St John's  Wort Literature Review

By

Camilla Cracchiolo, R.N.

(click on her name to visit her home page)

PLEASE NOTE

The manek.net website cannot take any credit for writing this article. This was done by the above author. All praise to her hard work. We only reformatted this exhaustive article into a web format.

This domain accepts no liability for any harm that may come to the user or non-user of St John's Wort. As with all information on the internet, you have to decide what to believe and what not to. It is up to you to verify any points made on this website.

This page was last updated on 19th September 1999.   As with all areas of science these days, things change. The author last revised the article on 10th December 1998. To see if it has been updated click here  to jump to the original site of this article.

CONTENTS:

Copyright Notice

Introduction and Disclaimer

1. What is St. John's wort?

2. Approved therapeutic uses in European countries

3. Treatment of depression

A. Efficacy and safety

B. By what mechanism does St. John's wort exert antidepressant effects?

C. What is the antidepressant agent in St. John's wort?

4. Adverse reactions and side effects

A. MAOI interactions with whole St. John's wort

B. Are any extracts of St. John's wort free of the risks of MAOI's?

C. Serotonin syndrome

D. Mania and hypomanic states

E. Seizures

F. Paralytic ileus

G. Photosensitivity

a. Mild photosensitive rash in humans

b. Fatal secondary photosensitization in animals

H. Peripheral nerve damage due to secondary photosensitization in humans

I. Minor side effects

J. LD50 and toxicology studies

5. Other drug interactions

6. Other pharmacological properties of St. John's wort

A. Effects on sleep

B. Anti-viral activity

C. Anti-bacterial and anti-fungal activity

D. Immunology effects

E. Wound healing properties

F. Other medicinal properties

7. Research on St. John's wort and pregnancy

8. "Herbal Phen-Fen"

9. Is St. John's wort useful in the treatment of cancer?

10. St. John's wort and Attention Deficit Disorder

11. Technical Appendices:

A. Precautions and suggested patient instructions

B. Dosage and administration

C. Pharmacokinetics

D. Chemical Constituents

E. Regulatory Status

11. References

St John's  Wort Literature Review By Camilla Cracchiolo, R.N.

(Hypericum perforatum and Hypericum augustifolia)

Note: This is a draft update. I don't have all the references nailed down yet; the section on SJW and ADHD remains to be written, I want to clarify some points about beta-sitosterol and I want to put it into HTML form. It also needs serious spell checking. However, due to significant new research on St. John's wort, I thought it more important to put up this latest draft than to make people wait until I've achieved literary perfection. :-)

 Last updated: December 10, 1998

COPYRIGHT NOTICE:

Copyright December, 1998 by Camilla Cracchiolo

This document may be reproduced in either electronic or written form for educational use in small quantities by patients, patient support groups, consumer advocates, health care providers and researchers as long as the document is reproduced in its entirety, credit is given and this notice remains attached. These people may charge a fee under $10.00 for any hard copies in order to cover the direct cost of reproduction.

This document may NOT be used by herb dealers as part of any sales or promotion.

INTRODUCTION:

NEW INFORMATION in this edition:

• Hyperforin has been identified as the probable main (but not only) antidepressant agent in SJW
• Reports of paralytic ileus and peripheral neuropathy
• Anecdotal reports of interactions with low dose oral contraceptives
• Discussion of the risk of mania to persons with bipolar depression.

I hope you find this article useful. I have tried to organise this document in such a manner that the less technical information is in body of the document and the more technical notes, such as chemical constituents and pharmacokinetics, are included as appendices. I have also used technical terminology but have provided a translation for non-medical people next to the word. Hopefully, this will allow lay people to obtain information easily while still providing the technical details that a medical or psychological practitioner needs when guiding patient care.

All of the prescribing information such as dosage and patient precautions have been attached as appendices. Those of you who wish to bypass the long explanations of what St. John's wort does and how it's believed to work can skip directly to the end to see how to use it. (Of course, I strongly recommend that you read the body of the article as well!)

You may also wish to look at the other articles in this page, especially _Herbal Medicine: Sometimes Helpful but Use With Care_ and the St. John's wort Medline abstracts.

DISCLAIMER:

Note for American readers: The U.S. FDA has not approved St. John's wort for any medical purpose. While other countries have approved and regulated the medicinal use of various herbs, including St. John's wort, their regulatory process is not as strict as that of the U.S. FDA and sometimes drugs used in other countries are found to have adverse effects that are screened out during the FDA approval process.

Because herbs are not well regulated in the U.S., there is no regulatory oversight of herbal product manufacturing, distribution and labelling. This means that, unlike in some European countries, the contents and potency of any herbal product in the United States cannot be guaranteed. There have been many cases where herbal products were found upon chemical analysis to differ greatly from what is stated on the label; in some cases these products were found to contain dangerous toxic compounds; some were even found not to contain herbs at all but to be composed of standard prescription drugs such as benzodiazepines (a class of tranquillisers including Valium and Xanax), non-steroidal anti-inflammatories and corticosteroids. Imports from China are a particular problem but this applies to imports from other countries and domestically produced products as well.

Due to this situation, the author does not and cannot endorse   any particular brand or herbal product.

It is possible to send individual herbal products to private laboratories to analyse the contents and compare them to the label. Several labs that perform these tests are listed in my FAQ on herbal medicine. However, all testing is at the expense of the user. At this time there is no government agency or consumer advocacy group that routinely monitors the contents of herbal products for purity.

Therefore, the use of an unregulated substance is at the patient's own risk.

NOTE: The terms "St. John's wort" and "Hypericum" will be used interchangeably in this document. You will also see the word "hypericin". Don't confuse this with Hypericum. Hypericum refers to the whole plant while hypericin is a particular chemical that can be isolated from Hypericum.

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1. WHAT IS ST. JOHN'S WORT?

The name St. John's wort refers to the plants Hypericum perforatum and Hypericum augustifolia.[2]

H. augustifolia is almost never used in commercially available preparations; so, unless otherwise stated, any reference in this article is to H. perforatum.

The flowering tops are the best source for extracts, but the entire above ground portion of the plant can be used. [2]

The St. John's wort monograph of the American Herbal Pharmacopoeia (AHP) states that St. John's wort consists of "the whole fresh or dried plant or its components, including not less than 0.04% naphthodianthrones of the hypericin group calculated as hypericin." [26].

H.perforatum is native to Europe, western Asia, North Africa, Madeira and the Azores. It has been transported and now grows wild in parts of Australia and North America, notably Oregon and the Pacific Northwest, where it is known as Klamath Weed.

H. perforatum is also known as :

• Qian Ceng Lou in Chinese;
• Sint-Janskruid in Dutch;
• Herba de Millepertuis, Herba de SaintJean and Toutsaine in French;
• Johanniskraut, Johannisblut, Blutkraut and Herrgottsblut in German;
• Perforata, Iperico and Pelatro in Italian;
• Zwieroboij in Russian; Hipericon in Spanish and Johannesort in Swedish. [26]

The Hypericum genus contains about 400 separate species.[1] The AHP states that Hypericum is in the family Clusiaceae; some authorities classify it as part of the Guttiferae family; others assign Hypericum it's own genus of Hypericaeae. [26] From what I can tell, the family Clusiaceae appears to supersede and include both the older families of Guttiferae and Hypericaeae.

Finally, Max Wichtl states in his classic textbook _Herbal Drugs and Phytopharmaceuticals_ that adulteration of St. John's wort is fairly common, most notably with other Hypericum species.

The most common adulterates of St. John's wort are H.maculatum, H. barbatum, H.hirsutum, H.montanum and H. tetrapterum. [26] In the wild, St. John's wort also can easily be mistaken for Rose of Sharon (H. calycinum). [1]

See my general article on herbal medicine for information on testing for adulterates and consumer rights re: adulterated herbs. http://www.primenet.com/~camilla/herbfaq.html

2. APPROVED THERAPEUTIC USES IN EUROPEAN COUNTRIES

(See Appendix A for a complete list of regulatory status by country.)

Since the U.S. FDA does not recognise therapeutic use for any herb, we must draw on the existing scientific literature and the regulations of European countries to determine the therapeutic value of St. John's wort. Unfortunately, European countries do not regulate herbs nearly as strictly as some herb distributors would lead you to believe. There is a strong movement in the European Union for bringing herbs under stricter controls. (See Appendix E for country-specific regulations.)

The most commonly approved indication in European countries external use in wound healing and bruising.

The next most often approved use is internally as an antidepressant and sedative.

Most herb researchers accept the German Commission E monographs as the world's best documented set of herb regulations and believe that they provide the most logical basis for product labelling. The Commission E monographs have failings: they are not as scientifically rigorous or up to date as one would hope and the commission itself has been disbanded. However, the situation in Germany is superior to that in the U.S. because at least there are requirements for product labelling and some SJW products have been tested extensively.

The German E Commission has approved St. John's wort for the following conditions:

Internal consumption:

• Psychogenic disturbances, depressive states, sleep disorders, anxiety and/or nervous excitement, particularly those associated with menopause.
• Oily Hypericum preparations are approved for stomach and gastrointestinal complaints and have anti-diarrhoeal activity.

External use:

• Oily Hypericum preparations are approved for the treatment and after-treatment of incised and contused wounds, muscle aches and 1st degree burns. [1]

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3. USE OF ST. JOHN'S WORT IN THE TREATMENT OF DEPRESSION

St. John's wort has recently come to popular attention in the U.S. primarily because of its scientifically documented antidepressant action.

As a result, many of the less scrupulous herb distributors have started marketing St. John's wort as "nature's Prozac" or even "nutritional support for depression". I recently saw an ad in a health food store of a smiling woman with a bottle of St. John's wort, simply stating "Get Happy Now".

While St. John's wort does indeed appear effective in the treatment of certain cases of depression, the real situation is considerably more complex. In fact, the antidepressants closest in action to St. John's wort are not SSRI's such as Prozac, but venlafaxine (Effexor) and bupropion (Wellbutrin). However, St. John's wort has effects on more systems than either of these drugs and the implications of these effects are not clear.

The most striking thing about St. John's wort is the fact that sexual dysfunction from St. John's wort has never been reported in the scientific literature. Anecdotal evidence indicates that sexual dysfunction from SJW is extremely rare.

Sexual dysfunction is perhaps the leading reason why people discontinue prescription antidepressants, and the reason behind why St. John's wort is receiving so much attention. Up to 70% of people on Prozac and a lower percentage of people on other antidepressants, both male and female, experience sexual problems including loss of libido, inability to achieve or greatly reduced orgasm and, in men, loss of the ability to have an erection.

An antidepressant that does not cause sexual dysfunction would be a great boon to many people with depression. So, the main question on most people's minds about St. John's wort right now is:

"How effective is it in treating depression and are there any adverse effects?"

A. Evidence of efficacy and safety:

In essence, there are a number of double-blind and placebo-controlled, but short, studies in humans and all demonstrate that St. John's wort has anti-depressant, anti-anxiety and mild sedative effects. While most of these studies are small, one was conducted on over 3200 patients.[6] However this study was not controlled; its primary value is in collecting reports of adverse reactions. Additionally, there is one study that suggests that St. John's wort may be effective in the treatment of Seasonal Affective Disorder [18] and a number of studies in animals demonstrating plausible mechanisms by which St. John's wort could exert antidepressant effects.

Human studies also consistently report that St. John's wort has far fewer side effects than conventional prescription antidepressants and is tolerated better by patients.

The most convincing evidence for the efficacy and safety of St. John's wort is a meta analysis published in the August 1996 issue of the British Medical Journal. The full reference is:

Authors: Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D; Title: St John's wort for depression--an overview and meta-analysis of randomized clinical trials.; Journal: British Medical Journal 313(7052), 253-258 (1996)

This study has caused the scientific and medical communities to sit up and take notice. The main reason for this is because BMJ is world renowned for their strict peer review standards. It's HARD to get published in the BMJ.

Another reason is the careful analysis and research techniques the authors applied to their review.

A meta analysis is one way to get around the inaccuracy of small studies. Small studies are less accurate than large ones because there is a greater possibility that the findings are just a statistical fluke: if you have 3 people in your study, and one has a side effect, that's one third of your study group. If you report this, you have may have grossly over-magnified the significance of the finding. On the other hand, maybe you run the same study on 100 people and only one as a bad reaction. In both studies, only one person reacted but the difference is that in one study, 33.3% reported adverse reactions and in the other 1.0% reported it. So, the more people in the study, the lower the probability that a particular finding is due to chance.

In a meta analysis, the researchers use statistical techniques to average together a group of small studies, making the population sampled larger and the results more like those of a large study.

The authors of the BMJ article reviewed 23 different controlled studies including a total of 1757 outpatients with mild to moderately severe depression. Twenty of the studies they reviewed were double-blind, one was single-blind, one was open label. They "quasi-randomized" the results by alternation.

The preparations used in the reviewed studies were all standardised as to hypericin content and most used a particular alcohol extract of Hypericum called LI 160. However, in the reviewed studies, the dose of whole herb varied considerably (from 300mg to 1000 mg daily) as did the dose of hypericin (0.4 to 2.7 mg daily).

Depressive symptoms were evaluated with generally accepted measurement scales such as the Hamilton Depression Scale (HAM-D).

The abstract gives the conclusion:

"Hypericum extracts were significantly superior to placebo... and similarly effective as standard antidepressants... There were two (0.8%) dropouts for side effects with hypericum and seven (3.0%) with standard antidepressant drugs. Side effects occurred in 50 (19.8%) of patients on hypericum and 84 (52.8%) of patients on standard antidepressants".

"There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe depressive disorders."[7]

This seems like pretty strong evidence in favour of St. John's wort. However, before we jump to conclusions and start telling everyone to take St. John's wort:

• All of the studies reviewed were of short duration. Most were 4-8 weeks in length. Most antidepressants become effective after a few weeks; but it may take longer than 8 weeks for antidepressants to build up to maximum effectiveness in certain individuals.

• The doses of antidepressants used in the control groups were relatively low. Thus, we don't know how well St. John's wort works when compared to a high dose of these drugs.

• Even though the compounds tested were standardised for hypericin content, it now turns out that hypericin is probably not be among the agents responsible for St. John's wort's antidepressant effects. This creates difficulty in comparing extracts.

• St. John's wort has never been compared to SSRIs (Prozac or Zoloft), to MAOIs or to any of the newer antidepressants like Effexor. It has only been compared in humans to tricyclic antidepressants (specifically amitriptyline, imipramine, and maprotiline) and in rats and mice to the above antidepressants plus a non-tricyclic called bupropion. It has been found similarly effective to the above antidepressants but there are a large number of people for whom tricyclic antidepressants don't work and animal studies don't necessarily carry over into human effects.

• St. John's wort has never been tested in severe depression. Anecdotal reports I've received suggest that its action is not as effective in severe depression.

• The authors of the BMJ article quoted above also stated that more information is needed before concluding that St. John's wort is as effective as standard antidepressants. They call for more studies comparing differing doses of St. John's wort to standard antidepressants.

• In a separate commentary accompanying the article, Peter DeSmet (one of the world's leading pharmacognosy researchers and editor of _Adverse Effects of Herbal Drugs_) and researcher Willem Nolen state that the data are promising but that more studies are needed. In particular, they want to find the most effective treatment dose, and want longer studies in order to evaluate the risk of relapse and late-emerging side effects. They also call for trials in severely depressed patients.[27]

The U.S. NIMH (National Institute of Mental Health) and the Office of Alternative Medicine have just begun a three year, multi-centre trial comparing St. John's wort to sertraline (Zoloft). [26] This study will permit the use of relatively high doses of both SJW and sertraline and will include severely depressed patients.

[Back to the Top]

B. By what mechanism of action does St. John's wort exert antidepressant effects?

Nobody knows.

Actually, this situation isn't very different from other antidepressants. Even though we have good theories about the actions of SSRIs, tricyclics and other antidepressants, we don't really know for sure how they work, either. But these drugs ARE much better studied than St. John's wort.

Two things seem clear:

1. Certain SSRIs such as Prozac (fluoxetine) and Zoloft (sertraline) are well known to have mild stimulant properties. Unlike these particular SSRIs, Hypericum has a significant sedative effect and stimulation is reported only rarely. This finding is more like that of some of the newer SSRI antidepressants such as venlafaxine (Effexor); thus sedation could be due to a sedative compound separate from the antidepressant agent or may be a direct effect of the antidepressant chemical(s). Whichever is true, this suggests that we are NOT dealing with "nature's Prozac".

2. Dry mouth has been reported only rarely, if at all, for Hypericum, suggesting that it does not have the anticholinergic action that tricyclic antidepressants are famous for. (Anticholinergic agents inhibit the key neurotransmitter acetylcholine and cause effects similar to those of the drug atropine: dry mouth, increased heart rate and pupillary dilation.) Crude Hypericum extract has significant receptor affinity for certain chemicals involved in brain neurotransmission, specifically: adenosine, GABA-A, GABA-B, serotonin, L-glutamate, benzodiazepine, inositol triphosphate and MAO-A and MAO-B [26]

Pharmacopsychiatry, a prestigious journal, recently devoted an entire supplementary issue to St. John's wort. The studies published in this issue suggest that the primary mechanism by which St. John's wort works is via inhibition of the reuptake of serotonin, norepinephrine and dopamine, in approximately equal amounts. (In other words, by preventing the brain from reabsorbing the neurotransmitters in question and so keeping serotonin, norepinephrine and dopamine levels in the brain at a higher level.) [14] [48,49,50,51,52,53] It also appears to inhibit reuptake of GABA and L-Glutamine. These two latter chemicals are the primary inhibitory (or"calming") neurotransmitters in the brain.

Older studies also support this theory:

A 1984 study on 6 women found that St. John's Wort increased the levels of norepinephrine metabolic by-products in the urine. This study also found St. John's Wort to have anti-depressive effects.[1]

A German study in 1995 also found that Hypericum extract caused 50% inhibition of serotonin uptake in in rat brains.[16] St. John's wort effects in animals are antagonised (reduced or stopped) by drugs known to reduce dopamine functional activity. These drugs include haloperidol, sulpiride, a-methyltyrosine and g-butyrolactone.[26] This would suggest a mechanism of action probably similar to that of bupropion.

Another theory is that St. John's wort acts on many levels simultaneously, creating an accumulating effect via serotonin, norepinephrine, and dopamine-reuptake inhibition, a low-level MAOI effect and by action on the hypothalamus inhibiting cortisol secretion.[14]

Hypericum's high affinity for GABA receptors has been proposed as one of the main mechanisms of action. GABA stands for gamma-aminobutyric acid. To grossly oversimplify, GABA is one of the main neurotransmitters involved in calming the central nervous system. It has mostly inhibitory effects on neurotransmitter reactions and is found throughout the brain. GABA is also involved in controlling reactions involving dopamine.

Research from the mid-1980s suggests that GABA may also be involved in antidepressant reactions.[ ] There is now a significant amount of research on GABA and depression. Certain agents that enhance GABA's activity, notably fengabine, have been reported to have antidepressant effects.

Researchers have also found that GABA plasma levels are low in depression of both the unipolar ("regular") and bipolar (formerly called "manic-depressive") type. Interestingly, atypical benzodiazepines such as aprazolam have been reported to have antidepressant as well as anti-anxiety effects. Unfortunately, their antidepressant effects have not worked that well in clinical practice, but they are still used in the treatment of depression with anxiety.

One highly respected researcher, JM Cott at NIH, conducted an in-vitro study to determine the receptor affinity of Hypericum for many different neurotransmitters. He argues that, while Hypericum shows receptor affinity for many neurotransmitter receptors, it does so only very weakly. His analysis suggests that only the affinity for GABA is strong enough for clinical effect. However, more recent research suggests a clinically significant effect on other receptors. His results may be due to an idiosyncrasy of the particular Hypericum product that he was studying. []

A 1997 study found that flower extracts from three different Hypericum species, including H. perforatum, block GABA and benzodiazepine binding sites in rat brains. Benzodiazepines (drugs such as Valium, Xanax and Klonopin) are believed to exert their sedative actions via increasing GABA's effects. That Hypericum enhances the activity of GABA certainly provides a plausible mechanism of action for the sedative and anti-anxiety effects of St. John's wort.[17]

Another very intriguing theory has recently been proposed: an immune stimulating chemical called interleukin-6 may cause depression in some people. [26] Interleukin-6 is found normally in the human body and is part of the system that stimulates lymphocytes and other white blood cells to defend the body. This theory might explain in part why glucocorticoids such as cortisone (strong immune suppressant agents) improve mood. St. John's wort does inhibit interleukin-6 production but much more research needs to be done on this theory.

D. What is the chemical responsible for St. John's Wort's antidepressant effects?

Again, nobody knows for certain. In fact, there are not one but several antidepressant agents in the plant. However, the strongest candidate for a single antidepressant agent is hyperforin, a phloroglucine found in the plant. Research has shown that hyperforin inhibits the reuptake of serotonin, norepinephrine and dopamine in approximately equal amounts. (In other words, all three remain at higher levels in the brain because they are not reabsorbed). [48,49,50,51,52]

This mechanism of action is unique and may partly account for the lower incidence of antidepressant related side effects with St. John's wort. Many antidepressants inhibit reuptake of two of the above three: SSRIs and tricyclics usually affect norepinephrine as well as serotonin; stimulants increase dopamine and norepinephrine. [stahl, paper & Essential Psychopharm] The only other agents I'm aware of that inhibit all three of  the above neurotransmitters are venlafaxine (Effexor) and bupropion (Wellbutrin), and these do not have equal effects on all three neurotransmitters. (i.e. they are strong on two, very weak on the other).

Most important, hyperforin has been shown to be a dose related marker for antidepressant efficacy in humans. This means that antidepressant effects appear to be directly related to how much hyperforin is in the product. These results have been replicated by separate teams of researchers, making them highly significant.

Human studies:

A research team at the Pro Science Private Research Clinic GmbH in Linden, Germany conducted a randomized, double-blind and placebo controlled parallel-group study on three groups of 18 volunteers each to determine the effects on EEG of two extracts with the same hypericin content and differing amounts of hyperforin. They found no effects on EEG for hypericin, but found the effects on EEG to be proportional to hyperforin content. They suggest that SJW products containing high amounts of hyperforin have a "shielding" effect on the central nervous system. [53] This team had previously confirmed a similar effect on the EEG of rats. [54]

Researchers at the Dept. of Psychiatry at the University of Munich in Munich, Germany conducted a multicenter study of the clinical efficacy and safety of two different extracts of St. John's wort in 147 male and female outpatients suffering from mild or moderate depression. They were evaluated using the Hamilton Depression Scale (HAMD). The study was randomized, double-blind and placebo-controlled. At the end of the treatment period (day 42), the patients receiving a 5% hyperforin solution exhibited the largest HAMD reduction followed by the group receiving 0.5% hyperforin and then by the placebo group. [48]

Animal and in vitro (test tube) studies:

A team at the Department of Pharmacology, Biocenter University of Frankfurt, Germany compared hyperforin to hypericin and kaempferol (other agents in SJW) to see how certain adrenaline and serotonin receptors reacted in rat brains. Hyperforin caused down-regulation of these receptors while neither hypericin nor kaempferol showed any effects.[49]

A team headed by SS Chatterjee at the Pharmacology Department, of Dr. Willmar Schwabe GmbH & Co., Karlsruhe, Germany (a private company and manufacturer of one of the most widely used and best tested SJW products, Jarsin (TM), a methanol extract of SJW also called LI 160) found that not only did hyperforin inhibit serotonin, dopamine and noradrenaline reuptake, but it also inhibited reuptake of GABA and L-Glutamate, the two major inhibitory (or "calming") neurotransmitters in the brain. [52]

Chatterjee was also part of another Hypericum research team at the Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varansai, India. This team compared LI 160 (about 5% hyperforin) with a carbon dioxide extract high in hyperforin (39%). [50]

Thus, the scientific evidence for hyperforin as the main active agent in St. John's wort seems very strong. Hopefully, herbal drug manufacturers will start standardizing their product for hyperforin content, providing for the first time a reliable indicator of antidepressant potency of a given Hypericum product. It may also soon be possible to compare extracted hyperforin to whole SJW. Since hyperforin does not appear to inhibit MAO, it may prove a safer alternative to whole SJW.

It's also now known that hyperforin and some of the biflavones (known to be CNS depressants) are involved in the  sedative effects of the plant.[2]   However, hyperforin is far from the only antidepressant chemical in St. John's wort. Until recently, most people thought that the antidepressant agent in St. John's wort was hypericin, and that hypericin  worked by inhibition of the enzyme monoamine oxidase.

(See section 4A and 4B for more info on MAO inhibitors.)

However, researchers today question whether hypericin  inhibits MAO. Some researchers have proposed certain flavonoids as candidates for the MAO inhibiting agent in St. John's wort because they bear a chemical structural similarity to known MAO inhibitors such as toloxotone and brofaromine [26]

Amentoflavone is another compound believed to have significant antidepressant effects. In a recent paper, several researchers have proposed that amentoflavone works by binding benzodiazepine receptors in the brain. [28]

Additionally, most researchers believe that the effects of St. John's wort are due to a synergistic interaction between  several compounds. Thus, the search for a single agent may well  be the wrong approach.

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4. ADVERSE REACTIONS AND SIDE EFFECTS

One important note about St. John's wort: at least in the industrialized world, most herbal products are not used by large enough numbers of people to really determine safety and side effects. St. John's wort is a notable exception to this rule: 66 million doses were taken in Germany in 1994 alone (26).

St. John's wort is now the leading antidepressant agent prescribed by physicians in Germany. Hypericum products account for over 50% of the antidepressant market in Germany and many thousands of people there use St. John's wort every year. [26]

This means that we have a significant database to work from when drawing reports of adverse effects.

However, we must remember that "absence of evidence does not equal evidence of absence." Most drug side effects are discovered during the kinds of large scale human trials conducted for FDA drug approval. SJW has never been through this process, although the US National Institute of Mental Health is now conducting such a trial. Furthermore, even with large numbers of people using St. John's wort, there is no one organization charged with collecting adverse reports to herbal drugs. We are still forced to rely on a few studies and on individual practitioners who write up adverse effects and submit the articles to medical journals. We should also remember that even though there are no reports of serious problems from St. John's wort in Europe where herbs are better standardized and controlled, this does not necessarily apply to the US where herbs are virtually unregulated. Certainly there have been a number of U.S. reports of new side effects from St. John's wort that have not been noted by European researchers.

A. MAOI Interactions with whole St. John's wort:

The question of greatest concern to most health practitioners is whether St. John's wort can cause stroke via drug interaction with a monoamine oxidase (MAO) inhibitor contained in the plant. This matter is somewhat controversial: several studies have suggested that the MAOI concentrations in SJW are so low that they have no clinical effect.[] Furthermore, the greatest concentration of MAOI in the plant is in the roots; the roots are not commonly used in theraputic SJW preparations.

MAO is the enzyme responsible for breaking down the key neurotransmitters norepinephrine and dopamine, both of which have a stimulating effect on the brain and which are also involved in the regulation of blood pressure. Drugs that inhibit MAO are called MAO Inhibitors or MAOIs. By inhibiting MAO, norepinephrine and dopamine remain at higher levels in the brain, producing antidepressant effects.

Most commercially available MAOIs are antidepressant drugs, with the best known MAOIs being Parnate (tranylcypromine) and Nardil (phenylzine). Other common MAOIs include selegiline (Deprenyl) and isocarboxyzid (Marplan). Certain antimicrobial agents such as furazolidine (Furoxone) and an anti-cancer drug called procarbazine (Matulane) also inhibit MAO. Some herbs contain MAOIs.[29] In addition to whole St. John's wort, yohimbe and large doses of licorice root contain clinically significant amounts of MAOIs.

MAOIs are highly effective in combatting depression, but are used only to treat depression resistant to all other drugs. This is because MAOIs are notorious for dangerous drug and food interactions.

When something interferes with the action of MAO, certain compounds that stimulate the sympathetic nervous system have much stronger effects on the body. In particular, the consumption of foods containing large amounts of tyramine (a metabolite of the amino acid tyrosine and a key chemical precursor of the neurotransmitters dopamine and norepinephrine) and/or particular drugs, such as stimulants and most antidepressants, can cause a very dangerous sudden sharp rise in blood pressure when taken by people using MAOIs. This reaction can cause strokes. Even so, these reactions are fairly rare; nonetheless, there ARE fatalities on record from adverse MAOI interactions with drugs.

Therefore, most doctors who prescribe MAOIs give their patients long lists of drugs and foods to avoid.

Because crude St. John's wort appears to contain an MAOI, a controversy has arisen:

Should people taking St. John's wort follow the same precautions that people taking prescription MAOIs do? A number of researchers, notably J.M. Cott at NIH, have suggested that the in vitro MAO receptor binding activity of SJW is so weak that no clinically significant MAOI action can be expected.[ ]

Unfortunately, this is no longer a theoretical issue. In November of 1997, the Minneapolis Star-Tribune published an editorial from physician Mary Arneson reporting a stroke in an elderly woman who was using St. John's wort. This patient was also using a drug for bladder spasms that stimulates the sympathetic nervous system. I'm in touch with Dr. Arneson, who informs me that this woman had a hypertensive crisis characterized by a blood pressure of 260/140 and uncontrollable gross tremors within two days of beginning St. John's wort, resulting in a stroke leading to right sided paralysis. Contrary to previous rumors, the patient did not die (although she could have), but paralysis is certainly terrible in its own right. I am trying to find out more about this case, especially what product she was using and whether it has been tested by the FDA to see if it was adulterated.

A newspaper article is pretty far from a scientific article in a peer reviewed medical journal and cannot be relied upon in the same way. However, Dr. Arneson is a trained observer (a rarity in most anecdotal reports). After corresponding with Dr. Arneson I believe that it is highly probable that this was a real MAOI reaction and that St. John's wort is a likely suspect for the cause. Elderly persons are at risk of strokes, but it is very unusual for their strokes to be due to a such a sudden rise in blood pressure. Very few things cause such a reaction. Strokes in elderly persons are usually due to atherosclerotic blockage of blood vessels or else to "worn out" blood vessels in the brain finally breaking open. I think that this woman was most likely using a whole herb or adulterated St. John's wort product. Until we have the lab analysis of the product in question, we won't know if this was a real effect of SJW or due to some other agent.

Many people promoting St. John's wort will tell you that it does not work by inhibiting MAO and therefore MAOI interactions are not a problem. [rewrite here, add more studies and in vitro binding info] This statement is based upon a study which gave a methanolic extract of St. John's wort to rats and which found that extremely high doses of the extract (far beyond pharmacologically active doses) were needed to achieive MAO inhibition.[12]

Unfortunately, what these people don't tell you is that this statement applies ONLY to hypericin, to the portion of St. John's wort that can be extracted in methanol and to certain very specific brands of SJW that have been subjected to pharmacologic chemical analysis. The jury is out on all other forms of Hypericum. The MAOI in St. John's wort is probably contained in the fraction of the plant that is soluble in oil. Hence it is critical to know whether a given St. John's wort product was properly extracted in methanol or carbon dioxide.

There is also the problem of product concentration. A recent study by the Good Housekeeping institute tested several of the leading brands of SJW, all labelled as 300 mg. SJW per capsule and 0.3% hypericin. They found a 13 fold difference in hypericin concentration and a 17 fold difference in pseudohypericin content, despite what the labels said.[] It may be that a highly concentrated SJW product would have more MAOI effect than a weak one.

(LA Times survey here)

There are many anecdotes from people who have mixed St. John's wort with foods known to cause bad interactions with MAOIs, and who have had no adverse effects at all. There is also an impressive record of safety in European use, where herbs are regulated as pharmaceuticals, albeit not as strictly as in the US.

However, MAOI reactions are dose related, occurring normally in only about 4% of the people who mix MAOIs with foods or drugs and often are mild so that the symptoms are ignored. MAOIs come in two forms: reversible (which inactivates but does not destroy MAO) and irreversible (which does destroy MAO). Irreversible MAOIs are more dangerous than reversible ones and have many more drug and food interactions. There are also two types of MAO: MAO-A and MAO-B. MAO inhibitors can inhibit only one of the above, or can inhibit both. MAO-A works on serotonin and norepinephrine and is the only type of MAO involved in antidepressant effects. MAO-B inhibits other amines found in the brain, notably dopamine and phenylethylamine. Agents that inhibit only MAO-A have far less potential for causing a hypertensive crisis than agents that inhibit both MAO-A and MAO-B. [24]

The MAOI in crude St. John's wort appears to be of the more dangerous, irreversible form and inhibits both MAO-A and MAO-B in vivo (in living organisms). [1,12] It appears to be weak but people have varying sensitivity to MAOIs due to individual quirks of body chemistry.

Therefore, it is my personal opinion that, until this issue is resolved, persons using whole St. John's wort or extracts that are not confirmed to be properly extracted in methanol or CO2 should follow the full list of MAOI precautions.

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B. Are certain extracts of St. John's wort free of the risks of MAOIs?

A recent study on rat brains using a methanol extract of St. John's wort states that an extremely high dose of this herb is needed to actively inhibit MAO-A. The researchers suggest that another compound must therefore be the active agent. Although it's not entirely clear to me (since I'm working from a secondary source here), this paper apparently also found a comparable dose was needed before any inhibition of MAO-B occurred. [12] Studies on Hypericum compounds extracted in carbon dioxide and enriched with hyperforin also suggest that CO2 extracted products do not have significant MAO inhibiting properties.[]

The original study that caused people to think that St. John's wort worked by MAO inhibition was conducted by a researcher named Suzuki in 1984. Suzuki reported that hypericin inhibited MAO at doses of 50 mcg/mL. However, 2 other teams of researchers have been unable to duplicate this finding. The solution Suzuki worked with was only 80% pure and these other scientists have suggested that there may have been an MAOI in the other 20% of the solution. It's not clear to me if the 80% purity statement refers to an attempt to use pure hypericin or if this refers to oil-soluble impurities in an attempted alcohol extract. Either way, this is a strong argument for the use of only properly purified extracts in the treatment of depression.

Researchers have administered methanol extracts up to 300 mg/kg to rats without finding any MAO inhibition. However, rats may metabolize St. John's wort differently than humans: it appears that blood levels of St. John's wort in humans are lower than in rats when administered equivalent doses in mg/kg.

Methanol and CO2 extracts of St.John's may well be free of MAOI interactions at normally used doses. However, until a large scale human study on this is done, we won't know for sure. Rat brains are actually a fairly good model to test this stuff, but rats and humans do have some significant differences.

C. Serotonin Syndrome:

I have received several letters from people who developed symptoms highly suggestive of mild serotonin syndrome while using St. John's wort. Physicians have also begun reporting SS-like reactions to SJW in the medical literature. [ ] Serotonin syndrome is a very rare but potentially fatal complication of all compounds that increase levels of serotonin in the brain.

Signs of serotonin syndrome include confusion, fever, chills, hyperactive reflexes, sweating and difficulty with speech. Myoclonus, a shock-like contraction of a muscle or group of muscles is another sign. In the mouth, myoclonus can feel like a rapid fluttering of the soft palate, tongue or throat, often only on one side.

Serotonin syndrome is believed to occur when a chemical preferentially stimulates a few particular serotonin receptors, notably 5-HT1a and 5-HT2 (serotonin is 5-hydroxytryptamine or 5-HT for short). It occurs most commonly when combining two antidepressants; but can occur with just one serotonin increasing drug and can even occur with just one dose of the drug. Especially dangerous is combining serotonin increasing agents with MAOIs (and is distinct from the type of MAOI interaction reported in the previous section). Serotonin syndrome has also been reported in people combining the amino acid supplement L-tryptophan (a key chemical precursor of serotonin) with SSRIs such as Prozac. Tryptophan absorbed as part of a normal diet does not appear to increase the risk of serotonin syndrome.

In the letters I've personally received, the patients all reported a gradual onset of dizziness, cognitive difficulty, faintness when standing or walking, unsteadiness when walking, muscle spasms and racing heart beat.

In one young woman, it progressed over the period of 10 weeks to high blood pressure, hot flashes and night sweats, diarrhea, shortness of breath and muscle spasms in the chest and throat suggestive of myoclonus. She was eventually hospitalized with a blood pressure greater than 150/100 and very rapid heartbeat; she was given beta blockers which proved ineffective.

This particular woman was using Claritin, an antihistamine that contains 240 mg of pseudoephedrine per tablet. This could be an MAOI interaction, but the slow onset argues against it. The symptoms seem much more suggestive of serotonin syndrome. The symptoms finally went away after she was admitted to the hospital and discontinued the St. John's wort. Product concentration was again a factor in this woman's case. She had very mild symptoms on one product; but when her pharmacist ran out of the product, she switched to a different one with the same concentration on the label. This product caused an immediate severe exacerbation of her symptoms and she believes that it was much stronger than the other brand.

At four months later she was still having slight symptoms. Significantly, none of her physicians recognized what was happening because none of them thought to ask her if she was using any herbal drugs. I have encouraged her to try to get her doctor to publish the case report and I strongly encourage all health practitioners to routinely ask their patients if they are using any herbs or vitamin supplements. The other two reports were in people also using SSRI antidepressants (sertaline, marketed as Zoloft) concurrently without informing their physicians that they had begun using St. John's wort.[] A physician has also reported a case in a person using Paxil (a newer SSRI) and SJW.[]

There are more than 40 serotonin receptors and more are being identified each day. Since we don't know exactly which serotonin receptors St. John's wort affects, we can't accurately judge the risk of this disorder when combining it with other serotonergic agents.

I do not regard St. John's wort as any more dangerous in this regard than other antidepressants; however these cases suggest that medical supervision while using St. John's wort may be a good idea. Absolutely, people should NOT combine St. John's wort with other antidepressants without close medical supervision. Patients should also be alert for signs of serotonin syndrome and immediately report them to a physician.

D. Mania and Hypomanic states:

There are anecdotes suggesting that Hypericum can cause mania in some people but no published case reports or studies exist on this subject.

E. Seizures:

A physician on the healthfraud mailing list recently reported that an epileptic patient of hers experienced seizures a few days after beginning therapy with St. John's wort. The patient was previously stable on antiseizure medication. Approximately 48 hours after beginning St. John's wort he developed repeated seizures, approximately 25 in a 48 hour period of time. The patient returned to baseline when the St. John's wort was discontinued.

F. Paralytic Ileus:

One case has been reported where a patient developed paralytic ileus, a condition where the motion of the intestines stops. This leads to abdominal pain, nausea and vomiting. SJW is well known to affect the motility of the intestines and is sometimes given for this purpose prior to GI tract X-rays in Germany. This particular case resolved by itself once the SJW was discontinued. [ ]

G. Photosensitivity:

a. Primary photosensitivity in humans:

H. Nerve damage due to secondary photosensitization in humans

Researchers at Boston's Beth Israel Deaconess Medical Center recently reported that a 35-year-old women experienced temporary nerve damage after taking a Hypericum product. [56] According to the report, the woman began to experience sharp pains in areas exposed to the sun (her face and hands) after she began taking 500 milligrams of St. John's Wort per day. They stated that sunbathing was followed by painful sensitivity on her arms and legs.

I. Minor side effects:

Several of the St.John's wort studies note that some people dropped out due to side effects, although at a far lower rate than with standard antidepressants.

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J. LD50 and toxicity:

5. OTHER DRUG INTERACTIONS:

It has been shown in animal studies that the effects of St. John's wort are reduced by agents that reduce the activity of dopamine, such as haloperidol. We do not know if this is the case in humans or not. [26]

6. OTHER PHARMACOLOGIC EFFECTS OF ST. JOHN'S WORT

Even though all the recent publicity has been over the use of St. John's wort to treat depression, Hypericum has many other effects.

A. Effects on sleep:

One study has found that St. John's wort increased deep sleep and slightly decreased REM sleep. [19]

B. Anti-viral activity

The American Herbal Pharmacopoeia (AHP) monograph on St. John's wort states that Hypericum is currently undergoing early trials as an antiviral agent in the United States. Unfortunately, I don't have any more details. [26]

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C. Anti-bacterial and anti-fungal activity

Two Russian St. John's wort preparations have been tested against Staphylococcus aureus in vitro (in test tubes) and in vivo (in living organisms) and found to be more effective than sulfanilamide.[1]

A resin fraction of an alcohol extract of St. John's wort called LI 160 has been shown to have minor antifungal and "significant" action against gram positive bacteria.[26] Tannins and flavonoids in St. John's wort have been reported to inactivate Escherichia coli at dilutions of 1:400 and 1:200. [26]

H.perforatum essential oil is anti-fungal. [1]

D. Immunologic effects:

A polyphenol compound has been identified that stimulates the activity of certain white blood cells called mononuclear phagocytes and "cellular and humeral immunity". [10,11] An oil-soluble fraction has been found that exerts mild immune suppressant effects. It suppresses the release of Interleukin-6. [11]

A freeze dried preparation of St. John's wort has been found to suppress inflammation and white blood cell infiltration in vivo.[1]

Hypericin inhibits the release of arachidonic acid and leukotriene B. These are precursors of several important chemicals in the body including prostaglandins and cytokines (chemicals that activate lymphocyte and T-cell activity). This has been proposed as a mechanism behind St. John's wort's traditional use as an antiinflammatory.

E. Wound healing activity:

A burn ointment made from St. John's wort flowers has been tested in the treatment of 1st, 2nd and 3rd degree burns. According to the AHP monograph "First degree burns healed in 48 hours. Second and third degree burns healed at least three times as rapidly as burns treated with conventional methods and keloid formation was inhibited". [26]

St. John's wort has also been compared with Calendula, another herb commonly used to heal wounds. St. John's wort applied topically was shown more effective than Calendula. [26]

Many of St. John's wort effects on wounds and burns are probably due to the anti-bacterial and anti-fungal effects mentioned above. However, the antiinflammatory and other immunologic effects mentioned in the previous section probably also play a role.

F. Other properties:

St. John's wort has antioxidant activity. [5]

St. John's wort appears to have antispasmodic effects on the gastrointestinal tract. [2]

A water/alcohol extract has been observed to have a protective effect on the livers of animals. Increased bile duct flow has been observed in rats, and this extract also reduced the damage from CCl4 (carbon tetrachloride, extremely toxic to the liver) when given intraperitoneally to mice first treated with barbiturates. [26]

A procyanidin fraction of Hypericum has been shown to have vasodilating effects on an isolated preparation made from guinea pig heart and also in coronary arteries from pigs. These procyanidins antagonized coronary artery spasms caused by histamine and by prostaglandin F2-delta. These procyanidin fractions acted in much the same manner as procyanidins from hawthorne, an herb long known to possess vasodilating properties.[26]

It has been shown that St. John's wort may be useful in the treatment of chronic tension headaches, probably due to sedative effects. [26]

7. HERBAL "PHEN-FEN"

Unscrupulous herb distributors have recently been cashing in on the fact that the diet drug fenfluramine has been pulled from the market. There are now many products combining St. John's wort with either Ma Huang (Chinese ephedra) or phenylalanine being sold as the herbal equivalent of "Phen-Fen" (phentermine and fenfluramine).

I regard these products as unsafe and believe they should be pulled from the market.

This marketing ploy is based on the idea that the "Phen-fen" regimen combined an agent that increases serotonin (fenfluramine) with an agent that that is a stimulant and increases norepinephrine and dopamine (phentermine). Thus, since St. John's wort supposedly is serotonergic and Ma Huang (which contains ephedrine and pseudoephedrine) is a stimulant, these promoters are claiming that these products will help with weight loss.

Unfortunately, ephedrine and pseudoephedrine are among the most common causes of stroke when given with MAO inhibitors. Given that we cannot guarantee the contents of any herbal product in the U.S., and given that whole and/or improperly extracted St. John's wort contains an MAOI, this is a classic set up for MAOI related strokes and deaths.

There are also no studies on are unfounded.

8. RESEARCH ON ST. JOHN'S WORT AND PREGNANCY:

St. John's wort should NOT be used while pregnant or if breast feeding.

First, hypericum extract has been shown to cause contraction of uterine muscles of rabbits and guinea pigs in test tubes.[21] Interestingly, Hypericum species were used by Native Americans and by Europeans in antiquity as abortifacients.[1, Riddle] This is not a great indicator of what it does in the human body, but why take any agent that could cause uterine contractions and so risk miscarriage?

Second, there is the possibility that certain chemicals in St. John's wort may cause birth defects. There is a lot of scientific debate about this. One study found that mutations occurred when Hypericum oil, tinctures and extracts were applied to cell cultures. Mutations in cell cultures suggest that a compound may alter DNA and lead to birth defects by chromosome damage or to cancer in living organisms. It has been suggested that quercetin was the mutagenic agent.[26] (Agents that cause birth defects are called teratogens.)

However, other studies both in test tubes and in animals did not confirm this finding. [26] A 1:4 water/alcohol extract has been tested for mutagenicity (the ability to change or alter DNA) against salmonella bacteria. This is called the Ames test and is the standard method used to determine how likely it is that an agent can cause cancer or birth defects. St. John's wort has been found to have anti-mutagenic properties, which means it not only does not increase the rate of mutations, but it decreases them below normal.[2]

It's also been tested in test tubes (in vitro) against rat embryo cells with negative results.[22] The extract used in the rat embryo study mentioned above yielded 0.2 to 0.3% hypericin and 0.35mg/g of quercetin. This suggests that neither of these compounds are the agents that cause birth defects. If a mutagenic agent is present, the most likely place to look for it would be in the oily fraction. (This is what is most likely to be left behind after water/alcohol extraction, since oils do not mix well with water or alcohols.)

Even if it turns out that Hypericum doesn't cause cell mutations, there are are many mechanisms other than chromosomal damage by which birth defects can occur. Thalidomide, for example, probably causes birth defects by blocking the formation of new blood vessels between the 6th and 9th week of pregnancy. Thus, it's conceivable that an agent that passes the Ames test could still be teratogenic.

Of particular concern to me is the effect of an anti-depressant agent on the developing nervous system and brain of a fetus or newborn. This might actually be MORE of a risk in the last trimester of pregnancy or shortly after birth (when the infant brain is undergoing subtle but critical formation) so just avoiding the first 12 week "window of vulnerability" isn't sufficient.

A note of caution is also due regarding the estrogenic agents in St. John's wort. To my knowledge, beta-sitosterol has never been tested for teratogenic effects. We do know that certain estrogens, notably D.E.S. (diethylstilbesterol) cause deformities and cancers of the reproductive system and reduce fertility in people exposed to them in utero (while still in the womb). It can take many years for such problems to become evident: DES daughters did not develop vaginal cancers until well into adulthood.

I think we would do well to remember the effects of DES on both males and females, as well as the possible role of estrogenic organohalides in breast cancers and reduced male fertility. In other words, I personally wouldn't take any estrogenic agent during pregnancy if I could avoid it. If an anti-depressant is still needed during pregnancy, I'd use a standard prescription antidepressant that's had a long history of use and that we've got some data about in pregnant women. I'd use such a drug only if I couldn't get by without it (i.e. suicide or psychosis is an immediate danger) and for as short a period of time as possible.

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9. IS ST. JOHN'S WORT USEFUL IN THE TREATMENT OF CANCER?

The idea that St. John's wort might contain a useful anti-cancer agent is not off the wall: several important cancer chemotherapy agents were originally derived from plant sources. The most recent example is Taxol, made from the Pacific Yew. Vincristine and vinblastine are other common cancer chemo agents originally derived from a plant (marigold).

Neurosurgery (a highly respected medical journal) has published two articles by researchers at the University of Southern California in Los Angeles on the use of hypericin as an anti-glioma agent. Glioma is a rare type of brain cancer that is almost always fatal. One article demonstrated that hypericin inhibits the growth of glioma cells in test tubes in a dose dependent manner and suggested that the mechanism was inhibition of a chemical key to tumor cell reproduction called PKC (protein kinase C.) [3]

The second article was a case report on the use of hypericin on a person who had an inoperable glioma who was receiving radiation and tamoxifen. The patient went into remission for 22 months (pretty good, considering that the average survival time after diagnosis for glioma is under 12 months) and then had a recurrence of the tumor. When cells from the tumor were tested in a lab, they had lost sensitivity to tamoxifen. Because tamoxifen works by inhibition of protein kinase C, the researchers tested the cell culture against hypericin and found that the cells were killed by the hypericin. They also found that hypericin is a stronger inhibitor of protein kinase C than tamoxifen. [20]

Because it is not approved by the FDA, the authors never actually gave hypericin to this person. However, they suggest that it is a viable alternative to tamoxifen and that it may be useful both as a primary chemotherapy agent in this cancer and also as a second line drug to be used when tamoxifen fails. They urge that it be studied further and at the end of their article indicate that they were trying to get FDA approval for a full clinical study in humans. I don't know the result of their petition or whether further research is being conducted.

Hypericin has also been tested as an adjunct to laser surgery for skin cancer. Because hypericin is a photoactive agent, it may increase the efficacy of laser in destroying skin cancers. (The light from the lasers may turn hypericin into an even stronger PKC inhibitor.)

However MUCH more research is needed. At this point in time, it should NOT be promoted as a cancer cure or preventive. I personally would *not* use it in place of standard glioma treatments. However, it appears to be pretty safe, and I might take it as an adjunct to standard therapy. Certainly, a person whose tumor does not respond to standard treatments has nothing to lose by trying it.

NOTE: If you want to try hypericin for this purpose, you MUST let your doctor know about it. Seriously ill people should never take herbs or any over the counter drugs without informing their physician. Plant derived drugs can and do have interactions with standard pharmaceuticals, foods and other herbs. Also, it may be necessary to administer the drug intravenously. Don't assume that you can just go to the health food store and buy an orally consumed hypericin product and have it work for this purpose.

10. ST. JOHN'S WORT AND ATTENTION DEFICIT DISORDER

11. TECHNICAL APPENDICES

A. PRECAUTIONS:

First:

Don't self-treat serious depression! SEEK IMMEDIATE HELP IF YOU ARE HAVING SUICIDAL THOUGHTS.

Depression is a very serious illness and the suicide rate in untreated depression is at least 15% over the long term. An occasional case of the blues is one thing; a depression that lasts for weeks or months or where you have frequent thoughts of killing yourself is a whole different matter. Because depression so strongly affects a person's view of reality, it's very important for folks with depression to have someone else to check in with who can tell if things are to the point where suicide is a real risk.

Most cases of depression ARE treatable and if people need more information, I suggest that they check in on alt.support.depression and/or consult a physician or therapist. Call the local suicide prevention hotline (listed in the front of most phone books) if you have thoughts of killing yourself.

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SUGGESTED PATIENT INSTRUCTIONS:

(Health providers may duplicate and pass out this section without violation of copyright)

a. Immediately discontinue St. John's wort and consult a physician if you develop the following symptoms:

• Confusion or a feeling of being "high" or disoriented;
• Difficulty with speech;
• Fever not known to be due to a cold or the flu;
• Unexplained sweating;
• Shock-like contractions of the muscles anywhere in the
• body, including the mouth, tongue and throat (which may
• be felt as a "fluttering" sensation;
• Severe headache, particularly in the back of the head
• or over the temples, which may be "pounding" and
• worse when lying down;
• A sudden rise in blood pressure of more than 30 points
• or higher than 180/100.
• Pupil dilation;
• Rigidity of neck muscles;
• Heart palpitations or a racing and/or irregular
• heartbeat;
• Sharp pains in the arms, legs or face;

b. Don't take St. John's wort with other antidepressants including SSRIs and tricyclic antidepressants unless you are under a doctor's close supervision.

c. Do not take St. John's wort with MAOIs (monoamine oxidase inhibitors). If you are discontinuing or beginning an MAOI, allow a minimum of 4-8 weeks between use of St. John's wort and the MAOI.

Note: Most MAOIs are prescription antidepressants. If you are taking a prescription antidepressant and are not sure if you are taking an MAOI, ask your physician. However, this precaution also applies to certain herbs that contain MAOIs, particularly yohimbe and doses of licorice root in excess of 5 grams per day.

d. Do not stop taking prescription antidepressants without proper medical care. If stopping an MAOI, wait a minimum of 4 weeks before taking any other antidepressant including St. John's wort. If stopping St. John's wort to begin MAOI therapy, wait 8 weeks before beginning the MAOI.

e. Persons using whole herb St. John's wort products, or who are using a product not confirmed to be a properly purified methanolic or carbon dioxide extract should follow the full list of precautions for those using MAOI drugs. For a full list of foods and drugs known to adversely interact with MAOIs, see Dr. Bob's psychopharmacology web page at: http://uhs.uchicago.edu/~bhsiung/tips/maoi.html

f. Do not take St. John's wort for bipolar ("manic-depressive") illness.

g. Do not take St. John's wort if you have a history of seizure disorders.

h. Do not take St. John's wort if you are pregnant or breast feeding.

i. Do not use St. John's wort if you have previously developed a rash from it or if you are allergic to it.

j. Wear a sunscreen while using it, particularly if you are fair skinned.

k. Use care if you have a history of photosensitive rash or if you are taking certain medications that can cause photosensitive reactions such as tetracyclines, Thorazine (chlorpromazine) or Tegretol (carbamazepine).

l. Avoid theraputic ultraviolet therapy and/or tanning salons while using St. John's wort.

m. Do not take St. John's wort with haloperidol or other drugs known to decrease dopaminergic activity because they may reduce the efficacy of St. John's wort.

n. Stick to the standard dosage or the dose on the bottle and don't keep increasing the dose if it's not working.

o. If you have a serious systemic illness, do not take St. John's wort or any other herb without the supervision of a physician.

p. Do not take St. John's wort if you have an estrogen dependent cancer, such as certain breast and uterine cancers. St. John's wort contains a mild phytoestrogen. Even though the estrogenic agent in St. John's wort does not appear to affect breast tissue, not enough is known to state that it is safe to use in people with breast cancer. This agent DOES stimulate uterine and ovarian tissue.

q. Like all drugs, herbal or otherwise, St. John's wort should not be left within the reach of small children. r. Do not give St. John's wort to children. The effects of this herb in children have never been studied.

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B. DOSAGE AND ADMINISTRATION:

Unless otherwise prescribed, the standard dose is 2 to 4 grams of the raw herb or 0.2 to 1.0 mg of extracted hypericin per day. Some depression studies have used as much as 2.7 mg. of hypericin per day.

Methanol extracts and/or compounds extracted in carbon dioxide (CO2) and standardized for hypericin and hyperforin content are the only forms of St. John's wort that should be consumed internally. NOTE: A methanol extract is very different from a tincture containing ethanol (grain alcohol) and water. Christopher Hobbs states that an ethanol tincture CAN contain an MAOI.

Almost all medical studies have been conducted using a particular methanol extract called LI 160. This is also sometimes called research grade hypericum. (Note: the alcohol is used during the extraction process but does not remain in the end product, so LI 160 is safe for use by recovering alcoholics.)

We do not know if other forms, such as chopped raw St. John's wort or a tea, are as effective in treating depression or other illness. There is also the consideration that the oily residue of alcohol extraction may be the fraction that contains the MAOI and possibly agents that cause birth defects. However, St. John's wort can also be consumed in the following ways:

Max Wichtl states in _Herbal Drugs and Phytopharmaceuticals_ that St. John's wort can be taken orally as chopped or powdered herb, a liquid or semi-solid preparation or a water/grain alcohol tincture. Tea bags containing 2 grams of the raw herb are also available.

A tea can be made of St. John's wort by pouring about 1 cup of boiling water over 2 teaspoons (2-4 grams) of chopped raw herb, waiting for 5-10 minutes, then straining. 1 teaspoon of finely chopped St. John's wort equals about 1.8g.

(Even though Wichtl says to steep the herb, it's not clear to me whether simmering the herb might not be better. Slowly simmering an herb tends to boil off the volatile oils; however, I don't know if this also means that the solution picks up more of the oil as well. To simmer an herb, bring to a boil and then turn the heat down to where only a few bubbles reach the surface. Leave for 20 minutes.)

Two cups of the freshly prepared tea are drunk regularly morning and evening. (It's unclear in Wichtl, but given that the normal dose is 4 grams per day, I assume this means that the dose is divided into one cup in the A.M. and one in the P.M.)

Oily preparations are made by soaking St. John's wort flowers in glycerin or in olive, sunflower or wheatgerm oil. Wichtl states that it is necessary to use the compound over a period of several weeks or months to notice an effect.[2] It's possible that the sedative effects of St. John's wort may be felt quickly but that, like other antidepressant agents, it may take several weeks for the antidepressant effect to be noticeable.

C. PHARMACOKINETICS:

HYPERICIN:

Plasma levels:

A single dose oral administration of 250, 750 and 1500 micrograms of hypericin and 526, 1578 and 3156 micrograms of pseudohypericin was given to healthy volunteers. The median plasma peak levels were found to be 1.3, 7.2 and 16.6 mcg/liter for hypericin and 3.4, 12.1 and 29.7 mcg/liter for pseudohypericin. [8,9]

Half life:

After 2 week treatment with oral administration of 750 micrograms of extracted hypericin in one group and 1578 micrograms of pseudohypericin in another, the median half-life for absorption was 0.6 hours, distribution was 6.0 hours and elimination was 43.1 hours for the hypericin and 1.3, 1.4 and 24.8 hours respectively for the pseudohypericin.[8,9] Systemic availability:

The systemic availability is roughly 14% for hypericin and 21% for pseudohypericin.[8,9]

HYPERFORIN:

All information in this section is from:

Biber A, Fischer H, Romer A, Chatterjee SS Oral bioavailability of hyperforin from hypericum extracts in rats and human volunteers.

Dr. W. Schwabe GmbH & Co., Karlsruhe, Germany. Pharmacopsychiatry 1998 Jun;31 Suppl 1:36-43 HPLC and UV detection method were used to obtain the following results for rats. For humans, since therapeutic doses of Hypericum extracts are much lower than that used in rats, it was necessary to develop a more sensitive LC/MS/MS method. The lower limit of quantification of this method was 1 ng/ml.

Plasma peak: In rats, approximately 370 ng/ml were reached 3 hours after oral administration of a 300 mg/kg Hypericum extract.

In humans, after administration of 300 mg hypericum extract, containing about 14.8 mg of hyperforin, the plasma peak was approximately 150 ng/ml after 3.5 hours. Half-life: 6 hours in rats, 9 hours in humans. Quoting from Biber et al.:

"Hyperforin pharmacokinetics were linear up to 600 mg of the extract. Increasing the doses to 900 or 1200 mg of extract resulted in lower Cmax and AUC values than those expected from linear extrapolation of data from lower doses. Plasma concentration curves in volunteers fitted well in an open two-compartment model. In a repeated dose study, no accumulation of hyperforin in plasma was observed. Using the observed AUC values from the repeated dose study, the estimated steady state plasma concentrations of hyperforin after 3 x 300 mg/day of the extract, i.e., after normal therapeutic dose regimen, was approximately 100 ng/ml (approx. 180 nM)." [56]

Clearance value: 70 ml/min/kg in rats.

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D. CHEMICAL CONSTITUENTS:

Like most plant drugs, St. John's wort is a very complex substance with over two dozen bioactive compounds. According to Wichtl [2], Hobbs [1], and the AHP [26] the bioactive agents in St. John's wort of greatest interest are the naphthodianthrones, flavonoids, phloroglucinols, and essential oils.

All percentages and chemical classifications below are from the AHP. The percentages in any given plant may differ from those below because chemicals in herbs are affected by growing conditions, time of harvest, genetics of various strains and other factors.

1. Naphthodianthrones:

This class includes hypericin and its chemical relatives. These are pseudohypericin, isohypericin, protohypericin and their chemical precursors proto-hypericin and hypericodehydrodianthone. More distantly related compounds include frangula-emodin and anthranol.

Of these compounds, hypericin and pseudohypericin are the best studied.

Hypericin, pseudohypericin and related compounds make up about 0.05 to 3.0% of the total plant.

Hypericin and pseudohypericin were formerly believed to inhibit MAO. Today, most researchers believe that flavonoids are the MAO inhibiting compounds, although there is some controversy about this.

Both hypericin and pseudohypericin are photosensitizing agents, with pseudohypericin being less photosensitizing than hypericin.

H. perforatum appears to contain significantly more pseudohypericin than hypericin.[2] Pseudohypericin leads to higher plasma peak levels and has a longer half-life than hypericin. [8] It also appears to have fewer side effects. H. perforatum appears to contain less hypericin than H. augustifolia.[2]

Hypericin has antiviral effects against HIV [3]

Hypericin is an inhibitor of protein kinase C, a chemical important in the replication of cancer cells.

2. Flavonoids:

Flavonoids constitute about 11.71% of the leaves and 7.4% of the stalks. These include:

a. Flavonols: kaempferol, luteolin, myricetin, quercetin (2%) Quercetin has been shown in one study to inhibit MAO in vitro.[26]

b. Flavonol glycosides:

• hyperoside, also called hyperin (0.7-1.1%) ,
• quercitrin (0.3-0.524%) and isoquercitrin (0.3%)
• amentoflavone, also known as I3',II8-biapigenin (0.01-0.05% in flowers)
• I3-II8-biapigenin (0.1-0.5%)
• luteolin,
• rutin (0.3%)

The biflavones and hyperoside are believed responsible for St. John's wort's sedative effects. [2] Amentoflavone is believed to be an important serotonin-reuptake inhibitor. It has sedative effects and has also been shown to have antiinflammatory properties and to inhibit the development of ulcers [26]

3. Phloroglucinols & derivatives including hyperforin, adhyperforin and hyperoside (up to 3%) and leucocyanidin Hyperforin inhibits the reuptake of serotonin, dopamine and norepinephrine in approximately equal amounts and causes significant reuptake inhibition of GABA and L-Glutamate. It is the leading candidate for a single antidepressant compund in the plant. In addition, hyperforin possesses antibiotic properties and is chemically related to the bitter substances found in hops. It's believed to be the agent that inhibits S. aureus.[1]

4. Proanthocyanidins and procyanidins: approximately 12% of the aerial portions of the plant. These consist primarily of dimers, trimers, tetramers and high polymers of catechin and epicatechin. This class of chemicals is known to have antioxidant, antimicrobial, antiviral and vasorelaxant properties [26]

5. Tannins: between 6.5 and 15% Tannins are believed partly responsible for St. John wort's anti-diarrheal effects.[2] Compounds in this family generally have astringent, anti-inflammatory and styptic effects.

6. Coumarins: umbellifone and scopoletin

Umbellifone possesses anti-inflammatory and analgesic properties. Both compounds appear to have anti-tumor properties in test tubes. Even though some coumarins inhibit blood clotting, a thorough Medline search seems to indicate that umbellifone and scopoletin do not interfere with clotting times or platelet aggregation.

7. Epoxyxanthrophylls. These compounds may be involved in St. John's wort's effects on burns, by increasing available oxygen. [1]

8. Essential oils:

Essential oils constitute about 0.059-0.35% of the plant. Saturated hydrocarbons: 2-methyloctane (16.4%) Monoterpenes including alpha-pinene (10.6%), beta-pinene, limonene and myrcene. Mono-terpenes constitute about 0.05 to 3.0% of the plant.

Sesquiterpenes include caryophyllene and humulene.

Trace amounts: 2-methyldecane, 2-methybutenol, undecane, and various n-alkanes and n-alkanols.

2-methylbutenol is known to have sedative properties.

9. Amino Acids

Amino acids are the building blocks of most neurotransmitters and some, such as GABA, are pharmacologically active in their own right. Amino acids found in St. John's wort include: Cysteine, GABA (0.7 mg/g), glutamine, leucine, lysine, ornithine, proline, threonine.

GABA is the main neurotransmitter responsible for calming brain activity and is known to have sedative effects. GABA constitutes approximately 0.7 mg/g. of the plant. It is unclear to me whether the GABA in St. John's wort is orally active or not. (Many such compounds don't make it past digestion in the stomach or else are stopped at the blood/brain barrier and don't actually get into brain tissue.) However, such a low dose probably has no independent pharmacologic effect.

10. Beta-sitosterol: this is a mild estrogenic agent with the unusual property of blocking estrogen receptors in breast tissues. This may mean that it is an estrogen that does not carry the risk of breast cancer. Phytoestrogens such as beta-sitosterol and genistein are currently being explored as possible agents for estrogen replacement therapy and as chemotheraputic agents for women with breast cancer (if the estrogen receptors are blocked, then perhaps the body's own estrogen and/or HRT supplementation will not stimulate breast tissue and thus rate of new or recurring breast cancers will be lowered). Unfortunately, neither the AHP, Wichtl nor Hobbs list the amount of beta-sitosterol present in Hypericum. [1,2,26]

11. Other constituents:

Xanthones: 1.28 mg/100g These are found primarily in the roots. Xanthones have been shown to inhibit both MAO-A and MAO-B; however, the roots are not used in medicinal St. John's wort preparations. Phenolic carboxylic acids: caffeic (0.1%), chlorogenic, p-coumaric, ferulic, isoferulic, and gentisic acid Other organic acids: isovalerianic, lauric, myristic, nicotinic (0.12% in leaves), palmitic and stearic acids; Carotenoids [1]: (leutein, luteoxanthin, violaxanthin, cis-throllixanthin, throllicromone) Scopoletin, vitamin C, choline, pectin, phlobaphene and rhodan

E. REGULATORY STATUS:

H. perforatum is found in the official pharmacoepeias of the UK, Switzerland, Czechoslovakia, Poland, Romania and the former Soviet Union.

United States: The U.S. FDA has not approved St. John's wort for any medical purpose and does not allow manufacturers to make medical claims on the bottle. It currently occupies the regulatory limbo of "foods" and an hypericin-free extract is used to flavor vermouth. [1]

Australia: Included as an active ingredient in products listed in the Australian Register of Theraputic Goods.

Canada: Currently under review. The AHP monograph on St. John's wort states that the "accepted traditional indications" are for internal use as a sedative, nervine, diuretic, and as an antispasmodic agent in gastrointestinal disorders and topical use in wound healing and to shrink and soothe hemorrhoids. It's not clear to me from the monograph whether it is approved for these uses or not.

United Kingdom: The UK does regulate herbs and has an official herbal pharmacopoeia. It's considered a "licensed product" and classified as GSL, for external use only. However, the British Herbal Pharmacopoeia lists its actions as sedative and astringent. The accepted indications in the BHP include "menopausal neurosis", excitability, neuralgia, fibrositis (now called fibromyalgia), sciatica and externally as an analgesic and antiseptic.

Switzerland: It is required to contain a minimum of 0.08 total hypericin.

France: Approved for external use as an emollient for urticaria, chaps, bruises, frostbite, insect bites, sunburn and other minor burns and for the relief of pain in the mouth and throat.

Germany: The German E Commission has approved St. John's wort for the following conditions:

Internal consumption:

• Psychogenic disturbances, depressive states, sleep disorders, anxiety and/or nervous excitement, particularly those associated with menopause.
• Oily hypericum preparations are approved for stomach and gastrointestinal complaints and have anti-diarrheal activity.

External use:

• Oily hypericum preparations are approved for the treatment and after-treatment of incised and contused wounds, muscle aches and 1st degree burns. [1]

[Back to the Top]

11. REFERENCES:

1. Hobbs, Christopher St. John's Wort (Hypericum perforatum L.) A Review Pub: American Botanical Council and Herb Research Foundation HerbalGram No. 18/19 Fall 1988/Winter 1989 pp. 24-33 119 refs

2. Wichtl, Max Herbal Drugs and Phytopharmaceuticals (Translated from the German by Bissett, N.G.) 1994, CRC Press/ Scientific Publishers pp.: 273-275

3 Couldwell WT; Gopalakrishna R; Hinton DR; He S; Weiss MH; Law RE; Apuzzo ML; Law RE Hypericin: a potential antiglioma therapy Department of Neurological Surgery, University of Southern California School of Medicine, Los Angeles. Neurosurgery 1994 Nov;35(5):993]

4. Taylor RS, Manandhar NP, Hudson JB, Towers GH Antiviral activities of Nepalese medicinal plants. Department of Botany, University of British Columbia, Vancouver, Canada. J Ethnopharmacol 1996 Jul 5;52(3):157-163

5. Biofizika 1997 Mar;42(2):480-483 Antioxidant properties of a series of extracts from medicinal plants. (authors not listed, article in Russian.)

6. Woelk H, Burkard G, Grunwald J Benefits and risks of the hypericum extract LI 160: drug monitoring study with 3250 patients. Psychiatrisches Landeskrankenhaus und Akademisches Lehrkrankenhaus, Universitat Giessen, Germany. J Geriatr Psychiatry Neurol 1994 Oct;7 Suppl 1:S34-S38

7. Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D Projekt Munchener Modell, Ludwig-Maximilians-Universitat, Munich, Germany. St John's wort for depression--an overview and meta-analysis of randomised clinical trials BMJ 313(7052), 253-258 (1996)

8. Kerb R, 1996 Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericin. Antimicrob Agents Chemother 40(9), 2087-2093 (1996)

9. Staffeldt B, 1994 Pharmacokinetics of hypericin and pseudohypericin after oral intake of the hypericum perforatum extract LI 160 in healthy volunteers. J Geriatr Psychiatry Neurol 7, S47-S53 (1994)

10. Evstifeeva TA, 1996 The immunotropic properties of biologically active products obtained from Klamath weed (Hypericum perforatum L.) Eksp Klin Farmakol 59(1), 51-54 (1996)

11. Thiele B, Brink I, Ploch M Modulation of cytokine expression by hypericum extract. Medizinische Fakultat (Charite) der Humboldt Universitat zu Berlin, Germany. J Geriatr Psychiatry Neurol 7, S60-S62 (1994)

12. Kako MD, al-Sultan II, Saleem AN Studies of sheep experimentally poisoned with Hypericum perforatum. Department of Pathology, College of Veterinary Medicine, University of Mosul, Iraq. Vet Hum Toxicol 1993 Aug;35(4):298-300

13. Golsch S, Vocks E, Rakoski J, Brockow K, Ring J Dermatologische Klinik und Poliklinik am Biederstein, Technische Universitat, Munchen. Reversible increase in photosensitivity to UV-B caused by St. John's wort extract Hautarzt 1997 Apr;48(4):249-252

14. Nordfors M, Hartvig P Sodra Stockholms sjukvardsomrade. St John's wort against depression in favour again. Lakartidningen 94(25), 2365-2367 (1997)

15. Muldner H, Zoller M Antidepressive effect of a Hypericum extract standardized to an active hypericine complex. Biochemical and clinical studies Arzneimittelforschung 34(8), 918-920 (1984)

16. Perovic S, Muller WE Pharmacological profile of hypericum extract. Effect on serotonin uptake by postsynaptic receptors. Institut fur Physiologische Chemie, Universitat Mainz, Germany. Arzneimittelforschung 1995 Nov;45(11):1145-1148

17. Baureithel KH, Buter KB, Engesser A, Burkard W, Schaffner W Inhibition of benzodiazepine binding in vitro by amentoflavone, a constituent of various species of Hypericum. Dept. of Pharmaceutical Biology, University of Basel, Switzerland. Pharm Acta Helv 72(3), 153-157 (1997)

18. Martinez B, Kasper S, Ruhrmann S, Moller HJ Hypericum in the treatment of seasonal affective disorders. Psychiatrische Universitatsklinik Bonn, Germany. J Geriatr Psychiatry Neurol 1994 Oct;7 Suppl 1:S29-S33

19. Schulz H, Jobert M Effects of hypericum extract on the sleep EEG in older volunteers. AFB-Parexel GmbH, Klinische Pharmakologie, Berlin, Germany. J Geriatr Psychiatry Neurol 1994 Oct;7 Suppl 1:S39-S43

20. Zhang W; Hinton DR; Surnock AA; Couldwell WT Malignant glioma sensitivity to radiotherapy, high-dose tamoxifen, and hypericin: corroborating clinical response in vitro: case report. Department of Neurological Surgery, University of Southern California, Los Angeles, USA. Neurosurgery, 1996 Mar, 38:3, 587-90; discussion 590-1

21. Shipochliev T Uterotonic action of extracts from a group of medicinal plants. Vet Med Nauki 1981;18(4):94-98 [Article in Bulgarian]

22. Okpanyi SN, Lidzba H, Scholl BC, Miltenburger HG Genotoxicity of a standardized Hypericum extract. Steigerwald Arzneimittelwerk GmbH, Darmstadt. Arzneimittelforschung 1990 Aug;40(8):851-855 [Article in German]

23. The Merck Index, An Encyclopedia of Chemicals, Drugs and Biologicals 12th edition. Budavari, Susan; O'Neil, Maryadele; Smith, Ann; Heckelman, Patricia; and Kinneary, Joanne F; eds. Merck & Co., Inc., Whitehouse Station, NJ; 1996 pp:836-836

24. Goodman and Gilman's The Pharmacologic Basis of Theraputics_ 8th edition; Goodman Gilman A., Rall T. W, Nies A.S., Taylor, P. eds: McGraw-Hill, New York, 1993. pp: 244-268

25. Miller, Sue: A Natural Mood Booster Newsweek, May 15, 1997

26. St.John's Wort Monograph American Herbal Pharmacoepea and Theraputic Compendium HerbalGram #40 pp. 37-45; 1997, American Botanical Council

27. BMJ 1996 Aug 3;313(7052):241-242 St John's wort as an antidepressant. [EDITORIAL] De Smet PA, Nolen WA

28. Baureithel, Buter, Engesser, Burkhard & Schaffner Inhibition of Benzodiazepine Binding in vitro by Amentoflavone, a Constituent of Various Species of Hypericum. Pharm.Acta Helv. 72(3): 153-157, 1997.

29. American Medical Association Drug Evaluations Annual: 1995

30. Montejo-Gonzalez AL, Llorca G, Izquierdo JA, Ledesma A, Bousano M, Calcido A, Carrasco JL, Cuidad J, Daniel E, De la Gandara J, Franco M, Gomez MJ, Macias JA, Martin T, Perez V, Sanchez JM, Sanchez S, Vicens E SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline and fluvoxamine in a prospective, multicenter and descriptive clinical study of 344 patients Servicio de Psiquiatria, Hospital Universitario de Salamanca, Spain J Sex Marital Ther 1997:23(3):176-194

31. Mitchell PB Drug interactions of clinical significance with selective serotonin reuptake inhibitors School of Psychiatry, University of New South Wales, Sydney, Australia Drug Saf 1997 Dec;17(6):390-406

32. Sporer KA The serotonin syndrome. Implicated drugs, pathophysiology and management University of California, San Francisco, USA Drug Saf 1995 Aug:13(2):94-104

33. Demisch l, Nispel J, Gebhart P, Kohler C, Pflug B Nocturnal melatonin and cortisol secretions before and after subchronic administration of Hyperforat Abstract from the AGNP-symposium, Nuernberg 1991

34. Scmidt U, Harrer G, Kuhn K, Berger-Deinert W, Luther D Interaction of hypericum extract and alcohol Nervenheilkunde 13 (1993);6: 314-319

35. Cott, JM In vitro receptor binding and enzyme inhibition by Hypericum perforatum extract Pharmacological Treatment Research Program, National Institute of Mental Health, Rockville, Maryland, USA Pharmacopsychiatry 1997 30 Suppl 2 ():108-12 Sep

36. Arneson, Mary Regulatory Weakness Cost "Grandma" The Use Of Her Right Side And I'd Like To Know Why Minneapolis Star-Tribune, Nov. 19, 1997

37. Personal communication to me by Dr. Arneson.

38. Personal communication to me from patients.

39. Good Housekeeping Institute New Good Housekeeping Institute study finds drastic discrepancy in potencies of popular herbal supplement. News release, Consumer Safety Symposium on Dietary Supplements and Herbs, New York City, March 3, 1998.

40. Muller WE, Rolli M, Schafer C, Hafner U Effects of Hypericum Extract (LI 160) in Biochemical Models of Antidepressant Activity Department of Pharmacology, Biocenter Univesity of Frankfurt, Frankfurt Germany and Department of Psychopharmacology, Central Institute of Mental Health, Mannheim, Germany Pharmacopsychiatry 1997 30 Suppl 2 ( ):102-7 Sep

41. Cavagnini F, Invitti C, Pinto M, Maraschini C, Di Landro A, Dubini A. Marelli A. Effect of acute and repeated administration of gamma aminobutyric acid (GABA) on growth hormone and prolactin secretion in man. Acta Endocrinologica. 93(2):149-54, 1980 Feb.

42. Nahrstedt A, Butterweck V Biologically Active and Other Chemical Constituents of the herb of Hypericum perforatum L. Pharmacopsychiatry 1997 30 Suppl 2 ():129-34 Sep.

43. Cooper Jack R., Bloom Floyd E., Roth Robert H., The Biochemical Basis of Neuropharmacology Oxford University Press, New York 1996

44. Berges RR, Windeler J, Trampisch HJ, Senge T Randomised, placebo-controlled, double-blind clinical trial of beta-sitosterol in patients with benign prostatic hyperplasia. Beta-sitosterol Study Group. Department of Urology, Ruhr-University, Bochum, Germany. Lancet 1995 Jun 17;345(8964):1529-1532

45. Wargovich MJ, Chen CD, Jimenez A, Steele VE, Velasco M, Stephens LC, Price R, Gray K, Kelloff GJ Aberrant crypts as a biomarker for colon cancer: evaluation of potential chemopreventive agents in the rat. Department of Gastrointestinal Medical Onclolgy and Digestive Diseases, The University of Texas M.D. Anderson Cancer Center, Houston, USA. Cancer Epidemiol Biomarkers Prev 1996 May;5(5):355-360

46. Kennedy AR The evidence for soybean products as cancer preventive agents. Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia 19104. J Nutr 1995 Mar;125(3 Suppl):733S-743S

47. Murray, Michael T St. John's Wort Extract in Depression: Over Three million Prescriptions per Year in Germany American Journal of Natural Medicine, Vol. 3, No. 10, Dec. 1996

48. Laakmann G, Schule C, Baghai T, Kieser M St. John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Department of Psychiatry, University of Munich, Germany. Pharmacopsychiatry 1998 Jun;31 Suppl 1:54-9

49. Muller WE, Singer A, Wonnemann M, Hafner U, Rolli M, Schafer C Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Department of Pharmacology, Biocenter University of Frankfurt, Germany. Pharmacopsychiatry 1998 Jun;31 Suppl 1:16-21

50. Bhattacharya SK, Chakrabarti A, Chatterjee SS Activity profiles of two hyperforin-containing hypericum extracts in behavioral models. Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varansai, India. Pharmacopsychiatry 1998 Jun;31 Suppl 1:22-9

51. Chatterjee SS, Noldner M, Koch E, Erdelmeier C Antidepressant activity of hypericum perforatum and hyperforin: the neglected possibility. Research Department, Dr. Willmar Schwabe GmbH & Co., Karlsruhe, Germany. Pharmacopsychiatry 1998 Jun;31 Suppl 1:7-15

52. Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Muller WE Hyperforin as a possible antidepressant component of hypericum extracts. Pharmacology Department, Dr. Willmar Schwabe GmbH & Co., Karlsruhe, Germany. Life Sci 1998;63(6):499-510

53. Schellenberg R, Sauer S, Dimpfel W Pharmacodynamic effects of two different hypericum extracts in healthy volunteers measured by quantitative EEG. Pro Science Private Research Clinic GmbH, Linden, Germany. Pharmacopsychiatry 1998 Jun;31 Suppl 1:44-53

54. Dimpfel W, Schober F, Mannel M Effects of a methanolic extract and a hyperforin-enriched CO2 extract of St. John's Wort (Hypericum perforatum) on intracerebral field potentials in the freely moving rat (Tele-Stereo-EEG). Pro Science Private Research Clinic GmbH, Linden, Germany. Pharmacopsychiatry 1998 Jun;31 Suppl 1:30-5

55. St. John's Wort May be Associated with Nerve Damage The Lancet (1998;352:1121-1122). 56. Biber A, Fischer H, Romer A, Chatterjee SS Oral bioavailability of hyperforin from hypericum extracts in rats and human volunteers. Dr. W. Schwabe GmbH & Co., Karlsruhe, Germany. Pharmacopsychiatry 1998 Jun;31 Suppl 1:36-43

OTHER REFERENCES:

Bol'shakova IV, 1997 Antioxidant properties of a series of extracts from medicinal plants Biofizika 42(2), 480-483 (1997)

Kasper S, 1997 Hypericum perforatum in psychiatric practice (interview) Nervenarzt 68(2), 8 (1997)

[No authors listed], 1997 Antidepressive effectiveness and good tolerance Nervenarzt 68(2), 5-7 (1997)

[No authors listed], 1997 Chemical composition of Hypericum perforatum and its effects

Nervenarzt 68(2), 3-4 (1997)

[No authors listed], 1997 A plant extract with proven antidepressive effect Nervenarzt 68(2), 2 (1997)

Rampes H, 1997 Hypericum, an over the counter antidepressant? J Psychopharmacol (Oxf) 11(2), 191 (1997)

Rath G, 1996 Xanthones from Hypericum roeperanum. Phytochemistry 43(2), 513-520 (1996)

De Smet PA, 1996 St John's wort as an antidepressant [editorial; comment] BMJ 313(7052), 241-242 (1996)

Taylor RS, 1996 Antiviral activities of Nepalese medicinal plants. J Ethnopharmacol 52(3), 157-163 (1996)

Kartnig T, 1996 Production of hypericin, pseudohypericin and flavonoids in cell cultures of various Hypericum species and their chemotypes. Planta Med 62(1), 51-53 (1996)

Perovic S, 1995 Pharmacological profile of hypericum extract. Effect on serotonin uptake by postsynaptic receptors. Arzneimittelforschung 45(11), 1145-1148 (1995)

Rocha L, 1995 Antibacterial phloroglucinols and flavonoids from Hypericum brasiliense. Phytochemistry 40(5), 1447-1452 (1995)

Witte B, 1995 Treatment of depressive symptoms with a high concentration hypericum preparation. A multicenter placebo-controlled double-blind study Fortschr Med 113(28), 404-408 (1995)

Ernst E, 1995 St. John's wort as antidepressive therapy Fortschr Med 113(25), 354-355 (1995)

Davidov MI, 1995 Phytoperfusion of the bladder after adenomectomy Urol Nefrol (Mosk) 5, 19-20 (1995)

Diwu Z, 1995 Novel therapeutic and diagnostic applications of hypocrellins and hypericins. Photochem Photobiol 61(6), 529-539 (1995)

Rivera D, 1995 The ethnopharmacology of Madeira and Porto Santo Islands, a review. J Ethnopharmacol 46(2), 73-93 (1995)

Cott J, 1995 NCDEU update. Natural product formulations available in europe for psychotropic indications. Psychopharmacol Bull 31(4), 745-751 (1995)

Sommer H, 1994 Placebo-controlled double-blind study examining the effectiveness of an hypericum preparation in 105 mildly depressed patients. J Geriatr Psychiatry Neurol 7, S9-S11 (1994)

Wagner H, 1994 Pharmaceutical quality of hypericum extracts. J Geriatr Psychiatry Neurol 7, S65-S68 (1994)

Muller WE, 1994

Effects of hypericum extract on the expression of serotonin receptors. J Geriatr Psychiatry Neurol 7, S63-S64 (1994)

Harrer G, 1994 Clinical investigation of the antidepressant effectiveness of hypericum. J Geriatr Psychiatry Neurol 7, S6-S8 (1994)

Bladt S, 1994 Inhibition of MAO by fractions and constituents of hypericum extract. J Geriatr Psychiatry Neurol 7, S57-S59 (1994)

Thiede HM, 1994 Inhibition of MAO and COMT by hypericum extracts and hypericin. J Geriatr Psychiatry Neurol 7, S54-S56 (1994)

Johnson D, 1994 Effects of hypericum extract LI 160 compared with maprotiline on resting EEG and evoked potentials in 24 volunteers. J Geriatr Psychiatry Neurol 7, S44-S46 (1994)

Schulz H, 1994 Effects of hypericum extract on the sleep EEG in older volunteers. J Geriatr Psychiatry Neurol 7, S39-S43 (1994)

Woelk H, 1994 Benefits and risks of the hypericum extract LI 160: drug monitoring study with 3250 patients. J Geriatr Psychiatry Neurol 7, S34-S38 (1994)

Payk TR, 1994 Treatment of depression. J Geriatr Psychiatry Neurol 7, S3-S5 (1994)

Martinez B, 1994 Hypericum in the treatment of seasonal affective disorders. J Geriatr Psychiatry Neurol 7, S29-S33 (1994)

Harrer G, 1994 Effectiveness and tolerance of the hypericum extract LI 160 compared to maprotiline: a multicenter double-blind study. J Geriatr Psychiatry Neurol 7, S24-S28 (1994)

Vorbach EU, 1994 Effectiveness and tolerance of the hypericum extract LI 160 in comparison with imipramine: randomized double-blind study with 135 outpatients. J Geriatr Psychiatry Neurol 7, S19-S23 (1994)

Hansgen KD, 1994 Multicenter double-blind study examining the antidepressant effectiveness of the hypericum extract LI 160. J Geriatr Psychiatry Neurol 7, S15-S18 (1994)

Hubner WD, 1994 Hypericum treatment of mild depressions with somatic symptoms. J Geriatr Psychiatry Neurol 7, S12-S14 (1994)

Rocha L, 1994 An antifungal gamma-pyrone and xanthones with monoamine oxidase inhibitory activity from Hypericum brasiliense. Phytochemistry 36(6), 1381-1385 (1994)

Kliachko LL, 1994 The effect of medicinal herbs on lymphocyte rosette-forming function Vestn Otorinolaringol 2, 31-33 (1994)

Kako MD, 1993 Studies of sheep experimentally poisoned with Hypericum perforatum. Vet Hum Toxicol 35(4), 298-300 (1993)

Schmidt U, 1993 St. John's wort extract in the ambulatory therapy of depression. Attention and reaction ability are preserved Fortschr Med 111(19), 339-342 (1993)

Krylov AA, 1993 The use of an infusion of St.-John's-wort in the combined treatment of alcoholics with peptic ulcer and chronic gastritis Lik Sprava 2-3, 146-148 (1993)

Tada M, 1992 Analogues of natural phloroglucinols as antagonists against both thromboxane A2 and leukotriene D4. J Med Chem 35(7), 1209-1212 (1992)

Chen JY, 1992 Development of natural crude drug resources from Taiwan (X). Pharmacognostical studies on the Chinese crude drug "han-lian-cao". Am J Chin Med 20(1), 51-64 (1992)

Smyshliaeva AV, 1992 The modification of a radiation lesion in animals with an aqueous extract of Hypericum perforatum L. 2. Biol Nauki 4, 9-13 (1992)

Decosterd LA, 1991 A new phloroglucinol derivative from Hypericum calycinum with antifungal and in vitro antimalarial activity. Planta Med 57(6), 548-551 (1991)

Jayasuriya H, 1991 Synthesis and the biological evaluation of the structural units of H. drummondin C. Pharm Res 8(11), 1372-1376 (1991)

Holzl J, 1991 Is Hypericum perforatum phototoxic? (letter) Med Monatsschr Pharm 14(10), 304-306 (1991) (no abstract available)

Jayasuriya H, 1991 New antimicrobial filicinic acid derivatives from Hypericum drummondii. J Nat Prod 54(5), 1314-1320 (1991)

Melzer R, 1991 Vasoactive properties of procyanidins from Hypericum perforatum L. in isolated porcine coronary arteries. Arzneimittelforschung 41(5), 481-483 (1991)

Okpanyi SN, 1990 Genotoxicity of a standardized Hypericum extract Arzneimittelforschung 40(8), 851-855 (1990)

Ishiguro K, 1990 Sarothralin G: a new antimicrobial compound from Hypericum japonicum. Planta Med 56(3), 274-276 (1990)

Takahashi I, 1989 Hypericin and pseudohypericin specifically inhibit protein kinase C: possible relation to their antiretroviral activity. Biochem Biophys Res Commun 165(3), 1207-1212 (1989)

Zheng MS, 1989 An experimental study of the anti-HSV-II action of 500 herbal drugs. J Tradit Chin Med 9(2), 113-116 (1989)

Jayasuriya H, 1989 Antimicrobial and cytotoxic activity of rottlerin-type compounds from Hypericum drummondii. J Nat Prod 52(2), 325-331 (1989)

Kumper H, 1989 Hypericum poisoning in sheep Tierarztl Prax 17(3), 257-261 (1989)

Meruelo D, 1988 Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericin. Proc Natl Acad Sci U S A 85(14), 5230-5234 (1988)

Decosterd LA, 1987 Application of semi-preparative high-performance liquid chromatography to difficult natural product separations. J Chromatogr 406, 367-373 (1987)

Ishiguro K, 1987 Saroaspidin A, B, and C: additional antibiotic compounds from Hypericum japonicum. Planta Med 53(5), 415-417 (1987)

Okpanyi SN, 1987 Animal experiments on the psychotropic action of a Hypericum extract Arzneimittelforschung 37(1), 10-13 (1987)

Tammaro F, 1986 Plants used in phytotherapy, cosmetics and dyeing in the Pramanda district (Epirus, North-West Greece). J Ethnopharmacol 16(2-3), 167-174 (1986)

Kikuchi T, 1985 Studies on the constituents of medicinal and related plants in Sri Lanka. II. Isolation and structures of new gamma-pyrone and related compounds from Hypericum mysorense Heyne. Chem Pharm Bull (Tokyo) 33(2), 557-564 (1985)

Kosuge T, 1985 Studies on antihemorrhagic substances in herbs classified as hemostatics in Chinese medicine. IV. On antihemorrhagic principles in Hypericum erectum Thunb. Chem Pharm Bull (Tokyo) 33(1), 202-205 (1985)

Garrett BJ, 1982 Consumption of poisonous plants (Senecio jacobaea, Symphytum officinale, Pteridium aquilinum, Hypericum perforatum) by rats: chronic toxicity, mineral metabolism, and hepatic drug-metabolizing enzymes. Toxicol Lett 10(2-3), 183-188 (1982)

Araya OS, 1981 An investigation of the type of photosensitization caused by the ingestion of St John's Wort (Hypericum perforatum) by calves. J Comp Pathol 91(1), 135-141 (1981)

Shipochliev T, 1981 Uterotonic action of extracts from a group of medicinal plants Vet Med Nauki 18(4), 94-98 (1981)

Shipochliev T, 1981 Anti-inflammatory action of a group of plant extracts Vet Med Nauki 18(6), 87-94 (1981)

Wang ZQ, 1980 Studies on the constituents of hong han lian (Hypericum ascyron L.) Yao Hsueh Hsueh Pao 15(6), 365-367 (1980)

Avenirova EL, 1977 Effect of novoimanine on the cellular permeability indices of staphylococci Antibiotiki 22(7), 630-634 (1977)

Matei I, 1977 Value of Hypericum perforatum oil in dermatological preparations. I. Rev Med Chir Soc Med Nat Iasi 81(1), 73-74 (1977)

Palamarchuk OP, 1975 Chromatographic study of the flavonoid compounds in Hypericum erectum Farm Zh 2, 77 (1975)

El'iashevich OG, 1973 Growth sites of klamath seed (Hypericum perforatum L.) in Lvov Province and a determination of the quantity of extractable substances in the raw material Farm Zh 28(5), 92-93 (1973)

Derbentseva NA, 1972 Action of tannins from Hypericum perforatum L. on the influenza virus Mikrobiol Zh 34(6), 768-772 (1972)

Gurevich AI, 1971 Antibiotic hyperforin from Hypericum perforatum L Antibiotiki 16(6), 510-513 (1971)

Shakirova KK, 1969 Study of some species of Hypericum cultivated in Uzbekistan Farmatsiia 18(5), 32-35 (1969)

Taylor HL, 1969 The isolation of uliginosin A and uliginosin B from Hypericum uliginosum. Lloydia 32(2), 217-219 (1969)

Aizenman BIu, 1969 Antibiotic preparations from Hypericum perforatum L Mikrobiol Zh 31(2), 128-133 (1969)

Parker WL, 1968 The structure determination of antibiotic compounds from Hypericum uliginosum. II. The molecular and crystal structure of bromouliginosin B. J Am Chem Soc 90(17), 4723-4729 (1968)

Parker WL, 1968 The structure determination of antibiotic compounds from Hypericum uliginosum. I. J Am Chem Soc 90(17), 4716-4723 (1968)

Chaplinskaia MG, 1965 Study of the photodynamic action of Hypericum in its external use Farm Zh 20(2), 47-53 (1965)

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