Psychedelics for treatment-resistant depression: what the evidence shows

The FDA approved esketamine nasal spray for treatment-resistant depression in March 2019, and the EU followed in December 2019 — in both cases alongside an oral antidepressant.¹²

In January 2025 the FDA also approved it as a monotherapy, without a daily antidepressant.³

The benefit is real but moderate: about 4 points more improvement on the MADRS than placebo at four weeks.⁴

Staying on it helps: people who continued were much less likely to relapse (26.7% versus 45.3%).⁵

Head-to-head against quetiapine, more people reached remission with esketamine at week 8 (27.1% versus 17.6%).⁶

The rapid antidepressant effect of a single low-dose infusion was first shown in a small placebo-controlled trial in 2006 and has been replicated many times since.⁷⁸!

In a 403-person trial, ketamine was at least as effective as electroconvulsive therapy (ECT) for treatment-resistant depression: 55% responded versus 41% with ECT.⁹

Relief often fades within days to weeks once infusions stop, and nobody has settled the best maintenance schedule yet.⁸¹⁰

Racemic ketamine isn't licensed as an antidepressant, but it can be prescribed off-label; Norway, for example, now funds it in specialist care for treatment-resistant depression under set conditions.¹¹

Two Phase 3 trials of COMP360 psilocybin met their main goal. In the first (258 people), one 25 mg dose beat placebo by 3.6 points on the MADRS depression scale at week 6; in the second (581 people), 25 mg beat a 1 mg dose by 3.8 points.¹²¹³

Those are modest average differences, and individual results vary a lot. In the second trial, 39% of people on 25 mg saw their symptoms drop by at least a quarter by week 6, and those responses held to at least six months.¹⁴

In the first trial's open-label extension, about 80% of the 25 mg group took another dose; at one year their depression scores averaged about 13 points below where they started.¹⁵

The FDA agreed to a rolling review and gave COMP360 a national priority voucher, which can shorten review to one or two months once the application is complete. Compass expects to finish filing in Q4 2026.¹⁶¹⁷¹⁴

This builds on a 233-person Phase 2b trial published in the New England Journal of Medicine.¹⁸

Not every trial has been positive. In EPISODE, an academic Phase 2b trial in Germany (144 people), 25 mg didn't significantly beat an active placebo on its main measure: 17% responded, versus 11%. Thoughts of suicide on dosing days were slightly more common with psilocybin.¹⁹

In Australia, authorised psychiatrists have been allowed to prescribe psilocybin for treatment-resistant depression since 2023.²⁰

In a placebo-controlled Phase 2b trial of 81 people, published in JAMA Psychiatry, inhaled GH001 cut depression scores by 15.5 points more than placebo after 8 days; 58% were in remission, versus none on placebo.²¹

The FDA lifted its US clinical hold on GH001 in January 2026.²²

Intranasal BPL-003 met its main goal in a 193-person Phase 2b trial. An earlier open-label study in 12 people found most were ready to go home about 1.5 hours after the dose.²³²⁴

BPL-003's Phase 3 programme (ReConnection-1 and -2) was initiated in mid-2026, with results expected in early 2029. Eli Lilly agreed to buy the developer in July 2026.²⁵²⁶²⁷

GH Research still plans to start its own Phase 3 in 2026.²⁸

VLS-01, a buccal DMT film, is in a 156-person placebo-controlled Phase 2b trial in treatment-resistant depression. Dosing finished in July 2026; results are expected in Q4 2026.²⁶

In a Brazilian open-label trial of 14 people, inhaled DMT cut depression scores by about 21 points within a week, and 8 of the 14 were in remission. Everyone knew they got DMT, and there was no placebo group.²⁹

In a 29-person placebo-controlled trial in Brazil, one ayahuasca session reduced depression scores within a week more than placebo.³⁰