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.
Psychedelic Science