Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: effects on cognition

This double-blind, placebo-controlled study (n=20) with psilocybin (10, 20, 30mg/70kg) and DXM (400mg/70kg) finds no global cognitive impairment. The study does find (for both drugs) effects on psychomotor performance, working memory, episodic memory, associative learning, and visual perception.

Abstract of Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan

“Objectives 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).

Methods 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.

Results 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.

Conclusions 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.”

Authors: Frederick S. Barrett, Theresa M. Carbonaro, Ethan Hurwitz, Matthew W. Johnson & Roland R. Griffiths

Notes on Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan

This paper works with the same dataset/participants as Carbonaro and colleagues (2017) which studied the similarities and differences in the subjective experience of the participants.

• Comparison between psilocybin and another psychedelic, dextromethorphan on cognition
• No delirium or cognitive impairment for high doses of both psychedelics
• Different effects on the tests done (e.g. greater effect on working memory of psilocybin)

Dextromethorphan (DXM) is a dissociative hallucinogen (like ketamine). It’s more commonly known as a cough suppressant (not in the same quantities, of course). Its mechanisms of action include, 1) as a nonselective serotonin reuptake inhibitor, 2) as a sigma-1 receptor agonist, and 3) as an NMDA receptor antagonist.

“Psilocybin and DXM were compared on measures of psychomotor functioning, working and episodic memory, executive function, and visual perception. These are domains that are impacted by classic and/or dissociative hallucinogens, but that have not been directly compared during the acute effects of these drugs.”

The effects found were as described above. Interestingly is that some participants (4 in the DMX condition, 3 in the 30mg/70kg psilocybin condition) were not able to perform some or all of the tasks (i.e. they were too high). Overall the effects of the 20 or 30mg psilocybin were similar to 300mg of DXM.

“Thus, while global cognitive impairment and delirium (e.g., drug-induced impairment of all cognitive domains) were not observed, local cognitive impairments (e.g., more subtle impairments within individual cognitive domains) were observed and were both dose and drug dependent. Importantly, strong changes in perception and affect typical of classical hallucinogens were observed at the time that MMSE was administered (Carbonaro et al. 2018), strongly suggesting that subjective and cognitive effects of hallucinogens are not accurately described as being similar to clinical delirium states.”

Between the lines, they state here that psychedelics are not similar to episodes of insanity/delirium.

Summary of Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan