Allostatic Recalibration Theory (ART): Serotonergic Psychedelics Exert Transdiagnostic Therapeutic Effects by Recalibrating Allostasis to the Environment
SSRN Electronic Journal January 1, 2026 Dennis Parker Kelley, Gabriel Sturm, Katy Venable et al.
Serotonergic psychedelics show therapeutic effects across diverse neuropsychiatric, inflammatory, and cardiometabolic disorders, effects mediated largely by the serotonin 5-HT2A receptor. These drugs are exceptionally context-dependent, able to be anti-inflammatory or pro-inflammatory depending on setting. Each target pathology is linked to elevated stress exposure, which drives mitochondrial and allostatic dysregulation. The authors propose that psychedelics act as super-normal stimuli for the adaptive 5-HT2A receptor stress response, inducing a process called allostatic recalibration (AR). AR involves three phases: destabilizing, recalibrating, and consolidating updated allostatic programs. This recalibration replaces entrenched pathological allostatic programs with ones tuned to the safe context of psychedelic therapy, explaining their transdiagnostic effects.