THEPSYCHEDELICLIBRARY

Condition

Depression and treatment-resistant depression

What research shows on ketamine, esketamine, psilocybin, DMT and 5-MeO-DMT for depression, including depression that hasn't responded to treatment.

ReviewedLast updated September 25, 2026

Evidence by molecule

How strong the research is for each treatment, on our four-level evidence scale. Each links to the full molecule guide.

Ketamine: Treatment-resistant depression Moderate

Many randomised trials show fast symptom relief, often within a day, and a large 2023 trial found it comparable to ECT. Esketamine is approved. A single dose's effect usually lasts days to about a week, so research now focuses on repeated treatment.

Esketamine: Treatment-resistant depression Moderate

Several phase 3 trials found it beat placebo alongside an antidepressant, beat quetiapine in a 676-person head-to-head trial, and reduced relapse. Two trials missed their main goal, and blinding is difficult.

Psilocybin: Major depression Moderate

Randomised trials (24 to 104 people) show large, fast reductions in symptoms after one or two doses with support. A head-to-head trial against the SSRI escitalopram found no significant difference on its main measure.

Psilocybin: Treatment-resistant depression Moderate

A 233-person phase 2 trial found a single 25 mg dose beat a 1 mg control at three weeks, but not at 12 weeks. Two phase 3 trials have been reported as positive by the company running them.

DMT and ayahuasca: Major depression (IV DMT) Low

A 34-person phase IIa randomised trial found one IV dose of DMT with support reduced depression scores more than placebo at two weeks. Benefits lasted up to three months in open-label follow-up.

DMT and ayahuasca: Treatment-resistant depression (ayahuasca) Low

A 29-person randomised trial found one dose of ayahuasca reduced depression more than placebo over seven days, with 64% responding compared with 27%.

5-MeO-DMT: Treatment-resistant depression Moderate

An 81-person randomised trial of inhaled GH001 found a large drop in depression scores at day 8, with 57.5% in remission compared with 0% on placebo. A 193-person company-reported trial of the BPL-003 nasal spray also beat a low-dose control. Both are moving to phase 3.

Why treatment-resistant depression is the focus

Treatment-resistant depression is usually defined as depression that hasn’t improved after two or more treatments during the current episode. Relatively few people with it reach remission, and relapse is common.1 That’s where most psychedelic and ketamine research has concentrated, and where regulators have been most willing to consider new approaches.

Three different approaches

  • Fast, repeated treatment (ketamine and esketamine). Improvement can start within hours to a day,5 but a single dose usually fades within about a week, so treatment is repeated. See our ketamine and esketamine guides.
  • One or two long sessions with psychological support (psilocybin). The effects of one or two supervised doses can last weeks, but each session takes most of a day. See our psilocybin guide.
  • Very short sessions (DMT and 5-MeO-DMT). Newer trials use compounds whose effects last minutes to under two hours, to make treatment easier to deliver.67 See our DMT and ayahuasca and 5-MeO-DMT guides.

Head-to-head comparisons

Placebo-controlled trials show whether something works. Head-to-head trials show how it compares with what doctors already use:

  • Ketamine vs ECT (403 people): IV ketamine was at least as effective as electroconvulsive therapy, with less effect on memory.2
  • Esketamine vs quetiapine (676 people): 27.1% reached remission at eight weeks with esketamine, versus 17.6% with quetiapine.1
  • Psilocybin vs escitalopram (59 people): No significant difference on the main depression measure at six weeks.3

Established treatments

Antidepressant medicines, psychotherapy and, for severe depression, treatments such as ECT all have strong evidence behind them. The treatments on this page are mostly being studied for people who haven’t been helped by these options. Talk to a qualified health professional about your own situation.

Studies in the library

References

  1. Reif A, et al. Esketamine nasal spray versus quetiapine for treatment-resistant depression (ESCAPE-TRD). New England Journal of Medicine. 2023;389(14):1298–1309. Source
  2. Anand A, et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression. New England Journal of Medicine. 2023;388(25):2315–2325. Source
  3. Carhart-Harris R, et al. Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine. 2021;384(15):1402–1411. Source
  4. Goodwin GM, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. New England Journal of Medicine. 2022;387(18):1637–1648. Source
  5. Zarate CA Jr, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry. 2006;63(8):856–864. Source
  6. Cubała WJ, et al. GH001 vs placebo in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2026;83(6):561–569. Source
  7. Erritzoe D, et al. A short-acting psychedelic intervention for major depressive disorder: a phase IIa randomized placebo-controlled trial. Nature Medicine. 2026;32(2):591–598. Source