BEYOND THE TWITCH: ESTABLISHING A FOUNDATION FOR NEUROBEHAVIORAL PSYCHEDELIC STATES IN MICE

Psychedelic substances like psilocybin have shown promise in clinical trials for psychiatric conditions. In humans, 'set' (mindset) and 'setting' (environment) influence acute experiences and long-term therapeutic outcomes. However, these factors are largely neglected in preclinical research. Animal experiments typically involve stressful procedures—restrained injections, sleep-time testing, and barren environments—while employing brief recording periods and single outcome measures. This produces baseline states that poorly reflect clinical conditions and datasets that fail to capture the complexity of behaviour under psychedelics, limiting our understanding of the mechanisms underlying psychedelic therapy.
To address these issues, we developed an experimental paradigm that combines low-stress, naturalistic settings with multimodal behavioural recordings. Animals underwent extensive habituation and received psilocybin via stress-minimised, voluntary oral administration (VOA) in an enriched home cage during their active phase. Multi-day video and audio recordings enabled us to create individualised 'behavioural dictionaries' of individual animals on baseline and psilocybin days. VOA reliably induced head-twitch responses (HTRs), confirming drug action. Additionally, psilocybin modulated the frequency of multiple behavioural motifs for up to five hours—significantly outlasting the typical 1.5-hour HTR window.
These findings indicate that incorporating set-and-setting considerations alongside extended behavioural monitoring can reveal prolonged psychedelic effects not captured by conventional paradigms. This behavioural characterisation under low-stress conditions provides a baseline for future neural recordings aimed at investigating psychedelic-induced brain states under conditions more comparable to human clinical settings.