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Comparison of St. John's Wort and Fluoxetine Adverse Events—Commentary

8/27/2015 John H. Greist, MD, University of Wisconsin School of Medicine and Public Health|Madison Institute of Medicine;

"Man has an inborn craving for medicine. Heroic dosing for several generations has given his tissues a thirst for drugs. The desire to take medicine is one feature which distinguishes man, the animal, from his fellow creatures." —William Osler (1)

Diagnosable depression is a prevalent disorder causing distress, dysfunction, and sometimes death through suicide. Short-lived, subclinical depressed mood due to life stresses is even more common, and many people seek relief through over-the-counter drugs. Treatment with antidepressant medicines is often effective but also often causes adverse effects (AEs).

Some people believe that medicines born of nature are more likely to be helpful than synthetic medications and have fewer AEs.

“St. John’s wort is a popular herbal antidepressant. Its exact mechanism of action is not defined; however, bioactive compounds in St. John’s wort such as hyperforin, hypericin, pseudo-hypericin, and flavonoids are involved in inhibition of monoamine oxidase, binding to brain benzodiazepine receptors, and inhibition of serotonin reuptake” (2).

How effective St. John’s wort may be across the depression spectrum remains uncertain. Different studies have found it less effective, equivalently effective, and more effective than SSRI antidepressants, but also less effective than placebo. 

The Hoban et al study reported here confirmed, based on spontaneous reports, that St. John’s wort causes similar AEs as fluoxetine, a widely used SSRI antidepressant. While intensity of most AEs for each drug were mild or moderate, some were severe or life-threatening. 

St. John’s wort's several chemicals with multiple mechanisms of action, its many formulations, over-the-counter availability, limited regulatory oversight, and user naïveté permit sometimes startling AEs.

Beyond common and usually tolerable primary AEs of both drugs, drug-drug interactions may occur with each drug (3). For example, fluoxetine inhibits CYP2D6, increasing blood levels of drugs metabolized through this enzyme system. Conversely, St John’s wort induces CYP3A4, reducing blood levels of drugs metabolized thereby. Through this mechanism, two patients who took St. John’s wort on their own for depression after cardiac transplantation began to reject their hearts as cyclosporine levels fell below therapeutic levels (4).

What can we conclude about St. John’s wort beyond platitudes that there is greater benefit and safety when patients and practitioners have greater knowledge; that some deny, distort, or ignore what is known; and that effective medications also cause AEs? Well, the occurrence of significant AEs in this study shows it is important for physicians to ask about all medications patients take, including specifically those obtained over-the-counter; when asked, patients usually tell what they take if they understand and remember their pills, powders, and potions. Also, primary AEs of St. John’s wort and SSRIs are usually mild or moderate but can be severe or life-threatening; drug-drug interactions can cause secondary AEs of remarkable variety and severity.  

For depression, there are many effective remedies including medications, although the antidepressant benefits of St. John’s wort remain debatable. Ideally, every patient will have a latter day Osler who conducts a thoughtful and thorough evaluation before counseling sensible treatment balancing probable benefit and risk. In reality, many patients proceed on their own. Whatever works is trumps and some will claim laudable outcomes with St. John’s wort despite increasingly recognized risks.



1. Bean WB. Aphorisms of Sir William Osler. New York, Henry Shuman, 1950, number 210.

2. Hoban CL, Byard RW, Musgrave IF.  A comparison of patterns of spontaneous adverse drug reaction reporting with St. John’s Wort and fluoxetine during the period 2000–2013. Clinical and Experimental Pharmacology and Physiology 2015; 42:747–751.

3. Jefferson JW, Greist JH. Brussels sprouts and psychopharmacology: understanding the cytochrome P450 enzyme system.  Psychiatric Clinics of North America: Annual of Drug Therapy 1996; 3:205–222.

4. Ruschitzka F, Meier PJ, Turina M, Lüscher TF, Noll G.  Acute heart transplant rejection due to Saint John's wort. Lancet 2000; 355: 548–549.

See Dr. Greist's discussion of Anxiety Disorders in The Manuals.