Trial PaperTobacco/Nicotine Use Disorder (TUD)Substance Use Disorders (SUD)Safety & Risk ManagementPublic Health, Prevention & Behaviour ChangePsilocybin

Long-term follow-up of psilocybin-facilitated smoking cessation

This follow-up study (n=15) found that at 12 months 67% of participants didn't return to smoking (biologically confirmed). This was 60% at an average of 30-month follow-up. This study is the first (very positive) step in seeing if psilocybin-assisted psychotherapy (PAT) may be viable for people to quit smoking.

Authors

  • Albert Garcia-Romeu
  • Roland Griffiths
  • Matthew Johnson

Published

The American Journal of Drug and Alcohol Abuse
individual Study

Abstract

Background

A recent open-label pilot study (N = 15) found that two to three moderate to high doses (20 and 30 mg/70 kg) of the serotonin 2A receptor agonist, psilocybin, in combination with cognitive behavioral therapy (CBT) for smoking cessation, resulted in substantially higher 6-month smoking abstinence rates than are typically observed with other medications or CBT alone.

Objectives

To assess long-term effects of a psilocybin-facilitated smoking cessation program at ≥12 months after psilocybin administration.

Methods

The present report describes biologically verified smoking abstinence outcomes of the previous pilot study at ≥12 months, and related data on subjective effects of psilocybin.

Results

All 15 participants completed a 12-month follow-up, and 12 (80%) returned for a long-term (≥16 months) follow-up, with a mean interval of 30 months (range = 16-57 months) between target-quit date (i.e., first psilocybin session) and long-term follow-up. At 12-month follow-up, 10 participants (67%) were confirmed as smoking abstinent. At long-term follow-up, nine participants (60%) were confirmed as smoking abstinent. At 12-month follow-up 13 participants (86.7%) rated their psilocybin experiences among the five most personally meaningful and spiritually significant experiences of their lives.

Conclusion

These results suggest that in the context of a structured treatment program, psilocybin holds considerable promise in promoting long-term smoking abstinence. The present study adds to recent and historical evidence suggesting high success rates when using classic psychedelics in the treatment of addiction. Further research investigating psilocybin-facilitated treatment of substance use disorders is warranted.

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Research Summary of 'Long-term follow-up of psilocybin-facilitated smoking cessation'

Editorial

βBlossom's Take

This follow-up matters because it tests whether the striking early smoking-cessation signal held up after the acute novelty had passed. The abstinence rates remained high over many months, but the open-label design and self-selected sample mean the paper is best read as a strong feasibility signal for psilocybin-assisted smoking treatment, not as settled efficacy.

Introduction

Smoking remains a major global public health problem, causing millions of deaths annually and projected to increase in coming years. Existing smoking cessation treatments typically fail to produce long-term abstinence for most people, creating a need to explore novel approaches. Earlier work by the investigators described an open-label pilot that combined psilocybin, a 5-HT2AR agonist, with cognitive behavioural therapy (CBT) and reported an unusually high biologically verified 6-month abstinence rate (80%) in 15 participants, together with an acceptable acute safety profile. This paper reports previously unpublished long-term follow-up data from that pilot trial. Johnson and colleagues set out to assess smoking cessation outcomes at 12 months and at a later long-term follow-up (mean 30 months post-target-quit date), and to describe persisting subjective effects attributed to the psilocybin sessions. The aim was to evaluate the durability of abstinence and to explore relationships between session-related subjective experiences and smoking outcomes over the longer term.

Methods

The study was an open-label pilot conducted at Johns Hopkins, approved by the institutional review board; all participants provided informed consent. The analytic sample comprised 15 adult smokers (10 male), mean age 51 years, who reported a mean of 19 cigarettes per day for about 31 years and an average of six prior quit attempts. Individuals with histories of severe mental illness were excluded. Participants completed a 15-week combined treatment that began with four weekly preparatory meetings integrating cognitive behavioural therapy, elements of mindfulness training, and guided imagery. Psilocybin dosing was scheduled with a moderate dose (20 mg/70 kg) in week 5 serving as the target-quit date (TQD), followed by a high dose (30 mg/70 kg) approximately two weeks later. An optional third high-dose session was available in week 13. For 10 weeks after the TQD participants provided weekly breath and urine samples, completed questionnaires, and met with staff; follow-ups were conducted at 6 and 12 months, and a retrospective interview was offered at a mean of 30 months post-TQD. Smoking status was assessed using biomarkers and self-report. Breath carbon monoxide (CO) was measured with a Bedfont Micro+ Smokerlyzer and urine cotinine was analysed by an independent laboratory; self-reported daily cigarette consumption was captured continuously via the Timeline Follow-Back (TLFB) method. Participants completed a 143-item Persisting Effects Questionnaire one week after each psilocybin session and a retrospective version at 12 months to measure sustained changes in attitudes, mood, behaviour, relationships and spirituality. Acute mystical-type experiences were measured with the validated 30-item MEQ30 approximately seven hours after each psilocybin session. Analyses defined abstinence as CO ≤6 ppm, urinary cotinine <200 ng/mL, and no self-reported smoking in the prior seven days. Missing long-term data for three non-attenders were imputed from their 12-month values; non-attendance otherwise counted as smoking. Repeated measures ANOVA tested TLFB changes across time points; planned paired t-tests compared intake with end of treatment, 6-month, 12-month, and long-term follow-ups. Pearson correlations examined associations between mean MEQ30 and personal meaning/spiritual significance scores and long-term change scores on CO, cotinine, and TLFB. Normality of datasets for correlational analyses was assessed using Dallal-Wilkinson-Lilliefor corrected Kolmogorov–Smirnov tests.

Results

All 15 participants completed the 12-month follow-up; 12 participants (80%) returned for the long-term follow-up (mean interval 30 months, range 16–57 months). At 12 months, 10 of 15 participants (67%) were biologically confirmed abstinent, and 8 of those 10 reported continuous abstinence since the TQD. At the long-term follow-up, 9 of 15 participants (60%) were biologically confirmed abstinent, with 7 reporting continuous abstinence since the TQD. The three participants who did not attend the long-term visit had been confirmed daily smokers at 12 months and their 12-month biomarker and TLFB data were used for long-term imputation. Repeated measures ANOVA indicated a significant change in self-reported smoking on the TLFB across intake and subsequent follow-ups (end of treatment, 6 months, 12 months, long-term), although exact test statistics are not fully reported in the extracted text. Persisting Effects Questionnaire data showed substantially higher ratings of positive versus negative persisting effects across six domains (attitudes about life, attitudes about self, mood, relationships, behavioural changes, spirituality). Average negative-effect scores ranged from 3.2% to 8.1% of the maximum possible score, whereas average positive-effect scores ranged from 53% to 64% of maximum. At 12 months, 13 of 15 participants (86.7%) rated their psilocybin experiences among the five most personally meaningful experiences of their lives, and 13 (86.7%) rated them among the five most spiritually significant experiences. No participants reported increased bothersome visual disturbances at 12 months relative to baseline, and no spontaneous reports of clinically significant psychological sequelae were recorded at long-term follow-up. Acute safety findings from the earlier report were reiterated: physiological adverse effects were limited to mild post-session headache and modest transient elevations in blood pressure and heart rate. Six participants (40%) reported challenging acute session experiences; these resolved during the session day with staff support. Two participants sought outside counselling after sessions—one because of re-experiencing traumatic childhood memories who later reported benefit from additional counselling, and one for personal growth. Correlational analyses found that reductions in urinary cotinine from intake to long-term follow-up were significantly associated with mean ratings of personal meaning assessed one week after each session (r = -0.55, p = 0.04) and with mean MEQ30 scores from the end of each session day (r = -0.55, p = 0.03). The seven other correlations between psilocybin session attributes and smoking-related change scores did not reach significance (p range 0.10–0.36) but were directionally consistent with moderate effect sizes (r range -0.25 to -0.44).

Discussion

Johnson and colleagues interpret the long-term findings as indicating that psilocybin may be a feasible adjunct to smoking cessation treatment when combined with a structured therapeutic programme. They note that the observed 60% biologically verified abstinence at more than one year compares favourably to typical abstinence rates for the most effective smoking cessation medications, which often fall below 31% at 12 months. At the same time, the investigators acknowledge important limitations that constrain causal inference: the small sample size, open-label design, absence of a control condition, and potential participant self-selection bias since volunteers were motivated to quit and willing to undertake a time-intensive, uncompensated experimental intervention. These limitations, they state, preclude definitive conclusions about efficacy and may contribute to type II errors in some correlational analyses. To address these issues, the paper notes an ongoing randomized comparative efficacy trial (ClinicalTrials.gov Identifier NCT01943994) that is comparing a single high dose of psilocybin with a standard nicotine replacement therapy course, with both arms receiving the same CBT intervention. The authors discuss the possibility that lasting psychological and behavioural shifts following psilocybin may relate to salient acute subjective effects—often described as mystical or transcendent—and that such experiences were associated, in this sample, with greater reductions in cotinine. They also observe that participants frequently attributed spiritual significance to their sessions, raising questions about the role of spirituality in substance use treatment; previous literature linking spirituality and improved outcomes in addiction recovery is noted by the investigators to contextualise this finding. Finally, the discussion situates the results within historical and recent research suggesting potential therapeutic utility of classic psychedelics for various substance use disorders and advocates for further controlled research into psychedelic-facilitated treatments and underlying neurobiological mechanisms.

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METHODS

This study was approved by the Institutional Review Board of Johns Hopkins Medicine, and all participants provided informed consent. Participants were 15 smokers (10 males) without histories of severe mental illness, with a mean age of 51 years, who smoked on average 19 cigarettes per day (CPD) for a mean of 31 years at screening, with a mean of six previous quit attempts. Participants underwent a 15-week combination treatment consisting of four weekly preparatory meetings integrating CBT, elements of mindfulness training, and guided imagery for smoking cessation. Participants received a moderate (20 mg/70 kg) dose of psilocybin in week 5 of treatment, which served as the target-quit date (TQD), and a high dose of psilocybin (30 mg/70 kg) approximately 2 weeks later. Participants had the opportunity to participate in a third, optional high-dose psilocybin session in week 13 of study treatment. For 10 weeks following the TQD, participants returned to the laboratory to provide breath and urine samples to test for recent smoking, complete self-report questionnaires, and meet with study staff. Participants returned for follow-up meetings at 6 and 12 months post-TQD, and were later invited back for a retrospective interview probing potential mechanisms of the study treatment at a mean of 30 months post-TQD. For a detailed description of the study sample and intervention see. The current report presents previously unpublished data regarding smoking cessation outcomes at the 12-month and long-term follow-ups.

RESULTS

Participants were judged abstinent if breath CO value was ≤6 ppm, urinary cotinine was <200 ng/mL, and if no smoking was reported on the TLFB for the previous 7 days. Urine samples testing negative for recent smoking were scored as 0 ng/mL for all analyses, as laboratory results did not provide specific values for negative (<200 ng/mL) samples. Participants who did not report to a follow-up visit were considered to have smoked. The three participants who did not complete a long-term follow-up (which occurred at a mean of 30 months post-TQD for those who completed) had been confirmed as daily smokers at the 12-month follow-up. Thus, for these three individuals, carbon monoxide, urine cotinine, and TLFB self-reported daily smoking data for the long-term follow-up were imputed using their individual 12-month follow-up values. Repeated measures ANOVA tested for changes in TLFB self-reported smoking from study intake to longterm follow-up. Planned comparison two-tailed paired t-tests were used to compare TLFB data between study intake and each of the following time points: end of treatment (10 weeks post-TQD), and 6-month, 12-month, and long-term follow-ups. Descriptive statistics were calculated using Persisting Effects Questionnaire data to assess long-term positive and negative changes, personal meaning, and spiritual significance attributed to psilocybin session experiences one week after each session, and at 12-months post-TQD. To examine the hypothesis that greater mystical-type effects and more positive attributions regarding psilocybin sessions would be associated with greater smoking cessation success, Pearson's correlations were calculated between psilocybin session ratings (i.e., individuals' mean MEQ30 score across psilocybin sessions from the end of each session day, and individuals' mean ratings of personal meaning and spiritual significance across psilocybin sessions from one week after each session) and longterm change scores on each smoking-related measure (i.e., breath CO, cotinine, TLFB). Change scores were calculated as each participant's score at study intake subtracted from that participant's score at long-term follow-up. For the TLFB this was calculated as mean CPD in the 30 days preceding study intake, subtracted from mean CPD from TQD to long-term follow-up. All datasets examined via correlational analyses were normally distributed as determined by Dallal-Wilkinson-Lilliefor corrected Kolmogorov-Smirnov tests at an alpha level of 0.05.

CONCLUSION

These results, together with previously reported findings, indicate that psilocybin may be a feasible adjunct to smoking cessation treatment. In controlled studies, the most effective smoking cessation medications typically demonstrate less than 31% abstinence at 12 months post-treatment, whereas the present study found 60% abstinence more than a year after psilocybin administration. However, the current findings are limited by the small sample, open-label design, and lack of control condition, which preclude making definitive conclusions about efficacy. Furthermore, participant self-selection bias may have played a role in observed success rates, as the study enrolled only individuals motivated to quit and willing to undergo a time-intensive experimental treatment for no monetary compensation. Additional, carefully controlled research in larger, more diverse samples is necessary to determine efficacy. Toward this end, the authors are currently conducting a randomized comparative efficacy trial in a larger study sample (ClinicalTrials.gov Identifier NCT01943994). This study is evaluating smoking cessation outcomes between individuals receiving a single high dose (30 mg/70 kg) of psilocybin vs. a standard 8-to 10-week course of nicotine replacement therapy (i.e., patch), with both groups receiving the same cognitive behavioral smoking cessation intervention. Nevertheless, the present results suggest persisting effects of psilocybin-facilitated treatment well beyond the time course of acute drug action. Consistent with previous findings, results indicated greater mysticaltype effects and more positive attributions regarding psilocybin sessions were associated with greater smoking cessation success. The only significant correlations were between cotinine reductions and mystical-type psilocybin effects, and between cotinine reductions and ratings of session personal meaning. However, all other correlations between subjective effects of psilocybin and change in smoking-related measures were in the predicted direction with a moderate effect size. Therefore, the failure of these other correlations to reach significance might constitute a type II error related to small sample size. While the intervention used in this study was not explicitly "spiritual" in nature, participants consistently attributed a high degree of spiritual significance to their psilocybin session experiences, raising questions about the role of spirituality in smoking cessation. Several studies suggest that increased levels of spirituality are associated with improved treatment outcomes in substance dependence recovery, and pilot survey data indicate that 78% of smokers reported that spiritual resources would be helpful in quitting smoking. The lasting psychological and behavioral shifts observed following psychedelic administration may be mediated in part by the salient, often subjectively positive acute effects of 5-HT2AR agonists, which have sometimes been characterized as mystical or transcendent. Combined with historical data suggesting high success rates of psychedelic-facilitated treatment of alcoholism approximately doubling the odds of success at initial follow-up, and promising recent pilot data on psilocybin-facilitated treatment of alcohol dependence, the present findings indicate that 5-HT2AR agonists may hold therapeutic potential in treating a variety of substance use disorders in the context of a structured treatment program. Considering the often chronic and intractable nature of addictive disorders, further investigation of psychedelic-facilitated treatment of addiction and underlying neurobiological mechanisms represent important future directions for research.

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