CCNP Innovations in Neuropsychopharmacology Award

Psychedelics like psilocybin and LSD primarily activate serotonin 5-HT2A receptors but also affect other receptors and neural circuits, fostering transformative cognitive and mystical experiences. Unlike conventional psychiatric drugs, they influence brain networks such as the default mode network and the cortico–striato–thalamo–cortical network, and involve molecular mechanisms including neuroplasticity and epigenetics. This review argues that psychedelics' complex actions require a new conceptual framework in psychiatry to integrate brain, mind, and spirituality, and to avoid oversimplification when studying their therapeutic potential for mental disorders.

Study at a glance

Abstract

For 3000 years, psychedelics have been used in religious contexts to enhance spiritual thinking, well-being, and a sense of community. In the last few years, a renaissance in the use of psychedelic drugs for mental disorders has occurred in Western society; consequently, a pressing scientific need to elucidate the intricate mechanisms underlying their actions has arisen. Psychedelics mainly bind to serotonin (5-HT) receptors, particularly 5-HT 2A receptors, but may also bind to other receptors. Unlike conventional psychotropic drugs used in psychiatry, psychedelics introduce a distinctive complexity. They not only engage in receptor activation, but also exert influence over specific neural circuits, thereby facilitating transformative cognitive experiences and fostering what many have identified as a spiritual contemplation or mystical experience. This comprehensive review describes clinical studies that have examined the propensity of psychedelics to enhance spiritual, mystical, and transcendent cognitive states. This multifaceted nature, encompassing diverse components and paradigms, necessitates careful consideration during the investigation of psychedelic mechanisms of action to avoid oversimplification. The present review endeavours to elucidate the mechanisms underlying the actions of 2 principal psychedelic substances, psilocybin and lysergic acid diethylamide (LSD), with a focus on monoamine and glutamate receptor mechanisms; molecular aspects, such as neuroplasticity and epigenetics; as well as the impact of psychedelics on brain circuits, including the default mode network and the cortico–striato–thalamo–cortical network. Given their distinctive and intricate mechanisms of action, psychedelics necessitate a novel conceptual framework in psychiatry, offering insight into the treatment of mental health disorders and facilitating the integration of the realms of brain, mind, and spirituality.