Healthnotes Newswire (December 21 & 28, 2000)—Widely touted by the media as “Nature’s Prozac,” has the popular herbal antidepressant St. John’s wort (Hypericum perforatum) suddenly fallen from grace?

While the medical community continues to express interest in the potential of St. John’s wort as an alternative to prescription antidepressants for the treatment of mild to moderate depression,^{1 2} controversy continues to grow about the potential danger of the supplement in light of evidence that it may interact with some drugs, rendering them less effective over time.³ The net result has left many consumers, as well as healthcare professionals, confused about the potential benefits and risks of this herbal supplement.

Depression is a common illness that affects as many as 1 in 15 adults in the United States each year.⁴ This has resulted in antidepressants being among the most frequently prescribed and top-selling medications nationwide. The introduction of a new generation of antidepressants, known as selective serotonin reuptake inhibitors (SSRIs), has led to wider use of drugs to treat milder forms of depression. SSRIs include sertraline (Zoloft^®), paroxetine (Paxil^®), and fluoxetine (Prozac^®). While often useful at lower dosages, these medications can also make people feel “spaced out” during the day and are associated with sexual problems, such as loss of libido and erectile dysfunction.

St. John’s Wort vs. Prescription Antidepressants

Based on several clinical trials supporting its safety and efficacy for treating mild to moderate depression as well as on its popularity as an approved antidepressant medication in countries such as Germany,⁵ St. John’s wort has basked in the glow of being the herbal alternative to SSRIs. Over the past few years, studies have pointed to the herb’s success in the treatment of mild to moderate depression as being similar to that of low doses of tricyclic antidepressants, such as imipramine (Tofranil^®),⁶ and, perhaps most notably, of Prozac^®.^{7 8} In each clinical trial, St. John’s wort was not only found to perform as well as the comparable antidepressant drug, but it was also shown to have fewer side effects.

The ability of St. John’s wort to treat depression as effectively as SSRIs is currently the topic of a $4.3 million clinical trial funded by the National Institutes of Health (NIH) and coordinated by Jonathan Davidson, M.D., and colleagues at Duke University Medical Center in Durham, North Carolina. In addition to measuring whether St. John’s wort is more effective than placebo, the researchers are also measuring how it stacks up against Zoloft^® for treating more severe cases of depression.

However, Dr. Davidson feels mild depression is probably the better fit for St. John’s wort. “Research currently suggests that St. John’s wort may be effective in milder forms of depression, including reactions to stressful events,” said Davidson in a phone interview. “In this situation it might be a useful treatment option. We don’t yet know if it’s effective for more severe forms of depression.”

While the data on St. John’s wort as an antidepressant alternative looks impressive, it’s important to remember that it’s sold as a dietary supplement in the United States. That means that companies can talk about vague concepts such as “emotional balance” or “improved mood” but can’t say that it treats depression. The other glaring difference is the fact that guidelines for warnings on dietary supplements are virtually nonexistent compared with those established for drugs. That means that some companies take the high road and attempt to disclose potential side effects or drug interaction risks to the consumer while others figure the extra label space is better used for promotional jargon.

St. John’s Wort–Drug Interactions

The inconsistent labeling of potential risks associated with the use of St. John’s wort is a critical problem that has become the driving force behind the current controversy surrounding the herb. While most of people want to know whether supplements could interact with prescription or over-the-counter drugs they may be taking, a clear way to communicate that information for an herbal product doesn’t exist. So, instead of qualified healthcare professionals taking the lead to distill this information into a usable form that does not discount the herb’s positive effects, it is typically thrown to the court of public opinion—often driven by the media.

So, what’s important to know about St. John’s wort and potential drug interactions?

First and foremost, consumers should not take St. John’s wort if they are also taking prescription antidepressants, including SSRIs such as Prozac^® or Zoloft^®. The combination may lead to confusion, muscle twitching, and sweating.^{9 10 11} It is best to work with a doctor to safely go off these drugs before starting St. John’s wort.

While still being hotly debated in the scientific and medical communities, the other area of concern regarding St. John’s wort is growing evidence that suggests it may reduce blood levels of some drugs, making them less effective.

The most widely documented St. John’s wort–drug interaction has been with cyclosporine (Neoral^®, Sandimmune^®), a drug taken by transplant patients to fend off the immune system’s tendency to reject a transplanted organ. As blood levels of the drug decrease, the risk of organ rejection rises. The tendency for blood levels of the drug to decrease when people start taking St. John’s wort has been cited in several case reports in the medical literature,^{12 13 14} including a report totaling 45 transplant patients.¹⁵

Other reports in the medical literature of St. John’s wort–drug interactions include the protease inhibitor indinavir (Crivaxin^®), used to treat persons with HIV infection,¹⁶ as well as digoxin (Lanoxin^®), warfarin (Coumadin^®), theophylline (e.g., Slo-Bid^®, Theo-Dur^®), and birth control pills.^{17 18}

While there is no consensus as to why these interactions occur, evidence appears to suggest that St. John’s wort interacts with enzymes in the liver responsible for metabolizing drugs.^{19 20} Known as the cytochrome P450 system, these enzymes are the body’s way of ensuring normal clearance of drugs once they’ve done their job. St. John’s wort appears to induce some of these enzymes to act a bit more quickly than normal, leading to a drop in therapeutic blood levels of some medications.

In addition to the medications previously listed, persons should discuss the use of St. John’s wort with their doctor or pharmacist if they are taking anti-anxiety drugs such as alprazolam (Xanax^®), sleep medications, heart medications such as nifedipine (Procardia^®, Adalat^®), cortisone (internally), nonsedating antihistamines, estrogens, carbamazepine (Tegretol^®), and ketoconazole (Nizoral^®; internally). While there is no data to prove that St. John’s wort has interacted with these medications, each is metabolized by the part of the cytochrome P450 system with which St. John’s wort has previously been reported to interact. Thus, the potential exists for a St. John’s wort supplement to decrease blood levels of these drugs.

As is the case with drug-drug interactions, knowledge of potential herb-drug interactions is important for persons choosing to use herbal supplements. Armed with this knowledge, consumers should be able to make a more informed choice about whether to use St. John’s wort.

For persons wishing to treat their depression with St. John’s wort, the best advice is to see a doctor first. Depression can be a warning sign for a more severe underlying disease, such as anemia or low thyroid function. Be sure an antidepressant—drug or herbal—is what’s really needed.