Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience

This double-blind, placebo-controlled, randomized, within-subject study (n=36) with four experimental drug conditions investigated the effects of psilocybin (11.9mg/70kg) in combination with the selective 5-HT1A agonist buspirone (20mg/70kg) and non-hallucinogenic 5-HT2A/1A agonist ergotamine (3mg/70kg), to investigate how the interaction of these serotonin receptor subtypes affect altered states of consciousness. While ergotamine exerted no effect, buspirone selectively inhibited psilocybin-induced visual hallucinations, affective changes, derealization, and depersonalization via activation of 5 -HT1A and/or an interaction between 5-HT1A and 5-HT2A receptors.

Abstract

“Introduction: The mixed serotonin (5-HT) 1A/2A/2B/2C/6/7 receptor agonist psilocybin dose-dependently induces an altered state of consciousness (ASC) that is characterized by changes in sensory perception, mood, thought, and the sense of self. The psychological effects of psilocybin are primarily mediated by 5-HT2A receptor activation. However, accumulating evidence suggests that 5-HT1A or an interaction between 5-HT1A and 5-HT2A receptors may contribute to the overall effects of psilocybin.

Methods: Therefore, we used a double-blind, counterbalanced, within-subject design to investigate the modulatory effects of the partial 5-HT1A agonist buspirone (20 mg p.o.) and the non-hallucinogenic 5-HT2A/1A agonist ergotamine (3 mg p.o.) on psilocybin-induced (170 µg/kg p.o.) psychological effects in two groups (n=19, n=17) of healthy human subjects. Psychological effects were assessed using the Altered State of Consciousness (5D-ASC) rating scale.

Results: Buspirone significantly reduced the 5D-ASC main scale score for Visionary Restructuralization (VR) (p<0.001), which was mostly driven by a reduction of the VR item cluster scores for elementary and complex visual hallucinations. Further, buspirone also reduced the main scale score for Oceanic Boundlessness (OB) including derealisation and depersonalisation phenomena at a trend level (p=0.062), whereas ergotamine did not show any effects on the psilocybin-induced 5D-ASC main scale scores.

Discussion: The present finding demonstrates that buspirone exerts inhibitory effects on psilocybin-induced effects, presumably via 5-HT1A receptor activation, an interaction between 5-HT1A and 5-HT2A receptors, or both. The data suggest that the modulation of 5-HT1A receptor activity may be a useful target in the treatment of visual hallucinations in different psychiatric and neurological diseases.”

Authors: Thomas Pokorny, Katrin H. Preller, Rainer Kraehenmann & Franz X. Vollenweider

Summary

Abstract

Psilocybin induces an altered state of consciousness (ASC) in humans. The partial 5-HT1A agonist buspirone and the non-hallucinogenic 5-HT2A/1A agonist ergotamine reduced the ASC effects of psilocybin in humans, presumably via 5-HT1A receptor activation, an interaction between 5-HT1A and 5-HT2A receptors, or both.

1. Introduction

Serotonergic hallucinogens such as psilocybin, DMT, and LSD produce an altered state of consciousness.

Since the 1990s, a series of studies have been conducted in humans to identify the neurophysiological and molecular mechanisms of psilocybin-induced altered states of consciousness. These studies have focused on cognition, emotion regulation, and social interaction.

Psilocybin is rapidly dephosphorylated into the psychoactive metabolite psilocin, which acts as an agonist at 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptors in humans and rodents. The HTR is induced by 5-HT2A receptor activation, and is blocked by highly selective 5-HT2A receptor antagonists.

Although the prevailing view is that 5-HT2A receptor activation is responsible for many of the psychedelic effects of psilocybin in humans, data suggest that 5-HT1A receptor activation may also contribute to these effects, either directly or through functional interaction with 5-HT2A receptors.

While studies in animals suggest that 5-HT1A receptor agonists reduce 5-HT2A receptor mediated behaviour induced by hallucinogens, little is known about the role of 5-HT1A receptors in psychedelic symptom formation in humans.

To test the hypothesis that psilocybin reduces the subjective effects of 5-HT1A and 5-HT2A receptor agonists, we studied whether pretreatment with buspirone or ergotamine reduces or even abolishes the psychedelic effects of psilocybin in healthy human subjects.

2.1. Subjects

Forty healthy human subjects were recruited through advertisements placed at local universities and were randomly assigned to the buspirone or ergotamine group. Nineteen subjects completed the buspirone group and 17 subjects completed the ergotamine group.

The subject’s health was confirmed by a physical examination, and blood and urine analyses. Pregnant women were excluded, and psilocybin use was authorised by the Swiss Federal Office for Public Health, Department of Pharmacology and Narcotics, Berne, Switzerland.

2.2. Substance and dosing

A double-blind, placebo-controlled, randomized, within-subject design was applied to four experimental drug conditions. The subjects received placebo or buspirone followed by placebo or psilocybin after 1 h, and ergotamine followed by placebo or psilocybin after 100 min.

All substances were filled in gelatine capsules, and participants underwent resting state EEGs after intake of the second drug.

2.3. Acute subjective drug effects

The Altered State of Consciousness (5DASC) Rating Scale was used to assess the subjective effects in each drug condition. The 5DASC questionnaire consists of five scales, three of which comprise several item clusters, and the results are given as percentage scores of maximum absolute scale values.

2.4. Statistical analysis

Data were analyzed using STATISTICA 8.0 for Windows (StatSoft). A repeated measures ANOVA was used to analyze the effects of psilocybin on the 5D-ASC main scales, and a Tukey post-hoc test was used to investigate the contribution of specific symptoms.

3. Results

Pretreatment with buspirone or ergotamine differently modulated the psilocybin-induced 5D-ASC main scales, with buspirone + psilocybin significantly reducing the main scale VR and OB, whereas ergotamine + psilocybin did not significantly modulate any main scale scores compared to psilocybin alone. Psilocybin increased all five main scales of the 5D-ASC questionnaire compared to placebo in the ergotamine group.

4. Discussion

The 5D-ASC questionnaire main scales were significantly different between placebo and ergotamine + psilocybin, ergotamine and psilocybin, and ergotamine and ergotamine + psilocybin, and between ergotamine and ergotamine + psilocybin.

Buspirone significantly reduced the scores of the 5D-ASC main scale VR item clusters ele-hall, comp-hall, cha-mean, fac-mem, and fac-fan compared to psilocybin, while placebo and buspirone had no significant effect.

The 5-HT1A agonist buspirone significantly reduced the psilocybin-induced scores for Visionary Restructuralization (VR) and Oceanic Boundlessness (OB), while the nonhallucinogenic 5-HT2A/1A agonist ergotamine did not significantly modulate any of the psilocybin-induced main scale scores.

4.1. Buspirone group

Buspirone reduced the psilocybin-induced VR subscale scores for elementary and complex visual hallucinations, facilitated autobiographic memory recollection, facilitated imagination and changed meaning of percepts, but had no effect on audio – visual synaesthesia.

The serotonergic system is composed of several pathways, including the ascending serotonergic pathways originating in the dorsal and median raphe nuclei, which release 5-HT and modulate the excitability of cortical neurons and their discharge rate through pre- and postsynaptic 5-HT receptor subtypes.

In rodents, serotonin and 5-HT2A receptors exert opposite effects on neuronal activity. This is why serotonin and 5-HT2A receptors play a critical role in the formation of psilocybin-induced visual hallucinations and more generally in the formation of excitatory symptoms in healthy human subjects.

The present result suggests that the 5-HT1A receptor modulates the extent of psilocybin-induced excitation and hallucinations in humans, and that buspirone may reduce hallucinations via a direct stimulation of 5-HT1A receptors or indirectly via an interaction between 5-HT1A and 5-HT2A receptors located postsynaptically on pyramidal cells. Although both psilocin and buspirone are thought to have partial agonistic activity at 5-HT1A receptors, the effect of buspirone on psilocybin-induced symptoms may be due to a different 5-HT1A-mediated transduction mechanisms.

Buspirone reduces psilocybin-induced visual symptoms, which is also in accordance with the observation that the 5-HT1A agonist DOI blocks the HTR induced by the selective 5-HT2A agonist. However, whether buspirone may abolish psilocybin-induced PPI deficits in humans or rodents warrants further investigations.

4.2. Ergotamine group

Ergotamine, a non-hallucinogenic 5-HT2A/1A agonist, did not significantly affect the psychological alterations induced by psilocybin, and the increase in VR item cluster audio – visual synaesthesia was post-hoc statistically not significant.

Ergotamine may act as a partial agonist at 5-HT1A or 5-HT2A receptors and may have lower efficacy at the respective transduction mechanism when compared with classic 5-HT1A agonists such as buspirone or non-hallucinogenic 5-H1A/2A agonists such as S-lisuride.

5. Conclusion

Psilocybin induces positive-like symptoms in rats via activation of 5-HT1A and/or an interaction between 5-HT1A and 5-HT2A receptors. 5-HT1A agonists may be useful for adjunctive treatment of positive symptoms in schizophrenia and visual hallucinations in Parkinson’s disease.

Author disclosure

Funding for this study was provided by Swiss Neuromatrix Foundation and Heffter Research Institute Grant.