Psychedelic-assisted therapy

Caveat on this rating: With 34 participants the study is underpowered to detect small true effects, and the authors' own Bayesian analysis in the successfully blinded subgroup was inconclusive rather than clearly negative.

Caveat on this rating: The meta-analytic estimates rest on very little randomised data — two parallel RCTs (three comparisons, n=117) for efficacy and two RCTs (n=109) for adverse events — so the confidence intervals are wide and the review is better read as demonstrating absence of evidence than proving absence of effect. Several authors are affiliated with psychedelic research centres and one is chief medical officer of a psychedelics company (disclosed), so the null result is not coming from sceptics.

Caveat on this rating: Participants sourced and weighed their own material, so actual doses were unverified, and the sample was self-selected enthusiasts rather than people with a diagnosed condition. The authors are based at Imperial College's Centre for Psychedelic Research with a co-author from the Beckley Foundation, both proponents of psychedelic research — which cuts against, not toward, a bias explanation for this null result.

Caveat on this rating: Uncontrolled and unblinded: participants knew they were dosing, sourced their own substances, and were self-selected enthusiasts, so nothing here can separate drug effect from expectation. The authors say as much and explicitly call for dose- controlled research.

Caveat on this rating: Open-label by necessity (neither ketamine nor ECT can be masked), so subjective outcomes may favor the treatment patients preferred; population excluded psychotic depression, where ECT performs best.

Caveat on this rating: The racemic-vs-esketamine difference rests on indirect comparison across trials with different designs and populations; one coauthor (Zarate/NIMH) is an inventor on ketamine-related patents. An erratum was issued in 2021 (checked: not a retraction).

Caveat on this rating: This umbrella review's STRONG tier reflects its independent, systematic method — its actual conclusion is that the underlying MDMA evidence is weak. Read the tier as confidence in the review, not in MDMA.

Caveat on this rating: Diphenhydramine is a weak psychoactive control; the paper's own blinding assessment showed most participants correctly guessed their assignment, so expectancy effects cannot be excluded.

Caveat on this rating: Investigators are prominent psychedelic-research advocates; blinding was imperfect in both arms. The null primary endpoint is often glossed over in media coverage.

Caveat on this rating: Waitlist-controlled (no placebo), very small N, single site with strong psychedelic-research identity; effect sizes this large rarely survive larger placebo-controlled replication.

Caveat on this rating: Single site, N=29, 7-day primary horizon, and ayahuasca's intense somatic effects (nausea, vomiting) make blinding doubtful despite the inert placebo.

Caveat on this rating: Crossover design with a discriminable active dose means most participants likely knew their condition; Heffter-funded investigators are proponents of the therapy.

Caveat on this rating: Sponsor-employee coauthors and shareholders; N=34; the 3-month durability claim comes from an uncontrolled open-label phase.

Caveat on this rating: Small N, discriminable drug (unblinding likely), academic two-center trial; independent of MindMed/Definium, which is a strength.

Caveat on this rating: This was the single positive short-term pivotal trial; two sibling trials (TRANSFORM-1, TRANSFORM-3) missed their primary endpoints, which the approval package acknowledged. Sponsor employees authored the paper.

Caveat on this rating: Sponsor-funded with sponsor employees as authors; central raters were blinded, but participants were functionally unblinded by design of the drug itself. Phase 3 toplines (Voyage, Emerge, 2026) are positive but press-release-stage, not yet peer-reviewed.

Caveat on this rating: Randomized-withdrawal designs can overstate maintenance benefit (abrupt discontinuation effects count as "relapse"); sponsor-funded and sponsor-authored.

Caveat on this rating: Usona is a 501(c)(3), not a commercial company, but it is the sponsor-developer seeking FDA approval of this exact product — scored as industry funding for that reason. Niacin does not mimic psychedelic effects, so unblinding was likely.

Caveat on this rating: N=7; included for historical significance only.

Caveat on this rating: Same sponsor-developer structure and unblinding problem as MAPP1; FDA's CRL asked for a further trial, which the Aug 2026 resubmission does not include (it relies on an audit, a phase 1 cardiac study and VA follow-up data instead).

Caveat on this rating: Sponsor-developer-run trial. FDA's 2024 advisory committee voted 9-2 that effectiveness was not established, citing near-total functional unblinding and allegations of trial-conduct problems in the wider program; FDA issued a CRL in Aug 2024. The paper itself is not retracted, but three related phase 2 papers are.

Caveat on this rating: Sponsor-run trial by the company seeking FDA approval; benefit at week 3 faded for many by week 12 (sustained response was a minority outcome in the full paper).

Caveat on this rating: Treatment was delivered by Ambio Life Sciences, whose shareholders are coauthors and patent applicants; Stanford analysis was philanthropically funded and independent of the clinic. Uncontrolled design caps what this can show regardless.

Caveat on this rating: N=12 with 8 vs 4 allocation; MAPS-affiliated authorship; included for historical significance.

Caveat on this rating: The CONTESTED tier here reflects rock-bottom design score (uncontrolled, unregistered, self-report), not an active dispute; there is no controlled US evidence for ibogaine in opioid withdrawal at all.