Psilocybin restores deficits in the metabotropic glutamate receptor 2 (mGluR2) caused by alcohol, which leads to the reversal of pathological behaviors associated with alcoholism.
Alcohol use disorders remain a major public health problem, and current medications have limited success. Recent clinical trials suggest that psychedelics, especially psilocybin, combined with psychotherapy can reduce heavy drinking. This review connects two lines of research: how addiction alters metabotropic glutamate receptor 2 (mGlu2) function, and how psychedelics act through serotonin 2A receptors (2AR) to induce gene expression and neuroplasticity. Evidence indicates that mGlu2 and 2AR can regulate each other's signaling, either through crosstalk or by forming a 2AR-mGlu2 heteromer, and that 2AR activation can epigenetically modulate mGlu2 expression. The authors propose that targeting these pathways could restore mGlu2 function in AUD patients and reduce relapse risk.
Over a decade after the first edition of "Behavioral Neurobiology of Alcohol Addiction," the field faces persistent challenges and emerging opportunities in developing treatments for alcohol use disorder (AUD). The translational gap between preclinical findings and new treatments remains, exacerbated by a replicability crisis in animal research, publication biases, and limited predictive validity of existing models. Advances offering renewed hope include molecular and circuit-level technologies, AI-driven data analysis, real-world assessments, and new pharmacological candidates such as GLP-1 agonists and psychedelics. Recognition of inflammation, pain, and neuroimmune factors as integral to AUD is increasing. The authors caution against exaggerated claims and oversimplified models, and argue that neurobiological progress must be complemented by public health strategies to reduce stigma and improve access to care.