Acute & long-term neural, behavioural & psychological effects of psilocybin & 5-HT2A-mediated vasoactivity

Abstract

Background: Our understanding of psychedelic drug action has rapidly developed over recent years. Yet despite impressive progress, fundamental questions remain. Determining post-psychedelic long-term brain effects and neurobiological mechanisms underlying positive psychological change would hold significant value – not just for the field of psychedelic science, but for the wider fields of neuroscience and mental health. Moreover, serotonin 2A receptors – the key site of action for psychedelic drugs – are widely expressed across the vascular system in addition to their expression in the brain. This complicates our understanding of the neurophysiological correlates of the human psychedelic brain state which largely stems from indirect measures of neuronal activity by extraction of blood-flow related parameters. Aim: To address the knowledge gaps and further our understanding, this thesis investigated (i) post-psilocybin changes in pathological beliefs in patients with treatment-resistant depression (TRD), (ii) acute and long-term effects of psilocybin in healthy humans, and (iii) psychedelic vasoactivity in mice. Methods: STUDY 1 investigated changes in pessimism in TRD patients versus controls via an objective measure of cognitive biases. STUDY 2 measured the acute and long-term effects of psilocybin in healthy humans via multimodal neuroimaging and a broad repertoire of psychological and behavioural assessments. STUDY 3 characterised the behavioural and vascular effects of 25CN-NBOH in mice via behavioural pharmacology with the head twitch response (HTR) as a behavioural read-out and pulse oximetry, respectively. Results: STUDY 1: Psilocybin treatment remediated pessimism in TRD patients one week post-dosing. STUDY 2: Brain signal complexity was related to insightfulness experienced during the peak intensity of a high-dose psilocybin experience. Psychological insight modulated positive long-term outcomes and persistent brain effects correlated with positive long-term psychological changes four weeks after a high-dose psilocybin experience. STUDY 3: 25CN-NBOH induced a (i) dose- and time-dependent, ketanserin-sensitive increase in HTRs, which was subject to short-interval and subchronic tolerance, and (ii) temperature-dependant increase in heart rate, decrease in breath rate, and increase in arterial blood flow. Conclusions: This thesis revealed post-psilocybin treatment changes in pathological beliefs in TRD patients. In healthy participants, the present findings identify insight as a mediator of long-term positive outcomes, provide a potential neural correlate of acute insight during a high-dose psilocybin experience, and show persistent neural changes that correlate with well-being outcomes long after that experience. The vasoactivity intrinsic to psychedelic drug action revealed here in mice provides considerations for blood-flow based neuroimaging techniques to measure acute psychedelic brain states. Further, using optogenetics to image cortical activities in awake behaving mice might take our mechanistic understanding of the underlying processes from basic receptor pharmacology to systemic circuit dynamics. In conclusion, this thesis presents novel results that considerably broaden the field’s knowledge, provide inspiration for future work and potentially impact wider society and mental health care.