Side effects reported in studies of St. John's wort are minimal. One study that compared St. John's wort to sertraline and placebo found that the side effects of St. John's wort that were significantly different from those of placebo included anorgasm, frequent urination, and swelling.[Level of evidence: I] A meta-analysis of randomized controlled trials found that fewer patients withdrew from trials because of adverse effects from St. John's wort, compared with antidepressants.
It is important that a physician knows what drugs a patient is already using before that patient begins taking St. John's wort, which decreases the effectiveness of other concomitantly administered drugs. There are two important cautions when the use of St. John's wort for depression is being considered:
- As an herb, St. John's wort is regulated by the FDA as a food/dietary supplement. Although the FDA issued a final rule establishing regulations to require manufacturers of dietary supplements to prove good manufacturing processes and to correctly label their ingredients, the standardization of products such as St. John's wort with respect to the desired amount of potentially active ingredients is not carried out. Therefore, if hyperforin is the desired ingredient, the amount of hyperforin in any formulation of St. John's wort could differ substantially among brands.
- St. John's wort has been found to be metabolized within the cytochrome P450 system and has effects inhibiting as well as inducing various metabolic pathways. The pathways affected by St. John's wort are CYP3A4, CYP2C9, and CYP2D6. In one study in humans, effects on systemic concentrations of drugs via the CYP3A4 pathway were evident in as few as 14 days. Clinically, this means that the concomitant use of St. John's wort with other drugs could cause lower concentrations of drugs that are needed to have therapeutic effects. With respect to cancer and its treatment, St. John's wort has been shown to decrease concentrations of irinotecan in patients receiving treatment  and, in vitro, is suspected of reducing concentrations of docetaxel. Additionally, St. John's wort has been found to affect concentrations of cyclosporin A and tacrolimus, both important for transplant engraftment, as well as concentrations of indinavir for the treatment of HIV.
The bottom line regarding the use of St. John's wort for the management of depression is that despite a more tolerable side effect profile, there is a lack of evidence demonstrating an advantage to using this herbal agent over approved antidepressant therapy. The data do not support a strong effect on major depressive disorder or even on mild to moderate depression. This fact, combined with concerns about drug interactions and lack of standardization, makes St. John's wort an unattractive alternative for depression management.