Growing evidence supports the use of psychedelics in the treatment of substance use disorders (SUDs). These compounds may be uniquely positioned to intervene across multiple levels of addiction pathology, with emerging research suggesting that psychedelics may exert therapeutic effects by modulating maladaptive neural circuitry, increasing cognitive flexibility, and disrupting rigid patterns of self-related thought. (1) These processes are deeply implicated in addiction, where the brain network dysregulations underlying compulsive behaviours are often reinforced by co-occurring psychiatric symptoms such as depression and anxiety, domains where conventional treatments frequently show only modest efficacy. (2)
A randomized clinical trial evaluating psilocybin for smoking cessation, published in JAMA Network Open, adds important clinical context to this broader discussion. (3) Conducted by researchers from Johns Hopkins University School of Medicine, including Mathew Johnson and Albert Garcia-Romeu, the study offers a valuable opportunity to consider how theoretical promise may translate into measurable treatment outcomes.
Among the different classes of compounds that fall under the psychedelic umbrella, we focus here on classic psychedelics, those acting primarily as partial agonists at the 5-HT2A receptor, given that the present study investigates psilocybin. Readers interested in the intersection between SUDs and the broader psychedelic pharmacological landscape, including dissociative anaesthetics and other atypical compounds such as ibogaine, are encouraged to revisit our previous piece for an overview.
NICOTINE ADDICTION AND THE LIMITS OF CURRENT TREATMENTS
Nicotine addiction remains one of the leading causes of preventable morbidity and mortality worldwide. Despite widespread awareness of its risks, long-term cessation rates remain relatively low, i.e., many attempt to quit, but sustained abstinence is remarkably difficult to achieve (4).
At a mechanistic level, nicotine addiction is strongly driven by reinforcement learning processes and habit formation within cortico-striatal brain circuitry, the central player integrating goal-directed behaviours. Different striatal regions mediate so-called bottom-up processes, such as reward expectation and the motor actions required to obtain that reward. On the other hand, cortical regions (broadly, in the frontal cortex) oversee top-down executive functions such as planning, emotional control, and the behavioural inhibition required to keep those bottom-up processes in check (5, 6). Repeated nicotine exposure strengthens associations between environmental cues and cigarette use, debilitating top-down processes and allowing bottom-up drives to dominate behavior, eventually leading to automatic, cue-triggered actions that resist conscious control. Eventually, smoking shifts from being primarily reward-driven to serving the avoidance of withdrawal and the maintenance of those entrenched routines, becoming a behaviour no longer under the control of top-down processes, but mediated by these (7, 8).
Current first-line treatments typically combine pharmacological and behavioural approaches. Nicotine replacement therapy (NRT), for example, aims to reduce withdrawal symptoms by delivering controlled doses of nicotine without the harmful byproducts of smoking. However, while studies have demonstrated that NRT improves quit rates compared to placebo, effect sizes remain limited, relapse is common, and adherence is very modest (7). Cognitive behavioural therapy (CBT) targets the psychological components of addiction by helping individuals identify triggers, develop coping strategies, and restructure maladaptive thought patterns (8). While effective for some, CBT often requires sustained effort and engagement, and its impact can be constrained by the very cognitive rigidity that characterizes addiction.
HOW PSYCHEDELICS MAY ACT ON ADDICTION
The rationale for treating SUDs with psychedelic compounds builds on decades of research, as these substances represented a very promising avenue for the treatment of alcohol and opioid use disorders from the 1950s through 1970s (9, 10), although varying degrees of rigor and regulatory restrictions put these efforts and their success rates to sleep for the following four decades (11).
More recently, already as part of the “Psychedelic Renaissance”, theoretical work by Michael Bogenschutz and Matthew Johnson proposed that classic psychedelics could address addiction by inducing profound psychological experiences that promote emotional insights and behavioural changes (12), while others have argued specifically for the use of psilocybin in tobacco cessation due to its capacity to occasion experiences that may catalyse shifts in motivation and long-term priorities, allowing the possibility of sustained abstinence (13, 14).
A more neuropsychopharmacological perspective that could provide a mechanistic account for why classic psychedelics might represent a promising avenue for the treatment of tobacco addiction is the argument that they increase neural plasticity and cognitive flexibility by transiently destabilizing high-level predictive models in the brain (15). Remember those once protective top-down cognitive processes that were now maladaptively mediating the smoking habits? According to this model, classic psychedelics would reduce the influence of that hierarchical constraint by relaxing those higher-level, top-down “priors”.
Functionally, the effect is a reduction in the confidence with which the latter are encoded, therefore rendering them more responsive to new incoming bottom-up information, which, in the right setting and with appropriate support, can enable the restructuring of maladaptive beliefs (15). Now, translated to the broader context of addiction, this may allow individuals to break out of rigid behavioural loops and reevaluate deeply established habits, which could play a critical role in motivating change and, ultimately, prolonged abstinence (12, 13).
Lastly, naturalistic and survey-based studies have further suggested that psychedelic use is associated with lasting reductions in substance misuse across multiple drug classes (16). While such findings are limited by the often discussed issues of self-selection and lack of control conditions, they provide converging evidence that psychedelics may influence addiction-related behaviours in ways that extend beyond acute pharmacological effects.
FROM THEORY TO TRIAL: PSILOCYBIN VS NICOTINE PATCHES
This randomized clinical trial, Psilocybin or Nicotine Patch for Smoking Cessation: A Pilot Randomized Clinical Trial (3) represents one of the most rigorous tests to date of this therapeutic model, comparing psilocybin-assisted therapy with standard NRT (transdermal patches) in 70 adult participants diagnosed with nicotine dependence who were motivated to quit smoking.
Participants allocated to the experimental group received a high psilocybin dose (30mg/70kg, comparable to 3 to 5 grams of dried psilocybin mushrooms) in a controlled therapeutic context, involving one or more dosing sessions in a supervised environment, with preparatory and integration sessions designed to support the psychological process surrounding the experience (the critical relevance of set and setting is also addressed in our previous number).
Importantly, both treatments were administered alongside structured behavioural support in the form of CBT, ensuring that the groups received comparable behavioural support to better isolate the treatment effects. The primary outcome was smoking biologically verified abstinence at several follow-up points, using different biomarkers to ensure objective confirmation of self-reported abstinence. Secondary outcomes included measures of smoking reduction, craving, and other behavioural and psychological variables.
The observations are nothing short of striking. At the six-month follow-up, 40% in the psilocybin group achieved sustained abstinence, compared to roughly 10% in the nicotine patch group, suggesting that psilocybin-assisted therapy significantly outperforms a standard treatment under controlled conditions.
THE MILLION-DOLLAR QUESTION… AND A BIT OF HISTORY
These results support the theoretical framework we outlined earlier. Combining pharmacological interventions with psychological support, psilocybin seems capable of producing clinically meaningful changes in behaviour that extend well beyond the acute treatment window.
To investigate the neurobiological mechanisms underlying these effects, a subsample of participants underwent functional magnetic resonance imaging (fMRI) before and after treatment. However, these results, along with those from the 12-month follow-up, will be shared separately in a future publication. We shall patiently await those, but, in the meantime, one key question we can ask ourselves concerns the relative contribution of pharmacological versus experiential factors.
Unlike NRT, which primarily acts on nicotinic acetylcholine receptors to reduce withdrawal, psilocybin engages both neurobiological and psychological processes simultaneously. This raises, yet again, the eternally returning million-dollar question in the field: can the therapeutic effects of psychedelics be separated from the subjective experience? While the present study does not directly answer this question, its design implicitly compares a treatment that includes a profound subjective experience with one that does not, and its results support a model in which experience is not merely an epiphenomenon.
In that regard, it is important to note that the current trial does not emerge in isolation but rather stems from a couple of influential studies conducted over the past decade. The first investigation of psilocybin for smoking cessation was conducted by a very similar team in 2014 (17). At the time, it was one of the first modern studies on classic psychedelics for any clinical indication and played a pivotal role in bringing back psychedelic research into the domain of addiction. This small, open-label pilot study reported remarkably high biologically verified abstinence rates among participants receiving psilocybin-assisted CBT, with 80%, 67%, and 60% remaining abstinent at 6, 12, and 30 months after the target quit date (17, 18). Most relevant to our case, however, is that while the 2014 pilot study did not include any brain imaging, it did include many questionnaires that the 2026 study did not… These included the Fagerström Test for Cigarette Dependence, Questionnaire on Smoking Urges, Visual Effects Questionnaire, Mystical Experiences Questionnaire, States of Consciousness Questionnaire, and a tuned-up version of the “Persisting Effects Questionnaire”. An excerpt of those results is included in the table below.
| Subscale / Item | Mean (SEM) Session 1 | Mean (SEM) Session 2 | Mean (SEM) Session 3 |
| How personally meaningful was the experience? (1–8) | 5.4 (0.5) | 6.3 (0.2) | 6.3 (0.3) |
| How spiritually significant was the experience? (1–6) | 3.4 (0.4) | 4.2 (0.2) | 4.4 (0.4) |
| Did the experience change your sense of well-being or life satisfaction? (−3 to +3) | 1.4 (0.5) | 2.5 (0.2) | 2.7 (0.3) |
As part of their pilot study, Johnson et al. (2014) included three extra questions at the end of the Persisting Effects Questionnaire. Thirteen participants (87%) rated at least one psilocybin session among the 10 most meaningful experiences of their lives, 73% rated at least one psilocybin session among the 5 most spiritually significant experiences of their lives, and 87% reported that their life satisfaction had increased as a result of at least one psilocybin session (17).
The observations regarding the long-term durability were particularly notable given the nature of nicotine use disorder, motivating subsequent qualitative research that explored those subjective experiences in detail, highlighting themes of increased self-awareness, emotional catharsis, and a re-evaluation of life priorities following psilocybin sessions (14). Furthermore, when participants were asked to evaluate the mechanisms by which they believed psilocybin had facilitated smoking cessation, 6.7% declared that “sessions did not help me quit or stay quit”. In contrast, 67.7% endorsed “changing priorities in life, so that reasons to quit outweighed reasons to smoke”, 73.3% “changing the way you orient yourself concerning the future”, and 73.3% “strengthening your belief that you have the ability to quit and stay quit” (17).
These accounts consistently highlight the importance of meaning-making, emotional processing, and shifts in identity, factors that are difficult to capture through quantitative measures alone but may be central to mechanisms and therapeutic outcomes.
IMPLICATIONS FOR TREATMENT AND RESEARCH
By directly comparing psilocybin-assisted therapy with a standard treatment, this trial provides some of the strongest evidence to date that psychedelics may offer a viable alternative for smoking cessation, particularly for individuals who have not responded to existing approaches.
The implications for psychedelic medicine are broad, to say the least. In a moment when the pharmacology-driven models are gaining ground in psychedelic therapy, unavoidably at the expense of approaches emphasizing preparation, therapeutic support, and integration (19), these studies highlight the critical relevance of combining substance with structured psychological care (20). And, at the same time, implicitly remind readers of the difficulty of reconciling these resource-intensive models with the practical demands of standardization, scalability, and affordability (21).
As the field moves forward, enhancing conceptual clarity will be paramount to keep clinical innovation grounded in a nuanced, balanced, and respectful understanding of the complex biopsychosocial frameworks in which therapeutic mechanisms and the psychedelic experience coexist (22, 23).
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AUTHOR
Sergio is a PhD student with a passion for understanding how psychedelics reshape the brain.
His academic journey began with a degree in Biotechnology from the Universidad Politécnica de Madrid. He then completed a traineeship in regenerative neuroscience at the GlowLab at the University of Zagreb. Following this, he pursued a Research Master’s in Cognitive and Clinical Neuroscience at Maastricht University in the Netherlands, where his fascination with the neurobiology of psychedelics developed.
Sergio was awarded the atai Fellowship for the Neuroscience of Psychedelics, which allowed him to join the Center for the Neuroscience of Psychedelics (CNP) at Massachusetts General Hospital, Harvard Medical School.
As a PhD student at the CNP, he specializes in fundamental research to investigate how natural and synthetic psychedelics, along with other neuroplasticity modulators, can drive structural and functional changes in the brain.
