Psychedelics for depression

Researchers are studying classic psychedelics, such as psilocybin and DMT, in prepared and supported sessions within a psychotherapy programme. These substances act mainly on the serotonin 5-HT2A receptor.²¹

In trials, each session is preceded by preparation and followed by integration sessions, and the person is supported throughout the effect.^1,20 What is studied is the combination of substance and support, not the substance on its own.

In treatment-resistant depression, a phase 2 trial published in 2022 showed that a single dose of psilocybin, with psychological support, reduced symptoms at three weeks more than a control dose.¹ Adverse effects were common and suicidal thoughts or behaviour occurred in all groups, which underlines the need for close clinical follow-up.¹

Two phase 3 trials of a synthetic psilocybin formulation in treatment-resistant depression met their primary endpoint, according to company announcements in 2025 and 2026.^2,3 As of October 2026, the application is being submitted to the FDA on a rolling basis, with completion expected by the end of 2026, and there is no approval yet.⁴ The FDA’s 2018 Breakthrough Therapy designation speeds up development but is not an approval.⁵

In major depression, randomised trials showed a reduction in symptoms compared with a waiting list and with an active placebo.^6,7 In a trial against an SSRI antidepressant, there was no significant difference in the primary outcome.⁸ A phase 3 trial in major depression completed its main phase in 2026, with no results released yet.⁹

They are at an earlier stage. Ayahuasca is a traditional preparation that contains DMT and alkaloids that slow its breakdown in the body, which changes its profile of effects and interactions.²¹ In a small placebo-controlled trial in treatment-resistant depression, it had a rapid antidepressant effect, assessed over one week only.¹⁰

Short-acting intravenous DMT had positive results in a phase 2a trial in major depression,¹¹ and an inhaled formulation of 5-MeO-DMT, a related molecule, in a phase 2b trial in treatment-resistant depression, both published in 2026.¹²

Ketamine and esketamine, which work through another mechanism, have a page of their own: Ketamine and esketamine in treatment-resistant depression.

The main one is how hard it is to blind treatment. Because psychedelic effects are obvious, participants and staff often know who received the substance, and expectation can inflate the estimated effect.^13,15 When the comparison uses the placebo response seen in antidepressant trials, the estimated effect of psilocybin becomes smaller.¹⁴

Trials have generally included carefully selected people, with short follow-up, and the phase 3 results known so far were announced by the company before scientific publication.^2,3,13

The personal and family psychiatric history is assessed: people with a history of psychosis or bipolar disorder are usually excluded from these trials.²⁰ The following are also assessed:

• cardiovascular health, because classic psychedelics moderately raise blood pressure and pulse;²⁰
• suicide risk, monitored throughout the trial;¹
• other medication and substance use, including, for ayahuasca, the interactions of the alkaloids it contains;²¹
• the arrangements for preparation, support during the session and integration.²⁰

Intense, transient anxiety may occur during the session; it is the most likely adverse reaction and is managed with preparation and support.²⁰

In the European Union, no medicine containing psilocybin, MDMA, LSD or DMT is authorised; in Portugal, the clinical use of these substances is limited to clinical trials.¹⁷ The European Medicines Agency recognises the particular challenges of these trials and requires, as for any medicine, a positive benefit–risk balance.¹⁶

Other EU countries have exceptional, restricted routes: the Czech Republic has allowed restricted therapeutic use of psilocybin since 1 January 2026, and Germany has had a compassionate use programme in treatment-resistant depression since 2025.¹⁸ In Australia, since July 2023, authorised psychiatrists may prescribe psilocybin for treatment-resistant depression, although no registered medicine exists.¹⁶ In the United States, the FDA published final guidance on clinical trials with psychedelics in July 2026.¹⁹

• How much of the effect comes from the substance, from psychological support and from expectation.^13,15
• How long the benefit lasts and when repeating a session makes sense.¹
• Who benefits most, and who should be excluded, beyond the selected trial populations.¹³
• The full, peer-reviewed results of the phase 3 trials.^2,3,9

• In my case, which approved treatments have not yet been tried?
• Is there a clinical trial under way for which I might be eligible?
• Does my personal or family history rule out these approaches?
• How can I tell a clinical trial from an offer without a proper framework?
• What support is there before, during and after?