Psilocybin links binocular rivalry switch rate to attention and subjective arousal levels in humans

Based on the theory that a slow switching rate on a binocular rivalry task is associated with psychosis, this study (n=10) shows that psilocybin (15mg/70kg) significantly reduces the switching rate, even when 5-HT2A receptor activity is blocked with ketanserin.

Abstract

“Rationale: Binocular rivalry occurs when different images are simultaneously presented to each eye. During continual viewing of this stimulus, the observer will experience repeated switches between visual awareness of the two images. Previous studies have suggested that a slow rate of perceptual switching may be associated with clinical and drug-induced psychosis.

Objectives: The objective of the study was to explore the proposed relationship between binocular rivalry switch rate and subjective changes in psychological state associated with 5-HT_2A receptor activation.

Materials and methods: This study used psilocybin, the hallucinogen found naturally in Psilocybe mushrooms that had previously been found to induce psychosis-like symptoms via the 5-HT_2A receptor. The effects of psilocybin (215 μg/kg) were considered alone and after pretreatment with the selective 5-HT_2A antagonist ketanserin (50 mg) in ten healthy human subjects.

Results: Psilocybin significantly reduced the rate of binocular rivalry switching and increased the proportion of transitional/mixed percept experience. Pretreatment with ketanserin blocked the majority of psilocybin’s “positive” psychosis-like hallucinogenic symptoms. However, ketanserin had no influence on either the psilocybin-induced slowing of binocular rivalry or the drug’s “negative-type symptoms” associated with reduced arousal and vigilance.

Conclusions: Together, these findings link changes in binocular rivalry switching rate to subjective levels of arousal and attention. In addition, it suggests that psilocybin’s effect on binocular rivalry is unlikely to be mediated by the 5-HT_2A receptor.”

Authors: Olivia L. Carter, Felix Hasler, John D. Pettigrew, Guy M. Wallis, Guang B. Liu & Franz X. Vollenweider

Summary

Abstract

Binocular rivalry occurs when different images are simultaneously presented to each eye. This phenomenon may be associated with psychosis.

This study used psilocybin, a hallucinogen found naturally in Psilocybe mushrooms, to induce psychosis-like symptoms in ten healthy human subjects.

Psilocybin significantly reduced binocular rivalry switching rate and increased the proportion of transitional/mixed percept experience. Ketanserin blocked the majority of psilocybin’s “positive” psychosis-like hallucinogenic symptoms, but had no influence on the drug’s “negative-type” symptoms.

Introduction

When two different images are presented to the left and right eye, the observer will experience repeated switches between awareness and suppression of the two “rivaling” images. The observer will generally report seeing either only vertical or only horizontal gratings.

Binocular rivalry has been used to investigate the physiological processes underlying consciousness and the factors influencing perceptual grouping and awareness. However, there is increasing evidence that binocular rivalry may also reflect brain processes involved in determining more global aspects of conscious state.

Despite growing evidence for an association between rivalry switching rate and subjective changes in conscious state, none of the current “mutual inhibition” models address this issue. Instead, one model proposes that perceptual switches characteristic of all forms of rivalry are driven by large fluctuations in brainstem activity.

This model suggests that the raphe nuclei, ventral tegmental area, and locus coeruleus are involved in the release of serotonin, dopamine, and noradrenalin, which are involved in binocular rivalry switching.

Psilocybin, the main psychoactive compound found in Psilocybe “magic” mushrooms, can alter sensory processing, cognitive function, and induce mystical-type experiences. It is used to study the pharmacological mechanisms underlying different clinical symptoms in both human and animal models of psychosis.

Psilocybin is believed to act through the 5-HT2A receptor, but also acts through the 5-HT1A and 5-HT2C receptors. The 5-HT2A receptor is located on the apical dendrites of pyramidal cells of the cortex, and the 5-HT1A receptor is located in the raphe nucleus of the brainstem.

Psilocybin reduces the rate of binocular rivalry switching by inhibiting 5-HT release from the raphe nucleus and increasing cortical activation, which is consistent with the subjective changes in conscious state.

The 5-HT2A receptor was found to be the main factor contributing to the hallucinogenic properties of psilocybin, and the selective 5-HT2A antagonist ketanserin was used to determine if the changes in perceptual rhythms could be dissociated from the drug induced “psychosis-like” psychological changes.

Ten healthy human subjects were tested under four drug conditions: placebo, psilocybin, ketanserin, and psilocybin plus ketanserin. Perceptual switching patterns were measured 45 min before and 30 min after psilocybin/placebo intake.

Ten healthy volunteers were recruited from a local university and technical college. All had normal or corrected to normal vision and were free to withdraw from the study at any time.

Psilocybin (215 g/kg), ketanserin (50 mg), and lactose placebo were administered in gelatine capsules of identical appearance. Ketanserin was given at a dose that caused significant, but not total, blockade of psilocybin’s effects.

Binocular rivalry was induced by presenting a green vertical and horizontal grating to the subject’s left and right eye, respectively, using liquid crystal goggles.

Subjects were instructed to focus on the vertical or horizontal orientation of gratings and report their respective predominance by pushing the appropriate button. If a mixed percept was experienced, they were instructed to report any period of mixed percept.

Before each binocular rivalry session, subjects viewed a 1-min movie of simulated rivalry. They were given the same viewing and reporting instructions as those outlined for binocular rivalry, but the catch trial movie showed clean switches between vertical and horizontal gratings.

The AMRS consists of 60 adjectives representing different mood states. The scores were grouped into seven main factors: performance-related activity (PRA), general inactivity (GI), extroversion (EX), general positive mood (GPM), emotional excitability (EE) and dreaminess (DR).

The 5D-ASC measures alterations in waking consciousness associated with mood, perception, experience of oneself and of the environment, and cognitive processing. It consists of 94 individual statements that are scored from 0 to 100, and are grouped into five main factors: oceanic boundlessness, anxious ego dissolution, visionary restructuralization, and reduction of vigilance.

The study was double-blind and the order of dose assignment was counter-balanced. Blood pressure and heart rate were monitored at hourly intervals throughout the day, and binocular rivalry was measured 45 min before and at 30, 60, 90, 135, 180, 240, 300, 360, and 420 min after psilocybin intake.

Subjects were additionally tested on attentional tracking and spatial working memory measures at pretest and 120 min post-administration.

Results

Binocular rivalry was measured using a repeated measures analysis of variance. Psilocybin alone and after pretreatment with ketanserin increased phase duration significantly at 60, 90, and 135 min, but at 180 min only psilocybin alone remained significantly greater than placebo.

The amount of mixed percept increased with time and dose, and psilocybin plus pretreatment with ketanserin increased the amount at 135 min.

Key press responses to the catch-trial movie were assessed with respect to response accuracy and response time. Psilocybin and ketanserin led to slower response times at the 60-min time point, but not at any other time point.

The subjective effects of the four drug conditions were assessed using the AMRS and the 5D-ASC. Psilocybin caused a significant increase in only one of the seven factors, DR, compared to placebo, but three factors showed significant changes after pretreatment with ketanserin.

Psilocybin increased four of the five factors of the 5D-ASC rating scale compared to placebo, but only the RV factor was significantly affected after pretreatment with ketanserin. Ketanserin alone caused no significant subjective effects.

Ketanserin pretreatment was unable to block either psilocybin’s slowing of binocular rivalry or the psychological effect pertaining to reduced arousal and vigilance. However, a relationship between rivalry rate and levels of arousal/attention was seen in some subjects.

Discussion

Psilocybin, a mixed 5-HT1A/2A agonist, significantly slowed the rate of perceptual switching and increased the proportion of time experiencing the mixed/ transitional percept during binocular rivalry.

The apparent lack of involvement of the 5-HT2A receptor was contrary to our expectations, as the 5-HT2A receptor is more important for psilocybin’s subjective effects. The results of this study show that the 5-HT2A receptor is the biological target for psilocybin. Ketanserin pretreatment blocks the influence of psilocybin on the three core dimensions of the 5D-ASC rating scale, but not on the RV dimension.

This study suggests that it may be possible to separate the “positive” psychosis-like effects of psilocybin from the “negative” symptoms associated with apathy and a reduction in general levels of arousal and attention.

Ketanserin did not block any of the “psychosis-like” effects of psilocybin, but rather had no effect on the binocular rivalry rate, suggesting that binocular rivalry rate may be more associated with the “negative” symptoms of psychosis than the “positive” symptoms.

The 5-HT2A receptor was not found to be involved in the slowing of binocular rivalry rate by psilocybin, suggesting that the 5-HT1A receptor may be involved. However, the role of the 5-HT1A receptor must be tested directly with a selective agonist/antagonist.

The timing of raphe activity, the reduction in 5-HT released into the cortex, or the result of any number of different downstream processes may all be involved in the slowing of binocular rivalry switch rate.

Psilocybin reduced rivalry rate and arousal, and increased the proportion of time subjects experienced the mixed/transitional state of “cross-hatch” or “patchwork” rivalry. This suggests that attention may be involved in the neural mechanisms by which attention can influence conscious perception.