Pilot study of the 5-HT 2A R agonist psilocybin in the treatment of tobacco addiction

“The Fagerström Test for Cigarette Dependence (FTCD; formerly Fagerström Test for Nicotine Dependence) is a 6-item questionnaire widely used to characterize the level of dependence of cigarette smokers (Fagerström, 2012; Heatherton et al., 1991).”

“The TLFB is a self-report calendar completed retrospectively by participants indicating the number of cigarettes smoked each day (Sobell and Sobell, 1992).”

“Two measures of recent smoking, exhaled carbon monoxide (CO) and urinary cotinine level (Benowitz et al., 2002), were assessed at intake, weekly throughout the intervention, and at 6-month follow-up.”

“This 100- item questionnaire has previously been used to characterize the subjective effects of psilocybin (Griffiths et al., 2006, 2011).”

“For example, when paired with 12 brief weekly counseling meetings, pharmacotherapies have shown seven-day point prevalence abstinence rates of 24.9% to 26.3% (bupropion) and 33.5% to 35.2% (varenicline) at approximately 6 months post-TQD (Gonzales et al., 2006; Jorenby et al., 2006).”

“For example, when paired with 12 brief weekly counseling meetings, pharmacotherapies have shown seven-day point prevalence abstinence rates of 24.9% to 26.3% (bupropion) and 33.5% to 35.2% (varenicline) at approximately 6 months post-TQD (Gonzales et al., 2006; Jorenby et al., 2006).”

“Several plausible mechanisms of hallucinogen-facilitated treatments have been proposed (Bogenschutz and Pommy, 2012; Carhart-Harris et al., 2012, 2014; Ross, 2012; Vollenweider and Kometer, 2010).”

“Consistent with previous findings (Griffiths et al., 2006; Grob et al., 2011), blood pressure and heart rate were elevated during drug effects, with peak values occurring on average between 1.5 and 2.5 hours post-psilocybin administration.”

“For each session a physician was on call, and rescue medications were available in case of adverse cardiovascular or psychological events (Johnson et al., 2008).”

“Several plausible mechanisms of hallucinogen-facilitated treatments have been proposed (Bogenschutz and Pommy, 2012; Carhart-Harris et al., 2012, 2014; Ross, 2012; Vollenweider and Kometer, 2010).”

“Smoking lapses were defined as any discrete instances of smoking (even a puff of a cigarette) post-TQD, while relapses were defined as smoking on seven or more consecutive days after TQD (Hughes et al., 2003).”

“The Fagerström Test for Cigarette Dependence (FTCD; formerly Fagerström Test for Nicotine Dependence) is a 6-item questionnaire widely used to characterize the level of dependence of cigarette smokers (Fagerström, 2012; Heatherton et al., 1991).”

“The Questionnaire on Smoking Urges (QSU) is a multidimensional assessment of smoking craving with demonstrated sensitivity to smoking cessation (Tiffany and Drobes, 1991).”

“This 145-item questionnaire was designed to measure changes in attitudes, moods, behavior, and spiritual experience, and has demonstrated sensitivity to the intermediate and long-term effects of psilocybin (Griffiths et al., 2008, 2011).”

“Moreover, at 14-month follow-up, 61% of volunteers associated these experiences with moderate to extreme positive behavior change (Griffiths et al., 2008).”

“Several plausible mechanisms of hallucinogen-facilitated treatments have been proposed (Bogenschutz and Pommy, 2012; Carhart-Harris et al., 2012, 2014; Ross, 2012; Vollenweider and Kometer, 2010).”

“This 32-item questionnaire was designed to assess primary mystical experience across the lifetime (Hood, 1975), and has been employed extensively in research, demonstrating good validity, and cross-cultural reliability (Hood et al.”

“Although there is experimental evidence suggesting safety and efficacy of classic hallucinogens in the treatment of addiction, this is largely in relation to the use of LSD for treating alcoholism (Krebs and Johansen, 2012; Mangini, 1998).”

“The Smoking Abstinence Self-Efficacy scale (SASE) provides a measure of smokers’ confidence to abstain from smoking in 20 hypothetical situations, and temptation to smoke in those situations, and has been found to correlate with smoking cessation outcomes (DiClemente and Prochaska, 1985; DiClemente et al., 1985).”

“Urine cotinine levels of <200 ng/mL, and breath CO of ⩽6ppm were considered as biological verification of nonsmoking status (Bramer and Kallungal, 2003; Javors et al., 2005; Middleton and Morice, 2000).”

“Despite suggestive findings, this line of investigation was abandoned due to controversy surrounding the recreational use of hallucinogens and regulatory restrictions impeding subsequent research with 5-HT2AR agonists (Mangini, 1998; Nutt et al., 2013).”

“The Wisconsin Smoking Withdrawal Scale (WSWS) measures severity of smoking withdrawal and exhibits good validity and reliability in smoking cessation studies (Shiffman et al., 2004; Welsch et al., 1999).”

“The Wisconsin Smoking Withdrawal Scale (WSWS) measures severity of smoking withdrawal and exhibits good validity and reliability in smoking cessation studies (Shiffman et al., 2004; Welsch et al., 1999).”

“…was designed to assess primary mystical experience across the lifetime (Hood, 1975), and has been employed extensively in research, demonstrating good validity, and cross-cultural reliability (Hood et al., 2001), as well as sensitivity to the effects of psilocybin (Griffiths et al., 2006, 2011).”

“This approach was informed by studies of hallucinogen-facilitated substance dependence treatment in which investigators described an extended, time-limited, postsession period (sometimes referred to as an “afterglow”) associated with decreased substance use, elevated mood and energy, decreased anxiety, and increased c…”

“To probe for potential Hallucinogen Persisting Perception Disorder (Halpern and Pope, 2003), participants completed this 16-item questionnaire designed to assess occurrence, duration, and severity of visual disturbances (e.g. halos, strobe-like trails) at intake and 6-month follow-up.”

“Urine cotinine levels of <200 ng/mL, and breath CO of ⩽6ppm were considered as biological verification of nonsmoking status (Bramer and Kallungal, 2003; Javors et al., 2005; Middleton and Morice, 2000).”

“…scope of smoking-related mortality, and the modest success rates of approved smoking cessation treatments (Cahill et al., 2014; Gonzales et al., 2006; Jorenby et al., 2006; Mottillo et al., 2009), the novel approach presented here warrants further investigation with a randomized controlled trial.”

“…multiple sessions, which may work by extending the “afterglow” period through the time of greatest relapse risk, or by increasing the probability of a transformative mystical experience (Grinspoon and Bakalar, 1979; Halpern, 1996; Osmond et al., 1967; Savage and McCabe, 1973; Smart et al., 1966).”

“…suggest the feasibility of a psilocybin-facilitated intervention for addiction treatment, consistent with findings that increased levels of spirituality are associated with improved outcomes in drug dependence recovery (Cole et al., 2006; Galanter, 2006; Piderman et al., 2007; Piedmont, 2004).”

“Consistent with previous research administering psilocybin in controlled settings, these effects were readily managed (Griffiths et al., 2006, 2011; Grob et al., 2011; Johnson et al., 2008, 2012).”

“Urine cotinine levels of <200 ng/mL, and breath CO of ⩽6ppm were considered as biological verification of nonsmoking status (Bramer and Kallungal, 2003; Javors et al., 2005; Middleton and Morice, 2000).”

“Several plausible mechanisms of hallucinogen-facilitated treatments have been proposed (Bogenschutz and Pommy, 2012; Carhart-Harris et al., 2012, 2014; Ross, 2012; Vollenweider and Kometer, 2010).”

“For example, in two trials of extended smoking cessation treatments using a combination of bupropion, nicotine replacement, and CBT ranging from 5 to 12 months in duration, participants showed 45% to 59% seven-day point prevalence abstinence at approximately 6 months (Hall et al., 2009; Killen et al., 2008).”

“Although there is experimental evidence suggesting safety and efficacy of classic hallucinogens in the treatment of addiction, this is largely in relation to the use of LSD for treating alcoholism (Krebs and Johansen, 2012; Mangini, 1998).”

“…regarding tobacco addiction, combined with previous studies showing efficacy of 5-HT2AR agonists for treatment of alcoholism and opioid dependence (Chwelos et al., 1959; Hollister et al., 1969; Krebs and Johansen, 2012; Savage and McCabe, 1973), suggest higher-order psychological and/or…”

“…research area from the 1950s through 1970s involved the therapeutic use of 5-HT2AR agonist hallucinogens in the treatment of drug dependence, including alcohol and opioid dependence (Chwelos et al., 1959; Hollister et al., 1969; Ludwig et al., 1969; Savage and McCabe, 1973; Smart et al., 1966).”

“However, 5-HT2AR agonists do not engender compulsive drug seeking (National Institute on Drug Abuse, 2001, 2005), consistent with evidence that they are not reliably self-administered in animals (Fantegrossi et al., 2004; Griffiths et al., 1980; Poling and Bryceland, 1979).”

“…research area from the 1950s through 1970s involved the therapeutic use of 5-HT2AR agonist hallucinogens in the treatment of drug dependence, including alcohol and opioid dependence (Chwelos et al., 1959; Hollister et al., 1969; Ludwig et al., 1969; Savage and McCabe, 1973; Smart et al., 1966).”

“…research area from the 1950s through 1970s involved the therapeutic use of 5-HT2AR agonist hallucinogens in the treatment of drug dependence, including alcohol and opioid dependence (Chwelos et al., 1959; Hollister et al., 1969; Ludwig et al., 1969; Savage and McCabe, 1973; Smart et al., 1966).”

“For example, in two trials of extended smoking cessation treatments using a combination of bupropion, nicotine replacement, and CBT ranging from 5 to 12 months in duration, participants showed 45% to 59% seven-day point prevalence abstinence at approximately 6 months (Hall et al., 2009; Killen et al., 2008).”

“Although participants were not drug dependent, these results suggest the feasibility of a psilocybin-facilitated intervention for addiction treatment, consistent with findings that increased levels of spirituality are associated with improved outcomes in drug dependence recovery (Cole et al., 2006; Galanter, 2006; Pid…”

“…described an extended, time-limited, postsession period (sometimes referred to as an “afterglow”) associated with decreased substance use, elevated mood and energy, decreased anxiety, and increased capacity for close interpersonal relationships (e.g. Bowen et al., 1970; Pahnke et al., 1970).”

“As investigators have suggested, long-term abstinence may be enhanced by including multiple sessions, which may work by extending the “afterglow” period through the time of greatest relapse risk, or by increasing the probability of a transformative mystical experience (Grinspoon and Bakalar, 1979; Halpern, 1996; Osmon…”

“…trial of the Quit for Life CBT program that provided the primary foundation for the manualized intervention used in this study found a 17.2% abstinence rate at 6-month follow-up (Sykes and Marks, 2001), although participants in our study received substantially more contact with study staff.”

“Although participants were not drug dependent, these results suggest the feasibility of a psilocybin-facilitated intervention for addiction treatment, consistent with findings that increased levels of spirituality are associated with improved outcomes in drug dependence recovery (Cole et al., 2006; Galanter, 2006; Pid…”

“Several plausible mechanisms of hallucinogen-facilitated treatments have been proposed (Bogenschutz and Pommy, 2012; Carhart-Harris et al., 2012, 2014; Ross, 2012; Vollenweider and Kometer, 2010).”

“Study treatment also included two components of an effective group-based smoking cessation therapy (Zernig et al., 2008).”

“In four weekly preparation meetings, participants received smoking cessation CBT (Marks, 1993; Perkins et al., 2007), largely based on the Quit For Life program (Table 2), shown to be effective in controlled studies (Marks and Sykes, 2002; Sykes and Marks, 2001).”

“However, 5-HT2AR agonists do not engender compulsive drug seeking (National Institute on Drug Abuse, 2001, 2005), consistent with evidence that they are not reliably self-administered in animals (Fantegrossi et al., 2004; Griffiths et al., 1980; Poling and Bryceland, 1979).”

“Although participants were not drug dependent, these results suggest the feasibility of a psilocybin-facilitated intervention for addiction treatment, consistent with findings that increased levels of spirituality are associated with improved outcomes in drug dependence recovery (Cole et al., 2006; Galanter, 2006; Pid…”

“In a follow-up to the report by Johnson et al. (2014), Garcia-Romeu et al. (2014) reported that abstainers scored significantly higher on a measure of psilocybinoccasioned mystical experience.”

“It is further corroborated by recent open-label trials using psilocybin-assisted psychotherapy to treat tobacco addiction (Garcia-Romeu et al., 2014; Johnson et al., 2014) and alcoholism (Bogenschutz et al.”

“A recent pilot study of psilocybin as an adjunct in smoking cessation treatment resulted in remarkable rates of abstinence (80% point abstinence at 6-month follow-up) (Johnson et al., 2014).”

“Psilocybin has shown promise in the treatment of obsessive compulsive disorder (Moreno et al. 2006), alcohol (Bogenschutz et al. 2015) and tobacco addiction (Johnson et al. 2014) and anxiety related to terminal diagnoses (Griffiths et al. 2016; Ross et al. 2016; Grob et al. 2011).”

“Consistent with previously published data (4), no participants reported an increase in bothersome visual”

“…clinical development of psychedelics, RLC-H sees it as a potentially exploitable component—especially as it has been shown to be predictive of long-term clinical outcomes (eg, in Johnson et al, 2014; Bogenschutz et al, 2015; Griffiths et al, 2016; Ross et al, 2016; Carhart-Harris et al, 2016a,b).”

“While the bulk of MEQ data reported to date (Griffiths et al., 2006, 2011; Johnson et al., 2014; MacLean et al., 2012) were collected using the MEQ43 embedded within the full 100-item SOCQ, the second study in the original development of the MEQ30 (MacLean et al., 2012) validated the factor…”

“Some scales, however, such as the MEQ-30, have been validated in experimental studies with controlled doses of psilocybin (32), although even the MEQ-30 was validated using a narrow range of drug doses and was restricted to one hallucinogenic compound.”

“The rates and severity of both acute and enduring problems shown in the survey are notably higher than those we and others have observed in laboratory research studies involving administration of high doses of psilocybin to carefully screened, wellprepared, and closely monitored volunteers (e.g. Griffiths et al., 2006…”

“Furthermore, a growing body of evidence suggests that when administered to wellprepared clinical populations in controlled settings, psilocybin and similar drugs may hold considerable therapeutic potential in the treatment of a variety of conditions including end-of-life anxiety, and smoking addiction [20-22].”

“The EDI correlated strongly with the MEQ-derived measure of unitive experience (rho = 0.735), demonstrating convergent validity.”

“Furthermore, a single-arm trial of smoking cessation involving up to three administrations of psilocybin yielded abstinence rates of 80% at long-term follow-up, more than doubling abstinence rates typical of approved contemporary tobacco dependence interventions (Johnson et al., 2014).”

“For example, consistent with the core processes of ACT, qualitative analysis of first-hand accounts of tobacco smokers in a clinical trial examining the effect of psilocybin-assisted therapy (Noorani et al., 2018; Johnson et al., 2014), suggested that their psychedelic experiences helped them see themselves in the con…”

“The first modern laboratory study examining a serotonergic psychedelic for addiction was an open-label pilot study that employed psilocybin with manualized cognitive behavioral therapy in 15 treatment-resistant tobacco/nicotine-dependent smokers, conducted by one of the present authors and colleagues.(19) After four p…”

“Approximately 30% of participants in each of three highly controlled experimental studies (total sample: 69 participants and 204 sessions – Griffiths et al., 2006, 2011; Johnson et al., 2014) involving a high dose of psilocybin (0.”

“Impairments in cognitive flexibility have been found in depression [9, 10], as well as obsessive-compulsive disorder [11] and substance use disorders [12], which are disorders that may also be amenable to psychedelic therapy [1, 5, 6].”

“Several of the key clinical studies have been primarily supported by private foundations rather than federal institutions such as NIH (Bogenschutz et al., 2015; Griffiths et al., 2016; Johnson et al., 2014; Ross et al., 2016).”

“…United States, published an open-label pilot trial in 2014 using moderate (20mg/70 kg) and high (30mg/70 kg) doses of psilocybin given to 15 otherwise psychiatrically healthy subjects with tobacco addiction undergoing a structured 15-week smoking cessation treatment (Johnson et al., 2014).”

“…psychotherapy) for obsessive compulsive disorder (OCD) (Moreno et al., 2006), treatment-resistant depression (TRD) (Carhart-Harris et al., 2016), smoking cessation (Johnson et al., 2014) and alcoholism (Bogenschutz et al., 2015), leading to an increasing body of positive evidence being developed.”

“Of these studies, five investigated substance use disorder, of which two studies explored Alcohol Use Disorder [AUD] (23, 49), two examined tobacco smokers and were based on the same population dataset (51) but with different follow-up periods (34, 50) and, one inspected cocaine dependency (24).”

“Clinical improvements have been observed with psilocybin-assisted psychotherapy for the treatment of tobacco (Johnson et al. 2014) and alcohol addiction (Bogenschutz et al.”

“There is increasing interest in the therapeutic use of psychedelics, especially for alcoholism (Krebs and Johansen, 2012), smoking cessation (Johnson et al., 2014), depression and other mental health problems (Baumeister et al.”

“tive behavioral therapy for smoking cessation [58].”

“…2008; Spitzer et al., 1996; Vollenweider et al., 1997), including a reemergence of clinical research examining psychedelics as potential treatments for addiction (Bogenschutz et al., 2015; Garcia-Romeu et al., 2015, 2016; Johnson et al., 2014, 2017a; Sessa and Johnson, 2015; Tupper et al., 2015).”

“…potential therapeutic effects of serotonergic hallucinogens, with trials focusing on anxiety and depression (Grob et al., 2011; Griffiths et al., 2016; Ross et al., 2016), substance abuse (Johnson et al. 2014, 2016; Bogenschutz et al., 2015), and obsessive-compulsive disorder (Moreno et al., 2006).”

“…first moderate to high-dose session (20 mg/70 kg or greater) for 184 volunteers from a total of 5 psilocybin studies (Griffiths et al. 2006, 2011; Johnson et al. 2014; Griffiths et al. 2016 and an unpublished study in beginning meditators) were pooled and submitted to confirmatory factor…”

“Recent pilot studies point to the potential of psychedelicassisted therapy to treat conditions including tobacco (15) and alcohol (16) addiction, obsessivecompulsive disorder (17), end of life anxiety/depression (18–20), major depression (21), and TRD (22, 23) – (see Carhart-Harris & Goodwin, 2017 for a review (24)).”

“Additionally, psilocybin was recently studied as a treatment for tobacco (Johnson et al, 2014) and alcohol (Bogenschutz et al, 2015) dependence.”

“Recent trials investigated psilocybin in patients with alcohol and nicotine use disorder Neuropsychopharmacology (Bogenschutz et al, 2015; Johnson et al, 2014), major depression, and anxiety (Carhart-Harris et al, 2016a; Griffiths et al, 2016; Grob et al, 2011; Ross et al, 2016).”

“Early-stage clinical trials of psilocybin for nicotine dependence (Johnson et al., 2014) and alcohol dependence (Bogenschutz et al., 2015) have recently been completed, and further trials are currently under way.”

“Evidence from two open-label studies showed improvements in symptoms of tobacco (n = 15 [72], extracted from [55]) and alcohol (n = 10 [73], extracted from [55]) dependence with administration of two psilocybin doses.”

“A pilot study looking at psilocybin for the treatment of tobacco addiction found a significant correlation between mystical experience measures and smoking cessation outcomes (Bogenschutz & Johnson, 2016; Johnson et al., 2014).”

“Indications of efficacy have been reported for conditions including treatment-resistant depression, anxiety related to end-of-life care and addictive disorders (Griffiths et al., 2006; Grob et al., 2011; Johnson et al., 2014; Carhart-Harris et al., 2016).”

“, 2018) and recovering addicts (Johnson et al., 2014; Bogenschutz et al., 2015; Bogenschutz and Johnson, 2016) and lasting improvements in psychological well-being in healthy populations (Griffiths et al.”

“…found that two to three doses of psilocybin (20 mg/70 kg and 30 mg/70 kg) in combination with cognitive–behavioral therapy for smoking cessation resulted in an 80% success rate at 6 months, with 12 of 15 participants demonstrating biologically verified smoking abstinence (Johnson et al., 2014).”

“In recent years, several early-phase clinical trials have provided evidence that classic serotonergic psychedelics—in most cases psilocybin, but also lysergic acid diethylamide (LSD) and the dimethyltryptamine (DMT)-containing brew ayahuasca—may occasion substantial and often sustained symptom reductions in patients t…”

“…provides the opportunity to directly experience altered cognitive and emotional states, which can then be leveraged in ongoing counselling to ultimately challenge and replace maladaptive thought and behaviour patterns such as tobacco craving and cigarette smoking (Johnson et al., 2014).”

“…et al., 2019), and may have long-term therapeutic value in treating a variety of neuropsychiatric disorders without the adverse reactions associated with current medication (Bogenschutz et al., 2015; Carhart-Harris et al., 2016a; Griffiths et al., 2016; Johnson et al., 2014; Ross et al., 2016).”

“…anxiety associated with advanced cancer(Gasser et al., 2015; Grob et al., 2011), obsessive compulsive disorder(FA Moreno et al., 2006), tobacco(MW Johnson et al., 2014) and alcohol(Bogenschutz et al., 2015) addiction and cluster headaches(Sewell et al., 2006) have been completed over the last 10…”

“Large observed decreases in depression severity, despite a potential floor-effect,(2) constitute a meaningful parallel to recent controlled trials using ayahuasca or psilocybin in clinical settings, including the treatment of drug dependence (Bogenschutz et al., 2015; Johnson et al., 2014; Thomas et al., 2013), depres…”

“…Gasser et al., 2014; Carhart-Harris et al., 2016a, 2017a; Dos Santos et al., 2016; Griffiths et al., 2016; Ross et al., 2016), obsessive-compulsive disorder (Moreno et al., 2006), and addiction (Bogenschutz and Johnson, 2016) to alcohol (Bogenschutz et al., 2015) and tobacco (Johnson et al., 2014).”

“Qualitative studies described treatment experiences among patients with EOLA (Belser et al., 2017; Malone et al., 2018; Swift et al., 2017), TRD (Kaelen et al., 2018; Watts et al., 2017), and substance use disorder (SUD; Bogenschutz et al., 2018; Nielson et al., 2018; Noorani et al., 2018).”

“Psilocybin has also been shown to improve symptoms of addiction (Bogenschutz et al., 2015; Johnson et al., 2014), anxiety (Griffiths et al., 2016; Grob et al., 2011; Moreno et al., 2006; Ross et al., 2016) and depression (Carhart-Harris et al., 2016a; Griffiths et al., 2016; Ross et al., 2016) when…”

“The first is the non-directive one (Grof and Halifax, 1978; Johnson et al., 2014; Bogenschutz et al., 2015; Carhart-Harris et al., 2016), in which therapists only aim at keeping the participants’ attention inward and provide verbal and non-verbal support during challenging moments.”

“However, taken in combination with preliminary clinical findings (46, 49, 54, 80) andpreviousanonymous survey studies (40, 55), these results further bolster the potential utility of serotonergic psychedelics as aids in the treatment of addiction.”

“…for conditions such as substance dependence, OCD, and PTSD also have parallels in research on therapeutic effects from psychedelics in full doses (Abramson, 1967; Bogenschutz et al., 2015; Johnson et al., 2014; Krebs & Johansen, 2012; Nichols, 2004; Schenberg et al., 2014; Thomas et al., 2013).”

“…et al., 2015; Carhart-Harris et al., 2017, 2018b; Gasser et al., 2015; Griffiths et al., 2006, 2008; Haijen et al., 2018; Hendricks et al., 2015; Johnson et al., 2014; Osório et al., 2015; Moreno et al., 2006; Ross et al., 2016); (c) political perspective (Lyons and Carhart-Harris, 2018a; Nour…”

“These compounds may in fact have anti-addictive properties (Johnson et al., 2014; Bogenschutz et al., 2015; Pisano et al., 2017).”

“…Christie et al., 2022; D ’ Souza et al., 2022; Dominguez-Clave et al., 2019; Doss et al., 2021; Gouzou-lis-Mayfrank et al., 2005; Grof et al., 1973; Johnson et al., 2014; Kast, 1967; Kast and Collins, 1964; Moreno et al., 2006; Nicholas et al., 2022; Pahnke et al., 1969; Roseman et al., 2018;…”

“And contemporary pilot studies with psilocybin therapy for alcohol addiction (67) and psilocybin therapy for nicotine addiction (68) have demonstrated positive results.”