Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: effects on cognition
Classic psychedelics (serotonin 2A receptor agonists) and dissociative hallucinogens (NMDA receptor antagonists), though differing in pharmacology, may share neuropsychological effects. These drugs, however, have undergone limited direct comparison. This report presents data from a double-blind, placebo-controlled within-subjects study comparing the neuropsychological effects of multiple doses of the classic psychedelic psilocybin with the effects of a single high dose of the dissociative hallucinogen dextromethorphan (DXM).
Twenty hallucinogen users (11 females) completed neurocognitive assessments during five blinded drug administration sessions (10, 20, and 30 mg/70 kg psilocybin; 400 mg/70 kg DXM; and placebo) in which participants and study staff were informed that a large range of possible drug conditions may have been administered.
Global cognitive impairment, assessed using the Mini-Mental State Examination during peak drug effects, was not observed with psilocybin or DXM. Orderly and dose-dependent effects of psilocybin were observed on psychomotor performance, working memory, episodic memory, associative learning, and visual perception. Effects of DXM on psychomotor performance, visual perception, and associative learning were in the range of effects of a moderate to high dose (20 to 30 mg/70 kg) of psilocybin.
This was the first study of the dose effects of psilocybin on a large battery of neurocognitive assessments. Evidence of delirium or global cognitive impairment was not observed with either psilocybin or DXM. Psilocybin had greater effects than DXM on working memory. DXM had greater effects than all psilocybin doses on balance, episodic memory, response inhibition, and executive control.
KeywordsDextromethorphan Psilocybin Hallucinogen Psychedelic drug Cognition
We thank Mary Cosimano, M.S.W., Taylor Marcus, Darrick May, M.D., Albert Garcia-Romeu, Ph.D., Mary Sweeney, Ph.D., William Richards, Ph.D., Brennan Kersgaard, and Eileen Rosello for their roles as session monitors; Dr. Annie Umbricht, M.D., and the medical staff at the Behavioral Pharmacology Research Unit for medical screening and medical coverage; and Lisa Schade for the technical assistance. We also thank David Nichols, Ph.D., for synthesizing the psilocybin. The study was conducted in compliance with United States laws.
This research was supported by NIH grant R01DA03889 to RRG. FSB and TC were supported in part by NIH grant 5T32 DA007209. FSB was supported in part by NIH grant R03DA042336. MWJ was supported in part by R01DA035277. TC is an employee of the U.S. Food and Drug Administration (FDA); however, the views presented in this article do not necessarily reflect those of the FDA and no official support or endorsement of this article by the FDA is intended or should be inferred.
Compliance with ethical standards
Conflict of interest
RRG is a board member of the Heffter Research Institute. The remaining authors declare that they have no conflicts of interest.
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