Treatment-Resistant Depression: Psilocybin, Ketamine and Esketamine Evidence

Quick answer

Three different things are often grouped together here, and they should be kept apart. Esketamine nasal spray is an FDA-approved medicine for treatment-resistant depression (TRD) in adults. Ketamine itself is not FDA-approved for any mental health condition, although clinics offer it off-label. Psilocybin is still investigational, with mixed results so far. This page describes research, not treatment advice. If you are in crisis in the US, call or text 988, or call 911.

Evidence labels: approved medicine (a regulator has approved it for that use), promising but limited, mixed, and insufficient evidence. TRD is commonly defined as depression that has not responded to two or more consecutive treatments in the current episode. [1]

Esketamine (approved medicine, US)

The FDA label for Spravato (esketamine) lists adults with TRD, alone or with an oral antidepressant, and adults with major depressive disorder and acute suicidal thoughts or behavior, together with an oral antidepressant. [2] The label says its effect in preventing suicide has not been demonstrated. [2]

Safety rules are strict. It is given under a healthcare provider's supervision, patients are monitored for at least 2 hours at each session, and it is available only through a restricted program called a REMS. The boxed warning covers sedation, dissociation, respiratory depression, abuse and misuse, and suicidal thoughts and behaviors. [2] Esketamine is a Schedule III controlled substance. [2] Read the esketamine guide and the ketamine vs esketamine comparison for the difference between the two.

Label: approved medicine (US); the acute effect is modest in the pooled data. [4]

Ketamine (off-label, not approved for depression)

NIDA states that ketamine is FDA-approved as an anesthetic, is not approved for any mental health disorder, and that dozens of US clinics offer it off-label. [5] Research results:

• A pooled analysis of patient-level data from 17 of 25 eligible trials (809 people) found ketamine infusions reduced depression severity at about 24 hours and about 7 days, with larger effects in people with more prior treatment failures. [6]
• ELEKT-D (403 randomized, open-label) found ketamine noninferior to electroconvulsive therapy (ECT) for response (55.4% vs 41.2%). ECT was linked to a decline in memory recall at 3 weeks and ketamine to dissociation. [7] Open-label means people knew which treatment they got.

Label: promising but limited for short-term relief; durability beyond the follow-up in these studies is not established by these sources. NIDA also reports that unsupervised ketamine use carries serious health risks, including respiratory depression. [5] See the ketamine guide.

Psilocybin (investigational)

• Goodwin 2022: Phase 2 trial, 233 adults with TRD, a single session of a synthetic psilocybin formulation with psychological support, compared across three amounts. The highest-amount group improved more than the control group at week 3; the middle group did not. Sustained response at 12 weeks was not supportive. Adverse events occurred in 77%, and suicidal thoughts, suicidal behavior or self-injury occurred in all groups. Funded by COMPASS Pathfinder. [8]
• EPISODE trial 2026: Phase 2b, 144 adults in Germany, antidepressants withdrawn, psilocybin vs a nicotinamide active placebo. The main outcome (response at week 6) was not significantly different (17.0% with the highest psilocybin amount, 10.6% with placebo). Suicidal ideation on dosing days was 4% vs 1% to 2%. Two serious adverse reactions followed the highest amount, including one case of hallucinogen persisting perception disorder. The authors called it an inconclusive trial. [9]
• Follow-up: In the naturalistic follow-up of that trial, depression scores stayed lower than baseline at 6 and 12 months across groups. Participants could pursue other treatments, so this is not a controlled result. [10]

Label: mixed. Results differ between trials and no psilocybin product was found approved in the sources read. NIDA says the FDA has granted Breakthrough Therapy designation to two psilocybin formulations, which is not approval. [11] See psychedelics for major depressive disorder.

Safety and limits

Trials with active placebos, central raters and follow-up are needed because many participants recognize strong drug effects. [12] Do not stop or change a prescribed antidepressant on your own; talk with the prescriber. This page does not tell anyone how to obtain or use any of these.