What Else Is in 5-HTP SeroTonic™

(St. John’s Wort)
for Depression

By Will Block

N ewsweek has felt the pulse of the nation and concluded in a front-cover bannered article (May 5, 1997) that the world needs a natural alternative to Prozac® (and other SSRIs). With just one mention each of pregnenolone and 5-hydroxytryptophan (5-HTP), they take up the case for St. John’s Wort, also known as hypericin. And the case for using hypericin in the treatment of minor depression is good, although not as well substantiated as that for pregnenolone, or better yet, for 5-HTP.

The antiviral aspects of hypericin were first drawn to our attention several years ago because of its reported use by the AIDS treatment underground.1 At that time, we saw only the tip of this herbal iceberg. As the most active component in an herb known as St. John’s Wort, hypericin has been in use for a wide variety of conditions since at least the time of ancient Greece.2 Among its areas of use are improved wound healing, anti-inflammatory effects,3 antimicrobial activity,4 sinusitis relief (perhaps due to its bioflavanoid component, quercetin),5 seasonal affective disorders, (SAD)6 and especially depression. Back in the classical Mediterranean world and throughout the folk medicine of the middle ages, St. John’s Wort’s earned its reputation as a powerful mood-altering substance. And now science is confirming this reputation. This property is why Life Enhancement includes a synergistic amount of St. John’s Wort in its breakthrough product, 5-HTP SeroTonic.

Although its antiviral benefits are not in dispute, the very large amounts of hypericin needed to achieve this benefit render the user highly susceptible to ultraviolet excesses.7 In livestock known to eat large quantities of the St. John’s Wort plant, there is an increased sensitivity to sunlight, which has resulted in the blistering of skin and even death. This side effect was also observed in a recent clinical trial of hypericin. A few of the subjects had skin rashes and irritation severe enough to prevent them from venturing outdoors. Oddly, light appears necessary for the antiviral benefits.8

With smaller amounts, however, hypericin can be quite beneficial and does not require the avoidance of direct sunlight. In Germany, where it is used for depression, it is so popular that over 66 million daily doses were prescribed in 1994.9 The British Journal of Medicine published a review of the treatment literature in 1996.10 Twenty-three randomized trials of St. John’s Wort involving a total of 1,757 outpatients with mild to moderately severe depressive disorders were analyzed. The conclusions were quite clear: hypericin was significantly superior to placebo, and seemed to be comparable in effectiveness to standard antidepressants (other than SSRIs) for mild depression. All this occurred with fewer side effects — including impairment of cognitive performance — which has only rarely been observed. Unlike pharmacological antidepressants (5-HTP excluded), hypericin does not lead to any impairment of attention, concentration or reaction.11

Many of the controlled studies measuring hypericin’s efficacy in depression compared the herb (alone or combined with other plant extracts) with placebo and/or a standard antidepressant.10 Most trials were double-blinded and lasted from 4 to 8 weeks. The measures used in these studies included improvement in depressive symptoms and evaluation with the commonly used Hamilton Depression Rating Scale (HAMDS) and the Clinical Global Impressions (CGI) Scale. The daily dose of hypericin varied widely, although the most common amounts were the equivalent of between 100 and 300 mg of 0.3 % extract for a total of 300 to 900 µg per day.

Fifteen of the studies were placebo-controlled (14 testing single preparations and one using a combination with other plant extracts), and 8 compared hypericin with an antidepressive drug (6 testing single preparations and 2 testing combinations).

The most common side effects associated with hypericin were gastrointestinal symptoms, allergy and fatigue. Those taking standard antidepressants were almost twice as likely to encounter severe side effects (35.9% vs. 19.8%). A total of 4% of patients receiving hypericin preparations dropped out of trials because of side effects, as did 7.7% of those receiving standard antidepressants.

In a meta-analysis of the data, the researchers acknowledged the difficulty of drawing conclusions because of the differences in the amounts of the hypericin and other variables. Also complicating matters was the undoubted variation in the contents of the extracts (the same extract was not used in all the studies) and the possibility that other active ingredients were present that fail to show up in a non-standardized extract.

Nevertheless, the meta-analysts found enough evidence to conclude that hypericin is better than placebo in treating some depressive disorders. They could not judge whether hypericin is as good as the standard pharmaceutical antidepressants, although it appears to cause fewer side effects than these drugs. (Hypericin has not been directly compared with 5-HTP.)

In an editorial accompanying the meta-analysis, it was agreed that the data on hypericin are promising but not yet sufficient to accept it as an effective antidepressant preparation.9 (What else is new?). What is required to understand the efficacy is: 1) dose standardization studies; and 2) longer trials.

How does hypericin work as an antidepressant? Although hypericin is a mild monoamine oxidase (MAO) inhibitor, a recent study found no support for this as an explanation.12 A more likely, but so far unsubstantiated, hypothesis involves hypericin’s relatively strong affinity for gamma-aminobutryic acid receptors (GABAa) an activity attributed to the herb’s flavonoid property?3

Another explanation posits the vascular relaxation effect of the procanidin fractions of hypericin, which prevents or antagonizes histamine- or prostaglandin-induced arterial contractions.14

A final intriguing possibility: In animal studies, hypericin has been shown to enhance the exploratory activity of mice in a novel environment. At the same time, the animals’ narcotic-induced sleeping time was significantly prolonged on a dose-dependent basis.15 As with many — if not most — other antidepressants, hypericin administration decreased aggressiveness in socially isolated male mice.

When our researchers and formulators were working on the ingredients of 5-HTP SeroTonic, they were quite aware of the studies on hypericin, which is why they started with the average amount used in the meta-analysis studies. It was immediately clear, however, that the synergy of 5-HTP with hypericin was so great that the effect of 5-HTP was doubled when just a small amount of hypericin was included. We knew we had a real winner on our hands even before the market responded. What we had created in 5-HTP SeroTonic was a product that was truly greater than the sum of the parts.


  1. Lavie G, Valentine F, Levin B, Mazur Y, Gallo G, Lavie D, Weiner D, Meruelo D. Studies of the mechanisms of action of the antiretroviral agents hypericin and pseudohypericin. Proc Natl Acad Sci. 1989;,86:5963–5967.
  2. Tammaro F, Xepapadakis G. Plants used in phytotherapy, cosmetics and dyeing in the Pramanda district (Epirus, North-West Greece). J Ethnopharmacol. 1986;16:167–174.
  3. Zaichikova SG, Grinkevich NI, Barabanov EI, et al. Healing properties and determination of the upper parameters of toxicity of Hypericum herb. Farmatsiya. 1985;34:62–64.
  4. Barbagallo C, Chisari G. Antimicrobial activity of three hypericum species. Fitoterapia. 1987;58:175–180.
  5. Razinkov SP, Yerofeyeva LN, Khovrina MP, Lazarev AI. Validation of the use of Hypericum perforatum medicamentous form with a prolonged action to treat patients with maxillary sinusitis. Zh Ushn Nos Gorl Bolezn. 1989;49:43–46.
  6. Martinez B, Kasper S, Ruhrmann S, Moller H-J. Hypericum in the treatment of seasonal affective disorders. Nervenheilkunde. 1993;12:302–307.
  7. Kubin A, Alth G, Jindra R, Jessner G, Ebermann R. Wavelength-dependent photoresponse of biological and aqueous model systems using the photodynamic plant pigment hypericin. J Photochem Photobiol. 1996;36:103–108.
  8. Hudson J.B, Harris L, Towers GHN. The importance of light in the anti-HIV effect of hypericin. Antiviral Res. 1993;20:173–178.
  9. De Smet PA, Nolen WA. St. John’s Wort as an antidepressant. Brit Med J. 1996;313:241–247. Editorial.
  10. Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D. St John’s wort for depression: An overview and meta-analysis of randomized clinical trials. Brit Med J. 1996;313:253–258
  11. Schmidt U, Sommer H. Extract of St. John’s wort in the treatment of depression: Attention and reaction remain unimpaired. Fortschr Med. 1993;111:37–40.
  12. Bladt S, Wagner H. Inhibition of MAO by fractions and constituents of hypericum extract. J Geriatr Psych Neurol. 1994;7(Suppl):S57–S59.
  13. Cott J. Natural product formulations available in Europe for psychotropic indications. Psychopharmacol Bull. 1995;31:745–751.
  14. Okpanyi SN, Weischer ML. Animal experiments on the psychotropic action of a Hypericum extract. Arzneimit. 1987;37:10–13.
  15. Melzer R, Fricke U, Holzl J. Vasoactive properties of procyanidins from Hypericum perforatum L. in isolated porcine coronary arteries. Arzneimit. 1991;41:481–483.

Will Block is the publisher and editorial director of Life Enhancement magazine.

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