St. John’s wort revisited: What clinicians should know now

Almost three decades ago, St. John’s wort (SJW) made headlines as a promising lower-side-effect alternative to prescription antidepressants, especially for mild-to-moderate depression. But the herb hasn’t quite lived up to its initial promise. Still very appropriate for some patients, its significant drug interactions have kept it from entering mainstream treatment. While much of the literature on St John's wort (Hypericum perforatum) is outdated and somewhat conflicting, a 2016 systematic review of 35 studies involving nearly 7,000 patients found SJW superior to placebo and comparable to conventional antidepressants for mild-to-moderate depression. A 2017 meta-analysis of 27 studies had a similar finding: For mild-to-moderate depression, both SJW and SSRIs were effective, with SJW having lower discontinuation rates due to adverse events.Backing up those earlier studies, more recently, a smaller systematic review and meta-analysis examined treatments for mild depression, pooling randomized controlled trials up to late 2024. It found that SJW performed similarly to fluoxetine, with no significant difference in treatment response or discontinuation rates between the herbal supplement and the SSRI. Notably, study results on SJW and major depression have been less convincing. Based on the accumulation of evidence, the Canadian Network for Mood and Anxiety Treatments has stated SJW monotherapy may be considered for mild-to-moderate unipolar depression, writing: “For Major Depressive Disorder, of mild to moderate severity, exercise, light therapy, St. John’s wort, omega-3 fatty acids, SAM-e, and yoga are recommended as first- or second-line treatments. Adjunctive exercise and adjunctive St. John’s wort are second-line recommendations for moderate to severe MDD.”Adverse effects According to the professional version of the Merck Manual, potential side-effects, similar or less in impact than prescription anti-depressants, include:dry mouthconstipationphotosensitivitydizzinessconfusionmania (in patients with bipolar disorder).Where SJW draws the most concern is with drug interactions. St. John’s wort can significantly speed up the body’s metabolizing of many medications by inducing liver enzymes and transport proteins, potentially lowering the effectiveness of those drugs. Among the interactions are those with oral contraceptives, transplant drugs, antidepressants, other supplements (like iron supplements) and more. (See extensive list below.) According to “Clinical relevance of St. John's wort drug interactions revisited,” published in 2020 the British Journal of Pharmacology, 20 years after concerns first emerged about SJW’s prescription drug interactions, the research has pinpointed the issue: Hyperforin, one of the plant’s active compounds, in higher doses can speed up the body’s breakdown of many medicines.The authors thus recommend low-hyperforin SWJ products, suggesting that products provide no more than 1 mg of hyperforin per day to avoid drug interactions. Many commercial products contain much higher levels (typically 2% to 5% per daily dose) because hyperforin is believed to be the primary compound responsible for the antidepressant effects. (According to Health Canada, St. John’s wort products sold as licensed Natural Health Products must meet quality and labeling requirements, though formulations can vary.) These authors, however, dispute that, noting that earlier studies showed when comparing low‐hyperforin (0.5%) to high‐hyperforin (5%) SJW products, no clinically relevant difference could be found. Keeping hyperforin low is especially important for patients who are on medications with known interactions. Depending on the exact medications and the number of them a patient is on, it may be a reason to avoid SJW altogether. But for patients not on those medications who are suffering from mild-to-moderate depression, it may be a worthwhile treatment, that shows fewer or similar side-effects as prescription anti-depressants.Meanwhile, SJW shows some promise and is being studied for treatment of menopausal symptoms, ADHD, anxiety, skin disorders (including psoriasis) and PMS, according to the Merck Manual. Some research suggested it looked promising for treating HIV, but is no longer advised, as it has adverse interactions with protease inhibitors and non-nucleoside reverse transcriptase inhibitors often prescribed to HIV patients.

St. John’s wort revisited: What clinicians should know now

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