A pilot randomized clinical trial recently published in JAMA Network Open reported that psilocybin-assisted‑ therapy, delivered in conjunction with structured cognitive behavioral therapy (CBT), was associated with substantially higher smoking cessation rates than standard nicotine patch therapy paired with the same behavioral support.1 The findings introduce a potential new, albeit still investigational, approach to treating tobacco use disorder.
The study enrolled 82 psychiatrically healthy adults who smoke (mean age 47.6 years) with a history of unsuccessful quit attempts. Participants were randomized 1:1 to receive either a single high dose of psilocybin (30 mg/70 kg) administered on the target quit date or an eight- to 10-week course of FDA-approved transdermal nicotine replacement therapy. Both groups completed a 13-week‑ manualized CBT program for smoking cessation.
At six months following the target quit date, 40.5% of participants in the psilocybin group achieved biochemically verified prolonged abstinence, defined as continuous abstinence following a two-week grace period, according to investigators. In contrast, only 10.0% of participants assigned to nicotine patches met this primary outcome. The adjusted odds ratio for prolonged abstinence favored psilocybin (OR 6.12; 95% CI, 1.99-23.26; P = .003).
Secondary outcomes similarly favored the psilocybin intervention. Seven-day point prevalence abstinence at six months was observed in 52.4% of psilocybin-treated participants vs 25.0% in the nicotine patch group (OR 3.30; 95% CI, 1.32-8.70; P = .01). Exploratory mixed effects modeling of daily cigarette consumption demonstrated significantly lower cigarette use after the quit date in the psilocybin group during the follow-up period.
Psilocybin differs fundamentally from conventional cessation pharmacotherapies. It does not act on nicotinic acetylcholine receptors or directly modulate withdrawal physiology. Instead, investigators hypothesize that its efficacy may involve alterations in higher-order psychological processes, including smoking-related self-schema (the cognitive structure in which a person defines themselves as a “smoker,” integrating the habit into their personal identity), motivation, and behavioral flexibility.
“The drug causes brain changes that result in a subjective experience that often leads to psychotherapeutic processes, shifts in perspective-taking, and insights,” said lead author and principal investigator Matthew Johnson, PhD, Associate Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University in Baltimore. These mechanisms align with emerging evidence from psychedelic-assisted trials in alcohol use disorder and major depressive disorder.
From a safety perspective, no serious adverse events were attributed to either treatment. Expected physiological effects—transient elevations in BP and heart rate—were observed during psilocybin administration and were managed with monitoring alone in nearly all cases. Headache, nausea, and visual disturbances were more frequently reported in the psilocybin group on the dosing day but were self-limited. Importantly, adverse events commonly associated with prolonged pharmacotherapy exposure were not observed, given the single-dose nature of the psychedelic intervention.
These findings underscore the continued evolution of smoking cessation science. “This helps toward creating the foundation for more larger, more complex clinical trials,” said Frank T. Leone, MD, MS, FCCP, Director of University of Pennsylvania’s Comprehensive Smoking Treatment Program and Professor of Medicine at the Perelman School of Medicine. “It’s a great contribution to the literature, and the results continue to suggest that there’s a signal here. It expands our point of view on what constitutes appropriate types of interventions for addictive behaviors and how new learned pathways in the brain are formed and reformed over time.”
Tobacco use disorder remains a principal driver of preventable pulmonary morbidity and mortality, contributing to COPD, lung cancer, cardiovascular disease, and interstitial lung disease. Although pharmacotherapies approved by the US Food and Drug Administration—including nicotine replacement products, varenicline, and bupropion—offer benefits, long-term abstinence rates remain relatively modest in clinical practice, according to the investigators. The current trial’s nicotine patch outcomes were consistent with published meta-analytic benchmarks, supporting the validity of the comparator they added.
In discussion of the study’s limitations, the authors noted that it was unblinded, raising the possibility that expectancy effects contributed to outcomes. The sample was predominantly White, highly educated, and exhibited unusually high rates of prior psychedelic exposure, which they noted may limit generalizability to broader pulmonary clinic populations. In addition, total therapeutic contact time differed between groups, driven largely by the prolonged supervised dosing session in the psilocybin arm.
“We tested it the way you test a new psychotherapy where blinding is not possible, and the placebo effect was at play for both experimental and control groups,” Dr. Johnson noted. Although the psilocybin group received substantially greater contact time than the nicotine patch group, he said that “it was relatively not much more than the control group, so it seems unlikely to have produced results this large.”
The practical utility of this class of drugs is really where the limitations will lie, Dr. Leone said. “With questions like who and how will it be administered and monitored? How do you manage adverse events? What are the long-term complications? What do you do if it doesn’t work the first time? Those questions will continue to be worked out over time.”
Future investigations will need to compare psilocybin-assisted‑ therapy with more efficacious pharmacologic comparators in larger phase 3 trials, evaluate cost-effectiveness, and clarify its role relative to established guideline-recommended interventions. Dr. Johnson said the team is currently conducting a blinded phase 2 randomized clinical trial.
References
1. Johnson MW, Naudé GP, Hendricks PS, Garcia-Romeu A. Psilocybin or nicotine patch for smoking cessation: a pilot randomized clinical trial. JAMA Netw Open. 2026;9(3):e260972. doi:10.1001/jamanetworkopen.2026.0972
