Allostatic Recalibration Theory (ART): Serotonergic Psychedelics Exert Transdiagnostic Therapeutic Effects by Recalibrating Allostasis to the Environment

Abstract

Serotonergic psychedelics produce therapeutic effects in clinical trials of diverse neuropsychiatric disorders, and preclinical models of inflammatory, cardiometabolic, and neuropsychiatric diseases. These effects appear largely mediated by the serotonin 5-HT2A receptor (5-HT2AR). How could psychedelics elicit transdiagnostic therapeutic effects through a single receptor across tissues as diverse as the immune, cardiometabolic, and central nervous systems (CNS)? Psychedelic effects are exceptionally context-dependent; psychedelics can be anti-inflammatory and anxiolytic, but can also be pro-inflammatory, anxiogenic, and even traumatic (i.e., bad trips) in other contexts. Each pathology for which psychedelics are therapeutic is associated with elevated stress exposure, an established driver of the mitochondrial and allostatic dysregulation also associated with these conditions. Allostasis is the anticipatory regulation of metabolic and physiological stability through stress-induced perturbations, and is managed by mitochondrial, physiological, and CNS allostatic regulatory networks. Allostatic programs refer to the tuning of allostatic regulatory setpoints, and their dynamics in response to stress. Diverse stressors increase systemic 5-HT2AR expression and signaling, which regulate adaptive phenotypic plasticity and help tune allostatic programs to a stressful environment to enhance survival. Stress-induced allostatic states are acutely adaptive, but can grow maladaptive and resistant to change after chronic or extreme stress, dysregulating physiology and metabolism, and driving disease. We hypothesize that psychedelics are super-normal stimuli for the adaptive 5-HT2AR stress response, inducing a process that we call allostatic recalibration (AR). In particular, psychedelics evoke a temporary window of allostatic plasticity during which allostatic regulatory programs can be recalibrated to the internal and external context of psychedelic administration (i.e., set and setting). We propose that three phases constitute AR: 1) destabilizing; 2) recalibrating; and 3) consolidating updated allostatic programs. Altogether, the transdiagnostic therapeutic effects of psychedelics may follow from AR, replacing the entrenched pathological allostatic programs that initiate and maintain pathology with updated programs tuned to the safe and supportive context of psychedelic therapy.