Psilocybin or Nicotine Patch for Smoking Cessation A Pilot Randomized Clinical Trial

Smoking is a leading cause of premature death worldwide, causing roughly 8 million deaths annually and about 480 000 in the US. Existing cessation treatments (varenicline, bupropion, nicotine replacement therapy, and counselling) outperform placebo but commonly fail within six months, leaving a large unmet need. Classic serotonergic (5-HT2A) psychedelics have shown preliminary therapeutic promise across psychiatric conditions, including addictions. Earlier work, including an open-label pilot by some of the current authors, reported high biologically verified abstinence rates following manualised cognitive behavioural therapy (CBT) combined with up to three psilocybin administrations for tobacco cessation, and epidemiological and naturalistic data have suggested associations between psychedelic use and reduced tobacco use. W. and colleagues designed a randomised clinical trial to compare a single dose of psilocybin (30 mg/70 kg) plus manualised CBT with a standard, FDA‑labelled nicotine patch regimen plus the same CBT. Nicotine patch was chosen as the active comparator because of its well-characterised safety and efficacy profile in smoking cessation. The trial aimed to evaluate whether psilocybin-assisted therapy could produce superior biologically verified smoking abstinence at clinically meaningful follow-up intervals, with 6-month prolonged abstinence prespecified as the primary outcome.

This pilot randomised comparative efficacy trial screened 152 individuals and randomised a final analytic sample of 82 participants; 70 were disqualified or declined participation. The study was approved by an institutional review board and followed CONSORT guidance; participants provided written informed consent. Sample size decisions were driven by available funding rather than statistical power calculations, with targets increased over time as funding permitted; a subsample underwent fMRI (results not reported here). Demographic data including self-reported race and ethnicity were collected using US Census categories. The intervention structure comprised four preparatory CBT visits with a target quit date in week 5, when treatment was initiated. Participants randomised to the psilocybin arm received psychoeducation during preparatory visits and a single supervised psilocybin dose of 30 mg/70 kg at the target quit visit, followed by a debrief the next day and ongoing integration/support sessions (weekly through week 7, then biweekly through week 13). During dosing participants reclined, used eyeshades, were encouraged to focus inward and listened to music. Participants randomised to the nicotine patch arm received standardised psychoeducation and began an 8–10 week nicotine patch regimen per FDA labelling (dose adjusted by baseline cigarettes per day), with the same schedule of counselling visits. Two facilitators who were aware of treatment assignments delivered the interventions. To reduce differential dropout, nicotine patch participants were offered a single crossover psilocybin administration after completing the 6‑month primary end point. Biological verification of smoking abstinence used exhaled carbon monoxide (CO) and urinary cotinine, assessed at intake and at 3, 6 and 12 months; CO was also measured at multiple interim visits. Self-report measures included a timeline follow-back (TLFB) calendar of daily cigarettes, the Fagerström Test for Cigarette Dependence (FTCD), the Contemplation Ladder (readiness to quit), and the Questionnaire on Smoking Urges. Adverse events (AEs) were captured at study visits by open inquiry and judged related or unrelated to the intervention based on timing, participant attribution, and investigator assessment. The prespecified primary outcome was prolonged smoking abstinence at 6 months, defined as no smoking following a 14-day grace period after the target quit date. A priori secondary outcomes included 7‑day point prevalence abstinence (no smoking in the 7 days prior to a visit) and mean post‑target quit date cigarettes per day (CPD). Abstinence determinations combined CO (≤5 ppm), cotinine (<200 ng/mL), and TLFB; when biochemical and self-report conflicted due to noncombustible nicotine use, participants were coded as abstinent only if TLFB and CO both indicated no smoking. An additional analysis treated any noncombustible nicotine product use or positive cotinine as nonabstinent. Analyses used an intention‑to‑treat approach: all randomised participants were included and those lost to follow-up or who discontinued were counted as nonabstinent. Statistical tests used R and GraphPad Prism. Between‑group abstinence rates were analysed using binary logistic regression without covariates (groups were highly comparable at baseline). An exploratory analysis of daily cigarette use from target quit date to 6 months employed generalised linear mixed‑effects models for overdispersed count data, with participant random intercepts and baseline CPD as a covariate; this analysis was restricted to participants who provided TLFB data through 6 months (n = 68). No data imputation was performed.

The trial randomised 82 participants after screening 152 individuals. Retention counts reported in the extracted text were 76 participants at week 2, 75 at week 4, 74 at weeks 6 and 8, 74 at week 13, and 68 at week 26; however, intention‑to‑treat analyses counted missing time points as nonabstinent. On the day after the target quit date, 38 participants in the psilocybin group were abstinent compared with 10 participants (25.0%) in the nicotine patch group (as reported in the extracted text). At the prespecified 6‑month primary end point, the psilocybin group showed substantially greater abstinence: logistic regression estimated odds of prolonged abstinence were greater in the psilocybin arm (OR 6.12; 95% CI 1.99–23.26; P = .003). For 7‑day point prevalence abstinence, the psilocybin group also had higher odds (OR 3.30; 95% CI 1.32–8.70; P = .01). The exploratory mixed‑effects analysis of daily cigarette use between the target quit date and 6 months indicated a strong treatment effect favouring psilocybin (incidence rate ratio 0.04; 95% CI 0.004–0.27; P = .002), with model predictions showing lower CPD in the psilocybin group. A zero‑inflated model provided a substantially better fit, consistent with a distinct abstinence‑related process. Model‑predicted CPD were 1.69 (95% CI 1.63–1.75) for the psilocybin group and 3.64 (95% CI 3.56–3.73) for the nicotine patch group, a 53.7% difference; observed mean (SD) CPD were 1.79 (3.32) and 3.73 (4.18), respectively. Exploratory analyses reported that prior lifetime psychedelic use (reported by 53 participants, 64.6%) did not significantly modify prolonged abstinence outcomes. Regarding safety, no serious study‑related adverse events were reported. Seventy participants (85.4%) reported at least one adverse event during the study (the extracted text truncates further detail). The authors characterised study‑related AEs as clinically nonsignificant and largely expected psilocybin effects (for example, transiently increased blood pressure, headache, and nausea) that were well managed during supervised sessions.

W. and colleagues interpret their findings as showing that a single supervised psilocybin administration combined with manualised CBT produced greater smoking abstinence than a standard nicotine patch regimen combined with the same CBT. At 6 months, psilocybin was associated with more than sixfold greater odds of prolonged abstinence (the primary outcome) and more than threefold greater odds of 7‑day point prevalence abstinence (a secondary outcome). Participants randomised to psilocybin smoked approximately 50% fewer cigarettes per day on average in the period from the target quit date to 6 months. The authors report no serious AEs attributable to psilocybin and describe the observed AEs as clinically nonsignificant, transient, and consistent with established psilocybin safety guidelines. The authors position these results within existing literature by noting that the nicotine patch group's abstinence rates were in line with prior NRT meta‑analytic results (the extracted text cites typical 6‑month prolonged abstinence of ~8% and 7‑day point prevalence ~20%), supporting the credibility of the comparator. They emphasise that psilocybin does not act directly on nicotinic acetylcholine receptors and therefore may operate via higher‑order psychological processes—such as changes in self‑concept and increased psychological flexibility—rather than by directly modifying drug reinforcement or withdrawal. The authors suggest that such psychological effects likely have accompanying biological correlates, though of a different and potentially more complex nature than those of traditional pharmacotherapies. The paper acknowledges several important limitations. The trial was nonblinded, raising the possibility that expectancy effects contributed to outcomes; the authors argue that functional blinding is rarely preserved in psychedelic trials and that an unblinded comparative efficacy design is appropriate for assessing outcomes in this context. Generalisability is limited: the sample had low ethnoracial diversity, was highly educated with high measured intelligence, and had a high prevalence of prior psychedelic use (64.6% v. ~13.8% in recent national data), suggesting potential recruitment bias and possible hesitancy among psychedelic‑naïve individuals to engage in such treatments. Although exploratory analyses indicated that prior psychedelic use did not mediate prolonged abstinence, the authors note this high prior‑use rate may limit external validity. Finally, because both arms received CBT, the trial cannot disentangle the independent contribution of psychotherapy from the pharmacological intervention. The authors recommend larger, ideally blinded trials to improve precision and generalisability of effect estimates.

In this pilot randomised clinical trial, a single supervised dose of psilocybin administered with manualised CBT produced significantly greater long‑term smoking abstinence than a standard nicotine patch regimen with the same CBT. The authors conclude that psilocybin is a promising candidate treatment for smoking cessation and suggest advancing it through the FDA process toward potential approval.