Tobacco/Nicotine Use Disorder (TUD)

This report summarises what Blossom’s database shows about psychedelic and dissociative compounds for tobacco use disorder, and what it does not show. The short version: this is a small evidence base with one genuinely interesting thread. Psilocybin, not ayahuasca or ibogaine, is the lead, on the strength of a famous Johns Hopkins pilot and, newly in 2026, the first controlled trial showing it beating the nicotine patch. The result is real and encouraging, but it rests on tiny, single-site, hard-to-blind studies, and the controlled abstinence figure is far below the headline pilot number.

A note before the evidence

This page is a research summary, not medical advice, and nothing here is a treatment recommendation. Psilocybin is not approved for smoking cessation anywhere; it is investigational and studied only in clinical trials with screening and psychological support. If you want to stop smoking, effective, approved help, including nicotine replacement, varenicline or bupropion and behavioural support, is available now and is the right place to start. Decisions about quitting belong with you and a clinician, not with an unregulated psychedelic.

This page sits within Blossom’s Substance Use Disorders hub and is scoped to tobacco specifically. A word on the numbers: Blossom tracks 64 papers and 5 trials tagged to this topic, and those counts appear on the page. The tag is leaky, pulling in general-addiction reviews, alcohol and opioid studies, population surveys and preclinical pharmacology, so the genuinely tobacco-specific clinical core is very small, on the order of five human studies, most of them a single Johns Hopkins lineage. Read the counts as breadth of coverage, not as the depth of the tobacco evidence.

Psilocybin: a striking pilot, and now a controlled test

The reason tobacco is interesting at all is one line of work. A Johns Hopkins open-label pilot gave 15 long-term heavy smokers two to three supervised psilocybin doses inside a 15-week cognitive behavioural programme, and 80% (12 of 15) were biologically confirmed abstinent at six months[1]J. Psychopharmacology, Johnson pilot (2014), a figure far above the under-35% typically seen with standard treatments. A long-term follow-up found 67% abstinent at one year and 60% at roughly 30 months[2]Am. J. Drug & Alcohol Abuse, long-term follow-up (2017), and a mediation analysis found that those who quit had stronger mystical-type experiences, independent of the raw intensity of the drug effect[3]Current Drug Abuse Reviews, mystical mediation (2015).

For years the obvious objection was that this was an uncontrolled, open-label pilot of fifteen self-selected people. In March 2026 the controlled test arrived. A pilot randomised trial (n=82) compared a single high psilocybin dose plus therapy against nicotine patch plus the same therapy, and found psilocybin clearly superior on biochemically verified prolonged abstinence at six months: 40.5% versus 10%, an odds ratio of 6.12[4]JAMA Network Open, pilot RCT (2026). That is a real, controlled win over an active standard treatment, which very few things in addiction psychiatry achieve.

Two things keep it honest. First, the 40.5% is roughly half the pilot’s 80%, a textbook illustration of how an open-label headline shrinks under control conditions. Second, the trial was openly unblinded, with an optional crossover, at a single centre, in psychiatrically healthy volunteers, wrapped in an intensive thirteen-week therapy programme. So the result genuinely strengthens the case, and it does not settle it: the central question of how much is the drug, how much is expectancy, and how much is the therapy remains open.

Ketamine and esketamine: little so far

Ketamine has been tried and has mostly disappointed for tobacco. A small double-blind, midazolam-controlled crossover pilot (n=18) in smokers who were not trying to quit found only a non-significant reduction in cigarettes (p=0.10) and no effect on craving or withdrawal[5]Brain Sciences, ketamine TUD pilot (2026). The one positive signal in the ketamine family comes from a very different population: an esketamine trial in 236 people with both lung cancer and major depression found higher confirmed abstinence than placebo[6]J. Affective Disorders, esketamine (2025), but there the smoking benefit is bound up with treating depression and does not generalise to ordinary smokers. For general tobacco use disorder, ketamine has not shown a clear effect.

Ayahuasca and ibogaine: observational only

Ayahuasca and ibogaine are frequently mentioned for tobacco, and this is where the existing framing has been most misleading. There are no tobacco-cessation trials for either. The ayahuasca evidence is survey data: an online survey associating stronger mystical experiences with quitting[7]Psychopharmacology, ayahuasca survey (2022) and a comparison finding lower tobacco and alcohol use disorder among members of an ayahuasca-using religious group[8]Frontiers in Psychiatry, ayahuasca cohort (2018). Both are retrospective, self-selected and unverified, useful for generating hypotheses, not for showing effect. Ibogaine has no tobacco-cessation data at all and appears here only in preclinical and cardiac-safety work.

It is worth stating plainly because it corrects a common inversion: for tobacco, psilocybin is the lead with real trials, and ayahuasca and ibogaine sit well below it on observational evidence. A wider correlational picture is mixed rather than uniformly positive, with a large national survey linking some psychedelics to lower nicotine dependence but LSD to higher[9]J. Psychopharmacology, naturalistic survey (2017), which is a reminder that population associations are not treatment effects.

How might it work?

The proposed mechanisms are plausible and still hypotheses. Psilocybin acts on the brain’s 5-HT2A serotonin receptors and appears to open a window of heightened neuroplasticity that, paired with quit-smoking therapy, may help break the automatic link between cue, craving and cigarette. The most consistent tobacco-specific finding is psychological rather than purely pharmacological: across the pilot and the surveys, the depth and meaning of the experience, the mystical-type shift in priorities and self-efficacy, predicts who quits, more than the raw intensity of the drug. That is why the therapy around the dose is treated as part of the treatment, and it is also why blinding is so hard, since a profound subjective experience is exactly what the participant notices.

Reading this honestly

So where does tobacco use disorder sit? On a very small base, it is one of the more encouraging stories in psychedelic medicine, and the only addiction indication besides alcohol with a controlled win to point to. Psilocybin produced a remarkable open-label result and then, unusually, beat an active standard treatment in a randomised trial. But the whole edifice rests on one academic centre, a few dozen patients, an unblinded design and a controlled abstinence rate well below the famous headline. The honest reading refuses both the breathless version, that psilocybin cures smoking, and the dismissive one, that a striking and now partly replicated result is nothing. For the many smokers failed by current treatments, a promising, real, but still unproven option is a reason for measured hope and for the larger trials that would turn a single centre’s encouraging numbers into something the field can rely on.