A new scoping review of clinical trials examining over-the-counter products for depression in adults under age 60 has found substantive evidence to support the benefits of only four supplements: St. John’s wort, saffron, probiotics, and vitamin D, according to lead author Rachael Frost.
The research, published to evaluate the landscape of mental health supplements, comes as millions of people turn to over-the-counter options before ever seeking professional care. “This research is very relevant, as so many people will try supplements before they ever even seek professional help,” says Alex Dimitriu, a psychiatrist, sleep medicine physician, and founder of Menlo Park Psychiatry and Sleep Medicine in Menlo Park, California, according to reported coverage.
Four Supplements Backed by Clinical Trials
To map out existing evidence, researchers conducted a scoping review looking at 209 trials investigating 64 different types of supplements. For 41 of those products, investigators found only a single study. According to Frost, a senior lecturer in health and social care at Liverpool John Moores University in England and a Western herbal practitioner, researchers defined “substantive evidence” as having more than 10 clinical trials for a specific product.
- St. John’s Wort: The review identified a total of 37 trials on the wild, flowering plant. More trials showed effects against a placebo than no effects, with results similar to or better than prescription antidepressants, according to Frost.
- Saffron: Eighteen trials evaluated saffron, showing effects similar to prescription antidepressants and greater effects than a placebo in certain trials.
- Probiotics: Across 16 trials, probiotics demonstrated greater effectiveness than placebos, which researchers note may be tied to gut health and mood stability.
- Vitamin D: Tested in 14 trials, vitamin D proved effective compared to a placebo, though Frost notes it did not outperform antidepressants. The vitamin plays a role in thyroid regulation, sleep, and mood.
Limited Evidence and Mixed Results for Other Products
Beyond the top four, evidence supporting other popular supplements remained limited, though trials suggested possible benefits for depressive symptoms from lavender, lemon balm, chamomile, tryptophan, rhodiola, zinc, and folic acid. Meanwhile, the review yielded mixed results for melatonin, magnesium, cinnamon, and vitamin C.
“Our review really calls for carrying out more trials into those products with promising evidence,” Frost emphasizes, noting that effectiveness varies widely by product rather than dividing cleanly into herbs that work and those that do not.
Study Limitations and Methodology
The review focused exclusively on randomized controlled trials, which are widely considered the gold standard of clinical evidence. However, researchers did not assess the quality of the included trials, choosing instead to map out available volume and identify research gaps. Frost explains that trial sizes varied from large, well-conducted studies to small pilot projects utilizing diverse dosages.
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