A single high dose of psilocybin combined with cognitive behavioral therapy produced more than 6 times the odds of prolonged smoking abstinence at 6 months compared with the nicotine patch plus cognitive behavioral therapy, according to a pilot randomized clinical trial published today in JAMA Network Open.
Tobacco smoking causes approximately 480,000 deaths annually in the US and 8 million worldwide—several-fold higher than alcohol or opioids. Most available cessation treatments, including nicotine replacement therapy (NRT), varenicline, bupropion, and counseling, fail within 6 months. The trial was conducted at Johns Hopkins Bayview Medical Center from January 2015 to May 2023 and enrolled 82 psychiatrically healthy adult smokers (mean age 47.6 years; 60% male) with more than 1 prior unsuccessful quit attempt.
Participants were randomized 1:1 to receive either a single oral dose of psilocybin (30 mg/70 kg) or an 8- to 10-week FDA-approved course of the nicotine patch, with both groups completing a 13-week manualized cognitive behavioral therapy (CBT) program. Randomization used urn stratification to balance intelligence, tobacco dependence severity, age, and sex. Participants and investigators were unblinded to treatment assignment—a design the researchers described as the reference standard for psychotherapy research, citing evidence that double-blind psychedelic trials are undermined by poor blinding integrity. An optional crossover to psilocybin was offered to nicotine patch participants following completion of the primary endpoint.
The primary outcome was biochemically verified prolonged abstinence at 6 months, defined as no smoking following an initial 14-day grace period after the target quit date. Abstinence was confirmed using exhaled carbon monoxide, urinary cotinine, and a Timeline Follow-Back self-report calendar. Intention-to-treat analysis counted all randomized participants; those lost to follow-up were counted as nonabstinent. Sixty-eight participants (83%) completed the 6-month follow-up.
At 6 months, 17 participants in the psilocybin group (41%) achieved biochemically verified prolonged abstinence vs 4 participants in the nicotine patch group (10%), yielding more than 6 times the odds of abstinence in the psilocybin group. On the secondary outcome of 7-day point prevalence abstinence—no smoking in the 7 days preceding the visit—22 psilocybin participants (52%) were abstinent vs 10 nicotine patch participants (25%), reflecting more than 3 times the odds of abstinence. An exploratory analysis of daily cigarette use between the target quit date and 6-month follow-up showed model-predicted use of 1.69 cigarettes per day in the psilocybin group vs 3.64 in the nicotine patch group, a 54% difference.
“These results suggest that psilocybin holds potential in the treatment of tobacco use disorder and, along with other psychedelics, should be investigated further for tobacco and other substance use disorders.”
No serious adverse events (AEs) were attributed to psilocybin or the nicotine patch. AEs were more common on the target quit date in the psilocybin group (88%) vs the nicotine patch group (28%), largely reflecting anticipated, transient elevations in blood pressure and heart rate monitored during psilocybin administration, as well as headache (50% vs 8%). One psilocybin administration required sublingual nitroglycerin to manage hypertension, with no further sequelae. Skin rash was more common with the nicotine patch (18% vs 0%), and vivid dreams were reported exclusively in the nicotine patch group (15%). Depression was reported in 30% of the psilocybin group and 23% of the nicotine patch group during the 6-month trial period, with no statistically significant difference between groups.
The nicotine patch group’s abstinence rates were consistent with published literature. A recent meta-analysis found standalone NRT yields approximately 8% prolonged abstinence and 20% 7-day point prevalence abstinence at 6 months; the current trial found 10% and 25%, respectively, in the patch group, supporting the credibility of the comparator arm. The researchers noted that the nicotine patch was selected in part because varenicline—a more efficacious comparator—requires administration prior to the quit date, which would have confounded planned pre-post functional magnetic resonance imaging (fMRI) analyses not reported in this paper.
The researchers proposed that psilocybin’s mechanism does not involve direct interaction with nicotinic acetylcholine receptors. Instead, they suggested the drug may act through higher-order psychological processes, including changes in self-concept and enhanced psychological flexibility—mechanisms also proposed to account for psilocybin’s transdiagnostic benefits in depression and anxiety. The researchers noted this positioned psilocybin’s efficacy as consistent with accumulating evidence for a general antiaddiction effect of classic psychedelics across substances including alcohol and opioids.
Psilocybin participants spent a median of 29.6 total hours in treatment visits vs 16.8 hours in the nicotine patch group, a difference the researchers attributed primarily to the psilocybin session (typically 8 to 9 hours) and the next-day debriefing visit. The researchers acknowledged this difference in contact time as a limitation that future studies should address by equalizing time between groups.
The researchers identified several limitations. The unblinded design means expectancy effects cannot be excluded, though they noted that one prior study found expectancy predicted antidepressant response to escitalopram but not psilocybin. The sample was predominantly White (89%) and highly educated (63% held at least a bachelor’s degree), limiting generalizability. Notably, 65% of participants reported prior classic psychedelic use—far exceeding the 14% national prevalence—suggesting possible recruitment bias, although exploratory analyses found no relationship between prior psychedelic use and abstinence outcomes. Because both groups received CBT, the study cannot isolate psilocybin’s contribution independent of psychotherapy. The sample size of 82 was determined by funding availability rather than a formal power calculation. The trial ran over 8 years, with COVID-19 contributing to enrollment delays and a shift to virtual visits for nondosing sessions.
The researchers concluded that psilocybin is a promising candidate for smoking cessation and should advance in the FDA regulatory process toward potential approval. They called for larger trials to generate generalizable outcome data and determine optimal dosing frequency, therapeutic support requirements, cost-effectiveness, and scalability. A 12-month follow-up, crossover data, and fMRI findings will be reported separately.
Disclosures are available in the research letter.
The study is available at JAMA Network Open
