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

Serotonergic hallucinogens such as psilocybin produce an altered state of consciousness (ASC) characterised by marked changes in perception, emotion, thought, and sense of self. Converging human and animal evidence indicates that many core psychological effects of psilocybin are primarily mediated by 5-HT2A receptor activation, yet these compounds also bind to other serotonin receptor subtypes including 5-HT1A. Animal studies and limited human data suggest that 5-HT1A receptor activity can modulate behaviours and subjective effects associated with 5-HT2A agonists, but the role of 5-HT1A receptors in shaping psychedelic symptom formation in humans is not well defined. Pokorny and colleagues set out to test whether pretreatment with a partial 5-HT1A agonist (buspirone) or a non-hallucinogenic 5-HT1A/2A agonist (ergotamine) alters the subjective effects of psilocybin in healthy volunteers. The study specifically examined whether these pretreatments reduce psilocybin-induced alterations in perception, emotion, thought, and self-experience as measured by the Altered State of Consciousness (5D-ASC) rating scale.

Forty healthy volunteers were recruited and allocated to two parallel groups: one group received buspirone as the pretreatment arm (n assigned =20) and the other received ergotamine as the pretreatment arm (n assigned =20). Following adverse reactions and dropouts, 19 participants (10 male, 9 female, mean age reported) completed the buspirone arm and 17 participants (8 male, 9 female) completed the ergotamine arm. Screening excluded current or past major psychiatric disorders, pregnancy, drug dependence, and significant medical abnormalities; informed consent and ethics approvals were obtained. A double-blind, placebo-controlled, randomized, within-subject design was used for each pretreatment group. Each participant attended four sessions separated by at least 2 weeks and received the four conditions in counterbalanced order: placebo+placebo, blocker (buspirone or ergotamine)+placebo, placebo+psilocybin, and blocker+psilocybin. Extracted dosing information reports buspirone 20 mg orally with psilocybin administered 1 hour later, and ergotamine 3 mg orally with psilocybin administered after 100 minutes; the psilocybin dose is reported in the text as 170 mg/kg p.o. Blood pressure was monitored every 20 minutes, participants had a resting-state EEG one hour after the second drug, and they were observed until effects subsided. Subjective effects were assessed using the 5D-ASC questionnaire, a 94-item visual-analogue instrument yielding five main scales: Oceanic Boundlessness (OB), Anxious Ego Dissolution (AED), Visionary Restructuralization (VR), Auditory Alterations (AA), and Vigilance Reduction (VIR). The questionnaire was completed 180 minutes after dosing to retrospectively rate the session. Statistical analysis used repeated-measures ANOVA with within-subject factors pretreatment (placebo, blocker), treatment (placebo, psilocybin), and 5D-ASC main scales, and group (buspirone, ergotamine) as a between-subject factor. Item-cluster follow-up ANOVAs were performed for scales divisible into clusters. Tukey post-hoc tests were used and significance was set at p<0.05 (two-tailed).

Final sample sizes were 19 in the buspirone group and 17 in the ergotamine group after a single participant in the buspirone arm reported nausea and three participants in the ergotamine arm experienced dizziness and did not complete the study. Repeated-measures ANOVA identified significant interactions involving pretreatment, treatment, main scale and group (F(4,136)=3.17, p<0.01) and treatment, main scale and group (F(4,136)=2.74, p<0.05), indicating differential modulation by buspirone versus ergotamine. In the buspirone group, pretreatment with buspirone significantly reduced the psilocybin-induced score on the Visionary Restructuralization (VR) main scale (p<0.001) and produced a trend-level reduction on Oceanic Boundlessness (OB) (p=0.062). There were no significant buspirone-related changes in Anxious Ego Dissolution (AED), Auditory Alterations (AA), or Vigilance Reduction (VIR). Psilocybin alone increased OB, AED, VR, and VIR relative to placebo (all p<0.05) in this group, and buspirone or buspirone+psilocybin differed from psilocybin alone on several main scales as described in the text. A focused repeated-measures ANOVA on VR item clusters showed significant interactions (pretreatment × treatment × item cluster: F(5,90)=5.64, p<0.001; treatment × item cluster: F(5,90)=6.90, p<0.001; pretreatment × item cluster: F(5,90)=11.42, p<0.001). Post-hoc tests indicated that buspirone+psilocybin significantly reduced the following VR item clusters compared with psilocybin alone: elementary visual hallucinations, complex visual hallucinations, changed meaning of percepts, facilitated autobiographical memory recollection, and facilitated imagination (all p<0.05). Audio-visual synaesthesia was not reduced by buspirone. In contrast, ergotamine pretreatment did not significantly alter any psilocybin-induced 5D-ASC main scale scores; comparisons of ergotamine+psilocybin versus psilocybin alone yielded p>0.8 for main scales. Psilocybin increased all five main scales compared with placebo in the ergotamine group (all p<0.01). The authors note an apparent 69% increase in the VR item cluster audio-visual synaesthesia for ergotamine+psilocybin versus psilocybin, but this was not statistically significant (p>0.1) and was driven by four subjects who reported synaesthesia only in the combined condition. In both groups, blocker alone did not differ from placebo on 5D-ASC main scales (all p>0.9).

Pokorny and colleagues interpret their findings to indicate that activation of 5-HT1A receptors can reduce specific components of the psilocybin-induced subjective state, most notably visual hallucinations encompassed by the VR scale. The investigators highlight that buspirone markedly attenuated elementary and complex visual hallucinations and, to a lesser extent, items linked to altered meaning of percepts, autobiographical memory recollection, and imagination. They propose mechanistic explanations grounded in receptor anatomy and physiology: 5-HT1A receptors are broadly expressed in cortical and limbic regions and exert inhibitory influence on pyramidal neurons, whereas 5-HT2A receptors are excitatory and implicated in hallucinatory phenomena. Co-expression of 5-HT1A and 5-HT2A receptors on pyramidal cells could allow 5-HT1A agonists to reduce 5-HT2A-driven excitation either directly or via interactions at the postsynaptic level; alternatively, presynaptic 5-HT1A autoreceptor activation in raphe nuclei could reduce serotonin release and thereby dampen downstream 5-HT2A-mediated effects. The discussion also notes that buspirone has D2/D3 antagonist activity, but the authors deem this an unlikely explanation because selective D2 blockade previously did not abolish psilocybin-induced hallucinations. With respect to ergotamine, the authors find its lack of effect unexpected given in vitro affinity for 5-HT1A and 5-HT2A receptors. They advance several caveats: ergotamine has very low oral bioavailability (reported as <1%), so the administered 3 mg p.o. dose may not have achieved sufficient central exposure to compete with psilocybin at receptor sites. Differences in intrinsic efficacy, pre- versus postsynaptic actions, and possible cellular selectivity (for example disinhibition of pyramidal cells at low doses) could also account for the absence of modulation. The investigators therefore call for further mechanistic work using multiple doses or alternative administration routes (for example intravenous) to clarify ergotamine’s central actions. Additional points raised include the alignment of the buspirone result with animal findings (for example blockade of head-twitch responses) and with the idea that improving sensory gating (indexed by prepulse inhibition in animals) might underlie reduction of sensory overload, although whether buspirone affects psilocybin-induced prepulse inhibition deficits in humans remains to be tested. The authors acknowledge limitations and uncertainties that temper interpretation: the ergotamine finding may reflect insufficient bioavailability or dosing rather than a true absence of 5-HT1A/2A interaction, and mechanistic inferences about receptor localisation and transduction require further direct study. They recommend additional experimental work to probe dose-response relationships, routes of administration, and underlying neurophysiological mechanisms.

The study concludes that 5-HT1A receptor activity plays an important modulatory role in psilocybin-induced symptom formation, particularly for visual hallucinations and related excitatory phenomena. Pokorny and colleagues suggest that 5-HT1A agonists such as buspirone can attenuate positive-like symptoms elicited by psilocybin via 5-HT1A activation and/or interactions between 5-HT1A and 5-HT2A receptors. Given reported alterations in cortical and limbic 5-HT1A receptor density in schizophrenia and the established role of 5-HT2A receptors in visual hallucinations, the authors propose that selective, regionally targeted 5-HT1A agonists warrant investigation as adjunctive treatments for positive symptoms in schizophrenia and for visual hallucinations in Parkinson’s disease.