St.

Johns Wort

Steven A. Witherly, Ph.D. San Antonio, 1998

Includes recent updates for 2004

Talk Outline
Serotonin chemistry and behavior SSRI Chemistry and Actions SJW chemistry SJW Clinical Research Unusual aspects of SJW NIH Trial of SJW vs Zoloft Future Directions and Research

Serotonin Facts:
5-Hydroxytryptamine is most prevalent in gut and brain neurons. L-Tryptophan serves as the precursor for 5-HT-- and is an essential AA. 5-HT can increase markedly with more precursors. Activity in synapse is terminated by reuptake into presynaptic vesicles.

Serotonin Facts:
Primary catabolism is MAO enzymes. MANY serotonin subtype exist (and variety of signal transduction mechanism) which affect different physiological states. Many receptor subtypes do NOT undergo compensatory regulatory changes. In CNS, 5-HT is involved in sleep, sexual behavior, circadian rhythms and feeding.

Serotonin Facts:
Serotonin is a neuromodulator of other transmitters in the CNS and Gut. Most CNS serotonin cell bodies are in the Raphe brain stem. Serotonin has inputs into the Medial Forebrain Bundle (Pleasure Center), hippocampus, amygdala, hypothalamus and neocortex.

Serotonin Facts:
Limbic System a big target for 5-HT. 5-HT sets the arousal tone for the organism. Serotonin and Anxiety are also linked. 5-HT receptors in gut responsible for side-effects of SSRIs.

Serotonin
Cell Bodies of 5-HT lie in the Raphe midbrain system. @15,000 neurons influence billions of brain cells. Most influence on limbic and neocortex. Largest number of receptors in the gut.

Types of Depression
Most common Psychiatric disorder Reactive/Endogenous/Mixed 25% population suffer from Depression Strong Genetic Link Major/Dysthymia/Bipolar

Alcohol and Depression

Rats bred to prefer alcohol drank 50% less when treated with SJW.

Dr. Amire Rexvani (1998)

Genetic Depression
Tryptophan Hydroxylase>>>5-HT Multifactorial Enzyme and phenotypic expression varies greatly.
Baldwin (1995), Int. Clin. Psychopharm, 9, S4, 41-

Non-Responders
30% patients dont respond to SSRIs Depression Multifactorial Genetics/Nutrition/Psychotherapy 30% respond to Placebo 10% another illness responsible

Depression Triangle: Present: Melancholy Past: Guilt Future: Anxiety

Euromed pamphlet on SJW

Women & Depression

Women have 52% less serotonin receptors than men Women prone to depression Men prone to aggression & alcoholism

Nutrition & Depression

B1, B6, B12 and Folic Acid DHEA & Pregnenolone DHA and Fish oils S-Adenosyl methionine Phosphatidylserine DMAE Chromium Picolinate Inositol Tryptophan or 5-OH Try. DL-Phenyalanine

Phytochemicals and Depression

St. Johns Wort (inc. bioamines) Ginkgo biloba (inc. bioamines, SB sites) Panax ginseng (inc. 5-HT) Ashwagandha (valium agonist) Bacopin (Ayurvedic) Gotu Kola Dong Quai (5-HT agonist) Kava Kava (5-HT antagonist)

AntiDepressant Medication
Tricyclic antidepressant (imipramine) Monoamine Oxidase Inhibitors (Parnate) Selective 5-HT Reuptake Inhibitors Prozac (fluoxetine) Zoloft (sertraline) Paxil (paraxetine) Effexor (venlafaxine) Serzone (nefazodone)

AntiDepressant Medication
Unknown mechanism: Buproprion (Wellbutrin) Trazodone (Desyrel) Saint Johns Wort

Potent Serotenergic Activity

LSD Mescaline Psilocybin Apiole/myristicin -- (essential oils) 5-HT2 agonists

Hypericum Extracts:
Relaxing & activating effects on CNS brain activity Reduce alpha, Increase Theta and Beta waves Show same effect as MAO drugs!!!

Depression Numbers
18 million sufferers 65 million anxiety disorders Millions with personality/eating/ADD and obsessive compulsive
Dr. Bloomfield, 1998

Hypericum Extracts
Unstable Need light activation Vary according to plant part used Many active components

New SJW Extract

5% Hyperforin content Standardized to Hypericin, Pseudohypericin & Hyperforin Ready for commercial launch Schwabe Company

Hypericin Extracts [Summary]

Inhibit II-6>dec. DRH>dec. Cortisol Inhibits reuptake of serotonin, Norepi and Dopamine MAO1 inhibitor (quercetin) L-Glutamate (?) Amentoflavone has diazepam activity

Hypericin Extracts [Summary]

Serotonin receptor upregulator of 5HT2 Dec. Prolactin Secretion Increases Melatonin concentration Inhibits COMT enzyme (extraneuronal catecholamines)

NIH Trial of SJW

Zoloft vs. SJW vs. Placebo 150mg Zoloft vs. 1800mg 0.3% SJW Using Kira (Lichter Pharma) Will file for IND or OTC and Rx status Similar supplements may qualify

NIH Trial of SJW

Doomed to failure: Using severely depressed High level of Zoloft Zoloft placebo effect Negative US doctors Pharmaceutical Co. backlash

SJW Active Component

Activity of whole extract is not explained by the combined actions of purified extracts
Dr. Nahrstedt, Anaheim Convention

St. Johns Wort Side-Effects

NO Drowsiness NO Drug Interactions NO Alcohol Interaction No GI Upset Compatible with SSRIs

SJW Side Effects II

St John's wort causes an induction of ethinyl estradiol-norethindrone metabolism consistent with increased CYP3A activity. Women taking oral contraceptive pills should be counseled to expect breakthrough bleeding and should consider adding a barrier method of contraception when consuming St Johns wort. Clin Pharmacol Ther. 2003 Dec;74(6):52535

St. Johns Wort Constituents

Substance Phloroglucins Xanthones BiFlavonoids Dianthrones Flavonoids Essential Oils Plant acids Example Hyperforin Norathyriol Biapigenin Hypericin Pseudohypericin Quercetin A-pinene Chlorogenic Caffeic Actions Antidepressant Antidepressant Antiviral + Antiviral + Antidepressant + Antidepressant? Neuralactive Neuralactive

N-Alkanols (+) means many other actions

SJW Effects Latest 2003

in vitro binding assays carried out using St John's wort extract demonstrated significant affinity for adenosine, GABA(A), GABA(B) and glutamate receptors St John's wort extract leads to a down regulation of beta-adrenergic receptors and an upregulation of serotonin 5-HT(2) receptors in the rat frontal cortex

SJW Latest Effects II

Recent neuroendocrine studies suggest that St John's wort is involved in the regulation of genes that control hypothalamic-pituitaryadrenal axis function Effects from: hypericin, the phloroglucinol derivative hyperforin and several flavonoids CNS Drugs. 2003;17(8):539-62.

Problems with SSRIs

Expensive Sexual Side-Effects-as in no interest or performance Dont work forever-- Prozac Poop-Out Intestinal side-effects never go away: Constipation/diarrhea Decrease memory performance Nasty withdrawal symptoms

Selectivity of SSRIs
Type Norepi MAO inh. ++ TriCyc. ++ Prozac Zoloft Serzone Wellbutrin Uppers + Serot ++ + +++ ++++ ++ ++++++ Dopamine ++ +++

SSRIs and Therapeutics

Prozac: Depression/Energizing/+++SE Zoloft: Depression/++SE Paxil: Depression/Anxiety/++SE Serzone: Depression/Anxiety/+SE Effexor: Severe Depression/+++SE SJW: Depression/Anxiety/NO SE

SE is Side Effects

SJW and Phototoxicity

13 volunteers exposed to UV A/B 0 to 3600mg of SJW, 0.3% Only minimal effects at high doses Flavonoids protect skin Oil is great for sunburn
Pharmacopsychiatry, 30, S2, 94-101, 1997

SJW & 5HT- Receptors

Take 2 weeks to work In rats, both 5-HT1A & 5-HT2A receptors were inc. By 50% by 26week administration Binding affinity remained unchanged
Pharmacopsychiatry, 30, S2, 113-6, 1997.

Depression & the Brain

Infant trauma permanently affects brain response to external stimuli. Psychotherapy can reroute some brain chemistry functions. Psychotherapy plus medication best solution to depression and anxiety. Depression often result of unresolved emotional conflict (subconscious).

St. Johns Wort & Clinicals:

5000 people tested in over 30 clinical trials 2000 subjects in controlled doubleblind 70% subjects show significant relief 30% subjects show Placebo relief pre-1985 studies often combined herbs

Clinical Meta-Analyses
British Medical Journal studied 23 clinical trials 15 studies versus placebo Eight clinicals vs. Antidepressants 55.1% responded to 22.3% for Placebo

Depression & DSM-IV

Major Depressive Disorder Dysthymia Adjustment disorder Bipolar Disorder Seasonal Affective Disorder (SAD)

Hyla Cass (1998)

St. Johns Wort & Taste

Individuals taking SJW often report improvements in the taste of food and internet chat-sites report that weight gain is a common side-effect of the herb.

St. Johns Wort & the Brain

There is a high probability that constituents in SJW accumulate in the brain (Hypericin) as seen in animal experiments.
Dr. Bloomfields book, 1996, p. 173

SSRI Sexual Side-Effects

First published in Playboy magazine

Serotonin Receptor

The book that started it all:

Saidit could make you better than well

Serotonin Pathways

Biosynthetic pathway for Catecholamines

Serotonin and Tryptophan

Latest SJW Studies

the proposed mechanism of action seems to be multiple: a non-selective blockade of the reuptake of serotonin, noradrenaline and dopamine; an increase in density of serotonergic and dopaminergic receptors and an increased affinity for GABAergic receptors Phytomedicine. 2003 Nov;10(8):688-99.

SJW Anti-inflammatory
St. John's wort (SJW) has been described to show anti-inflammatory properties due to its inhibitory effects on the expression of proinflammatory genes like cyclooxygenase-2, interleukin-6, and inducible nitric-oxide synthase (iNOS). J Pharmacol Exp Ther. 2003 Oct;307(1):254-61. Epub 2003 Sep 03

SJW and Juvenile Depression

St. John's wort may be an effective treatment for youths diagnosed with major depressive disorder 22 youths had their dose increased to 900 mg/day J Am Acad Child Adolesc Psychiatry. 2003 Aug;42(8):908-14.

SJW & Valerian

The studies quoted here prove that the symptoms associated with anxiety that severely afflict patients can be clearly improved more quickly with a combination therapy of St John's wort extract and valerian extract than with St John's wort monotherapy Phytomedicine. 2003;10 Suppl 4:25-30.

Final Comments
SJW effective in mild depression and anxiety Effects many neurotransmitter systems Speeds the breakdown of many drugs Affects changes in brain that are calming Virtually NO side effects High quality extracts should be used.