Psychedelics as a potential treatment for tobacco use disorder: a systematic review

Abstract

Introduction

Despite considerable efforts, tobacco use disorder persists as a significant public health issue. The effectiveness of current smoking cessation therapies is limited, leading to a growing interest in alternative treatment approaches such as psychedelics.

Aim

The aim of this review is to evaluate the scientific evidence regarding the role of psychedelics in smoking cessation.

Methods

To identify relevant literature on psychedelics and smoking cessation, a search was conducted in four academic literature databases PubMed, MEDLINE, PsycINFO, and Embase. Databases were searched from their inception up to March 24, 2024.

Results

Out of the 1073 articles identified in databases, 8 publications (both clinical and non-clinical studies) met the inclusion criteria, of which a total of 4 publications originated from a single study. The majority of the studies focused on psilocybin (n = 7), for which supportive evidence was suggested for the treatment of tobacco use disorder. Additionally, research was conducted with other psychedelics for smoking cessation, such as ayahuasca, mescaline, peyote, lysergic acid diethylamide (LSD), lysergic acid amide (LSA) and (dimethyltryptamine (DMT), but the evidence base for these psychedelics is too small to draw definitive conclusions.

Conclusions

There is, although limited, evidence that psychedelics, in particular psilocybin, may offer a potential avenue for combating tobacco use disorder, though more research is needed to understand their effectiveness and safety fully.

Introduction

The tobacco epidemic is one of the largest public health problems worldwide, claiming the lives of more than 8 million individuals annually, with approximately 1.2 million deaths attributed to second-hand smoke [1]. Despite extensive efforts to combat it, the abstinence rates of currently available smoking cessation therapies, including pharmacological or cognitive-behavior approaches, are modest, with less than a quarter of smokers remaining abstinent one year after treatment [2].

Existing smoking cessation therapies encompass self-help programs, counseling, cognitive behavior therapy, and pharmacotherapy. Among the pharmacotherapy options approved for treating tobacco use disorder are nicotine replacement products (i.e., patches, gum, spray, inhaler, and lozenges), the noradrenergic/dopamine reuptake-inhibitor bupropion (Zyban^®), and the selective nicotine α4β2 receptor agonist varenicline (Chantix^®) [3]. However, the efficacy of these pharmacological approaches is limited, with abstinence rates ranging from 16–22% at 6-month follow-up, highlighting the necessity for alternative pharmacological treatment interventions [4, 5].

In recent years, there has been growing evidence that psychedelics can be effective in the treatment of addiction, leading to increasing interest in their potential as pharmacological treatment for tobacco use disorder [6, 7].

The current prevailing theory suggests that psychedelics induce hallucinogenic experiences by reducing or suppressing the activity of the 5-HT2A receptor through the binding of an agonist [8]. The strong correlation between the psychedelic effects of psilocybin and the occupancy of the 5-HT2A receptor in the central nervous system provides evidence supporting this relationship [3, 9]. Classic psychedelics, such as LSD, mescaline, and DMT that induce hallucinations and alternated states of consciousness, preferentially target serotonin receptors in the brain, particularly the 5-HT2A receptors, while also downregulating them. These receptors are widespread in various brain regions involved in reward processing, emotional regulation, and cognitive functions [10]. Non-classic psychedelics, such as ketamine (N-methyl-D-aspartate (NMDA) receptor antagonist), and ibogaine (indole alkaloid), may produce similar effects as classic psychedelics through different neurochemical pathways [11].

Psychedelics induce neuroplasticity changes, supporting their clinical effects by triggering molecular, neuronal, synaptic, and dendritic transformations, leading to enhanced connectivity between brain regions [12]. Single or repeated psychedelic use can stimulate neurogenesis and elevate brain-derived neurotrophic factor levels in the brain (BDNF) [12]. It has been observed that individuals with addiction may have diminished levels of BDNF, which could contribute to disrupted neuroplasticity and potentially influence learning, memory, and changes in adaptive behaviour related to addiction [13]. The reasons why certain 5-HT2A agonists promote neuroplasticity while others do possibly not, are poorly understood [14].

One hypothesis proposes that psychedelic substances may affect addictive behavior through involvement in the mesolimbic pathway, associated with reward [15, 16]. Addictive substances cause changes in mesolimbic activity related to cravings, compulsive use, and depression after withdrawal [16, 17]. Psychedelics induce long-lasting neuroplastic changes in the mesolimbic reward circuit, moderating motivation for non-drug stimuli and compulsive cravings during substance use [16]. Additionally, negative emotions and self-referential thinking, associated with higher activities in the default mode network of the brain are thought to be implicated in substance use disorders [18]. Psychedelics may interfere with activities involving the default mode network, by temporarily disrupting this network and leading to a sort of reset [19]. This hypothesis is supported by the high densities of the 5-HT2A receptor in these neural networks’ nodes [16].

Another hypothesis is that the effects of psychedelics are based on mystical experiences. Although alternative definitions exist, mystical experiences are those peculiar states of consciousness in which the individual discovers himself to be one continuous process with God, with the Universe, with the Ground of Being, or whatever name he may use by cultural conditioning or personal preference for the ultimate and eternal reality [20].

Studies indicate that mystical experiences while using psychedelics as therapy may be predictive of desired outcomes, such as improved mood, reduced anxiety, and belief shifts [21]. These changes may be associated with decreased cravings and increased self-efficacy to reduce drug use [16, 22]. Factors like individual pharmacological actions, context and setting, motivations, overall mental state openness, and therapy integration impact subjective experiences [23, 24]. Although some researchers believe that psychedelic experiences while using psychedelics predict therapeutic effects in managing addiction, others tend to regard these experiences just as an unnecessary side-effect [23, 25–27]. The debate on whether mystical experiences are necessary for therapeutic effects persists.

This systematic review aims to synthesize existing scientific literature on the potential use of psychedelics as a therapeutic intervention for smoking cessation. Both clinical and non-clinical studies were included in the review.

Methods

Systematic search

This systematic review was conducted following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines (Moher et al. [28]). We developed the following search string to systematically identify all relevant studies on classic and non-classic psychedelics and smoking cessation: (“cessation” OR “quit” OR “quitting” OR “stop” OR “stopping” OR “giving up”) AND (“cigarette” OR “cigarette*” OR “nicotine” OR “smoking” OR “tobacco” OR “cigar” OR “cigar*”) AND (“psychedelic” OR “psychedelics” OR “psilocybin” OR “psilocybine” OR “indocybin” OR “hallucinogens” OR “serotonergic hallucinogens” OR “microdose” OR “microdosing” OR “microdoses” OR “ayahuasca” OR “hoasca” OR “mescaline” OR “dimethyltryptamine” OR “DMT” OR “peyote” OR “ibogaine” OR “lysergic acid diethylamide” OR “LSD” OR “MDMA” OR “midomafetamine” OR “ecstasy” OR "methamphetamine” OR “methylenedioxymethamphetamine” OR “ketamine” OR “ibogaine” OR “noribogaine”). The search was conducted in four scientific literature databases: PubMed, MEDLINE, PsycINFO, and Embase. A total of 1073 records remained after removing duplicates. Databases were searched from inception until March 24, 2024. The study was not preregistered in an international prospective register of systematic review protocols.

Eligibility criteria & study selection

Publications were included in the systematic review when the research: (1) focused on the relation between the use of classic or non-classic psychedelics and outcomes related to nicotine smoking (no other addictions), (2) utilized qualitative or quantitative empirical data (both clinical and non-clinical studies were included; case reports, systematic reviews, and case studies were excluded), (3) involved humans as participants, (4) was peer reviewed, and (5) was published in English. To identify all relevant literature, we applied no limitations on participant characteristics, methodology, study context or setting.

The titles and abstracts were scanned using ASReview [29]. This is machine learning-based software is designed to make the screening of large databases of literature in systematic reviews faster and more efficient. Throughout the screening process, the program presents the researcher with the record that has the highest probability of relevance based on the researcher’s previous decisions. With each decision, the model is updated, ranking the remaining entries by relevance and presenting the most relevant record based on the user’s previous decisions. A simulation study showed that ASReview found 95% of the eligible studies after screening between 8 and 33% of the total number of studies [29]. Based on existing guidelines, we screened titles and abstracts until 50 consecutive records were labeled irrelevant. After this point, the probability of finding relevant articles in the remaining literature database was very low. This point occurred after scanning 12.8% of all records.

Titles and abstracts were independently reviewed by two reviewers (S.K.S. and S.V.). After reaching a consensus on which studies were eligible, full-text articles were retrieved and assessed for relevance. In cases of uncertainty or disagreements, the inclusion of studies was discussed with a third assessor (H.K.). Reasons for exclusion were documented. Full text reviews and data extraction were carried out by two authors (S.K.S. and S.V.)

After screening records for relevance in ASReview, a total of 21 full texts were assessed for eligibility. In this stage, 13 publications were excluded for the following reasons: no focus on smoking or psychedelics (n = 7), and a wrong publication type (i.e. chapter of a book, duplicate, presentation or corrigendum) (n = 6). In total, 8 publications were included in the systematic review. The search procedures are depicted in the PRISMA flow chart as shown in Fig. 1.

Fig. 1.

PRISMA flow chart of study selection

Data extraction

We extracted the following data from the included studies: general study information (e.g. author, year of publication, country of study), characteristics of the study groups, intervention characteristics (if applicable), study design and methodology, type of psychedelic drug investigated, and the main findings. Due to the small size of the evidence base and the exploratory nature of this review, a formal risk of bias assessment was not conducted.

Results

Overview of the literature

The methodological approaches varied across the publications, including 3 open-label pilot studies, 2 retrospective cross-sectional (online) surveys, 1 retrospective cohort study, 1 retrospective cross-sectional (mixed-methods) study, and 1 qualitative (follow-up) study. A total of 4 publications were derived from one clinical study and its follow-ups [30]. Psilocybin was exclusively investigated in 4 out of the 8 publications, whereas only ayahuasca was examined in 1 out of the 8 publications. Additionally, 3 out of the 8 publications explored other psychedelics alongside psilocybin, such as peyote, mescaline, LSD, morning glory seeds, San Pedro cactus, and DMT. Among the 8 publications reviewed, psychedelic treatment was combined with cognitive-behavioral therapy in 4 publications (Johnson et al. 2014 and its follow-ups). Regarding the study populations, the majority of the studies had small sample sizes, ranging from 15 to 26,138 individuals. Most of the research, 6 out of 8 studies, was conducted in the United States. Additionally, one study each was conducted in Brazil and Europe (France). See Table 1 for the characteristics of the included studies.

Table 1.

Overview of included studies

Author, year	Country	Sample characteristics	Intervention	Study design	Psychedelic type	Main findings derived from study abstract
Daldegan-Bueno et al. 2022	Brazil	Online survey of 441 individuals who had quit or reduced smoking after ayahuasca experience (52.8% women, mean age: 34.2 years). 59.9% smoked more than ten cigarettes a day and 78.7% had one or more attempts to quit smoking. 44.6% of the sample had used ayahuasca more than 50 times	N/A	Retrospective cross-sectional mixed methods study	Ayahuasca	Of the 441 participants, 305 (69.2%) self-reported quitting smoking after the experience, 81 (18.3%) reported reducing smoking and 55 (12.5%) reported quitting for a period but returning afterwards (i.e. relapse). Most (88.7%) did not have the ayahuasca experience with the intention to quit smoking. Qualitative thematic analysis identified eight themes (e.g. acquired awareness, spiritual experience, increased motivation) related to the ayahuasca experience and the process of smoking cessation/reduction
Garcia-Romeu et al. 2014	United States	6-months follow-up of Johnson et al. 2014	See Johnson et al. 2014	Open-label pilot study, same participants as Johnson et al. 2014	Psilocybin	At the 6-month follow-up, abstainers (n = 12) scored significantly higher than participants still smoking (n = 3) on a measure of psilocybin-occasioned mystical experience. No significant differences in general intensity of drug effects were found between groups, suggesting that mystical-type subjective effects, rather than overall intensity of drug effects, were responsible for smoking cessation
Johnson et al. 2014	United States	15 mentally healthy smokers (10 men and 5 women) with a mean age of 51 years, mean lifetime quit attempts of 6, smoking a mean of 19 cigarettes per day for a mean of 31 years at intake, with 6-month follow-up measures	Participants underwent a 15-week smoking cessation treatment intervention, with moderate (20 mg/70 kg) and high (30 mg/70 kg) dose psilocybin sessions occurring in weeks 5, and 7 respectively, and an optional third high dose session in week 13. Participants had four weekly sessions for CBT-based smoking cessation and preparation for psilocybin treatment	Open-label pilot study	Psilocybin	12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up
Johnson et al. 2017a	United States	12-month and 30-month follow-up of Johnson et al. 2014	See Johnson et al. 2014	Clinical study: Open-label pilot study (follow-up). 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	Psilocybin	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 5 most personally meaningful and spiritually significant experiences of their lives
Johnson et al. 2017b	United States	358 individuals (52 females) who reported having quit or reduced smoking after ingesting a psychedelic in a non-laboratory setting > 1 year ago. On average, participants smoked 14 cigarettes/day for 8 years, and had 5 previous quit attempts before their psychedelic experience	N/A	Retrospective cross-sectional (online) survey	Psilocybin (“magic”) mushrooms, LSD, morning glory seeds, mescaline, peyote cactus, San Pedro cactus, dimethyltryptamine (DMT), and ayahuasca	Of the 358 participants, 38% reported continuous smoking cessation after psychedelic use (quitters). Among quitters, 74% reported > 2 years abstinence. Of the 358 participants, 28% reported a persisting reduction in smoking (reducers), from a mode of 300 cigarettes/month before, to a mode of 1 cigarette/month after the experience. Among reducers, 62% reported > 2 years of reduced smoking. Finally, 34% of the 358 participants (relapsers) reported temporary smoking reduction before returning to baseline smoking levels, with a mode time range to relapse of 3–6 months. Relapsers rated their psychedelic experience significantly lower in personal meaning and spiritual significance than both other groups. Changes in life priorities/values were endorsed as the most important psychological factor associated with smoking cessation/reduction
Jones et al. 2022	United States	Data are a sample from the National Survey on Drug Use and Health (2015–2019) of 214,505 individuals, of which 26,138 met criteria for past-month nicotine dependence	N/A	Retrospective study	Psilocybin (tryptamine), peyote (phenethylamine), mescaline, LSD (lysergamide)	Lifetime psilocybin use was associated with reduced odds of current nicotine dependence. Lifetime use of peyote and mescaline also conferred reduced odds of multiple subdomains of a main nicotine dependence measure (Nicotine Dependence Syndrome Scale [NDSS]). Conversely, lifetime use of LSD was associated with increased odds of nicotine dependence. Psilocybin, mescaline, and peyote use are associated with lowered odds of nicotine dependence
Noorani et al. 2018	United States	30-month follow-up of 12 out of 15 participants of Johnson et al. 2014	See Johnson et al. 2014	Qualitative (follow-up) study, same participants as Johnson et al. 2017b	Psilocybin	Study participants experienced profound insights into self-identity and smoking habits during psilocybin sessions, leading beyond quitting smoking, to lasting positive changes including increased aesthetic appreciation and pro-social behavior. Participants emphasized that the content of psilocybin experiences overshadowed any short-term withdrawal symptoms. Preparatory counselling, strong rapport with the study team, and a sense of momentum once engaged in the study treatment were perceived as vital additional factors in achieving abstinence
Romeo et al. 2023	France	Online survey of 173 individuals who reported having had a psychedelic experience while being smokers	N/A	A retrospective cross-sectional (online) survey. Participants reported on tobacco consumption in the 6 months preceding the psychdelic experience, the month following the psychedelic experience, and during the last 6 months	LSD, psilocybin/mushrooms, Ayahuasca, DMT, mescaline	Mean number of cigarettes smoked per day, and proportion of individuals with high tobacco dependency significantly decreased between the three time points. Participants who reduced or quit smoking had more intense mystical experiences during the psychedelic session and lower psychological flexibility before the psychedelic experience. The increase in psychological flexibility post psychedelic session, and the personal motives for the psychedelic experience were significant positive predictors of smoking reduction or cessation

Clinical studies

In 2014, Johnson et al. conducted an open-label pilot study to investigate the effectiveness, safety and feasibility of using psilocybin, in combination with cognitive-behavioral therapy (CBT), for the treatment of tobacco use disorder [30]. The study included 15 mentally healthy smokers (10 men and 5 women) with an average age of 51 years. These individuals were addicted to nicotine and had previously made on average six unsuccessful quit attempts. The participants underwent a 15-week smoking cessation program, consisting of up to three psilocybin sessions. Before starting the program, they attended four preparation sessions of CBT. In the first psychedelic treatment session, they received a moderate dose of psilocybin (20 mg/70 kg of body weight), and in the second and third sessions they were given higher doses (30 mg/70 kg). The different dosages make it challenging to determine the optimal dosage regimen. After the 15-week program, the participants were followed up for 6 months. At a follow-up of 6 months 80% of the participants successfully achieved seven consecutive days of abstinence from smoking, confirmed through self-reported and biochemical verification. The adverse effects linked to psilocybin lasted for less than 24 h including slight acute elevation in blood pressure, raising of the heart rate, dysphoric subjective experiences (e.g., anxiety, fear; lasting less than 7 h), and headaches as measured by the post-session States of Consciousness Questionnaire, rating acute adverse psychological effects, next-day headache rates, and a Visual Effects Questionnaire.

Using the same data, Garcia-Romeu et al. found that those who remained abstinent (n = 12) reported significantly higher levels of psilocybin-induced mystical experiences compared to those who continued smoking (n = 3) [31]. Notably, overall drug effects did not differ between the groups, suggesting that mystical experiences specifically contributed to smoking cessation. Sixty percent of participants (9 out 15) experienced “complete” mystical experiences. Smoking cessation outcomes were correlated with the intensity of mystical experiences during sessions and retrospective ratings of personal meaning and spiritual significance. These findings highlight the potential role of mystical experiences in psychedelic-assisted addiction treatment.

In a subsequent long-term follow-up study involving the same patients, the enduring effects of the psilocybin-assisted smoking cessation program of Johnson et al. (2014) were assessed [32]. All (n = 15) participants completed the 12-month follow-up, with 10 participants (67%) managed to stay abstinent. At a minimum follow-up of 16 months (range: 16–57 months; mean of interval of 30 months), nine participants (60%) remained smoke-free. Additionally, 13 participants (86.7%) reported that their psilocybin experiences ranked among the top five most meaningful and spiritually significant experiences of their lives. Participants were also asked why they thought psilocybin helped in quitting smoking. The most common reasons they reported were a changing orientation toward the future, so that long-term benefits outweighed immediate desires (73%); strengthening participants’ beliefs in their ability to quit (73%); and changing life priorities/values, such that smoking was no longer more important than quitting (68%).

In 2018, Noorani et al. conducted a qualitative study aiming to evaluate the processes that lead to smoking cessation in the research previously reported by Johnson et al. [32]. They were trying to gain insights into the experiences, potential psychological mechanisms mediating treatment outcomes, and long-term results of individuals who underwent psilocybin treatment [33]. The study involved retrospective follow-up interviews (conducted at an average of 30 months after the initial psilocybin session) with 12 participants who had participated in a previous pilot study of Johnson et al. in 2014. The data were analyzed using thematic analysis. The authors identified that participants gained valuable insights into their self-identity and the reasons for their smoking habits during their psilocybin sessions. They reported enduring experiences of connectedness, awe, and curiosity. The study highlighted the importance of the content of the psilocybin experiences, emphasizing its significance over short-term withdrawal symptoms. Factors such as preparatory guidance, a positive rapport with the research team, and a sense of progress were identified as crucial for achieving abstinence from smoking. Participants who received psilocybin treatment for smoking cessation reported feelings of love and a sense of unity and connectedness with their environment, which they considered as important factors to be able to quit smoking.

Non-clinical studies

In a retrospective online survey conducted by Johnson et al. in 2017, 358 individuals who had quit smoking or reduced their smoking behavior after using psychedelic substances were studied [34]. Participants were recruited through social media platforms, websites frequented by individuals interested in psychedelics, and the Multidisciplinary Association for Psychedelic Studies website. They were located in 27 different countries, with the majority from the United States (69.6%), Canada (7.5%), and the United Kingdom (7.0%). The survey included various psychedelics, with psilocybin mushrooms and LSD being the most commonly used. On average, participants smoked 14 cigarettes per day for 8 years and had attempted to quit five times before their psychedelic experiences. Results showed that 38% of participants achieved sustained smoking cessation after using psychedelics, with 74% of them remaining smoke-free for more than two years. Additionally, 28% reported a long-lasting reduction in smoking, reducing from an average of 300 cigarettes to one cigarette per month after the experience. Among those who reduced smoking, 62% maintained the reduction for more than two years. However, 34% experienced a temporary reduction in smoking followed by a return to their original smoking levels. Participants who were unable to quit smoking reported a lower personal and spiritual significance of their psychedelic experiences compared to the other groups. Interestingly, all groups reported experiencing less severe affective withdrawal symptoms, such as depression and cravings, after using psychedelics compared to their previous quit attempts. The key psychological factor associated with quitting or reduction was the change in life priorities and values following the psychedelic experiences.

Jones et al. conducted a retrospective study in 2022 to examine the association between the lifelong usage of classical psychedelics and the presence of current tobacco dependence [35]. They analyzed data from 214,505 adult participants in the National Survey on Drug Use and Health (USA) between 2015 and 2019, of which 26,138 met the criteria for past-month nicotine dependence. The findings revealed that individuals who had used psilocybin had significantly lower odds of current nicotine dependence, with adjusted odds ratios (OR) ranging from 0.87 to 0.93. Similarly, lifetime use of peyote and mescaline was associated with significantly decreased odds of various subdomains of nicotine dependence, with odds ratios ranging from 0.79 to 0.91. However, lifetime use of LSD was associated with increased odds of nicotine dependence, with odds ratios ranging from 1.17 to 1.24. The authors suggest that psilocybin, mescaline, and peyote use may be linked to lower odds of nicotine dependence. In contrast, LSD use was found to be associated with higher odds of nicotine dependence.

In a retrospective, cross-sectional study published in 2022 by Daldegan-Bueno et al. researchers examined the relationship between subjective experiences and successful cessation of nicotine use among individuals who had quit or reduced smoking after one or more ayahuasca experiences in the Brazilian population [26]. Participants (n = 441) were recruited through social media platforms. Additionally, direct contact was made with leaders of religious groups in Brazil that incorporate ayahuasca use. Of the participants in the study, 69.2% reported successful smoking cessation after the experience, 18.3% reported reducing smoking, and 12.5% reported quitting for a period but relapsing afterwards. The study found that the mystical experience and frequency of ayahuasca use were factors predicting smoking cessation. Those who used ayahuasca every two weeks or more often had a higher likelihood (odds ratio 2.16) of being in the smoking cessation group. Furthermore, individuals in the cessation group consumed more ayahuasca over their lifetime and required a greater number of ayahuasca rituals to quit smoking compared to the reduction/relapse group. This suggests that the process of using ayahuasca for smoking cessation involves repeated intake, similar to a “maintenance dose,” rather than a single dose. These findings remained significant after correction for demographic, ayahuasca-related, and smoking-related variables. A potential factor prediction smoking cessation was the presence of a positive mood during the mystical experience. Participants reported various positive changes associated with ayahuasca consumption, including reductions in drug use and the adoption of healthier habits.

In 2023, Romeo et al. investigated the impact of psychedelic experiences on tobacco use among smokers [36]. Through a retrospective online survey involving 173 individuals in France who reported having had a psychedelic experience while being smokers, the study examined demographic information, characteristics of the psychedelic experience, tobacco addiction, and psychological flexibility. Significant reductions in both daily cigarette consumption and tobacco dependency were observed across three retrospectively assessed time points (6 months before preceding psychedelic experience, during the month following the psychedelic experience, and during the last 6 months). Participants who reduced or ceased smoking reported more intense mystical experiences during their psychedelic sessions and lower psychological flexibility prior to the experience. Moreover, the study found that an increase in psychological flexibility following the psychedelic session, coupled with personal motives for the experience, were key predictors of smoking reduction or cessation. These findings highlight the potential role of psychedelic experiences in aiding smoking cessation efforts, particularly when accompanied by intense mystical experiences and enhanced psychological flexibility.

Discussion

Currently, there is very limited research on psilocybin and other psychedelics as treatments for TUD. A single clinical foundational study [30] was identified, characterized by diverse follow-up studies and outcome measures (both quantitative as qualitative). Unfortunately, this initial study comprised a prospective uncontrolled (pilot) study involving only 15 participants who received psilocybin treatment. The initial study and its follow-ups included assessments at 6 months, 12 months and a long-term assessment (average of 30 months), all involving the same group of participants and conducted by a single research group. In the follow-up study, a smoking abstinence rate of 67% was achieved at 12 months, while at an average of 30 months follow-up, the rate reached 60%, by far surpassing the success rates of other interventions [32].

Four separate surveys were conducted to explore the possible associations between subjective experiences with various psychedelics and successful smoking cessation. It is important to acknowledge that these studies had retrospective designs, with a substantial risk of selection as well as recall bias. Moreover, cross-sectional studies in this area faced challenges such as unknown dosages, heterogeneous study groups, and difficulties in establishing causality (reverse causality), thus preventing definitive conclusions based on their findings. Nevertheless, these surveys provide valuable data on the association between psychedelic use and tobacco use, helping to generate hypotheses for clinical studies.

Research on the therapeutic applications of psychedelics in treating tobacco use disorder is in its very early stages. Future research in this field should prioritize various key areas. Firstly, controlled (dose finding) studies and randomized double blind controlled trials are crucial to generate evidence in the context of TUD. In addition, studies would need to incorporate psychotherapy, preferably in a standardized international manner, to integrate profound insights and therapeutic changes resulting from psychedelic treatment into one´s daily life [37, 38]. Blinding issues, a limitation of the study of Johnson et al. (2014) and its follow-up studies, can be addressed by using an active placebo, such as niacin, to mimic subjective effects that are difficult to blind. Secondly, further investigating the combination of psilocybin and/or other psychedelics with existing smoking cessation treatments, like varenicline, nicotine replacement therapy, or cognitive-behavioral therapy, is important. Thirdly, determining the optimal dosing regimen is crucial for optimizing treatment outcomes. Fourthly, exploring the impact of positive mood during psychedelic experiences on addiction treatment is an essential area of focus [39]. Qualitative research can be valuable in understanding how mood influences the therapeutic effects of psychedelics. Valuable information for future research can also be drawn from studies with other addictive substances, such as clinical studies on alcohol addiction [40] and animal studies [41].

We eagerly await the definitive results from a clinical trial from the John Hopkins University studying psilocybin combined with a structured smoking cessation program for nicotine-dependent individuals. This study aims to examine the efficacy of this combined psilocybin and CGT treatment for smoking cessation (https://www.clinicaltrials.gov/study/NCT01943994). Additionally, another study from the same University is started in November 2023. This multi-site, double-blind, randomized clinical trial will investigate the use of the 5-HT2A receptor agonist psilocybin for smoking cessation, testing psilocybin against the “active placebo” niacin (https://www.clinicaltrials.gov/study/NCT05452772).

Conclusion

The very limited number of identified studies do not allow firm conclusions on treatment of tobacco use disorder with psychedelics. Still the identified studies warrant further clinical research of the treatment of tobacco use disorders with psychedelics, such as psilocybin. Given the substantial consequences of tobacco use on health, society and the economy, coupled with the limited effectiveness of existing treatments, exploring the potential of psychedelics as (part of) the treatment for nicotine dependence could provide a novel therapeutic option for addressing tobacco use disorder.

Author contributions

Author Contributions: S.K.S. and H.K. contributed to the conceptualization and methodology of the study. Both S.K.S. and H.K. were involved in writing the original draft and editing. S.D.V. contributed to the methodology and was involved in writing and editing. R.A.S. participated in writing, review, and editing of the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.