From June 2001 Issue of Nutrition Science News
By Jack Challem
If St. John's wort is as effective as prescription antidepressants at treating mild to moderate depression, and safer as studies show, why aren't more doctors recommending it?
In the 19th century, Hypericum perforatum was recommended for treating mania, hysteria and "demoniacs." With indications like those, it's no wonder today's medical professionals remain skeptical about the herb's health benefits.
Yet recent clinical trials have shown that St. John's wort works as well as Prozac, Zoloft and other leading antidepressant drugs for treating mild to moderate depression.
A study recently published in the April 18, 2001, Journal of the American Medical Association found the herb ineffective in treating severe depression.  It's important to note that St. John's wort has been indicated in the treatment of only mild to moderate depressionnot severe depressionfor which its efficacy has been well-demonstrated.
Pharmaceutical antidepressants are still the treatment of choice for severe depression. Although St. John's wort may have side effects, they are typically far less common and less severe than those caused by prescription antidepressants.
"Treating patients with mild to moderate depression can be a challenge," Helmut Woelk, M.D., recently wrote in the British Medical Journal. "The mild nature of the disorder often precludes the treatments commonly used in severe depression. Patients seen in general practice frequently prefer to bear the symptoms of depression rather than sustain the side effects of treatment with antidepressants."
Although an increasing number of studies support the efficacy of St. John's wort, it has yet to become a first-line treatment for depression. Why? The reasons range from a lack of marketing to a less-than-complete understanding of the herb's active ingredients and mechanisms of action. However, studies are beginning to amass data that compare the herb to the various pharmaceutical alternatives.
The Science Behind St. John's Wort
During the past year and a half, researchers have directly compared St. John's wort to antidepressant drugs in several well-designed clinical trials. All of these studies have been published in leading medical journals.
St. John's Wort Vs. Prozac: In a double-blind study conducted at seven German medical clinics, physicians treated 240 patients with mild to moderate depression for six weeks. A total of 126 patients received a standardized extract of St. John's wort (250 mg twice daily) and 114 received 20 mg/day fluoxetine (Prozac), a class of antidepressant known as selective serotonin reuptake inhibitors (SSRIs). Scores on the Hamilton Depression Scale (a standard clinical measure of depression) at the beginning of the study ranged from 16 to 24. By the end of the study, scores decreased to 11.54 in the St. John's wort group and 12.2 in the Prozac group. Further analysis by the researchers found that St. John's wort was slightly more effective than Prozac, and that about one-third more patients responded to the herb than to the drug. The main difference, though, was safety: 34 people (29.8 percent) taking Prozac reported side effects, including gastrointestinal problems, vomiting, dizziness, and erectile dysfunction, while only six (4.7 percent) of the patients taking St. John's wort reported side effects, and those were limited to only GI distress. 
St. John's Wort Vs. Zoloft: In another double-blind trial, Ronald Brenner, M.D., of St. John's Episcopal Hospital, Far Rockaway, N.Y., compared St. John's wort with sertraline (Zoloft), another SSRI. He gave 30 patients with mild to moderate depression 300 mg twice daily of standardized St. John's wort extract for one week, followed by 300 mg three times daily for six weeks; or 50 mg/day of Zoloft for one week, followed by 75 mg/day for the remainder of the trial.
Using the Hamilton Depression Scale and Clinical Global Impression Scale, Brenner noted substantial improvements in the St. John's wort group within two weeks. After six weeks, depression symptoms were reduced by an average of 47 percent among patients taking St. John's wort and 40 percent among those taking Zoloft, based on a 50 percent or greater improvement in the Hamilton scale scores. Once again, there were fewer side effects with the herb. Four patients stopped taking Zoloft because of side effects, and two patients continuing with the drug experienced either nausea or headache. In contrast, two of those taking St. John's wort developed dizziness. 
St. John's Wort Vs. Tofranil: Two recent studies have shown St. John's wort to be as effective as imipramine (Tofranil), a leading tricyclic antidepressant. This class of drugs is as effective at treating depression as SSRIs but enhances norepinephrine transmission rather than dealing with serotonin and has more side effects than SSRIs. In the first study, Michael Philipp, M.D., a psychiatry professor at the Imerem Institute for Medical Research Management and Biometrics in Nuremberg, Germany, and his colleagues gave 350 mg St. John's wort three times daily, 100 mg Tofranil (three total daily doses, one at 50 mg, two at 25 mg), or placebo to 263 people with moderate depression. When it came to improving the subjects' mental and physical well-being, the effects of St. John's wort were equivalent to Tofranil, and both were superior to placebo.  In this eight-week study, almost half of the patients taking the drug developed side effects, chiefly dry mouth and nausea. Only about one in five patients taking St. John's wort did.
In the second study, Helmut Woelk, M.D., of the University of Giessen, Germany, and colleagues treated 324 outpatients with mild to moderate depression. They were given either 250 mg St. John's wort twice daily or 75 mg Tofranil twice daily for six weeks for depression. Both herb and drug were equally effective at reducing signs of depression by almost half. Of the 157 who took St. John's wort, 68 (43 percent) had a 50 percent decrease in depression scores; of the 167 who took Tofranil, 67 (40 percent) experienced that same 50 percent decrease. However, St. John's wort was better at relieving anxiety. Patients taking St. John's wort had only one-third the incidence of Tofranil's side effects, again primarily dry mouth.
St. John's Wort Vs. Serafem: Last year, the Food and Drug Administration (FDA) approved the sale of Serafem, a form of fluoxetine indicated for the treatment of premenstrual syndrome (PMS). Although St. John's wort and Serafem have never been directly compared, the herb has been shown in an independent study to effectively treat the symptoms of PMS, and with fewer side effects than fluoxetine.
In a randomized, double-blind, placebo- controlled study of Serafem's effects on PMS done at McMaster University in Hamilton, Ontario, Canada, researchers gave 313 women with premenstrual dysphoric disorder (PMDD) either placebo or 20-60 mg/day Serafem through six menstrual cycles. There was an improvement in mooddecreased dysphoria, irritability, and tensionin 53 percent of those on the drug, compared to 28 percent on placebo. 
Edzard Ernst, M.D., of the University of Exeter, United Kingdom, asked 19 women with PMS to take 300 mg St. John's wort three times daily for two complete menstrual cycles. In more than two-thirds of the women, the herb reduced overall PMS symptoms by at least 50 percent. Women saw greatest improvements in anxiety, depression, nervous tension, confusion and crying. 
Overall, St. John's wort provides exceptional benefits and relatively few adverse reactions in patients with mild to moderate depression. So, with such an excellent benefits-to-risks ratio, why hasn't St. John's wort been warmly embraced by physicians? There are several possible reasons:
Herbs cannot be patented: No patent protection means no single company can exclusively market St. John's wort. Ergo, the limited potential for profit has discouraged U.S. pharmaceutical companies from investing money in marketing or advertising.
The pharmaceutical industry influences medical research, education and therapeutic practices. As profit-driven entities, drug companies are not unbiased in the products they promote.  To persuade people to use their products, drug companies collectively spend about $1 billion per year on consumer advertising and $500 million annually on medical journal advertising in the United States.  Drug companies also send sales people to explain to physicians, often on a one-to-one basis, how to prescribe drugsa service rarely provided by herb companies.
The emphasis in the United States is on drug therapy, not herbal medicines.Consequently, many physicians are unfamiliar with and unlikely to recommend herbs to patients. This is in contrast to Europe, where physicians have a long history of using herbs.
Although herbal supplements fall into a separate regulatory class under the Dietary Supplements Health and Education Act of 1994, there is a common misperception that herbs are unregulated and at best ineffective, at worst unsafe. In fact, herbs and dietary supplements are regulated by FDA, but they do not have to meet the same standard of clinical trials as prescription drugs. With respect to St. John's wort, levels of active compounds in the plant can varythey are influenced by weather, harvesting time and processing, among other variables. To that end, many standardized herbal products manufacturers have developed methods to ensure consistency crop to crop and batch to batch.
St. John's wort is more chemically complex than prescription drugs, hindering identification of its active ingredients. Plus, the herb's mechanisms of action are not fully understood. Unlike "mono molecule" drugs, any St. John's wort extract contains dozens, if not hundreds, of distinct compounds. Its principal chemical constituents are antioxidant polyphenols and flavonoids, including biapigenin, catechins, hyperforin, hypericin, proanthocyanidins and quercetin. It is likely that many of the compounds in St. John's wort function collectively, if not synergistically.
Controversy Raises Larger Issues
The ongoing controversy over the use of St. John's wort raises broader health care issues.
Is there an overlooked cause of depression? Nutrients provide the biochemical building blocks of brain chemistry. Depression may result from nutritional deficiencies, particularly B vitamins, which may affect behavior long before manifest physical symptoms.
Are drugs a cure for life? Chronic depression should be treated. However, psychologists and other mental health professionals debate whether behavioral problemssuch as mild depression, social anxiety and shynessshould be medically treated.
Who is the health care provider? During the past 20 years, consumer expectations have created greater demandsranging from treatments for chronic degenerative diseases such as osteoarthritis to ways to address heartburn and erectile dysfunction. At the same time, increasing costs have led to medical rationing, higher patient copayments for services and shorter visits with physicians.
With mounting frustration over a chaotic health system, those who are taking charge of their health need guidance.
Because pharmacists dispense both prescription and over-the-counter products, they are in a unique position to answer the questions their customers may have on such therapeutic options as St. John's wort.
Antidepressants Vs. St. John's Wort
The Nature of Depression and Antidepressants
St. John's Wort: Proceed with Caution
Jack Challem, known as The Nutrition Reporter, is author of "Syndrome X: The Complete Nutritional Program to Prevent and Reverse Insulin Resistance" (John Wiley & Sons, 2000)
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