Psychedelics and schizophrenia

Introduction

Schizophrenia is a chronic, disabling psychiatric disorder affecting about 1% of the population, with unclear aetiology involving both genetic and environmental factors. Traditional pharmacological research emphasised dopamine, prompted by the D2 receptor antagonism of early antipsychotics and the psychosis-provoking effects of amphetamines, but dopamine-focused explanations alone do not account for all clinical and pharmacological observations. Evidence implicating serotonin and glutamate has grown: many atypical antipsychotics have high affinity for the serotonin 5-HT2A receptor, and blockade of NMDA-type glutamate receptors by drugs such as phencyclidine (PCP) produces schizophrenia-like states. González-Maeso and Sealfon set out to synthesise recent findings that link the pharmacology of psychedelics (LSD-like 5-HT2A agonists) and dissociative NMDA antagonists (PCP-like drugs) with schizophrenia-related neurobiology. The review focuses on receptor, signalling and circuit mechanisms — in particular interactions between 5-HT2A and metabotropic glutamate (mGlu2/3) receptors — and discusses how these insights could reconcile serotonin- and glutamate-based hypotheses of schizophrenia and inform new antipsychotic strategies.