Pharmacological, clinical, and translational evidence for N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, and zalsupindole: a systematic review.
Chad Collyer, Gia Han Le, Maryam Hassan, Sabrina Wong, Roger S McIntyre
Progress in neuro-psychopharmacology & biological psychiatry October 6, 2026 DOI: 10.1016/j.pnpbp.2026.111966 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Interventions | N N-dimethyltryptamine (N N-DMT) 5-methoxy-N N-dimethyltryptamine (5-MeO-DMT) zalsupindole |
| Topics | 5-MeO-DMT DMT |
| Keywords | Pharmacodynamics Pharmacokinetics Psychedelics |
| Key findings | Across 51 publications, clinical evidence for short-acting tryptamines was most developed for depression, with N,N-DMT and 5-MeO-DMT associated with rapid reductions in depressive symptoms, and inhalable 5-MeO-DMT (GH001) meeting its primary endpoint in a Phase 2b treatment-resistant depression trial. Evidence for other conditions remained preliminary, and zalsupindole data came from a single preclinical study. The authors conclude that further research is needed to clarify mechanisms and whether neuroplasticity-promoting effects can be separated from hallucinogenic effects. |
Abstract
Short-acting tryptamine psychedelics are emerging as candidate psychiatric therapeutics with pharmacological profiles that may offer practical advantages over longer-acting psychedelics. N,N-dimethyltryptamine (N,N-DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) differ in pharmacokinetic, receptor, and phenomenological properties, while zalsupindole is a putatively non-hallucinogenic analogue. This systematic review aimed to synthesize pharmacological, clinical, safety, and preclinical behavioural evidence for these compounds. Ovid databases and PubMed were searched from inception to December 22, 2025, with an updated search on July 7, 2026. Two reviewers independently conducted screening, data extraction, and risk-of-bias assessment. Fifty-one publications met eligibility criteria. Intravenous N,N-DMT exhibited rapid pharmacokinetics, with acute effects resolving within 20-30 min, while sublingual 5-MeO-DMT had an elimination half-life of approximately 28 min. Clinical evidence was most developed for depression, with both compounds associated with rapid reductions in depressive symptoms. GH001, an inhalable 5-MeO-DMT formulation, met its primary endpoint in a Phase 2b treatment-resistant depression trial. Evidence for substance use disorders, post-traumatic stress disorder, and eating disorders remained preliminary. Zalsupindole evidence was limited to one preclinical study reporting antidepressant-like behavioural and neuroplasticity-related effects without a head-twitch response; however, human efficacy and hallucinogenic potential remain unknown. Common adverse events included nausea, headache, and transient cardiovascular increases. DMT-related compounds represent a pharmacologically heterogeneous group with emerging clinical relevance, particularly for depression. Further studies integrating dose-exposure relationships, receptor pharmacology, neurobiological markers, subjective effects, and clinical outcomes are needed to clarify mechanisms of response and whether neuroplasticity-promoting effects can be dissociated from overt hallucinogenic effects.
Comparable studies
Other systematic reviews and meta-analyses on 5-MeO-DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| A critical review of reports of endogenous psychedelic N, N-dimethyltryptamines in humans: 1955-2010. | 2012 | Systematic review | |
| Short-term safety and tolerability profile of 5-methoxy-N,N-dimethyltryptamine in human subjects: a systematic review of clinical trials. Healthy volunteers and patients with treatment-resistant depression | 2024 | Systematic review | n = 78 |
| Clinical Pharmacokinetics of N,N-Dimethyltryptamine (DMT): A Systematic Review and Post-hoc Analysis. Humans | 2025 | Systematic review | |
| Efficacy of N, N-dimethyltryptamine (DMT) psychedelic therapy for substance misuse: A systematic review and meta-analysis Individuals with substance misuse | 2026 | Systematic review and meta-analysis | |
| Clinical pharmacokinetics of N,N-dimethyltryptamine (DMT): a systematic review and post-hoc analysis Humans | 2025 | Systematic review |