From Toad Venom to Drug Development: The Clinical Pharmacology of Mebufotenin (5-MeO-DMT) in Treatment-Resistant Depression.
Robert Likić, Igor Radanović, Deni Rkman, Sanja Brnić, Gabriël E. Jacobs, Geert Jan Groeneveld
CNS Drugs November 4, 2026 DOI: 10.1007/s40263-026-01346-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Narrative review Randomized Peer reviewed |
|---|---|
| Duration | 6-month follow-up |
| Measures | Montgomery-Åsberg Depression Rating Scale (MADRS) |
| Topics | 5-MeO-DMT Depression DMT |
| Key findings | The authors report that in the pivotal phase 2b trial, inhaled mebufotenin (GH001) produced a day-8 placebo-adjusted MADRS reduction of 15.5 points and day-8 remission in 23/40 (57.5%) versus 0/41 (0%) with placebo, with 20/23 (87.0%) day-8 remitters still in remission at 6 months under as-needed retreatment. They conclude that evidence rests principally on a single randomised trial and requires replication in larger, more diverse phase 3 studies with formal blinding-integrity assessment. |
Abstract
Treatment-resistant depression affects about one-third of patients with major depressive disorder and remains a major unmet need. Mebufotenin (5-methoxy-N,N-dimethyltryptamine; 5-MeO-DMT), the principal psychoactive constituent of Incilius alvarius parotoid secretion and of several Amazonian plants, is a pharmacologically atypical serotonergic psychedelic in clinical development for this indication. This narrative review analyses its clinical pharmacology, drawing on a structured search of PubMed/MEDLINE, EMBASE, Scopus, ClinicalTrials.gov and grey literature through 15 August 2026, supplemented by regulatory and sponsor disclosures. Mebufotenin is a non-selective serotonin agonist with high affinity at 5-hydroxytryptamine receptor 1A (5-HT1A, Ki 3.0 nM) and markedly lower affinity at 5-HT2A, with reported selectivity spanning approximately 30-fold to 300-fold depending on whether the 5-HT2A receptor is agonist- or antagonist-labelled. Clearance is dominated by monoamine oxidase A; the cytochrome P450 2D6 (CYP2D6)-derived metabolite bufotenine has a receptor profile comparable to the parent compound rather than a distinct 5-HT2A-preferring one, and was below the limit of quantification in the only human study to measure it. In the pivotal phase 2b trial (GH001-TRD-201), inhaled GH001 produced a day 8 placebo-adjusted Montgomery-Åsberg Depression Rating Scale (MADRS) reduction of - 15.5 points (p < 0.001; d = - 2.0) and day 8 remission in 23/40 (57.5%) versus 0/41 (0%) with placebo, with 20/23 (87.0%) day 8 remitters in remission at 6 months under as-needed retreatment and no serious treatment-related adverse events. Median psychoactive duration was 9.0-14.0 min across doses, and 97.5% of patients were discharge-ready within 1 h. GH001 has been studied without protocol-mandated psychotherapy, although this does not establish that psychological support is unnecessary. Evidence rests principally on a single randomised trial, and replication in larger, more diverse phase 3 studies with formal blinding-integrity assessment is required.
Comparable studies
Other narrative reviews on DMT for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Registered clinical studies investigating psychedelic drugs for psychiatric disorders. Registered clinical trials on clinicaltrials.gov evaluating psychedelics for... | 2021 | Review | n = 70 |
| Role of Psychedelics in Treatment-Resistant Depression. | 2023 | Review | |
| Psilocybin and Other Classic Psychedelics in Depression. | 2024 | Review | |
| Benefits and Challenges of Ultra-Fast, Short-Acting Psychedelics in the Treatment of Depression | 2025 | Review | |
| Ayahuasca for the Treatment of Depression. | 2022 | Review |
Citations in the library
Cites 38
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
- Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Nature Neuroscience June 1, 2023
and 33 more in the library