Dextromethorphan Beyond the Cough: Exploring Its Psychedelic Potential: A Systematic Review.

UNLABELLED: BACKGROUND AND

OBJECTIVE

Dextromethorphan (DXM), widely used as an over-the-counter antitussive in the United States, exhibits psychoactive effects at supratherapeutic levels that overlap with those of classic and dissociative psychedelics. Reported psychoactive effects have generated interest in DXM as a potential therapeutic agent for treatment-resistant psychiatric disorders. Despite this emerging interest, its therapeutic dosing parameters, safety profile, and dose-response characteristics remain inadequately defined. This systematic review evaluates the existing literature on DXM administered for its psychedelic properties, with the aim of examining dose relationship patterns.

METHODS

This systematic review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and was preregistered in PROSPERO (CRD420251142239). PubMed, Embase, and the Cochrane Library were searched through August 8, 2025. Eligible studies included randomized controlled trials, cohort studies, case series, and observational studies reporting DXM effects on primary psychedelic outcomes including hallucinatory effects, subjective experiences, or cognitive effects and secondary outcomes focused on tolerability in human participants. Two independent reviewers conducted screening, data extraction, risk-of-bias assessment, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Because of substantial heterogeneity in study designs, samples, and outcomes, findings were synthesized narratively using normalized relative subjective and physiological response scores derived from reported peak effects, effect gradients, and comparative ratings.

RESULTS

Of 297 records identified, eight studies representing four unique samples met inclusion criteria. One was an ascending dose-sequence study (n = 12), two were crossover studies (n = 20; n = 32), and one was a single-dose study (n = 40) (n = 104 total). Doses ranged from 100 to 960 mg. Psychedelic effects were observed at 100 mg, while adverse effects, including nausea, vomiting, motor impairment, and cognitive slowing, became more prominent above 200 mg. Hallucinatory and mystical phenomena intensified at 300 and 400 mg. Risk of bias was generally rated as having some concerns or high risk, and certainty of evidence was low for most primary outcomes and moderate for secondary outcomes.

CONCLUSION

Although the evidence is too limited to evaluate true dose-response relationships, the literature showed DXM psychedelic effects beginning at 100 mg, with greater phenomenology intensity at 300 and 400 mg. Current findings support only a preliminary descriptive summary of reported psychedelic effects and highlight the need for larger, prospectively designed dose-finding and clinical applicability studies.