Double-Blind Comparison of the Two Hallucinogens Dextromethorphan and Psilocybin: Experience-Dependent and Enduring Psychological Effects in Healthy Volunteers
This double-blind experimental study (n=20) compares the effects of high-dose dextromethorphan (DXM; 400mg/70kg) to psilocybin (10, 20, 30mg/70kg) under conditions typical of therapeutic psychedelic trials. DXM and psilocybin showed increases over placebo in ratings of experiences predictive of psychological benefit at 1 week. However, psilocybin's effects were dose-dependent and more favourable, while DXM had poorer physical tolerability.
Authors
- Albert Garcia-Romeu
- Roland Griffiths
- Nathan Sepeda
Published
Abstract
Rationale
N-methyl-D-aspartate receptor-mediated dissociatives and serotonergic hallucinogens are being increasingly used in therapeutic interventions that involve nonordinary states of consciousness and may represent a unique mental health paradigm wherein pharmacologically induced experiences are conducive to psychological well-being.
Objective
The aim of this study was to further understand how the phenomenological and health-promoting effects of high-dose dextromethorphan (DXM) compared to psilocybin in the same participants when administered under experimental conditions that are typical of therapeutic psychedelic trials.
Methods
Single, acute oral doses of DXM (400 mg/70 kg), psilocybin (10, 20, 30 mg/70 kg), and inactive placebo were administered under double-blind and psychologically supportive conditions to 20 healthy participants with histories of hallucinogen use. Ratings of personal meaning, spiritual significance, psychological challenge, and psychological insight attributed to acute drug experiences were assessed 7 h (at session end) and 1 week after each drug administration. Persisting psychological effects were assessed 1 week after each drug administration.
Results
High-dose DXM and psilocybin produced similar increases over placebo in ratings of drug experience that was predictive of psychological benefit at 1 week, even when expectancy effects were minimized. These effects tended to favor psilocybin in a dose-dependent manner and were limited by poor physical tolerability for DXM.
Conclusions
This analysis suggests the utility of exploring clinical applications of dissociatives that occur within the supportive contexts that are characteristic of psychedelic research and that prioritize the optimization of psychologically valuable drug experiences.
Research Summary of 'Double-Blind Comparison of the Two Hallucinogens Dextromethorphan and Psilocybin: Experience-Dependent and Enduring Psychological Effects in Healthy Volunteers'
Introduction
Classic serotonergic hallucinogens (for example psilocybin) and NMDA receptor–mediated dissociatives (for example ketamine and dextromethorphan, DXM) are being revisited as rapid-acting treatments for mood and other psychiatric disorders. Previous work suggests that, despite distinct molecular targets, these two drug classes may share downstream effects on cortical network activity and glutamate-driven neuroplasticity, and that aspects of the acute subjective experience—such as mystical-type phenomena for classic psychedelics or dissociation for NMDA antagonists—could be relevant to clinical benefit. However, canonical constructs (for example ‘‘mystical experience’’ or ‘‘dissociation’’) do not capture all instances of therapeutic response, and there is a need to characterise drug-occasioned experiences in broader, meaning-oriented ways that may better predict enduring psychological effects. Mathai and colleagues report new analyses from a double-blind, within-subjects crossover trial in which healthy, hallucinogen-experienced volunteers received placebo, a high dose of DXM, and three doses of psilocybin under psychologically supportive conditions. The present paper focuses on data collected at the end of each session (~7 h postdose) and at 1 week, asking: how do participants rate the session as personally meaningful, spiritually significant, psychologically challenging, and psychologically insightful across drug conditions and time; how do persisting psychological effects attributed to the drug compare between conditions at 1 week; and how are end-of-session ratings related to persisting effects?
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Study Details
- Study Typeindividual
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- APA Citation
Mathai, D. S., Hilbert, S., Sepeda, N. D., Strickland, J. C., Griffiths, R. R., & Garcia-Romeu, A. (2023). Double-Blind Comparison of the Two Hallucinogens Dextromethorphan and Psilocybin: Experience-Dependent and Enduring Psychological Effects in Healthy Volunteers. Psychedelic Medicine, 1(4), 241-252. https://doi.org/10.1089/psymed.2023.0035
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