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St. John's Wort FAQ

Camilla Cracchiolo, R.N.

Table of Contents

Introduction and Disclaimer

What is St. John's wort?
Approved theraputic uses in European countries
Treatment of depression A. Efficacy and safety B. By what mechanism does St. John's wort exert antidepressant effects? C. The MAOI controversy D. What is the antidepressant agent in St. John's wort?
Other pharmacologic properties of St. John's wort

Effects on sleep
Anti-viral activity
Anti-bacterial and anti-fungal activity
Immunologic effects
Wound healing properties
Other medicinal properties

Adverse reactions and side effects

LD50 and toxicology studies
Photosensitivity
Minor side effects

Drug interactions
Research on St. John's wort and pregnancy.
Main pharmacologic agents in St. John's wort.
Is St. John's wort useful in the treatment of cancer?
Technical Appendices:

Precautions and suggested patient instructions
Dosage and administration
Pharmacokinetics
Chemical Constituents
Regulatory Status

INTRODUCTION:

I hope you find this article useful. I have tried to organize 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 first part as well!)

For further info, including abstracts and a general article on herbal medicine, (_Herbal Medicine: Sometimes Helpful But Use With Care_), check out my web page.

The address is: http://www.primenet.com/~camilla

Just so folks know: I neither sell nor distribute herbs or any other product and my home page is NOT an advertising site.

The herbal medicine article is:

http://www.primenet.com/~camilla/herbs

MEDLINE abstracts on St. John's wort are available on my web page as:

http://www.primenet.com/~camilla/hypercum.rev

The MEDLINE abstracts on St. John's wort can now also be obtained by automated e-mail reply!

Send a message to camilla@primenet.com containing the following words in the subject:

GET STJOHNS ABSTRACTS

The general herbal medicine article can be obtained by e-mail by sending a message to camilla@primenet.com with the following words in the subject:

GET HERB FAQ

If you wish to obtain a complete list of FAQs available from me by email, send a message to camilla@primenet.com with the following words in the subject:

GET FAQ LIST

Please remember that computers are real dumb and that you won't get the file if you don't spell the message exactly as above. Also, the computer only recognizes one FAQ request per letter, so you must send a separate message for each FAQ requested.

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 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 regulated in the U.S., there is no regulatory oversight of herbal manufacturing, distribution and labelling. This means that, unlike in many 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 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 analyze 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.

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; St. Jan's Kraut in Dutch; Herba de Millepertuis, Herba de Saint Jean 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 supercede 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. (See top of document for how to get a copy.)

2. APPROVED THERAPUTIC USES IN EUROPEAN COUNTRIES

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

Since the U.S. FDA does not recognize theraputic use for any herb, we must draw on the existing scientific literature and the regulations of European countries to determine the theraputic value of St. John's wort.

The most commonly approved indication in European countries is 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 they provide the most logical basis for product labelling.

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]

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". While St. John's wort does indeed appear effective in the treatment of certain cases of depression, the real situation is considerably more complex. It's not at all clear whether St. John's wort works in the same manner as Prozac, if it works more like dopamine stimulating agents such as bupropion (marketed as Wellbutrin in the U.S.), if it is more similar in action to tricyclic or other heterocyclic antidepressants or if a brand new mechanism of action is present.

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.

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 randomised clinical trials
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 has 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 standardized as to hypericin content and all 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 favor 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 standardized for hypericin content, it now turns out that hypericin may 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 Effexnor or Paxil. 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 it's 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]

Continued on Page 2

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