Reference: JAMA Netw Open. 2026 Mar 2;9(3):e260972
Practice Point: Psilocybin-assisted therapy may be promising for smoking cessation, but it remains experimental for now.
EBM Pearl: In behavioral and addiction research, knowledge of the treatment assignment is not always a source of bias to eliminate. It may actually be a crucial element of the treatment, especially when outcomes depend on modifying beliefs and expectations.
Quitting smoking is hard, and effective strategies to aid smoking cessation have been frustratingly hard to find. A range of treatments like counseling, nicotine replacement, antidepressants, text-message reminders, app-based programs, and even acupuncture have been tried, but long-term quit rates remain modest. As the quest for more successful treatment continues, it may be time to try more unconventional options. According to a recent pilot study published in JAMA Network Open, one of those options could be psilocybin.
The study enrolled 82 adults who smoked at least 5 cigarettes a day and had a history of at least one failed cessation attempt. Participants were randomly assigned to receive either a single high-dose psilocybin session plus a 13-week cognitive behavioral therapy (CBT) intervention or a standard 8- to 10-week nicotine patch regimen plus the same CBT program. Smoking outcomes were assessed using both self-report and biochemical verification, and prolonged abstinence was defined as no smoking following an initial 14-day grace period after the target quit date. The results were striking. At 6 months, smoking abstinence rates were 40.5% after a single dose of psilocybin vs. 10% with the nicotine patch. In a logistic regression analysis, this translated to 6 times greater odds of prolonged abstinence with psilocybin (odds ratio 6.12). The results were similar for biochemically verified 7-day point prevalence abstinence, with rates of 52% with psilocybin and 25% with the nicotine patch. Most participants experienced minor, transient side effects with psilocybin, including headaches and temporary increases in blood pressure and heart rate, but no serious adverse events occurred.
Although these results are compelling, every EBM-savvy reader probably noticed one glaring issue immediately: The study was unblinded. In a traditional pharmacologic trial, this would be a red flag, as knowledge of the treatment assignment can powerfully influence psychological and physiological responses. But this case is a bit different. Like all studies involving psychedelics, blinding would be difficult if not impossible here, as the sensory and mental effects of psilocybin are unmistakable. More importantly, in the context of smoking cessation, knowing you’re receiving a powerful cessation aid might actually be an important part of the treatment effect. Beliefs, motivation, and perceptions of self-efficacy are all key components to successfully quitting smoking. If psilocybin works by reshaping perspectives and expectations (as the authors of this study hypothesize), then attempting to subtract some of that effect in the name of blinding might miss the point.
This is still only a pilot study, and like most pilot studies it raises more questions than it answers. For example, how does psilocybin compare to other medications for smoking cessation, such as varenicline or bupropion, which might have greater efficacy than nicotine patches? How exactly does the treatment work, since psilocybin doesn’t directly interact with the nicotinic acetylcholine receptors in the brain that mediate nicotine addiction? Are these results generalizable to a broader population, and would most people even be willing to use this intervention? About 65% of participants in this study reported prior psychedelic use, a much higher percentage than the general public. Individuals without such history might be more hesitant to try psilocybin and might have different expectations of its efficacy. These are important questions to address, and therefore this study alone doesn’t justify changing clinical practice just yet. But it does lay a path for further research and challenges long-held assumptions about how to support smoking cessation. And that’s exactly what a good pilot study is supposed to do.
For more information, see the topic Treatment for Tobacco Use in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Claire Symanski, PhD, Medical Editor and Team Lead for ENT at DynaMed. Edited by Katharine DeGeorge, MD, MS, Executive Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; McKenzie Ferguson, PharmD, BCPS, Senior Clinical Writer at DynaMed; Rich Lamkin, MPH, MPAS, PA-C, Senior Clinical Writer at DynaMed; Michael Butler, PhD, Medical Writer at DynaMed; Matthew Lavoie, BA, Senior Medical Copyeditor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor II at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.