Exploring Psychedelics as Novel Therapeutics for Smoking Cessation: Mechanistic Insights from Animal Studies

Tobacco use remains a leading cause of preventable morbidity and mortality worldwide, and current smoking cessation treatments are limited by low long-term efficacy. An interplay between positive and negative reinforcement drives high relapse rates. Psychedelic compounds, particularly psilocybin, have shown promising clinical outcomes for smoking cessation, yet the neurobiological and behavioral mechanisms underlying these effects remain poorly understood. The present dissertation investigates the effects of psilocybin on multiple behavioral and molecular aspects of nicotine dependence using mouse models, with the goal of elucidating mechanisms relevant to substance use disorder (SUD) treatment. Psilocybin attenuated nicotine withdrawal-related behaviors in a dose and sex dependent manner. In addition, psilocybin altered conditioned reward, drug-primed reinstatement, and vapor self-administration. Psilocybin’s effects were not limited to nicotine, as reductions in opioid withdrawal signs were also observed, suggesting potential generalizability across SUDs. To explore underlying neurobiological molecular mechanisms, we assessed changes in gene expression following psilocybin administration. These analyses revealed psilocybin-induced modulation of nicotinic acetylcholine receptor subunits and neuroplasticity-related genes in brain regions implicated in addiction and withdrawal, providing novel molecular insight into how psychedelics may alter dependence-related circuitry and behavior. Together, these findings provide preclinical evidence that psilocybin targets key behavioral and neurobiological processes underlying nicotine dependence, including withdrawal and reward, which are critical drivers of relapse. This work advances our understanding of how psychedelic compounds may function as therapeutics for mitigating the substantial global burden of nicotine addiction and other SUDs.