St. John's Wort

Minnesota Health Technology Advisory Committee

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Minnesota Health Technology Advisory Committee. Minnesota Health Technology Assessments [Internet]. St. Paul (MN): Minnesota Department of Health; 1995-2001.

This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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St. John's Wort

Created: December 2000.

Executive Summary

The use of herbal products has increased rapidly over the last five years resulting in a record $9 billion in sales during 1999. This growth is being driven by a number of factors including aggressive marketing, low cost, easy access, minimal regulatory control, and a belief that because herbal products are "natural" they are safe. Herbal preparations are classified as dietary supplements and, therefore, are regulated by the Federal Drug Administration (FDA) under the Dietary Supplement Health and Education Act (DSHEA) of 1994. This act permits the sale of dietary supplements without the extensive premarket approval process required of new drugs. Concerns of inappropriate use, adverse reactions, questionable marketing, safety, and effectiveness have generated growing support to restore the FDA's original control of herbal products.

St. John's wort is one of many herbs that have been used for centuries. Currently, the most common use is in the treatment of mild depression. St. John's wort has been used effectively for the treatment of mild depression, but the exact mechanism of action is unknown. Some researchers believe that St. John's wort is a monoamine oxidase (MAO) inhibitor, while others suspect that high concentrations of flavonoids contribute to its antidepressant activity. Extracts from St. John's wort contain several active compounds, many of which have been shown to bind to the neuroreceptors in the brain.

To date, the majority of the studies are from Germany, consist of small sample sizes, and are short in duration. The classification of depressive disorders was inconsistent, and severity of depression did not always correlate with severity of symptoms according to scales. Different preparations for St. John's wort and the dose of the total extract varied considerably. However, the studies showed that there is evidence that St. John's wort is better than placebo and may work as well as other antidepressants in treating mild to moderate depressive disorders. One U.S. study found St. John's wort to be as least as effective as one selective serotonin reuptake inhibitor (SSRI) in the treatment of mild to moderate depression.

St. John's wort has not been systematically studied to document safety, side effects, and toxicity. Studies have shown St. John's wort to have fewer side effects than certain tricyclic antidepressants, however, additional scientific information on the interactions of St. John's wort with over-the-counter drugs, prescription drugs, other herbal products, and food needs to be studied.

Due to the limited amount of scientific information on St. John's wort and other herbal supplements, caution needs to be exercised in use of these products.

Conclusions

With the passage of DSHEA, the FDA has less stringent authority governing St. John's wort, and dietary supplements; therefore, clinical trials showing safety and effectiveness are not required. Variances exist in purity, strength, and potency.

Strong marketing and belief by consumers that herbal supplements are "natural," and therefore safe and effective, have resulted in increased use.

Herbal supplements are taken based on self-diagnosis, beliefs or customs, advice of friends, or advice of nontraditional providers. This has created the potential for severe problems by users.

Limited data exists demonstrating the effectiveness of St. John's wort with mild to moderate depression. Safety, interactions, and toxicity have not been fully studied. Clinically significant drug interactions have recently been reported with St. John's wort.

Recommendations

All persons using St. John's wort or herbal supplements should consult with their physician prior to using St. John's wort or other herbal supplements.

Additional data from well-designed, controlled studies is needed to determine the effectiveness and safety of St. John's wort and its potential interactions with other drugs.

Physicians should inquire if patients are taking any herbal supplements prior to prescribing any drug.

Pharmacists should inquire if patients are taking any herbal supplements prior to dispensing any drug.

Patients should be informed about possible complications, drug interactions, and food interactions that can occur with St. John's wort and other herbal supplements.

Patients who are currently taking indinavir, cyclosporine, or digoxin should not take St. John's wort. The use of St. John's wort has been shown to significantly decrease the concentration in the blood of indinavir (Crixivan®), cyclosporine, and digoxin.

Women should be informed that the effectiveness of oral contraceptives could be reduced by St. John's wort.

Due to a lack of clinical data, pregnant or nursing women should first contact their physician before taking St. John's wort or any herbal supplement.

Equal caution should be exercised when using herbal supplements and any drugs.

FDA rules should require herbal supplements to be systematically studied, (including interactions with other drugs) in order to protect the public from harm.

Introduction

Herbs have been in use worldwide for centuries. Today, the use of herbal products is common in approximately 80% of the world's population.¹ During the 1990s, the trend toward self-medication with herbal supplements, driven by strong marketing campaigns and consumerism, has increased in the United States. In 1996, sales of herbal supplements in the U.S. exceeded $1.2 billion and, in 1999, sales grew to an estimated $8.8 billion.² Herbal supplements are regulated in the U.S. by the Food and Drug Administration (FDA) as dietary supplements under the Dietary Supplement Health and Education Act (DSHEA). DSHEA has less stringent standards than those under which pharmaceutical drugs are regulated. Therefore, manufacturers of herbal supplements are not subject to the same approval process or quality control standards as pharmaceutical drug manufacturers.

It is estimated that more than 60 million people (23%) in the United States over the age of 18 use herbal supplements,^3,4,5 or approximately 790,000 Minnesotans in 1998. The new attraction to herbals for Americans may stem from a person's desire to use something inexpensive, easily obtainable, and perceived as natural (not manufactured). Other attractions to herbal supplements may include a person's aversion to seeing a physician or it may be a part of his/her cultural background. Most herbal supplements are used after an individual has performed a self-diagnosis of his/her health needs. In a 1997 national phone survey, it was reported that 12 percent of 2055 respondents had used herbal supplements within the last year. Of these, 15 percent saw nontraditional providers and had a mean of 2.9 visits over that year.⁵ In the U.S., an estimated 629 million visits to unconventional providers were made in 1997.⁵ Physicians were not consulted in most of these instances, and fewer than three in ten people reported the use of any unconventional therapy to their physician.^4,5

Due to the growing use of herbal supplements by the general public, an understanding of the benefits and risks of using herbal products should be part of a physician's base of knowledge. Lectures such as "Complementary and Alternative Pharmacotherapeutics" given at the University of Minnesota will help train physicians about herbs, but additional training is needed.^6-7 Not only should there be an understanding of the properties of commonly used herbs, but physicians and pharmacists must be knowledgeable about the possible adverse results from mixing herbal products with each other or with prescription medications. Although there are few scientific studies on the toxicities of herbal products, there have been enough reported incidences of complications to establish that potential risks exist and should not be ignored^2,7,9-15

FDA

Currently, herbal products (such as St. John's wort) are recognized by the FDA as dietary supplements and not as foods or drugs.^1,3,16-18 A dietary supplement is any product taken by mouth that contains a so-called "dietary ingredient" and the label on the product clearly states that it is a dietary supplement. A "dietary ingredient" may include vitamins, minerals, herbs, and amino acids, as well as substances such as enzymes, organ tissues, metabolites, extracts, or concentrates. Dietary supplement ingredients may not be regulated as food additives.

From 1962 to 1994, the FDA regulated herbal supplements as pharmaceutical drugs.^3,7 Before permitting the marketing of herbal products, the FDA required clinical trials to determine their effectiveness, safety, possible interactions with other substances, and appropriate dosage. In 1993, the FDA threatened to remove herbal supplements from the market altogether.⁷

As a result of different and varying pressures, the U.S. Congress passed the Dietary Supplement Health and Education Act of 1994. This act permits the sale of dietary supplements without FDA approval provided that manufacturers do not claim to: restore normal function; correct abnormal function; treat, diagnose, cure, or prevent a specific disease or class of diseases; or mitigate conditions of health.^17,18 Manufacturers may make claims associated with the maintenance of good health, structure, function, or mechanism, however, rules do not allow for implied disease claims. The promotion of unproven effects is allowed if there is an accompanying disclaimer stating that it has not been reviewed by the FDA for the purpose of medication. An FDA rule, effective February 7, 2000, changed the definition of disease so that it does not include "common conditions associated with natural states or processes that do not cause significant or permanent harm." This rule allows the manufacturers of dietary supplements to make claims for the treatment or mitigation of "natural states" such as hot flashes, mild memory problems, or hair loss associated with aging without proving that the products are safe or effective. However, as of March 23, 2000, the FDA will be requiring an information panel, entitled "supplement facts," to appear on all dietary supplements. This panel will be similar in format to the "nutrition facts" panel that now appears on most processed foods and will include serving size, nutrients, and other ingredients present in the product.

The Federal Trade Commission (FTC) primarily regulates the advertising and marketing of dietary supplements. In November 1998, the FTC issued the advertising guidelines for manufacturers and marketers of dietary supplements. The DSHEA does allow for the removal of herbal supplements from the market if health claims are made (as opposed to only structure or function claims) or if the FDA has proven the product unsafe.

Because herbal supplements are not regulated as drugs, manufacturers are able to sell herbal products without FDA approval and there is no requirement that manufacturers produce a product that meets set standards for uniformity and consistency. This raises concerns regarding variability of the same herbal product from one manufacturer to the next. Concerns include composition, quality, dosage, purity, and potency. Data are also lacking regarding safety, effectiveness, long-term toxicity, and adverse effects on specific populations (e.g., pregnant women, nursing mothers, and elderly patients with impaired liver function, cardiovascular problems, or other serious conditions).

With the increased use of herbal supplements, there is a growing concern that the FDA should reexamine the safety and efficacy of these products, as well as the distribution and marketing practices of their manufacturers. The original DSHEA law was not specific on a number of issues, so the FDA has developed rules and regulations to clarify the FDA's authority and the definitions of dietary supplements. Concern exists since the DSHEA does not permit the FDA the same regulatory powers for herbal supplements as for prescription drugs, and that herbal supplements are being promoted and used inappropriately.

On February 10, 2000, the FDA issued a warning letter to health professionals about St. John's wort. The letter stated: 'St. John's wort appears to be an inducer of an important metabolic pathway. Many prescription drugs used to prevent transplant rejection or pregnancy (oral contraceptives) are metabolized via this pathway; therefore, health care providers should alert patients about the potential drug interaction. Since herbal products are widely used in the United States and are available in various forms such as combination products and teas, it is important that health care professionals ask patients about concomitant use of products that contain John's wort (hypericum perforatum). This warning letter is based on an increasing volume of voluntary reports the FDA has been receiving over the last two years and upon a study completed by the National Institutes of Health (NIH).^19,20,21

Background

St. John's wort (Hypericum perforatum), also known as Hypericum, Klamath weed and goat weed, is a perennial weed native to Europe and Asia that was brought to the United States by European colonists.^16,22 The plant was named after John the Baptist in the first century and wort is an old English word meaning plant. St. John's wort has been used as an herbal medicine for centuries, both orally and topically, as an anti-inflammatory, sedative, analgesic, diuretic, antimalarial, and wound-healing agent.^16,23,24 Greeks and Romans thought it could protect them from evil spirits and used it to "ward off" depressive illness.

While Germany and other European countries have long utilized St. John's wort as an antidepressant,²⁵ in the U.S. it reached a high level of interest 10 years ago after gaining some notoriety as an antiviral herb.²⁶ It is now being used in the U.S. for treatment of depression, anxiety, and insomnia. The use of St. John's wort for the treatment of depression has made it the number five selling herb in Europe and one of the top 10 herbs used in the U.S. and Minnesota.^3,27 It is often referred to as "Nature's Prozac."²⁸ St. John's wort is still being used for wound healing, and a few studies have been undertaken to determine its effectiveness for this use.16 However, its most common use is for the treatment of mild depression and it is in this area that the vast majority of clinical research is being performed.^22,28,29

In 1977, when the FDA regulated herbs as prescription drugs, it declared St. John's wort unsafe since cattle who ate large quantities of the plant developed a sensitivity to the sun accompanied by severe sunburn and blisters.^{10,16,27,30,31}

Uses

St. John's wort has gained attention for treatment of depression, as a wound-healing agent and as an herb with potential antiviral benefits in the treatment of AIDS.²⁶ Its use in the treatment of mild depression is the most popular and will be the focus of this report.

Depression

St. John's wort, or an extract from the herb, is frequently being used for treatment of depression. Depression is a common disorder with an estimated lifetime prevalence of 17 percent in the United States.^25,32,33 According to the National Mental Health Association the estimated number of people afflicted with clinical depression is over 19 million.³⁴ Depression is characterized by many subjective symptoms including despondency, loss of interest, irritability, eating disturbances, and disruption of sleeping patterns. Depression is generally considered to have three degrees of severity: mild, moderate, and severe. Mild depression, the most prevalent form of depression, does not interrupt daily activities whereas moderate depression occurs with more frequency and may sometimes interfere with daily activities. However, severe depression leads to extreme functional impairment and sometimes suicide.^25,32,35

Medical researchers believe that depression is caused by a biochemical imbalance or by a combination of biochemical imbalances. One such imbalance is the deficiency of the neurotransmitters serotonin, dopamine, and norepinephrine. Neurotransmitters act as cellular messengers, enabling brain cells to communicate. They are secreted into the synapses, or spaces, between neurons and are "taken up" by receptors where they are subsequently stored or metabolized with the aid of an enzyme, monoamine oxidase. Compounds that interfere with or inhibit this process have been found to have a beneficial effect on depression. Another possible cause of depression is the over stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by inflammatory cytokines, such as interleukins and tumor necrosis factors, resulting in the excessive production of cortisol. It is believed that cytokines are involved in cell-to-cell communication in the immune and central nervous system, and may play a role in depression as neuromodulators. Prolonged increases in cortisol levels are known to reduce serotonin production and sensitivity of serotonin receptors, as well as to inhibit the secretion of melatonin. Deficient levels of melatonin have been found in patients suffering from depression.²²

Several groups of antidepressant medications are used to treat depressive disorders: tricyclics, monoamine oxidase inhibitors (MAOI), and selective serotonin reuptake inhibitors (SSRI).^25,36 Tricyclic antidepressants enhance the concentration of two neurotransmitter chemicals, norepinephrine and serotonin, and impede the reuptake process so that monoamines remain active longer. MAOIs regulate the metabolic degradation of norepinephrine, serotonin, and dopamine by inhibiting monoamine oxidase. SSRIs inhibit the uptake of serotonin. Bupropion, a newer antidepressant that is chemically unrelated to the other antidepressants, inhibits the uptake of norepinephrine and dopamine, more than serotonin, and does not inhibit MAO.³⁷

Wound Healing and Antiviral Activity

A burn ointment made from the extract taken from the flowers of St. John's wort has been promoted as assisting in the healing of first-, second-, and third-degree burns. There are references in literature which cite cases where 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.¹⁶ However, the most commonly cited reference is a single case report and not a scientific study.
St. John's wort is also being used for cuts and abrasions and a few older studies were found to support this use.^26,38,39,40

Studies have shown two of hypericum's components, hypericin and pseudohypericin, inhibit a variety of encapsulated viruses.^16,38,41 This antiviral activity is not completely understood.⁴⁰

Mechanisms of Action

The exact mechanism of action for St. John's wort, as an antidepressant, is unknown. There are several compounds found in extracts of the herb, including hypericin, hyperforin, pseudohypericin, xanthones, monoterpenes, β-sitosterol, flavonoids, bioflavonids, naphtodiantrons, melatonin, and catechin. Originally, hypericin was thought to be the primary active compound and is the substance from which extracts from the plant were and continue to be standardized. However, recent data from the NIH indicates that this may not be accurate and that some other compound, or combination of compounds, is responsible for its antidepressant effect.^42,43 It has been shown that many of the active compounds in St. John's wort bind to the neuroreceptors in the brain. These neuroreceptors are thought to be involved in depression, and the binding inhibits uptake and causes destruction of neurotransmitters. In addition, one or more of its compounds seemingly suppress the stimulation of the HPA axis and the subsequent overproduction of cortisol, thus effectively increasing production and secretion of serotonin and melatonin.^22,44

Early studies of the components of St. John's wort led researchers to be concerned that one of its mechanisms of action was as a monoamine oxidase inhibitor (MAOI). Subsequent study results have suggested that MAO inhibition can occur with very high concentrations of some components of St. John's wort, but these concentrations are not achieved with commercial preparations. In addition, the relative inhibitory potential of St. John's wort on the MAO system is well below that of the commonly used MAOIs.^22,43,45 Some researchers suspected that high concentrations of flavonoids were a contributing reason for inhibition. Some studies report that St. John's wort extract inhibits serotonin expression.^16,22

Findings

Depression

In a 1996 meta-analysis of 23 randomized clinical trials (Appendix I), Linde, et al. compared the effects of St. John's wort to placebo and tricyclic antidepressants. The trials involved more than 1757 patients with mild to moderate depressive disorders. Linde, et al. found that the St. John's wort extracts were superior to placebo and just as effective. With the tricyclic antidepressants, amitriptyline and imipramine, they found them to be slightly more effective, and had fewer side effects. Across all trials, patients improved 50 to 80 percent with St. John's wort, or at a rate similarly achieved with tricyclic antidepressants. In 13 of the 23 clinical trails that compared a single St. John's wort preparation with placebo, 55.1 percent of the subjects responded to St. John's wort, while 22.3 percent responded to placebo. The rate of side effects with St. John's wort was 4.1 percent and 4.8 percent with placebo.

Three clinical trials included in the meta-analysis compared St. John's wort (single preparation) with tricyclic antidepressants, resulting with 63.9 percent responding favorably to St. John's wort versus 58.5 percent for the tricyclic antidepressant. Of the 23 clinical trials, two compared a combination of St. John's wort and Valeriana with tricyclic antidepressants. Improvement was 67.7 percent for the combination and 50.0 percent for the antidepressants.

Several limitations existed in the clinical trails included in the 1996 meta-analysis comparing St. John's wort with tricyclic antidepressants. None of the studies were longer than 6 weeks in duration and all the antidepressants where given in daily amounts below or at the lower end of the usual dose range.³³ Linde, et al. concluded that additional long-term trials with standardized St. John's wort preparation methods and dose must be conducted. In addition, further studies are needed utilizing standard antidepressants in well-defined groups of patients, comparing different St. John's wort extracts and doses.^30,36,46,47 It's argued that the length of the studies is no longer or shorter than the length of recommended treatment (5 to 6 weeks), whether for St. John's wort or other antidepressants. Prozac®, an SSRI, was approved based upon studies that had treatment times of 6 to 8 weeks.⁴⁸ Others argue that herbal supplements should not be held to a higher standard of evidence than prescribed medications.⁴⁹

A recent U.S. study (April 2000) of 30 patients found that the use of hypericum was at least as effective as sertraline, an SSRI, in the treatment of mild to moderate depression.²⁴ The study found that 47 percent of the patients receiving hypericum had significantly reduced Hamilton Rating Scale for Depression (HAM-D) scores as well as reduced Clinical Global Impression Scale scores (Appendix VI). Forty percent of those receiving sertraline also had significantly reduced scores.

Of the studies that have proven St. John's wort to be an effective antidepressant medication,^{24,25,33,36,47,50-52} the clinical trials have been of short duration, had few participants, and had no standardization of dosages. The classification of depressive disorders was inconsistent, and severity of depression did not always correlate with severity of symptoms according to scales. Different preparation methods for St. John's wort and the dose of the total extract varied considerably.²⁸ Due to the popularity of St. John's wort, the National Institute of Mental Health (NIMH) is presently recruiting patients for a clinical research study on the efficacy of St. John's wort for the treatment of depression. The three-year study, Protocol Number: 99-M-0151, will include 336 patients with major depression who will be randomly assigned to one of three treatments for an eight-week trail. One-third of the patients will receive St. John's wort, another third will be given a placebo, and the final third will take a SSRI. Patients responding positively will be followed for another 18 weeks to determine if those receiving St. John's wort have fewer relapses than patients given placebo. The results from this study will not be available until the year 2003.⁵³

Wound Healing

Wound healing studies have shown antimicrobial activity, minor antifungal properties, and effectiveness against gram-positive organisms. Studies have reported that hyperforin and adhyperforin have a greater effect than sulfonilamide against Staphyloccus aureus infection,^16,27,50 and when used as an ointment, healing time and scarring from burns were reduced.²⁶ This healing property is attributed to the essential oil, phloroglucinols, and flavonoids.¹⁶ Additional studies are needed to demonstrate St. John's wort as an antibiotic.

Antiviral Activity

In the late 1980s, excitement developed over the apparent activity of St. John's wort against the AIDS virus. Numerous studies were launched because of the herb's activity against a virus that was similar to the HIV virus. This excitement was enhanced since St. John's wort displayed few toxicity characteristics. Although earlier studies have been inconclusive,^16,26 one clinical trial, published in March 1999, concluded that St. John's wort had no antiretroviral activity in the limited number of patients studied. The antiviral ability appears to involve a photoactivation process that forms singlet oxygen and inactivates viral fusion and syncytia formation.¹⁶ Other theories and studies report hypericin as a potent inducer of glioma cell death due to inhibition of protein kinase C (PKC).¹⁶ Further study is required in order to have a definitive understanding of the mechanisms involved and its effectiveness.

Dosage

There is no set dosage for St. John's wort when used as a treatment for depression. Studies have shown it to be effective in amounts of 200 to 900 mg with an optimum adult dosage at 900 mg (taken 300 mg three times daily and concentrations varying from 0.2 to 0.34 percent hypericum).^16,46,51,54 Like other antidepressant medications, St. John's wort needs to be taken for 2 to 4 weeks to develop its mood-elevating effects. Daily doses are necessary to keep blood levels consistently above 6 ng/mL. For hypericin, peak plasma concentrations occur within 2.0 to 2.6 hours. After 14 days of repeated doses (3 × 300 mg/day), steady concentration levels occurred after four days. The peak concentration was 8.5 ng/ml, with trough concentrations 14 hours after the last dose being 5.3.¹⁶

Safety

Due to differences in FDA regulations, St. John's wort has not been systematically studied to document safety and side effects. There is also a shortage of documented, scientific information on the interaction of St. John's wort with other over-the-counter drugs, prescription drugs, and other herbal products. For this reason, discussion between a patient and physician/pharmacist should occur prior to the use of St. John's wort.

The safety, effectiveness, long-term toxicity and adverse effects of St. John's wort for specific populations, such as pregnant women or nursing women, and elderly patients with impaired liver function, cardiovascular problems, or other serious conditions, has not been proven. Due to a lack of data, these persons should not use St. John's wort.

In an open trial of 3250 patients taking St. John's wort, only 2.4 percent reported side effects.⁴⁶ The most frequently reported side effects associated with St. John's wort are gastrointestinal symptoms, nausea, allergic reactions, fatigue, dizziness, and restlessness (Appendix II).

One component, hypericin, has been found to be photoactive and may cause photosensitivity, phototoxicity, or photoallergy in fair-skinned individuals. For this reason, persons consuming St. John's wort should use caution when exposed to the sun by wearing appropriate clothing and sunscreen.^10,22,31,47

Prescription drugs are systematically studied for safety and efficacy in order to receive FDA approval. However, St. John's wort, which is an herbal supplement, does not need to be studied resulting in a limited number of documented adverse effects. Therefore, while prescription drugs may seem to have more adverse events associated them, this may only be a result of the closer scrutiny required of them by the FDA.

Side effects of tricyclic antidepressants and MAOIs including cardiac (i.e., tachycardia, postural hypotension, hypertension) and anticholinergic reactions are listed in Appendix II. St. John's wort has thus far proven to be free of any cardiac or anticholinergic side effects.²⁵ However, because of its possible MAOI properties, caution is warranted.^46,55

Poison control centers, in a number of states, have been reporting adverse reactions to a variety of supplements. In New Mexico, during 1999, St. John's wort ranked first as the most reported herb for adverse reactions. The Pittsburgh Poison Control Center reports St. John's wort and ginseng as having the most reported herbal supplements incidences.²

Interactions Drug

Serotonin syndrome, a potentially fatal side effect, can result when more than one antidepressant is taken at the same time.²⁰ Therefore, unless under physician care, it is advised not to use St. John's wort concurrently with other antidepressants.

Dextromethorphan, which is found in many cough suppressants, may result in serotonin syndrome when used with MAOIs such as phenelzine sulfate (Nardil®), tranylcypromine sulfate (Parnate®); or with SSRIs such as, paroxetine hydrochloride (Paxil®), fluoxetine hydrochloride (Prozac®), or sertraline hydrochloride (Zoloft®). Although there have been no confirmed reports, Dextromethorphan may also interact with St. John's wort due to pharmaceutical properties similar to antidepressants.^20,56,57

St. John's wort should not be taken with amphetamines, meperidine, diet pills, asthma inhalants, nasal decongestants, or cold and hay fever medications.⁵⁸

St. John's wort is an inducer of the cytochrome P450 3A4 enzyme system (CYP3A4).^14,15,59 Drugs which are known substrates for CYP3A4 may also be subject to drug interactions with St. John's wort. Healthcare providers should be aware of the medications that are metabolized by CYP3A4.^19,20,21

Oral contraceptives are metabolized via the CYP3A4 pathway and patients should be aware of this potential drug interaction. The Food and Drug Administration issued a public health advisory stating that oral contraceptives may potentially be less effective when taken with St. John's wort.¹⁹

A 1999 single-blind, placebo-controlled parallel design study14 evaluated the effects of St. John's wort (92 mg of hypericin per 300 mg tablet of dried hypericum extract) on persons using digoxin (0.25 mg/d). Results showed a decrease in digoxin Cmax (peak plasma concentration), Ctrough (plasma concentration 24 after pervious dosing, and AUC(0-24) (area under the plasma concentration-time curve) values when compared to the group placebo. Comparison to the parallel placebo group after 10 days of co medication showed a reduction in Ctrough, Cmax, and AUC(0-24) of 33 percent (P=.0023), 26 percent (P=.0095), and 25 percent (P=.0035) respectively. After 10 days of co medication, Ctrough levels of digoxin were reduced by 37 percent (P=.0001) within the group using St. John's wort. Cmax levels and AUC(0-24) of digoxin were also reduced, 26 percent (P=.0013) and 28 percent (P=.0001) respectively. Use of St. John's wort did not affect the elimination half-life of digoxin. Data showed that a single dose of St. John's wort raised digoxin levels, suggesting that reduced digoxin levels were not due to impairment of absorption. It was hypothesized that the mechanism by which St. John's wort reduces serum digoxin levels may be induction of the transport protein, P-glycoprotein, which is important in the absorption of many drugs that are also metabolized by CYP3A4. There is also a threat of digoxin toxicity for patients who achieve therapeutic levels of digoxin while on St. John's wort once the St. John's wort is discontinued.¹⁴

The concentrations of indinavir (Crixivan®), an HIV drug, and cyclosporine, used to suppress transplant rejection, are both lessened when patients are taking St. John's wort.^14,19,21,59

St. John's wort increases the clearance of cyclosporine and indinavir. St. John's wort taken for 2 weeks with indinavir substantially decreased the AUC of indinavir plasma concentration by a mean of 57 percent and decreased the extrapolated minimum plasma concentration 8 hours after the dose by a mean of 81 percent.²⁰ St. John's wort has been associated with a drop in cyclosporine plasma concentrations, resulting in acute transplant rejection. In two cases, cyclosporine plasma levels had remained stable since the transplant was performed. After 3 weeks of using St. John's wort, the patients were admitted for acute heart rejection. No other abnormalities were found except a decrease in cyclosporine plasma levels. St. John's wort was stopped, and eventually plasma cyclosporine levels returned to baseline levels and remained within the therapeutic range.^19,21,59

Foods

Questions remain about the interaction of St. John's wort and amino acids. While St. John's wort has not demonstrated significant MAOI activity, the potential may still exist. Therefore, it is generally recommended that St. John's wort should not be taken with food or drink containing the amino acids tyramine and tryptophan. The chemical tyramine appears naturally in a variety of foods, especially those that are aged or fermented. When combined with MAOIs, tyramine can cause a sudden, dangerous spike in blood pressure. Caution should be used with St. John's wort because of its possible MAOI properties.^13,22,25,55 Tryptophan, which is found in high-protein foods, is the precursor of serotonin. The dietary sources for tryptophan include foods such as turkey, eggs, fish, dairy products, bananas, and walnuts. (See Appendix IV for a list of foods) Since there is some evidence that St. John's wort inhibits serotonin expression^16,22 there should be an awareness of possible interaction.

Issues of Controversy

Herbal preparations because they are perceived as "natural," may give consumers a false sense that they are safer to use than synthetic prescription drugs. However, they may contain some of the same ingredients as prescription drugs and should be treated with the same caution. Although synthetic drugs are increasing, it is not widely known that plants were the basis for most prescription drugs. At one time, 86 of the 150 top-selling prescription drugs contained compounds derived from plants. Aspirin, digoxin, antibiotics, many anticholinergic agents, anticoagulants, antihypertensives, and some antineoplastic agents are all drugs that were once derived from plants.³ Herbal supplements, as with manufactured drugs, can have the same potential benefits and risks associated with them. Therefore, all persons taking herbal supplements should consult their physician and exercise the same amount of caution given to prescription medications.⁵²

Patients and consumers should be strongly cautioned that herbal supplements might contain toxic materials. It has been found that up to 60 percent of Asian herbal products measured by weight, contain heavy metals such as lead, mercury, and arsenic, which were introduced to the product during the manufacturing process.^2,29 Published reports concerning the mixing of herbal products, have caused serious problems, such as kidney failure.⁶⁰

Voluntary reporting results in an underestimation of the number of incidences of adverse effects, limits the ability to identify all side effects, interactions, and toxicity of St. John's wort.

It is important to stay cognizant of new information as it becomes available. Appendix III is a listing of some web sites where information on St. John's wort and other herbal supplements can be found. Side effects, adverse reactions, FDA warnings, drug interactions, and uses for herbal supplements are some of the information that can be found.

Cost

No data currently exist evaluating the cost-effectiveness of St. John's wort for depression.

Comparing the cost of St. John's wort with other antidepressants is difficult due to varying dosages, strengths, and number of different medications available. The cost comparisons in this report are based upon antidepressant drug dosages and strengths from the 1999 Physicians' Desk Reference and St. John's wort dosages from the 1999 Physicians' Desk Reference for Nonprescription Drugs and Dietary Supplements.

Not all available prescription drugs are compared nor was a determination made whether the ones listed were more commonly used than others.

The price of St. John's wort and prescription drugs are reflected by the retail price obtained from local pharmacies, and may not reflect the cost to the patients. Third party payers do not pay for dietary supplements, and reimbursement for prescription drugs are dependent upon an individual's health plan benefits. Retail pricing varies from community to community and manufacturer to manufacturer. A cost comparison table can be found in Appendix V for the following:

St. John's wort

Hypericin - maintenance dose, one 300 mg (0.3% hypericin), three times a day.⁴⁶

Tricyclics

Imipramine Pamoate (Tofranil-PM®)- maintenance dose, 50 mg to 150 mg daily.⁴⁸ page 2092
Amitriptyline Hydrochloride (Elavil®)- maintenance dose, 50 mg to 100 mg daily.⁴⁸ page 3419

SSRIs

Fluoxetine Hydrochloride (Prozac°)- maintenance dose, 20 mg daily.⁴⁸ page 928
Paroxetine Hydrochloride (Paxil°)- maintenance dose, 30 mg daily.⁴⁸ page 3082

MAOIs

Phenelzine Sulfate (Nardil°)- maintenance dose, 45 mg daily.⁴⁸ page 2300