Drug Profile

More studies probably have been done on St. John's wort than on any other supplement reviewed on this website. For most other supplements, the quality of the studies typically improves over time, and later studies more often fail to show effectiveness. Although there are many studies claiming to demonstrate a benefit for St. John's wort in the treatment of depression, the most recent, best-conducted studies do not show any evidence of effectiveness.

Because of the supplement's lack of effectiveness, as well as its side effects, lack of standardization and significant interactions with many prescription drugs, we have designated it as Do Not Use.

Studies say...

By the late 1990s, dozens of randomized, controlled trials of St. John's wort for depression had been published. These have been summarized in a series of meta-analyses that generally concluded that St. John's wort is more effective than placebo.[2],[3],[4],[5] However, there are several problems with their conclusions. The great majority of studies were of very short duration (no more than six weeks), and many had no placebo controls; used poor statistical analyses; included only patients who completed the study (this omits people more likely to have not benefited from the drug or to have suffered adverse effects); used unclear diagnostic criteria for depression; or were plagued by publication bias (the selective publication of positive findings). Meta-analyses are only as good as the individual studies on which they are based, and the studies in the St. John's wort meta-analyses were generally weak. These meta-analyses included some studies that compared St. John's wort with other antidepressants and generally concluded that they had similar efficacy. However, the comparator drugs were invariably the older tricyclic antidepressants and the doses used were typically on the low end of (or even below) approved doses, so the trials were strongly biased in favor of St. John's wort.

Since these meta-analyses were completed, five randomized, placebo-controlled trials have been conducted, three of which were funded by St. John's wort manufacturers, one by a company that makes both antidepressants and St. John's wort, and one by the National Institutes of Health. The three funded by the St. John's wort manufacturers reported greater effectiveness than placebo, although the improvement on the main study outcome due to the drug itself was always less than the improvement that occurred with no treatment at all.[6],[7],[8] In two of the three studies, the benefit over placebo was quite modest. The most prominent of these three studies also included the tricyclic antidepressant imipramine (TOFRANIL, TOFRANIL PM) in a third study group, in addition to a group treated with St. John's wort and the placebo group.[8] St. John's wort was reported to be at least as effective as imipramine. However, as in previous studies comparing St. John's wort with other antidepressants, the authors used a low dose of imipramine. Moreover, the dose of St. John's wort used was considerably higher than that recommended for many St. John's wort formulations available in the United States.[9] This underscores the problem of lack of standardization of this product (and other dietary supplements). Such standardization would occur if the supplement was actually reviewed by the Food and Drug Administration (FDA).

Significantly, all of the first approximately 30 studies of St. John's wort reported a benefit for the supplement.[10] Even established antidepressants cannot be shown to be superior to placebo in up to 35 percent of trials,[11] suggesting either remarkable efficacy, inadequate study design and conduct, or selective publication of positive results for St. John's wort. In the last several years, however, two well-designed studies have been reported: one funded by a neutral body and the other by a company manufacturing St. John's wort and antidepressants.

In the first study, published in the Journal of the American Medical Association (JAMA), patients were randomized to receive either St. John's wort or placebo, and the authors concluded that St. John's wort "was not effective for treatment of major depression” and that “there currently is no credible evidence to support the efficacy of St John's wort for people with depression."[10] A second study, also published in JAMA, found no difference between St. John's wort and placebo.[12] This study also found that the selective serotonin reuptake inhibitor sertraline (ZOLOFT) was also little better than placebo. As noted above, even prescription antidepressants are often found to be no more effective than placebo in clinical trials. This leaves two possible interpretations for the second study's results regarding St. John's wort: either St. John's wort is ineffective (because it was no more effective than placebo) or the study was inadequately designed (because it could not distinguish sertraline from placebo). Regardless, the study shows no evidence for the efficacy of St. John's wort. The authors conclude that the use of St. John's wort, even in patients with mild depression, "cannot be supported until trials show clear evidence of efficacy."[12]

An article published by Prescrire International stated that the data available is too limited for a firm conclusion to be made about the effectiveness of St. John's wort in patients with severe depression. The clinical trials for St. John's wort did not determine conclusively whether it is less effective, more effective or similarly effective to traditional antidepressants such as tricyclics and serotonin selective reuptake inhibitors.

A small, preliminary study on the use of St. John's wort for social phobia was conducted to generate data upon which to base a larger study. The data collected did not provide information that could be used for a larger study, nor did it provide any information that demonstrated that St. John's wort is useful for treating social phobia.[13]

Interactions with Other Drugs

Patients must be made aware that there is a major risk of drug interactions associated with the use of St. John's wort.[14]

The British Medical Journal conducted a review of 22 trials that showed that St. John's wort has the potential to decrease the effect of many prescription drugs.[15]

St. John's wort is notoriously associated with interactions with a wide array of drugs — more so than most prescription drugs. This is partially because, depending how it is administered, St. John's wort can both inhibit and activate cytochrome P450, a key enzyme system involved in processing drugs.[16] Although the FDA has required some drugs that interact with St. John's wort to carry warnings of that danger, supplements containing St. John's wort itself are not required to do so. Moreover, the FDA has not been as rigorous as its counterpart in Britain, the Committee on Safety of Medicines, in warning about these interactions. In February 2000, the committee listed a number of drugs that interact with St. John's wort.[17] We combined the drugs on that list with those listed in Evaluations of Drug Interactions 2003 as being "clinically significant" or "highly clinically significant," as well as with reports in the medical literature[16],[18],[19] to yield the following list:

Even though St. John's wort has been better evaluated for its propensity to interact with other drugs than any other supplement, a recent review indicates that this evidence base is weak.[15]

In 2007, the Medicines and Healthcare products Regulatory Agency (MHRA, an agency in the U.K. similar to the FDA) issued an advisory warning that all antiepileptic drugs can interact with St. John's wort and that this interaction may occur by routes other than the cytochrome P450 pathway.[20]

In March 2014 the MHRA issued a drug safety update that St. John's wort, when used with hormonal contraceptives, reduces the effectiveness of the contraceptives and, thus, increases the risk of unplanned pregnancy.[21]

Side Effects

St. John's wort is generally well-tolerated. The most common side effects include gastrointestinal symptoms, fatigue, dizziness, headache and dry mouth.[16] However, St. John's wort also has been associated with a number of serious adverse reactions. These include mania or similar conditions,[22],[23],[24],[25] hypertension,[26],[27] and skin and nerve reactions, some of which are related to sun exposure.[28],[29],[30] St. John's wort also has been implicated in causing the array of symptoms known as serotonin syndrome, which includes mental status changes, agitation, muscle spasms, sweating, tremor and fever.[31],[32]