Psychedelics not beating placebo
New analyses and coverage suggest psilocybin and other psychedelics are struggling to outperform placebo in rigorously blinded antidepressant trials, with strong expectancy effects and blinding failure muddying results. Researchers are urging caution amid intense media and biotech enthusiasm. (technologyreview.com)
A two‑center, triple‑blinded phase 2b trial (EPIsoDE) randomized 144 adults with treatment‑resistant major depression to 25 mg psilocybin, 5 mg psilocybin, or 100 mg nicotinamide active placebo and found no statistically significant difference on the primary HAMD‑17 response at week 6 (published online March 18, 2026). (jamanetwork.com) The EPIsoDE paper reported clinically meaningful secondary reductions in depressive symptoms and collected MRI data in 97 participants, but the authors described the divergence between primary and secondary endpoints as rendering the findings inconclusive. (jamanetwork.com) A separate systematic review and meta‑analysis published March 18, 2026 pooled 24 trials and found psychedelic‑assisted therapy (8 trials; 249 patients) was no more effective than open‑label traditional antidepressants (16 trials; 7,921 patients), with an estimated difference of 0.3 points favoring antidepressants (95% CI, −1.39 to 1.98; P =.73). (jamanetwork.com) The JAMA authors and preceding methodological reviews identified functional unblinding as the defining bias in psychedelic trials—participants in high‑dose studies can often correctly guess assignment at rates reported up to ~95%, which inflates apparent drug effects. (jamanetwork.com) Published methodological proposals to address these biases include use of pharmacological active placebos, low‑dose control arms, and routine measurement of expectancy and blinding efficiency; a recent International Journal of Neuropsychopharmacology review catalogued candidate active‑placebo agents and trial design options. (academic.oup.com) Coverage in technology and science outlets on March 20–21, 2026 framed the JAMA trial and meta‑analysis as prompting calls from researchers to temper media and biotech enthusiasm and to prioritize more rigorous, blinding‑aware trials before declaring clinical superiority for psychedelics. (technologyreview.com)
