St. John

1
St. Johns Wort

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

Includes recent updates for 2004
2
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

3
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 re-uptake
  into presynaptic vesicles.

4
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.

5
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.

6
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.

7
Serotonin

• Cell Bodies of 5-HT lie in the Raphe midbrain
  system.
• _at_15,000 neurons influence billions of brain
  cells.
• Most influence on limbic and neocortex.
• Largest number of receptors in the gut.

8
Types of Depression

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

9
Alcohol and Depression

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

Dr. Amire Rexvani (1998)
10
Genetic Depression

• Tryptophan Hydroxylasegtgtgt5-HT
• Multifactorial Enzyme and phenotypic expression
  varies greatly.

Baldwin (1995), Int. Clin. Psychopharm, 9, S4,
41-
11
Non-Responders

• 30 patients dont respond to SSRIs
• Depression Multifactorial
• Genetics/Nutrition/Psychotherapy
• 30 respond to Placebo
• 10 another illness responsible

12
Depression Triangle

• Present Melancholy
• Past Guilt
• Future Anxiety

Euromed pamphlet on SJW
13
Women Depression

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

14
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

15
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)

16
AntiDepressant Medication

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

17
AntiDepressant Medication

• Unknown mechanism
• Buproprion (Wellbutrin)
• Trazodone (Desyrel)
• Saint Johns Wort

18
Potent Serotenergic Activity

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

19
Hypericum Extracts

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

20
Depression Numbers

• 18 million sufferers
• 65 million anxiety disorders
• Millions with personality/eating/ADD and
  obsessive compulsive

Dr. Bloomfield, 1998
21
Hypericum Extracts

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

22
New SJW Extract

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

23
Hypericin Extracts Summary

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

24
Hypericin Extracts Summary

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

25
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

26
NIH Trial of SJW

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

27
SJW Active Component

• Activity of whole extract is not explained by the
  combined actions of purified extracts

Dr. Nahrstedt, Anaheim Convention
28
St. Johns Wort Side-Effects

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

29
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 Dec74(6)525-35

30
St. Johns Wort Constituents
Substance Example Actions Phloroglucins Hyperfor
in Antidepressant Xanthones Norathyriol Antidep
ressant BiFlavonoids Biapigenin Antiviral
Dianthrones Hypericin Antiviral
Pseudohypericin Flavonoids Quercetin Antide
pressant Essential Oils A-pinene Antidepressant
? Plant acids Chlorogenic Neuralactive Caffei
c N-Alkanols Neuralactive () means many
other actions
31
SJW Effects Latest2003

• 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

32
SJW Latest Effects II

• Recent neuroendocrine studies suggest that St
  John's wort is involved in the regulation of
  genes that control hypothalamic-pituitary-adrenal
  axis function
• Effects from hypericin, the phloroglucinol
  derivative hyperforin and several flavonoids
• CNS Drugs. 200317(8)539-62.

33
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

34
Selectivity of SSRIs
Type Norepi Serot Dopamine MAO inh.
TriCyc. Prozac
Zoloft Serzone Wellbutrin
Uppers
35
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
36
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
37
SJW 5HT- Receptors

• Take 2 weeks to work
• In rats, both 5-HT1A 5-HT2A receptors were inc.
  By 50 by 26-week administration
• Binding affinity remained unchanged

Pharmacopsychiatry, 30, S2, 113-6, 1997.
38
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).

39
St. Johns Wort Clinicals

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

40
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

41
Depression DSM-IV

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

Hyla Cass (1998)
42
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.

43
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
44
SSRI Sexual Side-Effects
First published in Playboy magazine
45
Serotonin Receptor
46
The book that started it all
Saidit could make you better than well
47
Serotonin Pathways
48
Biosynthetic pathway for Catecholamines
49
Serotonin and Tryptophan
50
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 Nov10(8)688-99.

51
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
  pro-inflammatory genes like cyclooxygenase-2,
  interleukin-6, and inducible nitric-oxide
  synthase (iNOS).
• J Pharmacol Exp Ther. 2003 Oct307(1)254-61.
  Epub 2003 Sep 03

52
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
  Aug42(8)908-14.

53
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. 200310 Suppl 425-30.

54
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.