Keywords

Annual smoking-related mortalities are estimated at 480,000 in the USA (US Department of Health and Human Services 2014) and nine million annually worldwide (Murray et al. 2020). These numbers dwarf similar statistics for all other drugs of abuse. In the USA, smoking is responsible for approximately five to seven times more deaths than alcohol, and approximately 26 times more deaths than all illicit drugs combined (Danaei et al. 2009; Mokdad et al. 2004). Most behavioral interventions and pharmacotherapies for smoking cessation have only modest long-term success rates (e.g., typically <35% at 6 months post-quit attempt; Cahill et al. 2014; Mottillo et al. 2009). These statistics are particularly devastating because 68% of US smokers want to quit (Babb et al. 2017). The staggering death toll of smoking and unmet clinical need means that novel approaches are desperately needed.

This manuscript reviews research suggesting that classic psychedelics might be effective in treating substance use disorders including tobacco use disorder. The classic psychedelics are defined as drugs with agonist activity at 5-HT2A receptor (5-HT2AR) as a primary mechanism, with prototypes including psilocybin (which is a prodrug for psilocin), lysergic acid diethylamide (LSD), mescaline, and dimethyltryptamine (DMT). Within this context of classic psychedelics as potential anti-addiction medicines, a special focus will be placed on work examining psilocybin as a smoking cessation medication for tobacco use disorder. First, I will describe historical clinical research evidence from the 1950s to 1970s suggesting that classic psychedelics are associated with addiction recovery across pharmacologically distinct drugs of addiction. I will then review nonclinical lines of evidence suggesting that classic psychedelics may possess anti-addiction efficacy, including anthropological reports about ceremonial use of classic psychedelics by indigenous societies and syncretic religions, and epidemiological studies. Next, I will describe modern research examining psilocybin in the treatment of alcohol use disorder. Then I will review extensively the evidence related to psilocybin and other classic psychedelics and tobacco smoking cessation. I will conclude by recommending future directions.

1 Historical Research

Although anthropological evidence suggests that 5-HT2AR agonists have been used by various indigenous peoples as sacraments and healing agents before recorded history (Akers et al. 2011), in the mid-twentieth century they came to occupy a place at the cutting edge of psychiatric research (Johnson et al. 2008). Although studies generally did not meet modern scientific standards (Bonson 2018), over 1,000 papers were published during the mid-twentieth century that described the treatment of over 40,000 patients with 5-HT2AR agonists (Grinspoon 1981). In addition to basic research, therapeutic applications of 5-HT2AR agonists were investigated, with promising findings in the treatment of both addiction and cancer-related existential distress (Johnson and Griffiths 2017).

During the twentieth-century zenith of 5-HT2AR agonist research from the 1950s through the 1970s, addiction was a main therapeutic target. The primary form of addiction treated was alcoholism, and the most frequently studied classic psychedelic to treat alcoholism was LSD, although mescaline (e.g., Smith 1958, 1959) and dipropyltryptamine (Rhead et al. 1977) were also examined. Investigators in Saskatchewan, Canada hypothesized that classic psychedelics might mimic delirium tremens, which sometimes prompted sobriety (Chwelos et al. 1959; Dyck 2006; Smith 1958). However, undergoing delirium tremens was dangerous and sometimes fatal, so the rationale was to prompt a similar experience with a drug like LSD which was relatively safe physiologically. Instead of observing reactions resembling delirium tremens, researchers often observed “mind-manifesting” experiences that could be leveraged for psychotherapy and prompt sobriety. Some of the early studies in the literature showed nonsignificant positive trends for LSD, leading to conclusions that efficacy was undetermined (e.g., Abuzzahab and Anderson 1971; Mangini 1998). More recently, a meta-analysis examined all of the studies that randomized patients to an LSD or control condition (six studies; N = 536), and found in aggregate a significant and large decrease in alcohol misuse at the first follow-up (≥1 month post-treatment) for the LSD groups compared to control groups (Krebs and Johansen 2012).

Early research hinted that the classic psychedelics might have broad applicability in treating substance use disorders beyond alcoholism. Savage and McCabe (1973) tested LSD in the treatment of opioid dependence in a study of 78 heroin-using individuals under judicial correctional supervision. The study randomized individuals to undergo either a single administration of LSD (300–450 microgram) during a six-week residential stay or undergo a control condition with outpatient clinic visits, daily urine drug testing, and weekly group therapy. At all timepoints examined, the group that received LSD showed significantly greater biologically confirmed drug abstinence. At this longest follow-up of 12 months post-treatment, continuous abstinence rates were 25% and 5% in the LSD group and control groups, respectively. Although the results were limited by the fact that the LSD group received a six-week residential stay not experienced by the control group, the large difference in biologically confirmed abstinence indicated the approach was worthy of more intensive follow-up.

2 Resurgence of Modern-Day Research

Despite initial excitement, research on 5-HT2AR agonists became increasingly marginalized due to their growing use outside of clinical research settings, and their association with the counter-culture movement in the late 1960s and early 1970s. In the 1990s a small number of investigators in Europe and the USA re-initiated human studies with 5-HT2AR agonists (e.g., Spitzer et al. 1996; Strassman and Qualls 1994; Vollenweider et al. 1997). Non-human research in the intervening decades had identified agonist activity at 5-HT2AR as a key mechanism underlying the effects of classic psychedelics (e.g., Glennon et al. 1984), which include LSD as well as psilocybin (present in many mushroom species), mescaline (present in peyote and some other cacti), and dimethyltryptamine (DMT; present in a variety of plants). Studies by researchers since the 1990s have followed safety guidelines for administering 5-HT2AR agonists (Johnson et al. 2008). These guidelines involve careful screening and preparation before drug administration sessions, close monitoring during sessions, and follow-up care involving both clinically supportive discussion of session experiences and assessment for any adverse effects resulting from the session. Therapeutic effects of 5-HT2AR agonists have been reported for depression and anxiety related to cancer and other life-threatening illness (Gasser et al. 2014; Griffiths et al. 2016; Grob et al. 2011; Ross et al. 2016), major depressive disorder (Carhart-Harris et al. 2016, 2021; Davis et al. 2021; Palhano-Fontes et al. 2019), tobacco use disorder (Johnson et al. 2014, 2017a), and alcohol use disorder (Bogenschutz et al. 2015). Some studies have been randomized trials, while others have been initial non-randomized pilot studies designed to establish safety in new populations and test the waters for future randomized trials. Some of these studies have reported rapid efficacy persisting for at least 6 months after one or a few 5-HT2AR agonist administrations (for review, see Johnson et al. 2019).

3 Anthropological Evidence

Various anthropological reports have suggested that 5-HT2A agonist use in the context of ritualized sacramental practices of indigenous cultures is associated with high rates of recovery from addiction, achievement of long-term abstinence, and lower rates of addictive substance use. Such reports include those of peyote (5-HT2AR agonist mescaline) ceremonies within the Native American Church in the USA (Albaugh and Anderson 1974; Bergman 1971; Blum et al. 1977; Calabrese 1997; Menninger 1971; Pascarosa and Futterman 1976; Roy 1973) and ayahuasca (5-HT2AR agonist dimethyltryptamine) ceremonies within certain Amazonian societies and syncretic religions (Dobkin de Rios et al. 2002; Doering-Silveira et al. 2005; Fábregas et al. 2010; Halpern et al. 2008). It is not possible to definitively differentiate the causal role of the drug from the larger context of religious guidance and community support provided in these settings. However, one large survey of over 8000 people in over 40 countries reported regression results suggesting that the association of ayahuasca use and lower use of addictive substances was apparent even after controlling for religious and social variables (Perkins et al. 2022).

4 Epidemiological Research

Using 6 years of data from the National Survey on Drug Use and Health, one analysis among people who had ever used illicit opioids (N = 44,000) found that a lifetime history of 5-HT2AR agonist use was associated with a significant 27% reduced risk of opioid dependence in the past year (Pisano et al. 2017). My laboratory recently conducted an online survey of individuals (N = 343) with prior AUD reporting cessation or reduction in alcohol use following 5-HT2AR agonist use in nonclinical settings (Garcia-Romeu et al. 2019). Participants reported 7 years of problematic alcohol use on average before the psychedelic experience to which they attributed reduced alcohol consumption. We also recently conducted an online survey of individuals reporting cessation or reduction in cannabis, opioid, or stimulant use following 5-HT2AR agonist use in nonclinical settings (Garcia-Romeu et al. 2020). Participants (N = 444) reported 4.5 years of problematic substance use on average before the psychedelic experience to which they attributed a reduction in drug consumption. In both Hopkins survey studies, greater 5-HT2AR agonist dose, insight, and personal meaning were associated with greater reductions in substance use. Like the anthropological studies, these surveys cannot definitively address the causal role of 5-HT2AR agonist use on addiction. However, combined with the clinical research described above, these survey data are suggestive of anti-addiction efficacy. It should be noted that the uncontrolled use of 5-HT2AR agonists is also associated with demonstrable harms (Carbonaro et al. 2016; Johnson et al. 2008). If these survey findings are suggesting anti-addictive effects can occur with uncontrolled use, carefully conducted clinical research (that includes screening, preparation, monitoring, and aftercare) is expected to further minimize the risks associated with uncontrolled use and to maximize the efficacy of 5-HT2AR agonists to increase abstinence.

5 Modern Research in Alcohol Use Disorder

Bogenschutz et al. (2015) conducted the first modern research using a 5-HT2AR agonist to treat alcohol use disorder. They administered one or two doses of psilocybin (0.3 and 0.4 mg/kg) and motivational enhancement therapy to ten treatment-seeking volunteers meeting DSM-IV criteria for alcohol dependence in an open-label trial. The percentage of drinking days and the percentage of heavy drinking days significantly decreased after the first psilocybin session. At 36 weeks after treatment, the mean percentage of drinking days dropped from ~32.5% in the 4 weeks of treatment preceding the psilocybin session to ~12.5% in the 4 weeks following the psilocybin session, and ~17.5% during the final follow-up period of 21–32 weeks after the psilocybin session. Mean percentage of heavy drinking days (i.e., ≥5 drinks for men, ≥4 drinks for women) dropped from ~26% in the 4 weeks of treatment preceding the psilocybin session to ~8% in the 4 weeks following the psilocybin session, and ~13% at the final follow-up period 21–32 weeks after the psilocybin session. Consistent with earlier studies of LSD (Kurland et al. 1967; Pahnke et al. 1970), and contemporary pilot research of psilocybin treatment for tobacco use disorder (Garcia-Romeu et al. 2014), subjective effects of the drug experience (e.g., mystical-type effects, intensity) appeared to be potential key factors facilitating subsequent behavior changes (Bogenschutz et al. 2015; Nielson et al. 2018). Additional controlled research on the psilocybin-facilitated treatment of alcohol use disorder is currently underway (US National Library of Medicine 2021a).

6 Psychedelics in Tobacco Smoking Cessation

Given the older laboratory studies and anthropological studies suggesting anti-addiction efficacy of 5-HT2AR agonists across distinct classes of addictive drugs, my laboratory embarked on a line of research examining 5-HT2AR agonist psilocybin therapy for a previously unstudied target: Tobacco use disorder. We conducted an open-label pilot study in 15 nicotine-dependent, treatment-resistant cigarette smokers (Johnson et al. 2014). Participants consisted of ten men and five women. They were on average 51 years old, had been smoking for an average of 31 years, had made six prior serious cessation attempts, and smoked an average of 19 cigarettes per day. In addition to up to three psilocybin sessions, the intervention involved a 15-week program of manualized cognitive behavioral therapy (CBT) for smoking cessation. There were four preparation sessions for a collective total of approximately 8 h. These preparation sessions included CBT material in preparation for quitting smoking as well as preparation for the psilocybin sessions (see Johnson et al. 2008). The dose delivered in the first session was 20 mg/70 kg. We included two additional sessions at 2 and 8 weeks after the target quit date. The timing of these was determined by examining typical survival curves for smoking cessation, and selecting times during the portion of the survival curve with greatest risk of lapse. For the second and third psilocybin sessions, we administered a higher dose of 30 mg/70 kg unless the participant judged the first session dose to be sufficiently high. Only of the 15 participants opted to not increase the dose after the first session. Intermixed with the psilocybin administrations, participants came to the laboratory once per week, during which CBT material was covered.

As shown in Fig. 1, at 6 months post-target quit date, 12 out of 15 participants (80%) showed biologically verified 7-day point-prevalence abstinence (via breath CO and urine cotinine analysis) (Johnson et al. 2014). At 12-month follow-up, and at the very long-term follow-up which was an average of 2.5 years after the target quit date, biologically confirmed point-prevalence abstinence rates were 67% and 60%, respectively (Johnson et al. 2017a). As shown in Fig. 2, continuous abstinence rates were 53% and 47% at the 12-month and 2.5-year follow-ups, respectively. Nine of the 15 participants (60%) met the threshold criteria to qualify as having had a “complete” mystical-type experience in at least one of their multiple sessions (Garcia-Romeu et al. 2014). A mystical experience is defined as an experience entailing the qualities of unity (e.g., with all things and humanity), sacredness, noesis, positive mood, transcendence of time and space, and ineffability (Johnson et al. 2019). This psychological construct is nominally divorced from any endorsement of the supernatural or of religion. Previous research in our research group and other research groups has shown that mystical experience as assessed on the session day is related to several positive long-term psychological outcomes including increases in the personality domain known as openness to experience in healthy volunteers (MacLean et al. 2011), decreases in depression and anxiety symptoms in cancer patients (Griffiths et al. 2016; Ross et al. 2016), decreases in alcohol use among those with alcohol use disorder (Bogenschutz et al. 2015), and decreases in depressive symptoms in those with major depressive disorder (Roseman et al. 2018). Those who were smoking abstinent at 6 months had significantly higher mystical-type experience scores on their session days. Moreover, a significant relationship was shown between greater mystical-type experience score on their session days, and greater cigarette craving reduction from study intake to the six-month follow-up.

Fig. 1
figure 1

Seven-day point-prevalence abstinence data as originally reported in Johnson et al. (2014, 2017a). Self-report data were biologically verified by both breath CO and urinary cotinine assays. The 30-month timepoint is the mean of long-term follow-up intervals that varied considerably across participants (range = 16–57 months)

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Fig. 2
figure 2

Continuous abstinence rates for the psilocybin + CBT approach in the pilot study reported by Johnson et al. (2017a) compared to other smoking cessation results. The placebo, nicotine replacement, bupropion, and varenicline data are literature aggregate values provided by Jackson et al. (2019). CBT data are from primary care literature values provided by Wittchen et al. (2011). Although difference among studies preclude strict comparisons of values, the relative magnitude of continuous abstinence with psilocybin + CBT suggests that the pilot study was worthy of follow-up investigation

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At an average of 2.5 years after the target quit date, we conducted structured qualitative interviews with 12 of the 15 participants (Noorani et al. 2018). Key themes that emerge from participant interviews were that the psilocybin sessions had led to insights into self-identity and reasons for smoking, and participants were left with a lasting sense of interconnectedness, awe, and curiosity, which were helpful in remaining smoke-free. Participants also reported additional benefits of the sessions unrelated to smoking cessation, such as increased prosocial behavior. The promising data from our initial study paved the way for a currently running randomized comparative efficacy study, comparing the effects of a single psilocybin session to a standard course of transdermal nicotine patch treatment, with CBT as the psychosocial backdrop in both groups (US National Library of Medicine 2021b).

The Hopkins laboratory conducted a survey study examining individuals claiming to have quit or reduced smoking due to 5-HT2AR agonists (largely psilocybin and LSD) use in nonclinical settings (N = 781; with 358 individuals having had the psychedelic experience at least a year before survey completion). Participants who had the psychedelic experience at least a year before survey completion typically judged their withdrawal symptoms related to negative affect (e.g., depression, irritability, craving) to be much less severe after 5-HT2AR agonist use compared to previous occasions in which they quit smoking (Johnson et al. 2017b). Although these data cannot test a causal role of 5-HT2AR agonist use on smoking behavior, they are consistent with laboratory research suggesting a causal effect. Moreover, these results may suggest that affective processing is a commonality in psychedelic therapy, considering the studies showing 5-HT2AR agonists to decrease depressive symptoms (Carhart-Harris et al. 2016, 2021; Davis et al. 2021; Gasser et al. 2014; Griffiths et al. 2016; Grob et al. 2011; Palhano-Fontes et al. 2019; Ross et al. 2016).

7 Future Directions

The reviewed data suggests that classic psychedelics hold promise as treatments for substance use disorders. Pilot research suggests promise in using psilocybin in the treatment of both tobacco use disorder and alcohol use disorder. Additional rigorous research should explore both indications, including double-blind and larger trials. The field also needs research examining dose effects in the treatment of disorders. If results continue to look promising, the conduct of Phase III trials will be appropriate, which may lead to the approval of psilocybin for these disorders by the Food and Drug Administration in the USA and other medical regulatory agencies internationally. In this respect the recent funding by the United States National Institute on Drug Abuse of a multi-site trials of psilocybin for tobacco smoking cessation may provide critical information for potential advancement along the medical pathway (Grant number U01DA052174).

Unlike most medications for substance use disorders, it may be that these therapies work against a wide variety of substance use disorders, regardless of the class of addictive drug being treated. This is suggested by early clinical evidence for alcohol use disorder (Bogenschutz et al. 2015; Krebs and Johansen 2012), opioid use disorder (Savage and McCabe 1973), and tobacco use disorder (Johnson et al. 2014). Supporting evidence also comes from anthropological and survey methods (Dobkin de Rios et al. 2002; Doering-Silveira et al. 2005; Fábregas et al. 2010; Garcia-Romeu et al. 2019, 2020; Halpern et al. 2008; Johnson et al. 2017b; Pisano et al. 2017). A general anti-addiction effect across classes of addictive drugs would be consistent with the notion that the persisting positive behavior change prompted by psychedelic therapy is due to amplification of psychotherapeutic processes such as the construction of meaning, corrective emotional experiences, and a change in self-narrative (Nayak and Johnson 2021). Such psychological mechanisms may be at play with the treatment of not only distinct substance use disorders, but also other disorders such as depression and cancer-related distress.

Given these potential general mechanisms, additional substance use disorders and other disorders which can be broadly characterized as addictions should be explored as treatment targets for classic psychedelics. As suggested by survey data (Garcia-Romeu et al. 2020), these include opioids, cocaine, methamphetamine, and cannabis. An ongoing trial is examining psilocybin in the treatment of cocaine use disorder (US National Library of Medicine 2021c). Given ongoing concerns about the opioid crisis (Kolodny et al. 2015), we should test classic psychedelics in the treatment of opioid use disorder (e.g., clinicaltrials.gov: NCT04161066; NCT) and the treatment of chronic pain, an issue that partially drives the opioid crisis. In addition to substance use disorders, psychedelics should be examined as potential treatments for other disorders that could be considered forms of addiction. Examples include poor health behaviors such as obesity (Teixeira et al. 2021), problem gambling, and hypersexual disorder.

Another avenue for exploration is with other classic psychedelics compounds. While the large majority of therapeutic research in the last 20 years has been conducted with psilocybin, LSD was the classic psychedelic most frequently studied for addiction in the 1960s. Research should once again explore the efficacy and safety of LSD in substance use disorders. While LSD provides a much longer duration of action than psilocybin, which may possibly be beneficial in therapeutics, there should also be research with shorter acting classic psychedelics, including dimethyltryptamine (DMT) and 5-methoxy-dimethyltryptamine (5-MeO- DMT Ermakova et al. 2021) in the treatment of substance use disorders. If the longer duration is not always necessary for therapeutic effect, a shorter-duration treatment model would entail less cost and therefore increase dissemination. Beyond these, there are dozens of compounds that appear to be classic psychedelics awaiting both non-human and human research (e.g., Shulgin and Shulgin 1991, 1997).

Research should also examine how classic psychedelic therapy is delivered. One example is whether a particular psychotherapeutic backdrop (e.g., cognitive behavioral therapy, motivational enhancement therapy) or no formal therapy at all (but still including supportive preparation and follow-up sessions with treatment staff) is ideal for treating a particular disorder or type of patient with a disorder. The parameters of psychedelic therapy, including the use of eyeshades and encouragement toward introspection, are still yet to be experimentally tested. Indeed, a recent study experimentally manipulating the music played during sessions appears to be the only study to have randomized a “set and setting” variable in the context of the psychedelic treatment session (Strickland et al. 2021). Future research should manipulate a broader number of session variables (e.g., presence of music, extent of discussion, specific exercises such as examining a mirror or personal photos) to examine optimization of therapeutic response.

Given the staggering society costs of substance use disorders, including the mortality caused by tobacco smoking, it is critical that scientists conduct rigorous clinical trials to follow up on promising early findings to investigate with classic psychedelics in the treatment of substance use disorders and other addictions. To support this effort, it is time that public funding be provided to support such investigations. Twenty years of modern investigation indicates that such trials can be conducted with an acceptable level of safety when following appropriate research guidelines (Johnson et al. 2008). The costs and risks of not conducting research into classic psychedelics for addiction exceed those of conducting the science.