotine receptors
" muscarinic receptors $sensitie to muscarine from the fly agaric
mushroom, atropine al#aloids bloc# muscarinic receptors in the
parasymp.n.s.% (dried orange peel blocked by atropine suggest effect
on muscarinic receptors).
 !&h necessary for control of s#eletal muscles, acting as the
neurotransmitter at the neuromuscular junction.
 inoled in transmission in the autonomic nerous system.
'eried from amino acids
 catecholamines $dopamine, norepinephrine also #nown as
noradrenaline, epinephrine "adrenaline-%, they are intracellularly
degraded by monoamine o(idase.
Antidepressant Drugs; The monoamine oxidase (MAO) inhibitors
including the more modern MAO!A inhibitors.
"on!selecti#e MAO inhibitors are not as popular; side effects and
$ell kno$n interaction $ith tyramine in foods (aminoacid found in
red $ine pickled herring strong cheeses nuts and other
common foods ingestion of tyramine may lead to dangerous %&
e#en hypertensi#e crisis and death).
Adrenergic effects
! 'phedra
! Angelica sinensis; possibly beta!(!adrenergic receptor stimulation
might explain the effect in reducing experimental pulmonary
! Aconite; nocicepti#e effect in#ol#ing adrenergic rather than opioid
receptors of hypaconitine alkaloid.
 Indoleamines ; serotonin, deried from the aminoacid )-
tryptophan. $tryptophan is con#erted to )!hydroxytryptophan by an
en*yme )!+T& is con#erted to )!hydroxytryptamine (serotonin )!
+T) by an en*yme. ,n the pineal gland )!+T further con#erts to "!
acetyl serotonin and then to melatonin).
 The basic theory of tryptophan supplementation in depression
(and insomnia) is that it $ill increase the le#el of serotonin and
melatonin in the brain.
 Tryptophan a component of dietary protein chocolate oats
bananas dried dates milk cottage cheese meat fish turkey and
Amino acid neurotransmitters
 primary e(citatory $glutamate, aspartate%; glutamate may be
conerted to *!B!
 inhibitory $gamma-aminobutyric acid, *!B!, glycine%
" *!B! is the principal inhibitory neurotransmitter in the brain,
and also found in the spinal cord. There are seeral allosteric sites
on the *!B!a channel that enhance *!B! binding, these allosteric
modifiers include benzodiazepine, barbiturates, ethanol, steroids
such as alloprenanolone. *lycine has inhibitory role in lower brain
and spinal cord, antagonised by strychnine.
*!B! and benzodiazepine receptors
 +aleriana acts in part through the effect on the receptors on
inhibitory neurons sensitie to gamma-amino butyric acid.
,ther; -eurpeptides; eg &./,T.0, !&T0, /10, substance P,
-eurohormones " eg in the hypothalamus releasing factors; .
 adenosine, adenosine triphosphate $also play role in energy
metabolism% sere as neurotransmitters, stored in synaptic esicles
and released in response to action potential in widespread areas of
the nerous system.
Calcium channel activity
 2odification of moement of calcium ions through the channels
in the cell wall is common factor in many receptor mechanism; eg
opioid al#aloids such as protopine, tentrandene, and the effect in
ascular tissues for the pana(.
Mechanism of most drugs
 inole binding to a receptor, most common receptors are
proteins, including membrane proteins, enzymes, transporters and
structural elements.
 In the nerous system the main receptors of interest are
receptors for neurotransmitters, and hormones which hae a high
degree of selectiity.
- bind and imitate the endogenous lignand $agonist%
- partial agonist; not reaching full efficacy
- preenting binding of other lignands $antagonist%
 lignand-binding domain, where the hormone or neurotransmitter
 effector domain; which translates the binding in some form of
action $including enzymes with catalytic actiities, ion channels that
gate the transmembrane flu( of ion, receptors that actiate
intracellular messengers, regulating gene transcription.
 .eceptor regulation; continous stimulation may lead to
desensitization, understimulation may lead to sensitization, may
occur when antagonist is used for long time
 0erbs shown to act on adrenergic, muscarinic, 3-0T4! and 3-
0T5 receptors, dopamine, the benzodiazepine and the gamma-
amino-n-butyric acid binding sites
 2ight not reflect real clinical effect but indicate the wide
spectrum of possible actiities.
4. Purinergic effect $coffee, tea, cocoa, mate, guarana, #ola%
5. &holinergic effect $tobacco, lobelia%
6. 2onoaminergic effect $ephedra, coca%
-one direct stimulation but modulation of neuronal actiity.
'irectly stimulate e(citatory amino acids or bloc# inhibitory
amino acids hae e(citoto(ic, or conulsie effects eg strychnine
from nu( omica.
Purinergic stimulants
 acting on the purine neurotransmitters7 the methyl(anthines
$caffeine, theophylline, theobromine%
 Purine bases which includes the nucleic acids, 8anthine;
occurs as brea#down product of nucleic acid metabolism, o(idised in
the body to uric acid.
 antagonism at the leel of adenosine receptors.
 &affeine increases energy metabolism throughout the brain but
decreases at the same time cerebral blood flow, inducing a relatie
brain hypoperfusion.
 &affeine actiates noradrenaline neurons and seems to affect
the local release of dopamine. 2any of the alerting effects of caffeine
may be related to the action of the methyl(anthine on serotonine
 The half-life of caffeine aries widely, factors; as age, lier
function, pregnancy, some concurrent medications, and the leel of
enzymes in the lier needed for caffeine metabolism.
9 half-life in a newborn baby may be as long as 4:6 hours.
9 smo#ing can shorten caffeine;s half-life.
9 In healthy adults, caffeine;s half-life is appro(imately 6"< hours.
9 oral contracepties, increased to 3"4: hours, and in pregnant
women the half-life is roughly ="44 hours. 2etabolic clearance
depending on menstrual phase, and hormonal status, slower during
later phase.
9 &affeine can accumulate in indiiduals with seere lier disease
when its half-life can increase to => hours.
 &affeine is metabolized in the lier7 para(anthine $?<@%,
theobromine $45@%, and theophylline $<@%
 Para(anthine $?<@%7 increases lipolysis, leading to eleated
glycerol and free fatty acid leels in the blood plasma, to be used
as a source of fuel by the muscles.
 Theobromine $45@%7 'ilates blood essels and increases urine
olume. Theobromine is a asodilator that increases the amount
of o(ygen and nutrient flow to the brain and muscles.
 Theophylline $<@%7 .ela(es smooth muscles of the bronchi.
!lso acts as a chronotrope and inotrope $increases heart rate
and efficiency%
 &affeine readily crosses the blood brain barrier.
 Antagonist of adenosine receptors found in the brain. The
caffeine molecule is structurally similar to adenosine caffeine acts as
a competiti#e inhibitor. The reduction in adenosine acti#ity results in
increased acti#ity of the neurotransmitter dopamine largely
accounting for the stimulatory effects of caffeine.
 -affeine can also increase le#els of epinephrine.adrenaline
possibly #ia a different mechanism.
 -affeine also increases le#els of serotonin causing positi#e
changes in mood.
 %y blocking its remo#al caffeine intensifies and prolongs the
effects of epinephrine and epinephrine!like drugs such as
amphetamine methamphetamine or methylphenidate.
 ,ncreased concentrations of cAM& in parietal cells causes an
increased acti#ation of protein kinase A (&/A) $hich in turn
increases acti#ation of +0./0 AT&ase resulting finally in increased
gastric acid secretion by the cell.
*eneral actiity
 smooth muscle rela(ant; bronchodilatory effects, coronary
asodilator, increase cardiac blood flow, opposite howeer happens
in brain.
 'iuretic $increase urine production, glomerular filtration rate,
increased renal blood flow.
 &ardioascular effect; influence agal and asomotor areas in
brain, ascular, cardiac tissue, and hormone systems such as plasma
catecholamines, and renin-angiotensin. Increases BP, high dose;
tachycardia and arrhythmia.
 -euroendocrine; high dose produce stressli#e neuroendocrine
response, in humans in aboe 3::mg consumed $3 coffee%;
increased leel andrenocortictrophic hormone, beta-endorphin, and
 &erebral blood flow; decreases at 53:mg caffeine, mostly in
the motor and auditory areas, persisting for =: min, but increase in
brain metabolism, and glucose utilization. Those with an(iety, also
increase in brain lactate.
 &ognitie effects; Auic#en reaction time enhance igilance,
increase alertness, improe mood. 1ome tolerance might deelop,
but improement sustained on long term consumption. Improement
in problem soling, memory. &ognitie effects more so in coffee as
supposed to tea. *reater effects in female.
 &essation; fatigue, headache, increased an(iety, decreases in
mood. Physiological changes, such as altered adenosine receptors,
and effect on the release of dopamine.
 &ombined nicotine and caffeine; mental cloudiness, irritability,
muscular tension.
 &hronic use, lipid fraction of boiled coffee dose dependently
eleates cholesterol and )'), which is preented by the filtered
preparation of coffee. &an eleate homocysteine leels $lin#ed to
&+'%, same in filtered coffee.
 &offee consumption associated with reduced fertility,
miscarriage, growth retardation in utero, sudden infant death
 0igh doses; seizures, plus prolonging seizures.
"obelia; Indian tobacco, used as substitute for tobacco
 &ontains 4< al#aloids, lobeline the most significant, soluble in
 lobeline acts as partial agonist at nicotinic receptor, may act as
antagonist through persistent actiation and desensitizations of the
receptors. 'ecreases basal release of acetyl choline and also
reduces -2'!-eo#ed actelycholine release.
 )obeline; direct effects on mononamine systems, binding to the
esicular monoamine reupta#e transporter, inhibits dopamine upta#e.
Increases basal release of norepine ephrine, but norepine ephrine
release may be reduced at higher concentrations. .elease of
serotonins. lobelinie acts as antagonist at neuronal calcium channel.
 Physiological effects; similar to nicotine, lobeline - emetic
al#aloid; wor#s as refle( e(pectorant at subemetic doses.
)obeline similar to nicotine and used as aid to stop smo#ing
#hedra sinica
 used by chinese for more than 3::: years. as alternatie to
tea, and coffee, modern use since 4=56 with the identification of
 0alf life 3.5 hours, ma( concentration 6.= hours. Bphedrine is
agonist of alpha and beta adrenergic receptors, also increases
norepinephrine from the sympathetic neurons.
 *eneral effects
" Increase heart rate, increase systolic pressure, stimulate the
betareceptors in lung, promoting therefore broncho dilation.
" Csed for asthma and pseudoephedrine used as decongestant.
1timulation of alpha adrenergic receptors on smooth muscle increase
resistance to urine flow. &hronic doses may be associated with to(ic
 1e; headache, irritability, restlessness, an(iety, insomnia,
tachycardia, urinary disorders, omiting.
 'eath related to high dosis of ephedrine; cardiac to(icity,
hypertension, cardiac arrhytmia.
 &I hypertension, an(iety, glaucoma, prostate adenoma with
residual urine olume, phaeochromocytoma, thyroto(icosis.
 Interactions with heart glycosides, halothane, guanethidine,
2!, inhibitor, secale al#aloids, and o(ytocin.
 Bphedrine associated with dependence,
 B(ogenous $motiated by specific eents%
 Bndogenous $biological or chemical%; a biochemical recurrent
disorder, often chronic, tends to become more seere oer time if left
 &linical depression affects 6-3@ of population world wide
 C1!; 4E@ $Fessler 4==<%.
 1urey found that 3<@ of women with depression tried
complementary therapy
 Poor appetite with weight loss, or increased appetite with
weight gain
 Insomnia or hypersomnia
 Physical hyperactiity or inactiity
 )oss of interest or pleasure in usual actiities, decrease in
se(ual drie
 )oss of energy, fatigue
 /eelings of worthlessness, self-reproach or inappropriate guilt
 'iminished ability to thin# or concentrate
 .ecurrent thoughts of death or suicide.
 The presence of fie of these eight symptoms indicates clinical
depression; the indiidual with four is probably depressed.
!easonal affective disorder
 .egularly occurring winter depression freAuently associated
with summer hypomania.
/actors affecting mood and behaior7
 genetics
 enironment
 disease or lesion of the brain, which could cause aberrant
functional states
 conditions of the metabolicGhormonal system or the internal
biochemical enironment of the &-1.
 .esearchers discoered that when animals learned to be
helpless it resulted in alteration of brain monoamine content. The
drugs would restore proper monoamine balance and alter the
animalHs behaior, when animals with learned helplessness were
taught how to gain control oer their enironment their brain
chemistry also normalized.
 helping the patient to gain greater control oer their life will
actually produce een greater biochemical changes.
 correlation between an indiidualHs leel of optimism and the
li#eliness of deeloping not only clinical depression but other illnesses
as well.
 1tudies; patients were followed for a total of 63 years. Dhile
optimists rarely got depressed, pessimists were e(tremely li#ely to
battle depression and other psychological disturbances.
factors which contribute to the depression 4
 nutrient deficiency or e(cess
 drugs $prescription, illicit, alcohol, caffeine, nicotine, etc.%
 hypoglycemia
 hormonal IimbalanceH
 allergy
 enironmental factors
 microbial factors
 Pre-e(isting physical condition;
" diabetes
" heart disease
" lung disease
" rheumatoid arthritis
" chronic inflammation
" chronic pain
" cancer
" lier disease
" multiple sclerosis
 Prescription drugs
" antihypertensies
" anti-inflammatory agents
" birth control pills
" antihistamines
" corticosteroids
" tranAuilizers and sedaties
 1tressGlow adrenal function
 0eay metals
 0ypothyroidism
 1leep disturbances
&ognitie behaioural therapy.
 teaching the patient a different e(planation to dispute the
negatie automatic thoughts.
 Auestioning depression-causing negatie thoughts and beliefs,
and replacing them with empowering positie thoughts and beliefs.
 an eleated morning cortisol leel and a decreased '0B! leel.
 'efects in 0P! regulation seen in affectie disorders include
e(cessie cortisol secretion which is independent of stress
responses, abnormal nocturnal release of cortisol.
 increased endogenous release of cortisol mirror the effects of
e(ogenous cortisol7 depression, mania, nerousness, insomnia, and,
at high leels, schizophrenia.
 The effect on mood is related to induction of tryptophan
o(ygenase. .esulting in shunting of tryptophan to the #ynurenine
pathway at the e(pense of serotonin and melatonin synthesis. The
kynurenine path$ay is a metabolic path$ay leading to the production
of nicotinamide adenine dinucleotide ("AD0) from the degradation of
the essential amino acid tryptophan.
 .esulting in less tryptophan being deliered to the brain.
 the leel of serotonin in the brain is dependent upon the
amount of tryptophan deliered to the brain, cortisol dramatically
reduces the leel of serotonin and melatonin.
 cortisol Jdown-regulatesK serotonin receptors in the brain,
ma#ing them less sensitie to the serotonin that is aailable.
 nicotine7 stimulation of adrenal hormone, including cortisol,
 !lcohol, increases adrenal hormone output, interferes with
many brain cell processes, and disrupts normal sleep cycles. !lcohol
ingestion also leads to hypoglycemia. The resultant drop in blood
sugar produces a craing for sugar because it can Auic#ly eleate
blood sugar.
 one study found that, among healthy college students,
moderate and high coffee drin#ers scored higher on a depression
scale than did low users. The moderate and high coffee drin#ers also
tended to hae significantly lower academic performance.
 1eeral other studies hae shown that depressed patients tend
to consume fairly high amounts of caffeine $e.g. greater than E::
 Inta#e of caffeine inta#e has been positiely correlated with the
degree of mental illness in psychiatric patients.
 The combination of caffeine and refined sugar seems to be
een worse than either substance consumed alone.
 shown to increase the leel of endorphins, which are directly
correlated with mood.
 The best e(ercises are either strength training $weight lifting% or
aerobic actiities such as wal#ing bris#ly, jogging, bicycling, cross-
country s#iing, swimming, aerobic dance, and racAuet sports.
1eeral studies hae shown hypoglycemia to be ery common in
depressed indiiduals
'eficient itamin Behaioral effects
 The most common deficiencies are folic acid, itamin B45 and
itamin B> .
 Thiamin B4; Forsa#offHs psychosis, mental depression, apathy,
an(iety, irritability
 .iboflain B5; 'epression, irritability
 -iacin B6; !pathy, an(iety, depression, hyperirritability, mania,
memory deficits, delirium, organic dementia, emotional lability
 Biotin BE; 'epression, e(treme lassitude, somnolence
 Pantothenic acid B3; .estlessness, irritability, depression,
 Pirido(ine B>; 'epression, irritability, sensitiity to sound
 /olic acid B=; /orgetfulness, insomnia, apathy, irritability,
depression, psychosis, delirium, dementia
 &obalamin B45; Psychotic states, depression, irritability,
confusion, memory loss, hallucinations, delusions, paranoia
 +itamin &; )assitude, hypochondriasis, depression, hysteria
 /olic acid deficiency is the most common nutrient deficiency in
the world. In studies of depressed patients, 64"63@ hae been
shown to be deficient in folic acid.
 In elderly patients this percentage may be een higher. 1tudies
hae found that among elderly patients admitted to a psychiatric
ward, the number with folic acid deficiency ranges from 63 to =5.>@.
'epression is the most common symptom of a folic acid deficiency.
 The serotonin-eleating effects responsible for much of the
antidepressie effects of folic acid and itamin B 45. Typically the
dosages of folic acid in the antidepressant clinical studies hae been
ery high7 43"3: mg.
 !n insufficiency of omega-6 oils has been lin#ed to depression.
This may be related to the impact of dietary fatty acids on the
phospholipid composition of neurological cell membranes.
 1tudies hae suggested that lowering plasma cholesterol by
diet and medications increases suicide, homicide, and depression.
 There is a consistent association between depression and
coronary artery disease.
 The basic theory of tryptophan supplementation in depression
$and insomnia% is that it will increase the leel of serotonin and
melatonin in the brain.
 Tryptophan, found as a component of dietary protein, is
particularly plentiful in chocolate, oats, bananas, dried dates, mil#,
cottage cheese, meat, fish, tur#ey and peanuts.
)ea#y *ut 1yndrome
The gut-brain barrier in major depression7 intestinal mucosal
dysfunction with an increased translocation of )P1 from gram
negatie enterobacteria $lea#y gut% plays a role in the inflammatory
pathophysiology of depression.
!ntidepressant 'rugs
4. The monoamine o(idase $2!,% inhibitors, including the more
modern 2!,-! inhibitors
 2onoamine o(idase $2!,%7 inactiates neurotransmitters
inside the neuron that hae either been synthesised or hae resulted
from reupta#e
 They cause increased intraneuronal leels of neurotransmitters,
which does not necessarily lead to increased leels at receptors.
 -on-selectie 2!, inhibitors; side effects and well #nown
interaction with tyramine in foods $ aminoacid found in red wine,
pic#led herring, strong cheeses, nuts and other common foods,
ingestion of tyramine may lead to dangerous BP, een hypertensie
crisis and death%.
5. Tricyclic antidepressants
 boost norepinephrine, and serotonin leels.$1.B. sedation, dry
mouth, constipation, due to their anticholinergic tendencies%.
 'espite their long history of use, the mode of action of tricyclic
antidepressants is not fully understood, an(iolytic as well as
antidepressant properties. They are thought to act as competitie
inhibitors of the reupta#e of serotonin and noradrenaline.
 it is the delayed adaptie responses of the synapse $in terms of
altered receptor numbers, receptor sensitiity etc% which is thought to
determine the real antidepressant effect.
6. 11.I
 the clinical effects of 11.Is in depression probably result more
from the delayed postsynaptic adaptie responses, rather than the
acute inhibition of the reupta#e of serotonin.
 fluo(etine $Prozac% and sertraline $Loloft%.
 11.I deeloped in the 4=?:s $prozac -fluo(etine-, sertraline "
zoloft-, paro(etine, citalopram%, tolerability. -ot as many 1.B. as
some of the other antidepressants, but still may produce sedation,
loss of libido, delayed or denied orgasm, and other%
1erotonin 1yndrome
 It is most freAuently caused by the use of 11.Is and 2!,
 It can also occur with single drug therapy and oerdose.
 Blderly patients are more ulnerable and it is often seen now
with 11. oermedication.
 The clinical picture is nonspecific and there is no confirmatory
test. It can be mista#en for iral illness, an(iety or a neurological
 Dith drug therapy; 6:@ remain unimproed.
%yericum erforatum
 Primarily in the past used as wound healing.
 Dard of eil spirits, the name refers to perforated appearance.
 Blooms around Mune 5<th the feast of 1t Mohns, the red spot
isible on august the 5=th, the date 1t Mohn was beheaded.
 Turner; 4>th & if drun#en with water and honey, purgeth largely
choleric humour, must be ta#en continually till patient be whole.
Traditionally and present used for depression
 &ulpeper; a tincture of the flowers in spirit of wine, against
melancholy and madness.
 Today used in depression, an(iety and nerous unrest.
Csed the middle to the top portion of the plant $6:->:cm%, the lower
leaes haing less of the constituent concentration
 &omple( and elusie, different constituents all effect;
 Inhibition actiity $although contradictory results%.
 bind to benzodiazepine receptors
 inhibitory effect on neurotransmitter, an modulating effects,
 altering serotonin metabolism
 raising melatonin leels
 Preseration of the biochemical actiity reAuires Auic# drying
and aoidance of light e(posure.
 flaonol glycosides $Auercetin, hyperoside, rutin; some of them
e(hibits 2!,a inhibition actiity, concentration in e(tract so low, to be
seen as irreleant%.
 1ome of the flaonoids bind benzodiazepine receptors but
again low leels present. $-ahrstedt and Butterwec#, 4==E%.
 Biflaones $e(hibits central nerous system depressant actiity
and bind benzodiazepine receptors, but no in io e(perimental was
apparent suggesting they no not cross the blood brain barrier%.
 Tannins may account for the antibacterial and antiiral effects.
,ligomeric proanthocyanidins.
 Phloroglucinols $hyperforin the most important, labile to heat
and light, only found in the flowers and fruit%.
 lipophilic molecule so possible to penetrated the &-1.
0yperforin shown neurotransmitter inhibition and modulatory effects.
0yperforin may be important, accounts for 5-<@ of the content of
dried herb, prone to o(idation. 2ore stable in the hypericum
e(tracts , due to the presence of antio(idants in the plant cell matri(.
 B.,. monoterpenes, pinene, myrcene, limonene,
sesAuiterpenes; antifungal. 1ome similar to the one in &annabis
 !mino acids; gamma-aminobutyric acid, and endogenous
inhibitory neurotransmittor; concentration to low to be actie.
 -aphthodianthrones; hypericin, and pseudohypericin in the
perforations in the leaes. !ccount for the red colour in e(tracts, and
can lead to phototo(ic reactions. Das thought it has 2!,I actiity,
but later were unable to demonstrate this actiity with the pure
hypericin. It is apparent in the whole herb, esp if included the
flaonoids. ,ther hypothesis; hypericin alters serotonin metabolism,
by absorbing long wae light, thus reducing the depressie moods.
!lso claimed to increase melatonin leels, and so improing sleep.
 !nother theory; that hypericum modulates the cyto#ines, the
e(tract had shown an suppression of interleu#in-> release, and it was
hypothesised that it migh influence depression through effects on
corticotropin-releasing hormones.
 &n summary; the active ingredient has to be considered the
e'tract in total( as the single constituents are still un)no*n+
 comple( and different to current theories and models of
antidepressant actiity.
 the many in itro studies of the effects of 1MD on
neurotransmitter upta#es or leels are of dubious significance.
 In io; mode of action of 1MD is more li#e tricyclics than
11.Is. But a human study has shown that amitriptyline $a tricyclic% is
Auite different in its pharmacological effects compared to 1MD.
 !nother human study found that effects of 1MD were Auite
different to imipramine $another tricyclic%, concluded that its effects
could be noel and possibly lin#ed to dopamine metabolism.
mean@ deep sleep states increased from 4.3 to >@, slight reduction
in .B2 sleep latency of 4: min was seen, but oeral .B2 sleep
unchanged. $unli#e antidepressants, which typically delay .B2
onset, and reduce total .B2 time, not #now what this signifies.
 0ypericin half life 5< hrs, but still recommend TI'. 0yperforin;
distribution and elmination half life; 6 hours and = hours, normal tid
dose best.
 &linical studies; used 6:: to =:: mg per day; suggested in past
mild to moderate depression, partly because the research at that time
not necessarily of good Auality and the dearth of data concerning
patients with more seere disease. Then trial on 5:= seerely
depressed using >::mg tid, and was seen that 0ypericum could be
used in seere affected patients with less 1B
To(icity and side effects
 Photosensitiity; Brnst and colleagues estimated that it would
reAuired a dose of hypericum 6:-3: times greater than the daily
recommmended dose ta#en at one time. !nalytical data systematic
reiews ery few side effects. reiew in the conseratie medical
journal !merican /amily Physician
 concluded that 1t MohnHs wort $1MD% is safe and effectie for
the short-term relief of mild to moderate depression; based on
consistent eidence from high Auality systematic reiews.
'rug interaction
1MD decreases the plasma leels $and hence efficacy% of a ariety of
SJW is a potent inducer of the cytochrome P450 (CYP) enzyme CYP!4
(and perhaps other CYPs) and the drug transporter P"glycoprotein (P"
gp)# $his results in increased %rea&do'n and(or reduced intestinal upta&e
of the drug in )uestion#
 interacting drugs; anticancer drug irinotecan, the antidepressant
amitriptyline, the anticoagulants phenprocoumon and warfarin, the
antihistamine fe(ofenadine, the sedaties alprazolam and midazolam,
protease inhibitors, cyclosporin, digo(in, statin drugs, methadone and
seeral oral contracepties. 1MD is thought to augment or destabilize
the effects of prescribed antidepressant drugs, especially the 11.Is
$selectie serotonin reupta#e inhibitors%.
Interaction with antidepressants
 antidepressant drugs as a broad class are often referred to,
rather than the indiidual classes of drugs, implies that a less than
rigorous perspectie has been ta#en.
Is there an inherent issue in prescribing 1MD with antidepressantsN
 !ntidepressant drugs of different classes are often combined,
especially by psychiatrists, in patients who are resistant to treatment.
 The ris# of serotonin syndrome from doing this with drugs is
infreAuent and so is li#ely to be een lower when 1MD is combined
with antidepressants $gien that the mode of action of 1MD is unli#e
conentional drugs%.
 1MD There is currently no eidence from either in io models
or from controlled clinical trials that 1MD interacts with any class of
antidepressant drugs. 0oweer, there are a number of case reports in
the literature.
1MD and Tricyclics
There are no published aderse reports of pharmacodynamic
interactions for 1MD and tricyclics7 neither case reports nor trials.
 There is one credible clinical study for amitriptyline that showed
reduced plasma leels $and hence was a pharmaco#inetic
interaction%. 1ince nortriptyline is basically a metabolite of
amitriptyline this would probably apply for this drug as well.
$depending on hyperforin content%
1MD and 11.Is
The first case report of an alleged interaction between a 1MD
product $unspecified% and an 11.I $paro(etine, Pa(il% was
published in 4==?. The patient e(hibited symptoms of grogginess,
incoherence and slow moements, which could hardly be
described as serotonin syndrome. The authors incorrectly
described 1MD as a 2!, inhibitor.
 /our case reports of serotonin syndrome in elderly people were
described in one published report, due to an alleged interaction
between 1MD and sertraline.
 !n alleged interaction between 1MD and paro(etine resembling
serotonin syndrome was published in 5:::. ! manic episode
$possibly serotonin syndrome% attributed to an interaction between
1MD and sertraline was also published in 5:::. The Auality of all
such reports is low and no other reports appear to hae been
published since.
1MD and ,ther !ntidepressants
 There are few case reports in the published literature of
aderse pharmacodynamic interactions between 1MD and noel
antidepressant drugs. .eports e(ist of serotonin syndrome attributed
to the interaction of 1MD and the modified cyclics trazodone and
 !n aderse reaction between the selectie noradrenaline
reupta#e inhibitor enla(afine and 1MD. !gain the Auality of these
reports is low.
 The research has shown that pharmaco#inetic drug interactions
should not be an issue for doses of 1MD less than 5 g herb per day
$or its eAuialent% or any doses of a 1MD preparation low in
hyperforin $such as a tincture or fluid e(tract%. These preparation and
dosage guidelines should be followed wheneer there is a
reAuirement to recommend 1MD to patients ta#ing any of those drug
medications #nown to interact with this herb.
 There is currently no eidence from either in io studies or
controlled clinical trials to support the contention that 1MD interacts
with any class of antidepressant drugs. There are no case reports of
an aderse pharmacodynamic interaction between 1MD and tricyclic
 the guidelines should be strictly obsered in all patients ta#ing
any form of the oral contraceptie pill.
 depressed patients not ta#ing any of the problem drugs it is
best to recommend preparations which delier a reasonable dose of
hyperforin $in the range 43 to 6: mgGday%. $tablets or capsules
containing a dried e(tract.%
 In terms of potential pharmacodynamic interactions, the e(act
mode of action of 1MD on monoamine neurotransmitters is not
#nown. .esults from comparatie in io studies suggest that its
pharmacological profile is Auite different to 11.Is and tricyclics.
 Dhile there are a few case reports of aderse interactions
between 1MD and 11.Is suggestie of serotonin syndrome, the
Auality and number of such reports is low $gien the widespread use
of the herb%.
 If clinically appropriate, it is suggested that, 1MD &!- be
combined with antidepressant drugs under professional superision.
! low dose should be recommended at first both as a caution and to
reassure the patient.
1tudies hae shown 1t MohnHs wort e(tract produce improements in;
 depression
 an(iety
 apathy
 sleep disturbances
 insomnia
 anore(ia
 feelings of worthlessness.
 Pharmaco#inetic drugs reactions no an issue for doses less
than 5 g of herb per day, or any doses low in hyperforin content $such
as tinctures and fluid e(tracts%.
"avendula officinalis
 In aromatherapy used to calm an(iety and boost mood.
 1mall double blind trial using 6ml of 473 per day to compare
with imipramine, a third of patients too# both.
 Tincture of benefit but not as effectie, higher doses might hae
been more effectie.
 &ombination better than imipramine alone, without any
accentuation of the drugHs side effects.
!alvia officinalis
 2ood and cognition enhancement
 1age has long been suggested to improe memory and mood.
 1eeral randomized controlled trials proide e(cellent eidence
for the use of sage for these purposes, een in stressful situations.
 study demonstrated improed mood and cognitie performance
following the administration of single doses of sage leaf to healthy
young participants.
 !n e(tract of sage leaf e(hibited dose-dependent, in itro
inhibition of acetylcholinesterase and, to a greater e(tent,
 &ognitie performance effects7 1age may hae anticholinergic
actiity and may improe cognition. In a placebo controlled study in
!lzheimer;s patients, an ethanol e(tract of sage $>: drops daily%
produced a significant improement in cognition after four months.
'ried sage leaf $6:: or >::mg% has been shown in a double-blind,
placebo controlled, crossoer study to improe mood, alertness, and
cognitie performance.
 Post iral e(haustion and depression. Poor memory from
nerous causes eg an(iety.
 Trials shown reduction in insomnia, emotional instability,
somatisation $physical symptoms caused by mental or emotional
factors%, not effectie in self esteem e(cept when used in high doses
$>?:mg per day eAuialent to <-?g of root per day%.
 !daptogenic, antistress actiity; in depression the stress
hormone such as cortisol and indieed the hypothalamic-pituitary-
adrenal a(is are oeractiated and do not switch off the
appropriatelyia the normal negatie feedbac#. 1tress chemicals
$stress #inases% released by cells play a role in this, they inhibit the
sensitiity of receptors in the brain to cortisol.
 .hodiola decreased the release of stress #inases and cortisone
in response to stress. 1o it inhibits the stress induced actiation of
stress #inases in depressed patients and so restores the impaired
sensitiity of their brain receptors to cortisone.
 This IresistanceH of the cortisol receptors is a noted feature in
many patients with major depressions, just as resistance to insulin is
a #ey feature in type 5 diabetes.
 -o 1B
 the proposed mechanism Auite different to conentional
anitdepressant drugs, and unli#ely to interact with those drugs, is a
major adantage.
-urnera diffusa
 1hown in small placebo controlled study improing se(ual
desire and satisfaction
 a combination product including ginseng, damiana, and ging#o
shown in small placebo controlled study, improed se(ual desire and
 &onstituents; beta-sitosteroil, essential oil with alpha-pinene, p-
cymene, 4,?-cineol, tannins, resins, arbutin.
 Csed by indigenous people in 2e(ico as inigorator and
aphrodisiac, for muscular and nerous debility, esp after long
journeys or hunts $although may hae been fabricated%, and in
inflammatory condtions such as orchitis and nephritis Tyler indicates
that it was introduced as an aphordisiacal eli(ir in the C1! in 4?E<,
and was soon e(posed as a fraud. )oyd in 4=:< remar#ed on the
fraud, and the gossip still continous.
 In inflammatory conditions used such as orchitis and nephritis.
 In western herbal medicine tradition; nerine tonic, with
application to lowered libido. !ntidepressant, stomachic, nerous
dyspepsia, an(iety neurosis.
 !n(iolytic actiity in mice, and aphrodisiac actiity in rats found.
 1e(ual an(iety, impotence with frigidity. 'epression with
physical wea#ness.
!cutellaria lateriflora
 Traditionally used for nerous tension and epilepsy.
 Bclectics used for nerousness with fatigue or depression.
Tonic, antispasmodic, benefits for nerous disorders characterised by
irregular muscular action such as twitching, tremors, and
 &ontemparory few; nerous tension due to chronic stress,
illness, e(haustion, neuralgia, insomnia as well as depression.
 .estlessness, #eeping your head on, sthenics.
 Insomnia with restlessness and irritability. 2inor epilepsy with
other herbs.
Avena sativa
 0ildegard on Bingen; oats are a happy and healthy food for
people who are well, furnishing them with a cheerful mind and a pure,
clear intellect. ,ne is irgichtiget, and from it has been made a bit
mad, with diided mind and crazy thoughts, should ta#e a sauna
bath. 0e should pour the water in which the oats hae been coo#ed
oer the hot roc#s, if he does this often he will become himself and
regain his health.
 /ol# usage as sedatie for nerous states and insomnia.
 In io; improement of actie stress response, an
enhancement of shoc# aoidance learning and an increased
synchrony in social behaiour. It may be concluded that the wild
green oat e(tract is suitable to improe behaioural initiatie in
different situations.
 Dea#ness, feebleness, lac# of nere force, adrenal e(haustion,
end of term remedy, se(ual debility, melancholia with peishness,
trmore, palpitaion, insomnia in sthenic people, melancholia and
confusion in the menopause, P21 with adrenaline sensitiity,
recoery from addiction $add &apsicum%
 2ild sedatie and hypnotic properties.
 Indole al#aloids
 in aryuedic medicine; decoction of ordinary oats used in opium
withdrawal treatment, lead to research into nicotine withdrawal, using
fresh e(tract.
 /ound to hae better results than the placebo.
!chisandra chinensis
 In chinese medicine; Auiets the spirit, while calming and
containing the 0B!.T OI, hence is used to treat irritability,
palpitation, dream-disturbed sleep, insomnia, neurasthenia, tonic,
particularly in fatigue.
 Indigenous siberians used the berries to combat fatigue during
hunting trips, the hunters roamed for days, nothing to eat, eating the
berries, and no signs of fatigue.
 0orse; improed race times, reduced heart rater, and facilitated
 Cncontrolled trials; enhances mental and physical efficiency in
healthy. Benefitted patients with hallucinations, paranoia and
 ,bserational study; improed general physical and mental well
being of < out of ? pt. with schizophrenia. &omplete recoery in all 4:
cases of astheno- depressie syndrome.
 Improed in wor# capacity healthy.
.erbena officinalis
 Dea#ness, oerstriing, tension, feers, tension in upper body,
paranoia, post iral e(haustion, insomnia in sthenics with e(cessie
 Dith pulsatilla for stress insomnia. /or people who wor# to hard
and e(haust themseles.
 +erbena was considered a sacred plant in northern Burope
where it was purportedly used as a defense against illnesses and as
a component of loe potions.
/in)go biloba
 5<@ gin#go flaonglycosides and >@ terpenoids
 antidepressant effects, especially in patients oer the age of 3:
 .esearchers became interested in the antidepressie effects of
*in#go biloba e(tract as a result of the improement in mood
reported by patients suffering from cerebroascular insufficiency who
were treated with gin#go in double-blind studies.
 These obserations led to seeral double-blind studies of the
efficacy of gin#go in depression.
'ouble blind study
 In double-blind study, <: older patients $age range, 34"E?
years% with depression who had not benefited fully from standard
antidepressant drugs were gien either ?: mg of *in#go biloba
e(tract three times daily or a placebo.
 By the end of the fourth wee# of the study, the total score on
the 0amilton 'epression 1cale was reduced on aerage from 4< to E.
!t the end of the ? wee# study, the total score in the *in#go biloba
e(tract group had dropped to <.3. In comparison, the placebo group
only dropped from 4< to 46. This study indicates that *in#go biloba
 conclusion of study; e(tract can be used with standard
antidepressants and it may enhance their effectieness, particularly in
patients oer 3: years of age.
 antidepressant effects in a number of animal models including
the learned helplessness model. able to counteract one of the major
changes in brain chemistry associated with aging " the reduction in
the number of serotonin receptor sites.
 Typically, with aging there is a significant reduction in the
number of serotonin receptor sites on brain cells. !s a result, the
elderly are more susceptible to depression, impaired mental function,
insomnia, and sleep disturbances.
 The study was designed to determine whether *in#go biloba
e(tract could alter the number of serotonin receptors in old $5<-
month-old% and young $<-month-old% rats.
 !t the beginning of the study, the older rats had a 55@ lower
number of serotonin binding sites compared with the younger rats.
The results of chronic treatment with *in#go biloba e(tract for 54
consecutie days demonstrated that there was no change in receptor
binding in young rats, but in the older rats there was a statistically
significant increase $by 66@% in the number of serotonin binding sites.
These results indicate that *in#go biloba e(tract may counteract at
least some, if not all, of the age-dependent reductions of serotonin
binding sites in the aging human brain as well.
 The e(act mechanism of *in#go biloba e(tractHs effect on
increasing serotonin receptors has not yet been determined;
howeer, *in#go biloba e(tract may address two major reasons why
serotonin receptors decline with age7 impaired receptor synthesis, or
changes in cerebral neuronal membranes or receptors as a result of
free radical damage. *in#go biloba e(tract has demonstrated an
ability to increase protein synthesis. In addition, *in#go biloba e(tract
is #nown to be a potent antio(idant.
 The most li#ely e(planation is that it is a combination of these
two effects $and others% rather than one single mechanism.
Melissa officinalis
 &ontains essential oils.
 'eried from IBeeH
 *erard; comforts the heart, drieth away all melancholy and
sadness, ma#es the heart merry and joyful, and strengtheneth the
ital spirits
 &ulpeper J&auses the mind and heart to become merry, drieth
away all troublesome cares and thoughts out of the mind , arising
from melancholy and blac# choler.K
 )ongleity, *riee; Mohn 0ussey or 1ydenham lied to the age
of 44>, brea#fasted for 3: years on balm tea sweetened with honey,
and so did Prince of /lamorgan, who died in his 4:? year.
 Csed for tenseness, restlessness, irritability, symptomatic
treatment of digestie disorders.
 Present research confirmed its use in old age, and as antiiral.
 trial to e(amine effects of three doses of lemon balm on
cognition and mood ; The results demonstrated a sustained increase
in Paccuracy of attentionP after ingesting >::mg and reductions in
Psecondary memoryP and Pwor#ing memoryP that were time- and
dose-dependent. Patients reported reductions in PalertnessP after the
administration of =::mg and reported that PcalmnessP was eleated
after the administration of 6::mg. ! limitation of this study is the
small sample of young, healthy subjects not representatie of the
population of patients with dementia who may benefit from lemon
 ! sustained improement in Paccuracy of attentionP following
>::mg of lemon balm and time- and dose-specific reductions in both
Psecondary memoryP and Pwor#ing memoryP factors were
demonstrated in the treatment group.
 1elf-rated Pcalmness,P as assessed by Bond-)ader mood
scales, was reported to be eleated at the earliest time points by the
lowest dose, and PalertnessP was reported to be significantly reduced
at all time points after the highest dose.

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