Subjective features of the psilocybin experience that may account for its self-administration by humans: a double-blind comparison of psilocybin and dextromethorphan

This double-blind, placebo-controlled, cross-over study (n=20) investigated which features of psilocybin may account for its high rates of non-medical use, by comparing it to dextromethorphan (DXM). Nine subjective effects of psilocybin were linked to its reinforcing effects (i.e. motivation to use again), which were: liking, visual effects, positive mood, insight, positive social effects, increased awareness of beauty, amazement, meaningfulness, and mystical experience.

Abstract

“Rationale: Although both psilocybin and dextromethorphan (DXM) produce psychedelic-like subjective effects, rates of non-medical use of psilocybin are consistently greater than DXM. Objective: New data are presented from a study of psilocybin and DXM relevant to understanding the features of psilocybin subjective effects that may account for its higher rates of non-medical use.

Methods: Single, acute oral doses of psilocybin (10, 20, 30 mg/70 kg), DXM (400 mg/70 kg), and placebo were administered under double-blind conditions to 20 healthy participants with histories of hallucinogen use.

Results: High doses of both drugs produced similar time courses and increases in participant ratings of peak overall drug effect strength. Nine subjective effect domains are proposed to be related to the reinforcing effects of psilocybin: liking, visual effects, positive mood, insight, positive social effects, increased awareness of beauty (both visual and music), awe/amazement, meaningfulness, and mystical experience. For most ratings, (1) psilocybin and DXM both produced effects significantly greater than placebo; (2) psilocybin showed dose-related increases; 3, DXM was never significantly higher than psilocybin; (4) the two highest psilocybin doses were significantly greater than DXM. These differences were consistent with two measures of desire to take the drug condition again.

Conclusions: This analysis provides new information about domains of psilocybin subjective effects proposed to be related to its reinforcing effects (alternatively described as the “motivation” to use). Observed differences on these domains between psilocybin and DXM are consistent with the relative rates of non-medical use of psilocybin and DXM.”

Authors: Theresa M. Carbonaro, Matthew W. Johnson & Roland R. Griffiths

Summary

Psilocybin and dextromethorphan both produce psychedelic-like subjective effects, but psilocybin is more commonly used non-medically.

Introduction

Psilocybin and other classic psychedelic drugs have been used for centuries, often in religious or spiritual ceremonial settings or with therapeutic, religious, spiritual, or psychological insight intent.

Psilocybin does not cause uncontrollable drug-seeking behavior, does not reliably increase ratings on a classic measure of euphoria, does not reliably self-administer by monkeys in a standard model used to assess drug abuse potential, and does not produce cross-generalization to classic drugs of abuse.

Dextromethorphan (DXM) is sometimes used nonmedically as a hallucinogen at high doses, but its primary mechanism of action is blockade of excitatory amino acid N-methyl-D-aspartate (NMDA) receptors.

The present study examined the subjective effects of psilocybin, a psychedelic drug used at modest rates non-medically, by comparing the effects of placebo, three doses of psilocybin, and a high dose of DXM in participants with histories of use of classic psychedelics.

Participants

The 20 participants were medically and psychologically healthy and had a history of psychedelic drug use. Nineteen participants were Caucasian and one was Asian American.

General procedures

General procedures have been described in more detail previously (Carbonaro et al. 2018). Participants lied down on a couch while wearing eyeshades and headphones and focused their attention on their inner experiences.

Participants were told they could receive placebo or doses of 38 psychoactive drugs from a variety of drug classes, and were monitored on two occasions before the first drug session, 1 to 2 days after each experimental session, and at 1 week and 1 month after the last session.

In a crossover study, participants received psilocybin, dextromethorphan HBr, and placebo in identically appearing opaque, size 0 gelatin capsules.

Participants rated overall drug effect and liking on a scale from 0 to 10 before and after capsule administration.

Measures assessed at the end of the session, approximately 7 h after capsule administration

Psilocybin and DXM produce dose-related increases on the Hallucinogen Rating Scale, which is a 100-item questionnaire. Participants rated the degree to which the session experience was personally meaningful, spiritually significant, psychologically insightful, and psychologically challenging.

Measure assessed 1 week after the last session

Participants completed a 202-item questionnaire after each of the five drug sessions to facilitate the differentiation of drug effects between the different drug conditions. The questionnaire was comprised of selected items from the four questionnaires administered 7 h after capsule administration.

Measure assessed 1 month after the last session

Participants were given copies of their written session descriptions to review and ranked the order of their session experiences in regard to preference for repeating the drug condition again, psychological insight, personal meaning, and spiritual significance.

Data analysis

Data were analyzed with IBM SPSS Statistics (IBM Corporation, Armonk, NY). Repeated measures ANOVAs were used to compare drug conditions, and Fisher’s LSD post hoc tests were used to compare drug conditions 1 week after the last session.

Subjective ratings of drug effect magnitude and liking

Psilocybin and DXM produced orderly time-related effects during the sessions. The time course of DXM was similar to that of the high psilocybin doses, with maximal effects occurring at 2 to 4 h and effects decreasing at the 6-h time point.

Ratings of subjective domains proposed to be related to reinforcing effects

Participants rated their drug session experiences retrospectively 7 h after drug administration. The ratings were arranged under 9 labels reflecting different domains of subjective experience. Psilocybin was significantly greater than placebo on 36 out of 37 measures, and DXM was significantly greater than placebo on 25 out of 37 measures. Psilocybin was significantly higher than DXM on 9 out of 26 measures and DXM was significantly higher on 32 out of 37 measures.

A HRS question asked participants how soon they would like to repeat the experience. The results showed that the highest dose of psilocybin was significantly higher than DXM.

Participants rated their drug session experiences retrospectively 1 week after the last drug session. Psilocybin produced significantly greater effects than placebo on 26 of the 27 measures, and DXM produced significantly greater effects than placebo on 14 of the 27 measures.

The four active dose conditions produced significant increases in participant ratings on all four measures, and psilocybin produced dose-related increases.

Ratings of nausea, physical distress, and psychological challenge

Participants’ ratings of nausea and physical distress were significantly higher than placebo, 10, 20, and 30 mg/ 70 kg psilocybin, and DXM, respectively, at 1 week after the last session.

Participants found all four active drug conditions significantly more challenging than placebo. Psilocybin produced numerically and often statistically dose-related increases.

Discussion

This report was undertaken to shed light on the conundrum that psilocybin has been used non-medically for centuries in various cultures, but lacks many of the usual features that have been used to predict the repeated taking of psychoactive drugs by humans.

Psilocybin and DXM produced similar subjective effects, but psilocybin produced higher ratings of disposition for future self-administration and higher ratings of drug strength than DXM. These findings are consistent with epidemiological data showing that psilocybin produces higher rates of non-medical use than DXM.

Data are presented for nine domains of subjective experience that have been proposed to be predictive of the self-administration of classic psychedelic drugs: (1) classic abuse liability subjective effects; (2) visual effects; (3) positive mood; (4) insight; (5) positive social effects; (6) increased awareness of beauty; (7) meaningfulness; (8) mystical.

All nine subjective effect domains proposed to be predictive of subsequent self-administration differentiate psilocybin from placebo as well as psilocybin from DXM, and the highest dose of psilocybin was significantly greater than the lowest dose of DXM on most assessed measures.

The authors of this study proposed nine domains of psychedelic experience based on their observations of hundreds of psilocybin research participants and thousands of written accounts of psilocybin experiences. These domains are likely not completely independent of each other.

The results indicate that peak participant ratings of drug liking during the session do not correspond with retrospective ratings of liking after the drug session. In particular, psilocybin produced significantly higher ratings of liking than DXM.

The present analysis examined the relationship between subjective domains of psychedelic experience and subsequent self-administration of psilocybin. It did not include domains of experience that might be expected to be negatively related to subsequent self-administration.

Microdosing of psilocybin, a psychoactive compound, is gaining popularity, although little rigorously controlled research has been conducted. The current study tested the effects of microdosing at much greater doses than typical protocols.

The present study sought to explain why psilocybin is used at modest rates non-medically, by analyzing the effects of psilocybin on behavior. It used the conceptual description of the experimental analysis of behavior, which assumes that psilocybin reinforcement is not limited to activation of the same neurobiological systems underlying food consumption and sexual behavior.

A double-blind study comparing psilocybin and DXM in non-medical users of hallucinogens showed that all nine subjective effect domain factors differentiated psilocybin from placebo and from DXM, and were consistent with two measures of desire to take the drug condition again.