Psychedelics Aren’t Better Than Antidepressants—Once You Account for Unblinding
REVIEW OF: Williams ZJ et al, JAMA Psychiatry March 18 2026 and Mertens LJ et al, JAMA Psychiatry 2026
STUDY TYPE: Systematic review and meta-analysis; Randomized, triple-blind controlled trial
FUNDING: Independent for Williams; German government grant for Mertens
Background
As psychedelic-assisted therapy moves closer to FDA approval, researchers are questioning the validity of its trials. The problem: These studies are difficult to control with a placebo because most participants (90-95%) can tell if they got a placebo or a psychedelic.
Many of these trials compared psychedelics to antidepressants, but the poor blinding inflates the benefits of the psychedelic. To arrive at a more fair comparison, this new paper compared psychedelics with trials of open-label antidepressants, where both patients and providers know what’s being taken.
Unblinding the Trials
They pooled eight psychedelic-assisted therapy trials (249 patients) and 16 open-label traditional antidepressant trials (7,921 patients), all in outpatient adults with non-psychotic major depression. The primary outcome was symptom improvement on the HAM-D depression rating scale from baseline to the primary endpoint.
Psychedelic-assisted therapy and open-label traditional antidepressants performed nearly identically — a difference of just 0.3 HAM-D units favoring traditional antidepressants, well below the 3-point minimum clinically important difference. In this study, the chance that psychedelic-assisted therapy is more effective than traditional antidepressants is very low (0.2%). Blinding had a modest effect on outcomes with traditional antidepressants outcomes but didn’t change psychedelic-assisted therapy outcomes at all—consistent with the idea that true blinding in psychedelic-assisted therapy trials isn’t possible.
This blinding problem confounds psychedelic trials in several ways:
- Those who know that they got a psychedelic are more inspired
- Those who know they got an antidepressant are more disappointed
Also…
- Therapists can tell if someone has a true psychedelic reactions and may engage more actively with them
- 1 in 8 US adults have tried psychedelics on their on, and these trials attract those who’ve had good past experiences on them while steering away those who’ve had problems on them
Another Setback
Psychedelics were dealt another blow in a negative trial published the same week (Mertens LJ et al, JAMA Psychiatry 2026). This was a triple-blind trial of psilocybin in 144 adults with treatment resistant depression.
The study attempted to preserve the blind by using two psychoactive compounds as the placebos: nicotinamide and low-dose psilocybin. However, 86% were still able to correctly guess whether they got the active treatment, full-dose psilocybin.
That kind of unblinding would likely exaggerate psilocybin’s benefits, but in this trial it failed to separate from the placebos even with the unblinded advantage. Some of the secondary outcomes were positive, but that could be due to random flux so the study is still considered negative.
This study also detected two problems with psilocybin — a higher rate of suicidal ideation (4% vs 1-2%), and one patient developeddeveloped hallucinogen persisting perception disorder. This visual disturbance is common after excessive use of psilocybin or LSD, causing people to see snow, color trails, or halos. It can be permanent.
Practice Implications
- Psychedelics have come a long way, but unblinding is a serious problem that may get in the way of their approval
- Unblinding was one of the reasons that MDMA was rejected in 2024
- There is an irony here. If a treatment is rapid and powerful, won’t people know that they received it? But wait… the blind held up in trials of SNT (SAINT) TMS — an intensive form of transcranial magnetic stimulation that brings 80-90% of difficult to treat depressions to full remission.
- Suicidality and persistent visual disturbances (hallucinogen persisting perception disorder) are potential side effects.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
What’s Your Take? Share in Comments
- Do you think psychedelics should be FDA approved? Why or why not?
