St. John's Wort Study Flawed by Poor Design, Focus
A Response to Negative Findings
By
Hyla Cass, MD
A clinical study on the popular herb St. Johns wort (SJW) was recently published in the Journal of the American Medical Association (JAMA). The study conducted by Dr. Richard C. Shelton of Vanderbilt University was sponsored by Pfizer, the pharmaceutical manufacturer of sertraline (Zoloft®), a leading anti-depressant drug.(1)
The study was a placebo-controlled, double-blinded trial that involved 200 subjects. Over an eight-week period, half of the subjects received SJW and half received a placebo (or dummy pill). During the course of the study, neither the individuals nor the researchers knew who was getting which product. The dose was 900 mg a day for 4 weeks, increasing to 1200 mg a day if there was no response, for a total of eight weeks. The report concluded that St. Johns wort was not effective in treating major or severe cases of depression.
I question the JAMA articles negative conclusions about St. Johns wort for a number of reasons. To start, the study group in the JAMA study was far too small (200 subjects) to reach a valid conclusion. Meanwhile, the author of the JAMA study discounted the validity of nearly 30 studies on over 1,700 patients that found that SJW indeed did provide beneficial effects.
Additionally, the majority of studies previously conducted on St. Johns wort and depression focused on mild-to-moderate, not severe, depression. The author of the JAMA article also overlooked or failed to address Dr. Vorbachs successful study with SJW and severe depression (see St. Johns Wort and Depression).
Most importantly, the JAMA study design must be questioned, due to the surprisingly low placebo response: 4.9% versus an expected 20-50% placebo response in other studies (and the SJW group still did three times as well!). This may be because no “active” drug was given, which may have prejudiced examiners. They would expect no effects from a dummy pill--especially since there was no chance of either pill being an “active, successful antidepressant.” (Beware, ye of little faith!)
The article questions, with little basis, the validity of nearly 30 studies done to date on the use of SJW in mild to moderate depression. While these “questionable” studies were done in Europe, mostly in Germany, they were published in peer-reviewed journals, including the British Medical Journal (BMJ). I will summarize a 1996 review article below for comparison purposes.
St. Johns Wort Found Superior
The BMJ meta-analysis reviewed 23 controlled studies involving 1,757 depressed patients, [the JAMA/Pfizer study had only 98 patients] and found that St. Johns wort was three times more effective than a placebo, and as effective as prescription antidepressants, but without the side effects. (This is the same percentage as the JAMA study, though they considered this result insignificant.) Fifteen studies compared the herb with a placebo, and eight compared it with conventional prescription antidepressants.
The four-to-eight week placebo-controlled studies found St. Johns wort to be significantly superior. The daily dosage levels ranged from 350 mg to 1,000 mg of standardized 0.3% hypericum extract (0.4 mg to 2.7 mg per day of hypericin). An average of 55.1% of the hypericum users responded to the treatment, much higher than the 22.3% response rate of the placebo group.2
St. Johns Wort and Depression
There is, in fact, one published study using SJW in severe depression. Dr. Ernst-Ulrich Vorbach and colleagues in Germany conducted a multi-center study with 209 severely depressed patients, of whom 38 were hospitalized at the time.3 They were given 1800 mg daily, versus Sheltons 900 mg for 4 weeks, increasing to 1200 mg if no response, and compared it to imipramine, a tricyclic antidepressant. While the results in the two groups were similar, the side effects in the SJW group, despite the high dose, were far lower.
So, SJW may, after all, be useful for severe depression, given in the right dose. Can you imagine a Pfizer study that gives the patients a half dose of Zoloft, then concludes that their product was ineffective?
Poor Study Protocol
Other experts have commented on problems with the JAMA study protocol: In an American Botanical Council news release, Jerry Cott, Ph.D., former Chief of Psychopharmacology Research Program, at the National Institutes of Mental Health, makes this point: “What strikes me initially is the very low placebo response rate in this study. In my 25 years of psychopharmacology research, I have never seen a depression study with such a low placebo response. This alone is enough to invalidate the study.”
“Others might say the low response rate is due to the high quality of the investigators. And this is certainly true. They are all fine and experienced investigators. However, these are the same investigators that routinely see placebo response rates of 30-to-50% in their other drug company studies. So, why the difference now?” he asks.
Dr. Cott, an acknowledged expert on the effects of herbs as well as conventional drugs on mental disorders, including depression, suggested the following explanation: “I would venture to guess that the rate was low because of the possibly subconscious expectations of the investigators, the raters and the patients. Their expectations may have been low because there is no active drug in this study; they may not have expected much from the St. Johns wort in the first place. That is, in the minds of some, this was a clinical trial comparing two inactive treatments. Therefore, the expectation of all concerned is that no one would get better. And this was nearly the case, though one has to read very carefully to see that St. Johns wort did perform better than placebo.”
Dr. Cott added that this study would be considered a “neutral” study, since no active treatment group, i.e., no active pharmaceutical drug, was used in the design of the study to compare the SJW and the placebo to the activity of the drug. Moreover, “A better-designed study would have incorporated an active comparison, to raise the possibility in the minds of the researchers that a particular patient may be among the 30% on the active medication.”
According to Mark Blumenthal, founder and executive director of the nonprofit American Botanical Council (www.herbalgram.org), most of the previous clinical studies conducted in Europe on SJW targeted only mild to moderate cases of depression, not major or severe depression. Blumenthal points out that, “There is a significant body of research and clinical experience that documents the safety and efficacy of St. Johns wort to treat mild to moderate cases of depression.”
He adds, “Although federal law does not allow marketers of St. Johns wort to make claims for treating depression or anxiety disorders, most of the products I have seen in the United States appear to be targeting consumers who want to gently elevate their moods, not treat a severe case of depression.” (Dont forget about Dr. Vorbachs successful study with severe depression and SJW.)
Conclusion
In my own practice, and in the many e-mails I have received from now-happy users of SJW, I have to conclude that while SJW may not be the magic bullet for everyone, it certainly has a significant role in the treatment of depression. For those taking or considering taking SJW for mild to moderate depression, you have nothing to worry about. This study in JAMA does not negate the many fine studies published in other journals that have shown SJW to be just as good as the more expensive prescription antidepressants in treating mild to moderate depression, or “the blues.”
References:
1. Shelton et al. Effectiveness of St Johns wort in major depression: a randomized controlled trial. JAMA 2001; 285:1978-1986.
2. Linde K, et al, St Johns wort for depression -- an overview and meta-analysis of randomized clinical trials. British Medical Journal 313(7052), 253-258,1996.
3. Vorbach EU, Arnoldt KH, Hubner WD. Efficacy and tolerability of St. Johns wort extract LI 160 versus imipramine in patients with severe depressive episodes according to ICD-10. Pharmacopsychiatry 1997 Sep;30 Suppl 2:81-5.
Hyla Cass is a psychiatrist and renowned expert in nutrition and mental health. She is Associate Clinical Professor of Psychiatry at UCLA Medical School and has written best-selling books on natural treatments for depression, stress and anxiety, including:
• All About Herbs
(Avery, 1999)
• All About St. Johns
Wort (Avery,1999)
• Kava: Natures Answer
to Stress, Anxiety, and Insomnia (Prima, 1998)
• St. Johns Wort:
Natures Blues Buster (Avery, 1998)