Psilocybin performed no better than traditional antidepressants in two new clinical trials, adding to mounting evidence that psychedelics have been significantly overhyped as psychiatric treatments.
Both studies focused on psilocybin for depression and both grappled with the central problem haunting this field: blinding. In standard randomized controlled trials, volunteers should not know whether they received the drug or a placebo. With psychedelics, hallucinations make that effectively impossible.
The first trial, conducted by a team in Germany, enrolled 144 volunteers with treatment-resistant depression. Participants received either a high or low dose of psilocybin, or an active placebo with physical but non-hallucinatory effects, combined with psychotherapy. Neither volunteers nor investigators knew who received the drug. Those who took psilocybin showed some improvement, but not significantly more than those on placebo. A larger symptom reduction did appear at six weeks, but the authors write that “the divergence between [the two results] renders the findings inconclusive.”
The second study took a broader view.
Balázs Szigeti at UCSF and colleagues analyzed 24 open-label trials covering both psychedelics and conventional antidepressants — studies where participants knew what they were taking in both cases. The conclusion: psychedelics were no more effective than standard antidepressants. Szigeti said he entered the research expecting to demonstrate the opposite. “But unfortunately, the data came out the other way around,” according to the announcement.
His study also draws attention to a subtler distortion in psychedelic trials. In conventional antidepressant research, the placebo effect is already powerful — on standard symptom scales, antidepressant drugs typically reduce scores by around 10 points while placebos achieve roughly 8, leaving a net drug benefit of approximately 2 points. In psychedelic trials, the gap between drug and placebo appears wider, but for reasons that may have little to do with the drug’s actual efficacy. Participants who receive a psychedelic know they have received it and arrive expecting improvement. Those who receive a placebo also know it — and the disappointment that follows can actively worsen their reported symptoms. Szigeti calls this the “knowcebo effect,” describing it as “a negative psychedelic effect, because you have figured out that you’re taking the placebo.” David Owens, emeritus professor of clinical psychiatry at the University of Edinburgh, points to similar expectation dynamics on the active drug side.
Together, these forces can make a psychedelic look far more effective than it is, inflating the apparent benefit in trials that lack proper blinding controls.
Psilocybin, derived from magic mushrooms, has been studied over the past decade for depression, PTSD, addiction, and obesity, attracting substantial scientific and commercial interest. Most trials to date have been small. Results, the report notes, have frequently been underwhelming or inconclusive — and the two new studies suggest the methodological problems driving those outcomes are not close to being solved.
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