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Psychedelic Substancesunder Investigation

Psilocybin, MDMA, LSD, DMT and ayahuasca, and dissociative anaesthetics with psychedelic properties are the substances most studied in psychedelic therapy. For each one: what it is, what research shows and its legal status. The substances described on this page are presented for information. KETAMED uses only medicines authorised in Portugal, after individual assessment.

Each substance is introduced briefly here, with a link to its own page describing its history, mechanism of action, research protocols, safety and legal framework. The table summarises the main differences.

How the substances compare

SubstanceClassMain targetTypical durationMost studied areasStatus in the EU
Psilocybin Classic psychedelic 5-HT2A receptor About 6 hours Depression, cancer-related anxiety, alcohol Not authorised; restricted use in Czechia
MDMA Entactogen Serotonin release Sessions of about 8 hours Post-traumatic stress disorder Not authorised; controlled substance
LSD Classic psychedelic 5-HT2A receptor About 7 to 11 hours Anxiety; alcohol (older trials) Not authorised; controlled substance
DMT and ayahuasca Classic psychedelic 5-HT2A receptor (+ MAO-A in ayahuasca) DMT: minutes; ayahuasca: about 4 hours Depression Not authorised; DMT controlled
Ketamine and esketamine Dissociative anaesthetic NMDA receptor (glutamate) Up to about 1.5 hours Treatment-resistant depression Esketamine authorised (resistant depression)

Psilocybin

  • Phase 3 (sponsor data)

Classic psychedelic (tryptamine)

A classic tryptamine psychedelic found in several mushroom species; in the body it gives rise to psilocin, which stimulates the serotonin 5-HT2A receptor [1]. An oral dose acts for roughly six hours [2]. Psilocybin therapy pairs the drug with psychological support and is studied mainly in treatment-resistant depression [3]. In 2022, a phase 2 trial in treatment-resistant depression showed a reduction in symptoms compared with a minimal control dose [4]; in 2025 and 2026, the sponsor of a synthetic formulation announced phase 3 results still awaiting peer review [5] [6]. No psilocybin medicine is authorised in the European Union.

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MDMA

  • Phase 3 completed; not approved (FDA, 2024)

Entactogen (phenethylamine)

MDMA is an entactogen that mainly releases serotonin and is linked to greater emotional openness [7]. MDMA-assisted therapy pairs a few long drug sessions with a programme of psychotherapy [8]. MDMA for PTSD reached phase 3 trials, published in 2021 and 2023, with better results than placebo [8] [9]. In 2024 the FDA declined approval and asked for a new trial [10]. No medicine containing MDMA is authorised in the European Union [11].

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LSD

  • Phase 3 (sponsor data)

Classic psychedelic (ergoline)

LSD is a synthetic classic psychedelic of the ergoline family that acts mainly as a partial agonist at the 5-HT2A receptor [12]. Its effects take up much of a day [13]. The history of LSD in psychiatry spans two decades of studies, halted around 1970, and a return to clinical trials in Switzerland in 2014 [14] [15]. In 2025, a phase 2b trial of LSD-assisted therapy in generalised anxiety found improvement over placebo after a single dose [16]. In 2026 the sponsor reported phase 3 results that are not yet published, and LSD remains unauthorised as a medicine in the European Union [17] [18].

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DMT and ayahuasca

  • Phase 2

Classic psychedelic (tryptamine)

DMT is a classic psychedelic; ayahuasca is an Amazonian brew containing DMT plus alkaloids that inhibit MAO-A. The key point in DMT vs ayahuasca is route and duration: injected DMT acts for minutes, drunk ayahuasca for about four hours [19]. Both act mainly on the 5-HT2A receptor [1]. Depression is the most studied area, with a controlled ayahuasca trial in Brazil in 2019 [19] and an intravenous DMT trial in the UK in 2026 [20]. Neither is authorised as a medicine.

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Dissociative anaesthetics: ketamine and esketamine

  • Specific formulation authorised in the EU

NMDA receptor antagonists (arylcyclohexylamines)

Ketamine is a dissociative anaesthetic in clinical use since 1970, and esketamine is its isolated S form. Unlike classic psychedelics, it acts mainly by blocking the NMDA glutamate receptor [21]. With esketamine, dissociative symptoms typically resolve by about an hour and a half after a dose [22]. In treatment-resistant depression, a small controlled trial reported improvement within hours in 2000 [23], and in 2023 ketamine was non-inferior to electroconvulsive therapy in a randomised trial [24]. Esketamine nasal spray has been authorised in the European Union since 2019 for treatment-resistant depression, with an antidepressant and under supervision [22].

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These sections are educational and bring together research, safety and regulatory status. They are not treatment recommendations: each person’s clinical plan is defined in the assessment consultation. Open the references below to see the sources behind the clinical and scientific statements.

References

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  1. Nichols DE. Psychedelics. Pharmacol Rev. 2016;68(2):264–355. doi:10.1124/pr.115.011478Review
  2. Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016;3(7):619–627. doi:10.1016/S2215-0366(16)30065-7Clinical trial
  3. Jacobs E, Zahid Z, Hinkle J, et al. Psychedelic medicine: mechanisms, evidence, and translation to practice. BMJ. 2026;392:e081723. doi:10.1136/bmj-2024-081723Review
  4. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387:1637–1648. doi:10.1056/NEJMoa2206443Clinical trial
  5. Compass Pathways. Company announcement, 23 June 2025: first phase 3 trial (COMP005, n = 258) of COMP360 psilocybin in treatment-resistant depression met its primary endpoint (MADRS difference versus placebo at week 6: −3.6). Topline data, not peer reviewed. ir.compasspathways.comSponsor announcement, not peer reviewed
  6. Compass Pathways. Company announcement, 17 February 2026: second phase 3 trial (COMP006, n = 581) met its primary endpoint (25 mg versus 1 mg, MADRS difference at week 6: −3.8). Topline data, not peer reviewed. ir.compasspathways.comSponsor announcement, not peer reviewed
  7. Sessa B, Higbed L, Nutt D. A review of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy. Front Psychiatry. 2019;10:138. doi:10.3389/fpsyt.2019.00138Review
  8. Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27:1025–1033. doi:10.1038/s41591-021-01336-3Clinical trial
  9. Mitchell JM, Ot’alora G M, van der Kolk B, et al. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat Med. 2023;29:2473–2480. doi:10.1038/s41591-023-02565-4Clinical trial
  10. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Complete Response Letter, NDA 215455 (midomafetamine capsules), dated 8 August 2024; made public by the FDA in 2025 (openFDA complete response letter database). open.fda.govRegulatory source
  11. European Medicines Agency. Medicines data (centrally authorised and assessed human medicines), report of 9 October 2026: no medicine containing MDMA (midomafetamine) is listed. ema.europa.euRegulatory source
  12. Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A. The pharmacology of lysergic acid diethylamide: a review. CNS Neurosci Ther. 2008;14(4):295–314. doi:10.1111/j.1755-5949.2008.00059.xReview
  13. Holze F, Vizeli P, Ley L, et al. Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology. 2021;46(3):537–544. doi:10.1038/s41386-020-00883-6Clinical trial
  14. Nichols DE. Dark classics in chemical neuroscience: lysergic acid diethylamide (LSD). ACS Chem Neurosci. 2018;9(10):2331–2343. doi:10.1021/acschemneuro.8b00043Review
  15. Gasser P, Holstein D, Michel Y, et al. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J Nerv Ment Dis. 2014;202(7):513–520. doi:10.1097/NMD.0000000000000113Clinical trial
  16. Robison R, Barrow R, Conant C, et al. Single treatment with MM120 (lysergide) in generalized anxiety disorder: a randomized clinical trial. JAMA. 2025;334(15):1358–1372. doi:10.1001/jama.2025.13481Clinical trial
  17. Definium Therapeutics. Topline results of the phase 3 Panorama study of DT120 in generalised anxiety disorder, 14 September 2026: placebo-adjusted HAM-A change of 5.1 points at week 12; the company also reported a positive phase 3 study (Emerge) in major depressive disorder in June 2026 (SEC Form 8-K, exhibit 99.1). Not peer reviewed. sec.govSponsor announcement, not peer reviewed
  18. European Medicines Agency. Medicines data: list of medicines evaluated by the EMA (download consulted on 9 October 2026); no entry contains lysergide or LSD. ema.europa.euRegulatory source
  19. Palhano-Fontes F, Barreto D, Onias H, et al. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med. 2019;49(4):655–663. doi:10.1017/S0033291718001356Clinical trial
  20. Erritzoe D, Barba T, Benway T, et al. A short-acting psychedelic intervention for major depressive disorder: a phase IIa randomized placebo-controlled trial. Nat Med. 2026;32:591–598. doi:10.1038/s41591-025-04154-zClinical trial
  21. Zanos P, Moaddel R, Morris PJ, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev. 2018;70(3):621–660. doi:10.1124/pr.117.015198Review
  22. European Medicines Agency. European public assessment report (EPAR) and product information for esketamine nasal spray; marketing authorisation in the EU since 18 December 2019. ema.europa.euRegulatory source
  23. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351–354. doi:10.1016/S0006-3223(99)00230-9Clinical trial
  24. Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression. N Engl J Med. 2023;388(25):2315–2325. doi:10.1056/NEJMoa2302399Clinical trial

Frequently asked questions

Are these substances approved as medicines in Portugal?

Psilocybin, MDMA, LSD and DMT are not authorised as medicines in the European Union. In Portugal, they are only used in authorised research. For psilocybin, exceptional pathways exist in other EU countries (for example, in Czechia since 2026). In the dissociative anaesthetic family, one specific nasal formulation is authorised in the European Union for an indication in treatment-resistant depression, under the supervision of healthcare professionals. KETAMED uses only medicines authorised in Portugal, after individual assessment.

Does this page tell me which treatment I will have?

No. The page is educational. The plan and any medicine are decided individually, in the assessment consultation, within the Portuguese legal framework.

What does “phase 3” mean in a clinical trial?

It is the stage in which a treatment is compared in larger groups of participants, before any application for authorisation. Positive phase 3 results are not the same as approval.

Content reviewed by the KETAMED® clinical team, under medical direction, on .

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