Psilocybin-Induced Deficits in Automatic and Controlled Inhibition are Attenuated by Ketanserin in Healthy Human Volunteers

This placebo-controlled, double-blind study (n=16) investigated the effects of psilocybin (18.2mg/70kg) on sensorimotor gating, an automatic ability to filter unnecessary information, and controlled response inhibition, a deliberate ability to ignore conflicting information in healthy volunteers. Psilocybin disrupted both of these processes, and this effect was reversed by selectively blocking the serotonergic pathway with ketanserin (40mg) pretreatment.

Abstract

“Introduction: The serotonin-2A receptor (5-HT_2AR) has been implicated in the pathogenesis of schizophrenia and related inhibitory gating and behavioural inhibition deficits of schizophrenia patients. The hallucinogen psilocybin disrupts automatic forms of sensorimotor gating and response inhibition in humans, but it is unclear so far whether the 5-HT_2AR or 5-HT_1AR agonist properties of its bioactive metabolite psilocin account for these effects. Thus, we investigated whether psilocybin-induced deficits in automatic and controlled inhibition in healthy humans could be attenuated by the 5-HT_2A/2CR antagonist ketanserin.

Methods: A total of 16 healthy participants received placebo, ketanserin (40 mg p.o.), psilocybin (260 μg/kg p.o.), or psilocybin plus ketanserin in a double-blind, randomized, and counterbalanced order. Sensorimotor gating was measured by prepulse inhibition (PPI) of the acoustic startle response. The effects on psychopathological core dimensions and behavioural inhibition were assessed by the altered states of consciousness questionnaire (5D-ASC), and the Color-Word Stroop Test.

Results: Psilocybin decreased PPI at short lead intervals (30 ms), increased all 5D-ASC scores, and selectively increased errors in the interference condition of the Stroop Test. Stroop interference and Stroop effect of the response latencies were increased under psilocybin as well. Psilocybin-induced alterations were attenuated by ketanserin pretreatment, whereas ketanserin alone had no significant effects.

Discussion: These findings suggest that the disrupting effects of psilocybin on automatic and controlled inhibition processes are attributable to 5-HT_2AR stimulation. Sensorimotor gating and attentional control deficits of schizophrenia patients might be due to changes within the 5-HT_2AR system.”

Authors: Boris B. Quednow, Michael Kometer, Mark A. Geyer & Franz X. Vollenweider

Summary

Introduction

Automatic and controlled information-processing deficits are considered to constitute core symptoms of schizophrenia and appear to have a crucial role in the pathophysiology of schizophrenia.

The function of serotonin-2A receptors (5-HT2ARs) in particular is implicated in the pathogenesis of schizophrenia. Therefore, we investigated the role of 5-HT2ARs in automatic and controlled inhibition processes in healthy humans either pretreated with the 5-HT2A/2CR antagonist ketanserin or placebo.

Patients with schizophrenia display impaired prepulse inhibition (PPI), which is a measure of sensorimotor gating. Drug-induced PPI deficits have become an important translational model of the gating impairment in schizophrenia.

Hallucinogenic 5-HT2AR agonists such as LSD, 5-MeO-DMT, DOB, and DOI decrease PPI in rats, but the effect of 5-MeO-DMT on PPI may also be mediated by 5-HT1ARs. Moreover, polymorphisms of the 5-HT2AR, but not the 5-HT1AR, modulates PPI in humans.

The Color Word Stroop Interference Test measures response inhibition, attentional control, and cognitive flexibility. It is linked to the activation of the anterior cingulate cortex and dorsolateral prefrontal cortex. Schizophrenia patients consistently displayed increased susceptibility to interference effects in the classical card Stoop Test. Neuroimaging studies suggested a conflict-related hypoactivation of the ACC during Stroop interference in schizophrenia patients.

Acute tryptophan depletion, acute 5-HT release induced by dexfenfluramine or MDMA, and acute 5-HT2A/1AR agonists and antagonists have been shown to affect the Stroop Test. These results suggest that 5-HT2ARs are involved in controlled inhibitory mechanisms that are needed to accomplish tasks such as the Stroop Test.

We investigated the role of the 5-HT2AR in the modulation of automatic and controlled inhibition processes in healthy human volunteers using a placebo-controlled, crossed, counterbalanced, and double-blind design.

Materials and methods

Participants

A total of 16 healthy subjects were recruited from local universities. They were screened using the DIA-X diagnostic expert system, a semi-structured psychiatric interview, and standard psychometric instruments including the Freiburg Personality Inventory, the State Trait Anxiety Inventory, and the Symptom Checklist SCL-90R.

This study was approved by the Ethics Committee of the University Hospital of Psychiatry, Zurich, and all volunteers gave their written consent.

Psilocybin

Psilocybin, ketanserin, and lactose placebo were administered in gelatin capsules of identical appearance.

Study Design

The study was double-blind and placebo-controlled, and included four experimental days. Five occasional smokers were told to maintain their usual smoking habits to ensure that PPI was not influenced by smoking withdrawal.

Participants received placebo/ketanserin in capsules (0900 hours), and after another 40 min placebo/psilocybin. Startle measures were obtained 60 min after placebo/psilocybin intake, and the Stroop task and 5D-ASC rating were conducted 85 min after treatment.

Startle Response Measurement

PPI was recorded in 15 min sessions consisting of 52 trials presented in pseudorandom order and separated by intertrial intervals varying between 4 and 22 s (mean 13 s). The trials consisted of 12 PA trials, 24 prepulse-pulse trials (PP) and 6 no-stimulus trials.

The Altered State of Consciousness Rating Scale

The 5D-ASC rating scale is a visual-analogue scale consisting of 94 items assessing three key dimensions of ASC: oceanic boundlessness, anxious ego dissolution, and visionary restructuralization.

Stroop Task

A computerized version of the trial-by-trial Color Word Stroop Test was used to examine how quickly and accurately subjects could name the colors of German words presented in four different conditions: congruent trials, conflict trials, neutral X trials, and neutral W trials.

Facilitation was defined as the reduction of RT in the congruent condition, while interference was defined as the increase in RT in the conflict condition.

Statistical Analysis

All data were analyzed using STATISTICA 7.1 for Windows (StatSoft). ANOVA, 5D-ASC, and Pearson’s product moment correlations were used to examine the relationship between %PPI and Stroop task.

Psychological Effects of Psilocybin

Psilocybin produced an altered state that was characterized by derealization and depersonalization phenomena, affective changes, thought disorder, and perceptual alterations.

Psilocybin produced significant psychotomimetic effects on all scales, but the effect was most pronounced on the OB scale. Ketanserin reduced the psychotomimetic effects of psilocybin on the OB and VR scales, but not on the AED scale.

Effect of Psilocybin and Ketanserin on Startle Amplitude and Habituation

A 2-way ANOVA revealed that block and drug significantly affected startle response. Psilocybin alone had no effect, but ketanserin and psilocybin together had a significant effect.

Effect of Psilocybin and Ketanserin on Percent PPI

A 4-way ANOVA revealed an interaction of pretreatment*treatment and ISI, and post-hoc tests showed that psilocybin decreased %PPI in the 30 ms condition and that ketanserin reversed this effect.

Effect of Psilocybin on Stroop Test

A 2-way ANOVA showed that psilocybin increased error rates in the conflict condition, while ketanserin reversed this effect.

Psilocybin increased RT in all conditions, which was substantially reduced by ketanserin. Ketanserin alone did not alter RT.

Psilocybin increased Stroop interference and Stroop effect but neutralized by ketanserin. Ketanserin alone did not alter facilitation.

Relationships between PPI, Stroop Test, and Altered States of Consciousness

PPI change scores correlated significantly with OB and VR scores in psilocybin states, but not with Stroop scores. The correlation between AED and PPI was driven by thought disorder and loss of control over thinking and body.

Discussion

The 5-HT2A/2CR antagonist ketanserin abolished the disrupting effects of the 5-HT2A/2B/2C/1AR agonist psilocybin on automatic (sensorimotor gating) and controlled (Stroop interference) inhibition processes.

In a previous study, psilocybin reduced PPI at short (30 ms) and medium (60 ms) ISIs, but increased PPI at long (120 and 240 ms) ISIs. In the present study, the increase at 120 ms ISI was not significant. Psilocybin reduced PPI at short ISIs by its 5-HT2AR agonist action, whereas its 5-HT1AR agonist action increased PPI at long ISIs. This finding supports the assumption that PPI deficits in schizophrenia might be induced by 5-HT2AR changes.

We found a slight reduction in startle reactivity by ketanserin, which is partly in line with a previous study. However, the PPI-disrupting effects reported by Graham et al (2002) may be due to the strong reduction in startle amplitude found in their experiment.

Psilocybin increases PPI at 120 ms, which is not caused by the 5-HT1AR agonistic properties of the compound. This effect might be caused by an interaction between the 5-HT1A, 5-HT2A, or 5-HT2CR.

Psilocybin significantly increased RT and error rates in the conflict condition of a computerized trial-by-trial Stroop Test, a pattern of results that is similar to that reported for schizophrenia patients. Ketanserin prevented these deficits in the conflict condition, suggesting a dysfunction of conflict monitoring and/or inhibition processes.

The different interactions of psilocybin and ketanserin on various cognitive functions might be explained by the fact that 5-HT1ARs and 5-HT2ARs are colocalized in cortical pyramidal cells, and both receptor subtypes display opposing effects when stimulated.

Our data are consistent with two early studies showing that the 5-HT system is crucially involved in processes involved in the performance of the Stroop Test. The 5-HT system was also shown to be correlated with the 5-HT transporter density within the DLPFC measured with PET. Based on the present findings, we speculate that deficits in conflict monitoring and response inhibition in schizophrenia might be caused by changes in 5-HT2ARF.

Ketanserin blocks not only the 5-HT2A but also to a lesser extend the 5-HT2CR, and it has been speculated that the 5-HT2CR might also be involved in the effects of hallucinogens, but this is unlikely because several 5-HT2CR agonists and antagonists enhance while 5-HT2CR antagonists impair behavioral inhibition.

We did not find a significant correlation between PPI and Stroop Test performance. However, Scholes and Martin-Iverson’s study used an uncommon technique and might not be comparable with our approach. The inhibitory processes engaged in PPI and Stroop interference may tap into different regional 5-HT2AR populations, and psilocybin-induced PPI deficits may depend primarily on 5-HT2AR stimulation located in more basic modulatory structures of the startle circuit. Psilocybin affects Stroop interference in the ACC and DLPFC by increasing regional glucose metabolism, and by increasing 5-HT2AR occupation in these areas. This may explain the diverse alterations in several stages of information processing found in schizophrenia.

This study suggests that 5-HT2AR stimulation disrupts sensorimotor gating and Stroop interference in healthy human volunteers, and that these processes might depend on different regional 5-HT2AR populations.

Acknowledgements

This investigation was financially supported by the Heffter Research Institute, the Swiss Neuromatrix Foundation, the Deutsche Forschungsgemeinschaft, and the US Veterans Affairs VISN 22 Mental Illness Research, Education and Clinical Center.