REVIEW OF: Tzigkounakis G et al, J Integr Complement Med 2026
STUDY TYPE: Scoping review of umbrella reviews
This scoping review of nine umbrella reviews maps the evidence on seven supplements for depression: omega-3s, vitamin D, probiotics, saffron, St. John’s wort, zinc, and folate. The paper takes a birds-eye view of the data, so I have added insights from other analyses and my own review of the individual studies.
Omega-3s and vitamin D were the most studied, appearing across multiple reviews. Both showed signals of benefit, with omega-3 effect sizes in the small-to-moderate range (SMDs roughly –0.28 to –0.94 across reviews). Although the evidence is mixed for these, the individual studies show an important pattern. Omega-3 is more likely to work when the supplement has a higher ratio of EPA than DHA (2:1). Vitamin D is more likely to work when the levels are low (below 20).
Saffron had two high-quality umbrella reviews behind it, with effect sizes comparable to SSRIs in head-to-head trials. In the past, most primary studies of saffron came from Iran, but newer studies hail from Australia and Europe. It brings novel mechanisms, modulating dopamine, glutamate, opioid, melatonin, and stress hormones. Saffron is surprisingly lost cost ($15/month) and well tolerated, with potential benefits for sleep quality, sexual functioning, and weight loss.
St. John’s wort showed consistent efficacy against placebo in mild-to-moderate depression, but carries concerning CYP3A4 drug interactions. With a similar mechanism to antidepressants, and a similar effect size, St. John’s wort does not bring much new to the table.
Probiotics, zinc, and folate had less evidence and more inconsistent results. Magnesium and N-acetylcysteine are even more mixed, and I don’t generally recommend them for depression. Folic acid has more robust evidence when delivered as the brain active form (l-methylfolate) or when the levels are low.
A common misunderstanding is that supplements are for mild cases. Some supplements worked better for clinical, DSM depression than they did for mild depressive symptoms (eg, omega-3, vitamin D, and probiotics). All of those address deficiencies that are common in depression — low levels for omega-3 and vitamin D, and dysbiosis (poor gut health) for probiotics. That raises an untested possibility, that some patients with treatment-resistant depression do not respond to antidepressants unless those deficiences are correct.
For all seven, safety was generally good — mostly mild GI side effects.
Practice Implications
- Consider omega-3 for patients with complex comorbidities. This supplement has evidence in depression, bipolar, ADHD, autism, schizophrenia, borderline personality disorder, and general irritability.
- Saffron has a unique profile with associated benefits that patients appreciate.
- Probiotics, methylfolate, vitamin D, and omega-3 address common deficits in mental illness.
- Supplement quality is an issue, so stick with products certified by independent labs.
Share Your Input in Comments
- Which supplements have you found useful for depression?
- Which have been duds?
