Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties.

Classic psychedelics show therapeutic promise for neuropsychiatric disorders, partly through acute subjective effects (ASE) like mystical-type insights that correlate with long-term benefits. However, barriers such as high resource demands and exclusion of at-risk patients drive a search for compounds that retain therapeutic effects without ASE. Recognizing that psychedelics promote neuroplastic changes correcting aberrant neural circuitry, researchers are developing 'non-psychedelic' psychoplastogens that lack hallucinogenic activity yet show efficacy in preclinical models. This review examines clinical and preclinical evidence on whether ASE can be dissociated from sustained therapeutic properties and proposes clinical scenarios to clarify this question.

Study at a glance

Abstract

Recent research with classic psychedelics suggests significant therapeutic potential, particularly for neuropsychiatric disorders. A mediating influence behind symptom resolution is thought to be the personal insight - at times, bordering on the mystical - one acquires during the acute phase of a psychedelic session. Indeed, current clinical trials have found strong correlations between the acute subjective effects (ASE) under the influence of psychedelics and their enduring therapeutic properties. However, with potential barriers to widespread clinical implementation, including the healthcare resource-intensive nature of psychedelic sessions and the exclusion of certain at-risk patient groups, there is an active search to determine whether ASE elimination can be accompanied by the retention of persisting therapeutic benefits of these class of compounds. Recognizing the aberrant underlying neural circuitry that characterizes a range of neuropsychiatric disorders, and that classic psychedelics promote neuroplastic changes that may correct abnormal circuitry, investigators are rushing to design and discover compounds with psychoplastogenic, but not hallucinogenic (i.e., ASE), therapeutic potential. These efforts have paved the discovery of 'non-psychedelic/subjective psychedelics', or compounds that lack hallucinogenic activity but with therapeutic efficacy in preclinical models. This review aims to distill the current evidence - both clinical and preclinical - surrounding the question: can the ASE of classic psychedelics be dissociated from their sustained therapeutic properties? Several plausible clinical scenarios are then proposed to offer clarity on and potentially answer this question.