Effects of the 5-HT2A Agonist Psilocybin on Mismatch Negativity Generation and AX-Continuous Performance Task: Implications for the Neuropharmacology of Cognitive Deficits in Schizophrenia

This study (n=18) used psilocybin administration in order to investigate the neuropharmacology of schizophrenia. The authors suggest that 5-HT2A and NMDA receptors may be involved in the cognitive deficits observed in schizophrenic individuals.

Abstract

“Previously the NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (ERP) mismatch negativity (MMN) and the performance of an ‘AX’-type continuous performance test (AX-CPT)–measures of auditory and visual context-dependent information processing–in a similar manner as observed in schizophrenia. This placebo-controlled study investigated effects of the 5-HT(2A) receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin administration induced significant performance deficits in the AX-CPT, but failed to reduce MMN generation significantly. These results indirectly support evidence that deficient MMN generation in schizophrenia may be a relatively distinct manifestation of deficient NMDAR functioning. In contrast, secondary pharmacological effects shared by NMDAR antagonists and the 5-HT(2A) agonist (ie disruption of glutamatergic neurotransmission) may be the mechanism underlying impairments in AX-CPT performance observed during both psilocybin and ketamine administration. Comparable deficits in schizophrenia may result from independent dysfunctions of 5-HT(2A) and NMDAR-related neurotransmission.”

Authors: Daniel Umbricht, Franz X. Vollenweider, Liselotte Schmid, Claudia Grübel, Anja Skrabo, Theo Huber & Rene Koller

Summary

INTRODUCTION

Schizophrenic patients have deficits in higher cognitive functions such as attention, executive functions, and memory, as well as simple sensory memory tasks. Schizophrenic patients show deficits in auditory sensory memory, which is manifested in an impaired ability to match tones following a brief delay. These deficits can be demonstrated in an abnormal reduction of an event-related potential component that is generated in auditory sensory areas and is termed mismatch negativity (MMN). MMN is the manifestation of a preattentive process that compares the deviant stimulus to the transient sensory memory trace of the standard stimulus. MMN is generated when a stimulus violates a more abstract regularity that has been extracted from previously presented stimuli, and is an electrophysiological index of context-sensitive information processing at the level of the auditory sensory memory.

In 13 out of 15 studies, deficits in MMN generation were found in schizophrenia patients, demonstrating a deficient use of contextual information at a preattentive automatic level. Schizophrenic patients also exhibit deficient performance in complex tasks that engage the prefrontal cortex.

A growing body of evidence implicates deficient NMDA receptor-dependent neurotransmission in the deficits observed in schizophrenia. Ketamine and other NMDAR antagonists reduce MMN in healthy volunteers and induce deficits in AX-CPT performance that are characterized by a specific increase in context-dependent errors.

There is evidence that abnormalities in 5-HT2A receptor-dependent neurotransmission may also play a role in some symptoms and cognitive deficits in schizophrenia. This evidence comes from the observation that indoleamine hallucinogens such as LSD or psilocybin can induce psychotic symptoms that resemble symptoms of schizophrenia. Dysfunctional 5-HT2A receptors may play a role in abnormal gating mechanisms in schizophrenia, and may explain the modest ameliorative effects of atypical antipsychotic drugs on certain cognitive deficits in schizophrenia.

Psilocybin and ketamine increase dopamine release, and 5-HT2A agonists and NMDAR antagonists increase glutamate release. These effects may be due to dysfunctional 5-HT2A signaling, which may be an important factor in cognitive deficits in schizophrenia.

We investigated whether dysfunctional 5-HT2A receptor-dependent neurotransmission also contributes to deficits in MMN generation and AX-CPT performance in healthy volunteers, and whether shared pharmacological effects of NMDAR antagonists and 5-HT2A receptor agonists indeed constitute an important mechanism by which these psychotomimetics achieve their effects at both the preattentive and attention-dependent level.

Psilocybin is a naturally occurring indoleamine hallucinogen that binds to the 5-HT2A and 5-HT1A receptors and produces hallucinogenic and cognitive effects.

METHODS

The study was conducted in the Research Department of the Psychiatric University Hospital Zurich and approved by the ethics committee. Psilocybin was obtained from the Swiss Federal Health Office.

Subjects

Normal subjects were recruited from the local university and technical college through advertisement. They underwent a screening that included a structured clinical interview, a semistructured interview covering family psychiatric history, a physical examination, and laboratory tests.

18 right-handed subjects were enrolled in the study. Their mean age was 25.1 7 4.3 years and their mean verbal and performance IQs were 114 7 11 and 117 7 9, respectively.

Procedures

Subjects took psilocybin or placebo on two separate days, were blinded to drug order, and stayed under constant supervision until all drug effects had worn off.

Behavioral effects were assessed at the end of each ERP recording session using the Brief Psychiatric Rating Scale and the Modified Mini-Mental State interview.

ERP recordings were acquired during the presentation of 1517 auditory stimuli. The auditory stimuli consisted of 100-ms, 1000-Hz standard stimuli intermixed with 100-ms, 1500-Hz frequency deviants and 250-ms, 1000-Hz duration deviants.

EEG recordings were obtained from 28 scalp locations, amplified with a band pass of 0.1 – 100 Hz (6 dB down), and digitally filtered with a low-pass filter of 15 Hz (24 dB down). Digital tags were obtained to all auditory stimuli.

Analyses focused on the generation of N1 and P2 to standard stimuli, and MMN generation to frequency- and duration-deviant stimuli. MMN waveforms were mathematically referenced to an average-mastoid reference prior to peak detection.

In the AX continuous performance test, subjects were instructed to press a button whenever the letter A (correct cue) was followed by the letter X (correct target). This test consisted of 140 pairs of stimuli, with 50% of the sequences having a short ISI and 50% having a long ISI.

Statistical Analysis

ERP analyses were performed using N1 and P2 at Fz to the standard stimulus, and frequency and duration MMN at FCz. Psilocybin was analyzed using repeated-measures ANOVAs and paired t-tests.

DISCUSSION

In a previous study, ketamine reduced MMN generation and AX-CPT performance in schizophrenic patients. The present study investigated the effects of psilocybin on these measures, and found that psilocybin induced deficits in AX-CPT performance that were particularly characterized by a failure to use contextual information.

Psilocybin reduces MMN but not N1, and the profile of psilocybin-induced deficits in AX-CPT performance is similar to the deficits observed in healthy volunteers during ketamine administration and in schizophrenic patients. The pharmacological properties unique to ketamine and psilocybin are the important factor determining their effects on MMN and N1 generation.

NMDA and 5-HT2A receptors exert strong modulatory effects on dopaminergic and glutamatergic systems in rodents and humans. These effects can be blocked by group II metabotropic receptor agonists, and 5-HT2A receptors can even antagonize effects of NMDAR antagonists.

Ketamine and psilocybin induce cognitive deficits in healthy volunteers, but haloperidol and lamotrigine ameliorate these deficits differently. Increased glutamatergic tone may be the common denominator underlying these cognitive effects.

Studies of acute drug challenges in healthy volunteers suggest that deficits in long-latency ERPs may provide useful markers of specific receptor-related abnormalities, whereas abnormal performance in tasks such as the AX-CPT may be similar in patients whose primary abnormality lies within quite different receptor systems.

If excessive glutamate release (as a result of NMDA receptor hypofunction or excessive signaling through the 5-HT2A receptor) plays a role in these deficits, 5-HT2A receptor antagonists would be expected to exert beneficial effects. Atypical antipsychotics improve cognitive deficits that are secondary to disturbances in NMDAR-dependent neurotransmission, such as deficits in AX-CPT and possibly other cognitive tasks that tax attention and working memory, but not deficits hypothesized to be a direct manifestation of NMDAR hypofunction, such as deficient MMN generation.

Psilocybin administration decreased N1 amplitude, which is consistent with studies demonstrating a tight modulation of the so-called N1 intensity dependence by the serotonergic system. This effect might relate to dysfunction in 5-HT2A receptor-dependent neurotransmission in schizophrenic patients.

Psilocybin administration was associated with a small but nonsignificant decrease of MMN, but a significant effect on N1 was observed in a similar number of subjects. Furthermore, psilocybin had a more pronounced effect on MMN to frequency deviants than on MMN to duration deviants.

Psilocybin had no effect on MMN at a dose that induced significant deficits in higher cognitive function. This could mean that the processes underlying MMN generation are more impervious to abnormal 5-HT2A signaling.

Psilocybin caused deficits in AX-CPT performance similar to those observed in schizophrenia, but failed to reduce MMN generation. This suggests that abnormalities in both NMDA and 5-HT2A receptor systems may be involved in these deficits.

ACKNOWLEDGEMENTS

This study was funded by the Swiss National Science Foundation and the Heffter Research Institute. It was presented at the 54th Annual Convention of the Society of Biological Psychiatry.

Authors

Authors associated with this publication with profiles on Blossom

Franz Vollenweider
Franz X. Vollenweider is one of the pioneering psychedelics researchers, currently at the University of Zurich. He is also the director of the Heffter (sponsored) Research Center Zürich for Consciousness Studies (HRC-ZH).

Institutes

Institutes associated with this publication

University of Zurich
Within the Department of Psychiatry, Psychotherapy and Psychosomatics at the University of Zurich, Dr Mialn Scheidegger is leading team conducting psychedelic research and therapy development.

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