TYPE Systematic Review PUBLISHED 09 February 2023 DOI 10.3389/fpsyt.2023.1134454 Therapeutic effect of psilocybin in OPEN ACCESS addiction: A systematic review EDITED BY Grace Blest-Hopley, King’s College London, United Kingdom Pim B. van der Meer 1,2*, Juan J. Fuentes3,4,5 , Ad A. Kaptein6 , REVIEWED BY Jan W. Schoones7 , Marleen M. de Waal8,9,10 , Agus Supriyanto, Ahmad Dahlan University, Indonesia Anneke E. Goudriaan8,9,10 , Kees Kramers11 , Arnt Schellekens12,13 , John Brust, Metten Somers2 , Matthijs G. Bossong2 and Albert Batalla2 Columbia University, United States 1 *CORRESPONDENCE Department of Neurology, Leiden University Medical Center, Leiden, Netherlands, 2 Department Pim B. van der Meer of Psychiatry, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht, pbvandermeer@lumc.nl Netherlands, 3 Addiction Program, Institute of Neuropsychiatry and Addictions (INAD), Hospital del Mar, Barcelona, Spain, 4 Addiction Research Group, IMIM Hospital del Mar Medical Research Institute, Barcelona, SPECIALTY SECTION Spain, 5 Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Cerdanyola del This article was submitted to Vallés, Spain, 6 Department of Medical Psychology, Leiden University Medical Center, Leiden, Netherlands, Psychopharmacology, 7 Directorate of Research Policy, Leiden University Medical Center, Leiden, Netherlands, 8 Department a section of the journal of Research and Jellinek, Arkin Mental Health Care, Amsterdam, Netherlands, 9 Department of Psychiatry, Frontiers in Psychiatry Amsterdam University Medical Center, Amsterdam, Netherlands, 10 Amsterdam Institute for Addiction RECEIVED 30December 2022 Research, Amsterdam University Medical Center, Amsterdam, Netherlands, 11 Department ACCEPTED 23 January 2023 of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, Netherlands, 12 Nijmegen PUBLISHED 09 February 2023 Institute for Science Practitioners in Addiction (NISPA), Nijmegen, Netherlands, 13 Department of Psychiatry, Radboud University Medical Center, Nijmegen, Netherlands CITATION van der Meer PB, Fuentes JJ, Kaptein AA, Schoones JW, de Waal MM, Goudriaan AE, Kramers K, Schellekens A, Somers M, Bossong MG and Batalla A (2023) Therapeutic effect of psilocybin in addiction: A systematic Background: Psychedelic-assisted therapy [e.g., with lysergic acid diethylamide review. Front. Psychiatry 14:1134454. (LSD)] has shown promising results as treatment for substance use disorders (SUDs). doi: 10.3389/fpsyt.2023.1134454 Previous systematic reviews assessing the efficacy of psilocybin in SUDs only COPYRIGHT included clinical trials conducted in the last 25 years, but they may have missed © 2023 van der Meer, Fuentes, Kaptein, Schoones, de Waal, Goudriaan, Kramers, clinical trials assessing the efficacy of psilocybin that were conducted before the Schellekens, Somers, Bossong and Batalla. This 1980s, given much research has been done with psychedelics in the mid-20th is an open-access article distributed under the terms of the Creative Commons Attribution century. In this systematic review, we specifically assessed the efficacy of psilocybin License (CC BY). The use, distribution or in patients with a SUD or non-substance-related disorder with no publication date reproduction in other forums is permitted, restrictions in our search strategy. provided the original author(s) and the copyright owner(s) are credited and that the Methods: A systematic literature search was performed according to Preferred original publication in this journal is cited, in accordance with accepted academic practice. Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines from No use, distribution or reproduction is the earliest published manuscript up to September 2, 2022, in seven electronic permitted which does not comply with these terms. databases, including clinical trials in patients with a SUD or non-substance-related disorder evaluating the efficacy of psilocybin. Results: A total of four studies (six articles, of which two articles were long-term follow-up results from the same trial) were included in this systematic review. Psilocybin-assisted therapy was administered to n = 151 patients in a dose ranging from 6 to 40 mg. Three studies focused on alcohol use disorder, and one study on tobacco use disorder. In a pilot study (n = 10), the percentage of heavy drinking days decreased significantly between baseline and weeks 5–12 (mean difference of 26.0, 95% CI = 8.7–43.2, p = 0.008). In another single-arm study (n = 31), 32% (10/31) became completely abstinent from alcohol (mean duration of follow-up 6 years). In a double-blind, placebo-controlled randomized controlled trial (RCT, n = 95), the percentage of heavy drinking days during the 32-week double-blind period was significantly lower for psilocybin compared to placebo (mean difference of 13.9, 95% CI = 3.0–24.7, p = 0.01). In a pilot study (n = 15), the 7-day point prevalence of smoking abstinence at 26 weeks was 80% (12/15), and at 52 weeks 67% (10/15). Frontiers in Psychiatry 01 frontiersin.org van der Meer et al. 10.3389/fpsyt.2023.1134454 Conclusion: Only one RCT and three small clinical trials were identified assessing the efficacy of psilocybin combined with some form of psychotherapy in patients with alcohol and tobacco use disorder. All four clinical trials indicated a beneficial effect of psilocybin-assisted therapy on SUD symptoms. Larger RCTs in patients with SUDs need to evaluate whether psilocybin-assisted therapy is effective in patients with SUD. KEYWORDS psilocybin, hallucinogens, substance-related disorders, substance abuse, drug addiction, psychotherapy Introduction these agents are closely related to the endogenous neurotransmitter serotonin [i.e., 5-hydroxytryptamine (5-HT)] and induce their effect Globally, the 12-month prevalence of substance use disorder via activation of the 5-HT2A -receptors (10). Sometimes, a more broad (SUD) is 2.2%, with alcohol use disorder as the most prevalent definition of psychedelics is used, and dissociates, and deliriants (e.g., (1.5%) of all SUDs (excluding tobacco use disorder). The 12- ketamine and ibogaine) are included as well, which have a different month prevalence of SUDs is even higher among high-income mechanism of action (9). Swiss chemist dr. Albert Hoffman first countries (1). Alcohol use accounts for 4.2% of all disability- synthesized LSD in 1938, (11) while he first identified psilocybin adjusted life-years (DALYs), while drug use accounts for 1.3% of and its active metabolite psilocin as the psychoactive compounds all DALYs worldwide (2). In addition to the detrimental health of the psilocybe mushrooms in 1958. In the subsequent year, he consequences, there are also enormous economic consequences of synthesized psilocybin, which was later marketed as Indocybin by SUD, with an estimated cost of $249 billion from alcohol, $300 the pharmaceutical company Sandoz (12). Throughout the 1950s billion from tobacco, and $193 billion from other drugs a year in and 1960s, considerable research was conducted investigating the the United States of America (USA) alone. Despite these adverse efficacy of LSD and psilocybin for various conditions, including health and economic consequences of SUDs, therapeutic options anxiety, depression, and existential distress in patients with terminal are still limited. Food- and Drug Administration (FDA) approved cancer, in patients with opioid use disorder, and in patients with medications are available for alcohol, tobacco, and opioid use alcohol use disorder (6, 13). Possible therapeutic mechanisms of disorders. Still, for other SUDs, such as cocaine and cannabis use psychedelics might be at the biochemical, neural, and psychological disorders, no approved medications are available (3). Relapse rates level (14). remain high across all SUDs, with >75% of patients with primary Krebs and Johansen (15) conducted a meta-analysis of cannabis and cocaine use disorder and >65% of primary alcohol randomized controlled trials (RCTs) evaluating the efficacy of and opioid use disorder showing relapse throughout 12 months LSD for alcohol use disorder. They identified k = 6 eligible trials, after evidence-based treatment (4). Arguably, relapse rates are even including n = 536 patients, and found a beneficial effect of LSD higher in non-substance-related disorders, as >90% of patients on alcohol use disorder with comparable efficacy to disulfiram with gambling disorder who had recently quit gambling showed (15). Savage and McCabe (16) also found a beneficial effect of relapse throughout 12 months (5). This means, there is an LSD on heroin use disorder in n = 78 inmates of correctional unmet need for effective treatments of SUD and non-substance- institutions (16). However, in 1970, the Controlled Substances related disorders. Act was signed into law by former USA President Richard Nixon Psychedelics [e.g., with lysergic acid diethylamide (LSD)] have placing psychedelics such as LSD and psilocybin in Schedule 1 (i.e., shown promising results as treatment of SUDs. In the majority has a high potential for abuse, has no currently accepted medical of studies, some form of psychotherapy was given in combination use in treatment, and has a lack of safety for use under medical with the psychedelic treatment, but not in all, which is usually supervision), which hindered conducting psychedelic research (17). referred to as psychedelic-assisted therapy (6). Psychedelic-assisted Other factors, such as negative publicity about psychedelics, doubts therapy comprises three stages: (1) preparation; (2) the psychedelic regarding their efficacy, and allocation of funding to related research session; and (3) integration. Preparation is thought to be vital fields (e.g., schizophrenia), increasingly discouraged research on for maximizing the potential benefit from the psychedelic session, psychedelics (18). while integration is believed to be important for prolonging the Recent years have seen a resurgence in psychedelic research, a improvements (7). Currently, interest in the efficacy of psychedelic development sometimes referred to as the psychedelic renaissance. treatment for SUDs is increasing (8). The term “psychedelic” was Since 2016, three systematic reviews have been conducted evaluating first proposed by Oswald in 1957 and comes from the Greek the efficacy of psychedelics (i.e., psilocybin, but also other classic words “psyche” (i.e., mind) and “deloun” (i.e., manifesting) and serotonergic psychedelics such as LSD were included in these refers to the subjective effects of these agents. A categorization of systematic reviews) as a treatment for psychiatric disorders (i.e., psychedelics can be made based on their chemical structure into SUD, but also other psychiatric disorders such as depression three different classes: (1) tryptamines (e.g., psilocybin); (2) ergolines and anxiety were included in these systematic reviews) (19–21). (e.g., LSD); and (3) phenethylamines (e.g., mescaline) (9). All Although these reviews provide an excellent overview of clinical Frontiers in Psychiatry 02 frontiersin.org van der Meer et al. 10.3389/fpsyt.2023.1134454 trials published in the last 25 years, including multiple psychedelics Data extraction and conditions, they may have missed clinical trials evaluating the efficacy of psychedelics that were conducted before the 1980s From the included studies, the following data was collected: (19–21). As shown by Fuentes et al. (6), many trials have been names of authors; year of publication; study design; number and conducted assessing the efficacy of LSD in SUD in these early characteristics of patients; characteristics of the psilocybin and decades, which may have been an important era for psilocybin psychotherapeutic intervention; and non-substance-related disorder research as well (6). In addition, many trials evaluating the efficacy or SUD-related outcome(s). of psilocybin in SUDs have been started since 2016, some of which may already have been published and not yet included in previous systematic reviews. Therefore, we performed a systematic review Quality assessment without restrictions on publication date. Our aim was to assess the efficacy of psilocybin in patients with SUD and non-substance-related The Risk Of Bias In Non-randomized Studies—of Interventions disorders. In addition, a quality assessment was done of the included (ROBINS-I) tool was used to assess the risk of bias in the included clinical trials. non-randomized studies. The assessment of each included study in the review followed the following six steps: (1) to specify the research question through consideration of a target trial; (2) to specify the Methods outcome and result being assessed; (3) for the specified result, to examine how the confounders and co-interventions were addressed; Search strategy (4) to answer signaling questions for the seven bias domains; (5) formulate risk of bias judgments for each of the seven bias domains; We performed a systematic literature search up to September and (6) formulate an overall judgment on risk of bias for the outcome 2, 2022 (in each database from the earliest published manuscript, and result being assessed (low risk of bias, moderate risk of bias, which dates back to 1781 in the case of PubMed), in the serious risk of bias, critical risk of bias, or no information on which electronic databases: PubMed, Embase, Web of Science, Cochrane to base a judgment about risk of bias) (23). The revised Cochrane Library, Emcare, PsychINFO, and Academic Search Premier. The risk-of-bias tool for randomized trials (RoB 2) was used to assess the Preferred Reporting Items for Systematic reviews and Meta-Analysis risk of bias in the included randomized studies. Comparable as to (PRISMA) guidelines served as guiding principles for reporting in the ROBINS-I tool, the ROB 2 tool followed the following six steps: our systematic review (22). The search included a combination (1) specify results being assessed; (2) specify the effect of interest; (3) of terms related to “psilocybin” and “addiction.” The complete list the sources of information used to inform assessment; (4) answer search strategy can be found in the Supplementary material. Two signaling questions for the five bias domains; (5) judge risk of bias for authors (PM and JF) independently screened the articles by title and each domain; and (6) judge overall risk of bias for the result being abstract and full-text articles were obtained for all potentially relevant assessed (low risk of bias, some concerns, high risk of bias) (24). articles. In case of disagreement between the two authors, a third Quality assessment was based on the primary efficacy outcome in the author (AB) was consulted to decide whether or not the full-text included studies. article should be obtained. Subsequently, the full-text articles were reviewed for inclusion by the same two authors. The reference lists of these full-text articles were searched, but no additional studies were Results found. In addition, a systematic search was done in the electronic databases: clinicaltrials.gov, and clinicaltrialsregister.eu, to identify We retrieved a total of k = 6832 unique records through our ongoing trials evaluating the efficacy of psilocybin in SUDs and systematic search in various electronic databases (Figure 1). After non-substance-related disorders. screening titles and abstracts, k = 36 full-text articles were assessed for eligibility, and k = 6 articles were finally included in this systematic review. K = 2 articles were long-term follow-up results from the same Eligibility criteria clinical trial. All included clinical trials were conducted either in the USA or Poland. The following inclusion criteria were established: intervention A total of k = 130 registered clinical trials were identified through with ≥1 dose of psilocybin; clinical trial (open-label [pilot] studies, our systematic search in the two trial databases (Supplementary single-blind, or double-blind [placebo-controlled] trials); diagnosis Figure 1). After screening, k = 11 ongoing trials on September 2, 2022, of a SUD or non-substance-related disorder [i.e., diagnosed by were included in this systematic review. the general practitioner or by a structured clinical interview based on Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) criteria]; Alcohol an outcome assessing severity of substance use or abstinence; adult patients (≥18 years); ≥10 patients, and language of the manuscript Three studies were included assessing the efficacy of psilocybin- was English, Spanish, Portuguese, Dutch, Germany, or French. assisted therapy in patients with alcohol use disorder (Table 1). In The following studies were excluded: animal studies; experimental the first study by Bogenschutz et al. (25), n = 10 patients were studies in healthy volunteers; observational studies; review papers; included with a diagnosis of active alcohol dependence according to qualitative studies; opinion pieces or comments; letters or editorials; the DSM, 4th edition (DSM-IV), ≥2 heavy drinking days [defined as conference abstracts or posters; and case reports. a day of ≥5 standard drinks (i.e., 14 g of alcohol) for males and ≥4 Frontiers in Psychiatry 03 frontiersin.org van der Meer et al. 10.3389/fpsyt.2023.1134454 FIGURE 1 Flowchart of identified records and eventually included clinical trials. standard drinks for females] in the past 30 days, who were concerned Patients in the diphenhydramine treatment arm received two sessions about their drinking, and not currently in treatment. Patients at week 4 (50 mg) and week 8 (50–100 mg), and the same psychosocial received two sessions with psilocybin at week 4 (21 mg/70 kg) and intervention. The percentage of heavy drinking days during the week 8 (28 mg/70 kg), and a psychosocial intervention comprising 32-week double-blind period was significantly lower for psilocybin 12 sessions, 7 sessions of motivational enhancement therapy, 3 compared to diphenhydramine [mean 9.7 (SD = 26.2) vs. mean 23.6 preparation sessions, and 2 debriefing sessions. The percentage of (SD = 26.1), mean difference of 13.9, 95% CI = 3.0–24.7, Hedges heavy drinking days decreased significantly between baseline and g = 0.52, p = 0.01]. The percentage of patients completely abstinent weeks 5–12 [mean difference of 26.0% (SD = 22.4), 95% CI = 8.7– from alcohol during the 32-week double-blind period did not differ 43.2, p = 0.008]. Both percentage of drinking days and heavy drinking significantly between psilocybin 22.9% vs. diphenhydramine 8.9% days remained significantly lower compared to baseline during the (OR = 3.1, 95% CI = 0.9–10.4, p = 0.06). Almost all patients and study complete duration of follow-up of 36 weeks. Percentage of patients therapists correctly guessed the treatment assignment at the first (94 completely abstinent from alcohol was not reported. Treatment- and 92%) and the second (95 and 97%) session, respectively. No related adverse effects were all mild, five patients reported headaches, serious adverse events occurred in the psilocybin treatment arm (26). while one patient reported nausea, diarrhea, and insomnia (25). In the third study by Rydzyński et al. (27, 28), n = 31 patients In the second study by Bogenschutz et al. (26), a double-blind, with alcohol use disorder were included with ≥1 failed quit attempt placebo-controlled RCT, n = 95 patients with a DSM-IV diagnosis of regarding their alcohol use despite treatment and not treated earlier active alcohol dependence, ≥4 heavy drinking days (same definition with psilocybin and/or LSD. Patients first received psilocybin 6– for heavy drinking day as in the first study was used) in the past 30 mg (mean 12 mg), next LSD 100–800 mcg, and subsequently, 30 days and not currently in treatment were randomized 1:1 to for every 3 LSD sessions a psilocybin session. Each session had either psilocybin or active placebo diphenhydramine. Patients in the a 5–7 day interval. In addition, patients received psychotherapy. psilocybin treatment arm received 2 sessions at week 4 (25 mg/70 kg) Eventually, treatment with LSD was abandoned and only psilocybin and week 8 (25–40 mg/70 kg), and a psychosocial intervention. treatment was continued, because psilocybin had more favorable Frontiers in Psychiatry 04 frontiersin.org van der Meer et al. 10.3389/fpsyt.2023.1134454 TABLE 1 Clinical trials evaluating the efficacy of psilocybin in substance-use disorders. Article and Study design Participants Substance use Intervention Control group Follow-up Primary country disorder outcome Bogenschutz Non-randomized N = 10 (4 women and 6 Alcohol Psilocybin 21 mg/70 kg at No 36 weeks Percentage heavy et al. (25), men), mean age week 4 and 28 mg/70 kg at drinking days United States of 40.1 years (SD = 10.3), week 8 + a psychosocial baseline vs. America mean duration alcohol intervention (12 sessions) weeks 5–12 use disorder 15.1 years (SD = 11.5), recruited using advertisements in local media Bogenschutz Randomized N = 95 (42 women and Alcohol Psilocybin 25 mg/70 kg- at Diphenhydramine 36 weeks Percentage heavy et al. (26), 53 men), mean age week 4 and 25–40 mg/70 kg 50 mg at week 4 and drinking days United States of 45.8 years (SD = 11.6), at week 8 + a psychosocial 50–100 mg at week over a 32-week America mean duration alcohol intervention (12 sessions) 8 + a psychosocial period use disorder 14.2 years intervention (12 (SD = 9.7), recruited sessions) using advertisements in local media Rydzyński et al. Non-randomized N = 31 (31 men), mean Alcohol Alternating psilocybin No Mean 6 years Percentage (27, 28), Poland age 37.9 years (SD 6–30 mg (mean 15 sessions) abstinent from unknown), mean and LSD 100–800 mcg (mean alcohol duration of alcohol use 12 sessions) in 5–7 day disorder unknown, intervals + psychotherapy recruitment method (number of sessions unknown unknown) Johnson et al. Non-randomized N = 15 (5 women and 10 Tobacco Psilocybin 20 mg/70 kg at No 52 weeks Seven-day point (29, 30), men), mean age week 5; 30 mg/70 kg at week 7 prevalence United States of 51.0 years (SD = 10.5), and 9 + cognitive behavioral abstinence at 26 America mean duration of therapy (4 sessions) and 52 weeks smoking 31.0 years (SD = 9.9), recruited using advertisements SD, standard deviation. efficacy and fewer adverse effects, according to the authors. The of 30 months (range = 16–57 months)] 60% (9/15) of patients was percentage of patients that became completely abstinent from alcohol abstinent (30). All reported treatment-related adverse effects were (mean duration of follow-up 6 years) was 32% (10/31), 32% (10/31) mild. Six patients reported fear, fear of insanity, or feeling trapped was abstinent from alcohol for 6–12 months, and 58% (18/31) of during the psilocybin session, and eight patients reported headaches. patients had a “satisfactory therapeutic effect,” which was not further Two RCTs with a follow-up duration of 52 weeks are being defined by the authors. No treatment-related somatic nor psychiatric conducted, assessing the efficacy of a single dose of psilocybin serious adverse effects were observed (27, 28). vs. nicotine replacement and two doses of psilocybin vs. placebo At least 5 RCTs are ongoing assessing the efficacy of psilocybin in (niacin), respectively. patients with alcohol use disorder, including a double-blind, placebo- controlled RCT, in patients with comorbid alcohol use disorder and major depressive disorder (Table 2). Opioids No studies were identified that evaluated the efficacy of psilocybin Tobacco in patients with opioid use disorder. Currently, a double-blind, placebo-controlled RCT assessing the efficacy of psilocybin for opioid One study by Johnson et al. (29, 30) was included assessing use disorder in patients on opioid agonist (methadone) treatment the efficacy of psilocybin-assisted therapy in n = 15 patients who with ongoing opioid use and an open-label pilot study assessing met the following criteria: smoking ≥10 cigarettes per day, being the efficacy of psilocybin in patients with opioid use disorder on healthy as determined by medical interview, multiple unsuccessful buprenorphine/naloxone treatment is being conducted. past quit attempts, and the desire to quit smoking. The intervention consisted of three psilocybin sessions at week 5 (0.3 mg/kg), week 7, and week 9 (both 0.4 mg/kg), and four cognitive behavioral therapy sessions. Seven-day point prevalence of abstinence from smoking Cocaine at 26-week follow-up was 80% (12/15) based on both biomarkers assessing smoking status and self-report outcome measures (29). At No studies were identified evaluating the efficacy of psilocybin 52 weeks, 67% (10/15) of patients were confirmed abstinent from in patients with cocaine use disorder. A pilot double-blind, placebo- smoking, and at long-term follow-up [≥16 months, mean interval controlled RCT assessing the efficacy of psilocybin for cocaine use Frontiers in Psychiatry 05 frontiersin.org van der Meer et al. 10.3389/fpsyt.2023.1134454 disorder and MRI assessment to determine a potential biological assessment (15). This is in stark contrast with the number of clinical mechanism of psilocybin’s effect is ongoing. trials evaluating the efficacy of psilocybin in patients with SUD before the 1980s, which was only one, and was contrary to our expectations. One trial evaluating psilocybin in patients with alcohol use disorder Amphetamine and its derivatives conducted in the 1960s was excluded from this systematic review. It did not include an outcome assessing severity of substance use or No studies were identified evaluating the efficacy of psilocybin abstinence, but only evaluated treatment-related adverse effects (31). in patients with amphetamine (or derivatives) use disorder. An Three trials included in this systematic review were conducted in RCT evaluating the efficacy of psilocybin-enhanced psychotherapy the 21st century in the era after the Controlled Substances Act was in patients with methamphetamine use disorder is currently signed in 1970, while no trial has been conducted in the past four recruiting participants with its primary aim of assessing acceptability, decades evaluating the efficacy of LSD in SUD (6). Although it has feasibility, and safety. been claimed that >2000 publications have been published evaluating psychedelics in conditions such as SUD, it seems that the majority used LSD as intervention, not psilocybin (32, 33). Both LSD and psilocybin primarily act via stimulation of the 5-HT2A -receptors, but Benzodiazepines or hypnotics, caffeine, LSD exhibits additional affinity for dopaminergic and α-adrenergic cannabis, hallucinogens, ketamine, receptors (34). The acute effects of LSD (100 and 200 µg) were inhalants, or other (or unknown) directly compared to psilocybin (15 and 30 mg) in a double-blind, substances, gambling, and gaming placebo-controlled RCT in healthy volunteers. The two psychedelics showed qualitatively, and quantitatively very similar subjective effects No studies were identified evaluating the efficacy of psilocybin and differences in effect are dose-dependent rather than compound- in patients with benzodiazepines or hypnotics, caffeine, cannabis, dependent. The onset of effects is significantly earlier, and the hallucinogens, ketamine, inhalants or other (or unknown) substances duration is substantially longer in LSD compared to psilocybin (35). use disorder, nor in patients with a gambling or gaming disorder. A dose of 30 mg psilocybin, which is comparable to the dosages used by Bogenschutz et al. (25), Bogenschutz et al. (26), and Johnson et al. (29), (25, 26, 29) was found similar to 100 and 200 µg LSD (35). However, in the meta-analysis by Krebs and Johansen (15), Quality assessment of studies which showed a beneficial effect of LSD on alcohol use disorder, 83% (5/6) of included trials used a single fixed dose of ≥450 µg The risk of bias has been assessed in the three non-randomized LSD with a maximum of 800 µg LSD (15). It is unclear whether (Table 3) and the one randomized (Table 4) clinical trials higher and/or multiple dosages translate to a more favorable effect (Supplementary Table 1). The three non-randomized trials were than lower and/or single dosages of psilocybin or LSD. In addition, assessed as having a serious to critical risk of bias, and the randomized all the included studies in this systematic review adjusted psilocybin clinical trial was assessed as having some concerns of risk of bias. dose to body weight, (25–30) although there is no clear benefit for this adjustment and fixed dosing is more practical in clinical trials (35, 36). Discussion Proposed working mechanisms of psychedelics, including psilocybin, for improving psychiatric symptoms such as depression In this systematic review, four clinical trials (n = 151 patients) and SUD are both biological (e.g., by inducing brain neuroplasticity assessing the efficacy of psilocybin in SUD were included, of which through elevating Brain-Derived Neurotrophic Factor (BDNF) three clinical trials were in patients with alcohol use disorder and levels, which are diminished in psychiatric conditions) (34) and one clinical trial was in patients with tobacco use disorder. One of psychological (e.g., the degree to which a patient has a mystical- the trials in patients with alcohol use disorder was a double-blind, type experience during the psilocybin session seems an important placebo-controlled RCT; the other three trials were single-arm pilot mediator for the enduring effect of the psilocybin) (25, 37). The latter studies with a substantial risk of bias. All four clinical trials, which proposed working mechanism seems especially important in SUD combined psilocybin with some form of psychotherapy, provided as the mystical-type experience seems to induce behavioral change evidence for a significant beneficial effect of psilocybin-assisted in a patient with SUD. This working mechanism would also explain therapy in patients with either alcohol or tobacco use disorder. These why psychedelics seem effective in different SUDs as opposed to the encouraging results have resulted in several (double-blind, placebo- currently approved pharmacological treatments for SUD, which have controlled) RCTs currently ongoing in alcohol, tobacco, cocaine, a different working mechanism and are, in most cases, only effective opioid, and methamphetamine use disorders. Notable is the lack of in a specific SUD (e.g., disulfiram in alcohol use disorder). trials evaluating the efficacy of psilocybin in patients with cannabis In the design of clinical trials (with psilocybin treatment), several use disorder, despite the high prevalence and the lack of any approved important issues need to be taken into account, including an adequate medications for this condition. control group, randomization, blinding, and generalizability of the Fuentes et al. (6) showed in their systematic review that eight results. Regulatory agencies even recognize single-arm trials with eligible RCTs evaluating the efficacy of LSD in patients with alcohol external historical controls to assess promising treatments for specific use disorder and one eligible RCT in patients with opioid use indications. However, three trials in this systematic review were non- disorder were conducted in the 1950s, 1960s, and 1970s (6). Krebs randomized, had no adequate control group, and were therefore and Johansen (15) identified 33 clinical trials, of which only six prone to bias. Preferably, future trials are double-blind, placebo- met modern-day criteria of randomization, blinding, and outcome controlled RCTs to account for a potential placebo effect. Most Frontiers in Psychiatry 06 frontiersin.org Frontiers in Psychiatry van der Meer et al. TABLE 2 Clinical trials being conducted on September 2, 2022 evaluating the efficacy of psilocybin in substance-use disorders. Principle Study design Estimated Substance use Intervention Control group Follow-up Primary outcome(s) ID investigator enrolment disorder A. Fink-Jensen RCT N = 90 Alcohol Single dose of psilocybin Placebo (lactose) + psychological 12 weeks Change in percentage of heavy a NCT05416229 25 mg + psychological support support drinking days, from baseline until week 12 P. C. Nopoulos RCT N = 20 Alcohol Single dose of psilocybin Psychotherapy only 8 weeks Change in daily alcohol use over the a NCT05421065 30 mg + psychotherapy course of 8 weeks K. Preller RCT N = 60 Alcohol Single dose of psilocybin 25 mg Placebo (mannitol) 26 weeks Change in alcohol use behavior (i.e., a NCT04141501 daily alcohol use), from baseline until 6 months after intervention F. S. Barrett RCT N = 90 Alcohol and major Single dose of psilocybin Placebo (microcrystalline 52 weeks Change in percentage days a NCT04620759 depressive disorder 25 mg + psychotherapy cellulose) + psychotherapy abstinent/heavy drinking days, from baseline until 3 months after first drug intervention PSY-CLA Study RCT N = 160 Alcohol Psilocybin 25 mg (unclear single or Placebo + psychotherapy 24 weeks Mean number of heavy drinking days b 2021-006200-33 Contact multiple doses) + psychotherapy over 8 week treatment period M. W. Johnson RCT N = 95 Tobacco Single dose of psilocybin Nicotine replacement 52 weeks Urinary cotinine/breath carbon a NCT01943994 07 30 mg + psychotherapy therapy + psychotherapy monoxide, at 3, 6, and 12 months follow-up M. W. Johnson RCT N = 66 Tobacco Two doses of psilocybin 30 mg and Two doses of niacin 150 mg and 52 weeks Seven-day point prevalence a NCT05452772 30–40 mg 1 week 150–200 mg 1 week abstinence at 52 weeks apart + psychotherapy apart + psychotherapy M. W. Johnson RCT N = 92 Opioids Single dose of psilocybin Placebo + methadone maintenance 12 weeks Change in non-methadone opioid a NCT05242029 40 mg + methadone maintenance program use, from baseline until 3 months program after first drug intervention R. Brown Non-randomized N = 10 Opioids Two doses of psilocybin 4 weeks No 9 weeks Mean change in symptoms of opioid a NCT04161066 apart + (preparatory) counseling withdrawal up to 5 weeks P. Hendricks RCT N = 40 Cocaine Single dose of psilocybin Diphenhydramine 24 weeks Difference in percentage days a NCT02037126 0.36 mg/kg + psychotherapy 100 mg + psychotherapy abstinent from cocaine/difference in complete sustained abstinence from cocaine/time to cocaine relapse C. Stauffer RCT N = 30 Methamphetamine Two doses of psilocybin (25 and Treatment-as-usual 32 weeks Methamphetamine use (secondary a NCT04982796 10.3389/fpsyt.2023.1134454 30 mg) 2 weeks apart + psychotherapy outcome), from baseline until 2 months after discharge from admission a ClinicalTrials.gov. frontiersin.org b Clinicaltrialsregister.eu. van der Meer et al. 10.3389/fpsyt.2023.1134454 TABLE 3 Quality assessment of the included non-randomized intervention studies based on the risk of bias. References Confounding Selection of Classification Deviations Missing Measurement Selection Overall risk patients of from data of outcomes of reported of bias interventions intended results interventions Bogenschutz Serious Low Low Low Moderate Serious Low Serious et al. (25) Rydzyński et al. Critical Low Low Low Low Serious Serious Critical (27, 28) Johnson et al. Serious Low Low Low Low Moderate Low Serious (29, 30) Classifications of quality: low, moderate, serious, critical risk of bias, or no information. TABLE 4 Quality assessment of the included randomized intervention studies based on the risk of bias. Reference Randomization Deviations from Missing Measurement of Selection of the Overall risk of process intended outcome data the outcome reported results bias interventions Bogenschutz et al. (26) Low Low Low Some concerns Low Some concerns Classifications of quality: low, some concerns, high risk of bias. tobacco use disorder patients had a past use of psychedelics, which (therapy control); and (4) placebo + alcohol education. The greatest could have influenced the expectancy of these patients regarding the reduction in alcohol use was seen in the ketamine + psychotherapy efficacy of psilocybin and have thus an effect on the results (29). group vs. placebo + alcohol education (mean difference of 15.9, 95% Pretreatment-positive expectations about psychedelic microdosing CI = 3.8–28.1) (40). It seems the eventual treatment strategy will likely predicted improvements in psychiatric symptoms (38). A meta- consist of psilocybin combined with psychotherapy, given the latter analysis by Wilkinson et al. (39) evaluating the efficacy of ketamine seems to be needed to derive meaning from the psilocybin sessions for major depressive disorder or bipolar disorder showed a dramatic and incorporate insights from the psilocybin sessions into daily life reduction in effect size when comparing the impact of an inactive and change current substance use behavior. However, alternative (saline) to the active placebo midazolam (effect size d = 1.8, 95% hypotheses assume more direct pharmacological working mechanism CI = 1.4–2.2 vs. d = 0.7, 95% CI = 0.4–0.9) (39). Despite comparing of psychedelics, and thus microdosing would be a potential treatment psilocybin to an active placebo, Bogenschutz et al. (26) still observed eliminating the need for a psychedelic experience. However, so far, a medium effect size for the efficacy of psilocybin. However, even in a results with psychedelic microdosing are less promising (41). double-blind, placebo-controlled RCT, this problem with expectancy Currently, > 10 clinical trials are registered evaluating the effects, a key contributor to the placebo response, is not easily efficacy of psilocybin in SUD, most are in alcohol use disorder. accounted for given >90% of patients and study therapists correctly Other patient populations include tobacco, cocaine, opioids, and guessed treatment assignment to either psilocybin or the active methamphetamine use disorder. Conducting clinical trials in alcohol placebo diphenhydramine (26). Maintaining successful masking and tobacco use disorder can be understood from their high remains a major challenge in psychedelic clinical trials for which there prevalence worldwide. It is less clear why no clinical trials in is not yet an adequate solution. Another challenging problem is the cannabis use disorder are currently conducted as it is the most generalizability of the results. Johnson et al. (29) screened n = 323 common drug use disorder worldwide, especially among youth individuals, and only n = 15 (5%) patients were eventually included. (42). Other interesting patient populations to study the efficacy of (29) Bogenschutz et al. (25) screened n = 70 individuals, and only psilocybin would be benzodiazepines or hypnotics use disorder and n = 10 (14%) patients were eventually included (25). Bogenschutz gambling disorder, for which there is a pressing need for effective et al. (26) screened n = 569 individuals, and only n = 95 (17%) treatments. Almost all registered trials have a control group and are were eventually randomized (26). From a safety point of view strict randomized. The risk of confounding, which was serious to critical in- and exclusion criteria makes sense. Still, a risk is that external in the included non-randomized studies in this systemic review, validity is relatively low and that diminished effects will be observed is minimized. The registered RCT by Johnson (ClinicalTrials.gov with psilocybin in a therapeutic setting (33). Coadministration of Identifier: NCT01943994) is of special interest, evaluating the an extensive psychological treatment (motivational enhancement efficacy of psilocybin combined with psychotherapy versus an therapy and cognitive behavioral therapy) during the clinical trials approved pharmacological treatment (i.e., nicotine replacement makes interpretation of the treatment effect of psilocybin on alcohol therapy) combined with psychotherapy. Here, psilocybin will be and tobacco use disorder even more difficult (25, 26, 29). Ideally, compared for the first time with an approved active pharmacological an RCT would compare four different treatment arms as in the treatment (in patients with SUD). Maintaining masking in double- RCT by Grabski et al. (40) evaluating the efficacy of adjunctive blind, placebo-controlled RCTs evaluating psychedelics is usually ketamine in patients with alcohol use disorder to separate the unsuccessful, which may result in an increased effect size for different treatment effects. In this double-blind, placebo-controlled the efficacy of psilocybin. It is essential to know how psilocybin RCT, the four treatment arms were: (1) ketamine + psychotherapy; compares to approved pharmacological treatments and its effect size (2) placebo + psychotherapy; (3) ketamine + alcohol education in comparative efficacy trials. Given that psychological treatments Frontiers in Psychiatry 08 frontiersin.org van der Meer et al. 10.3389/fpsyt.2023.1134454 have high relapse rates in the long term, the limited number of Author contributions available approved pharmacological interventions for SUD, and the high adverse health and economic consequences of SUDs, alternative PM and AB designed the study. PM and JF reviewed the treatment options are highly warranted for this population. abstracts and the manuscripts, obtained the data from the selected Psilocybin has shown promising first results in SUD treatment manuscripts, and performed the quality assessment of the included that should be replicated and established in larger trials. Questions manuscripts. PM wrote the first and successive versions of the whether psychotherapy is a necessary treatment component for manuscript. PM, JF, AK, JS, MW, AG, KK, AS, MS, MB, and AB psilocybin to be effective and if so, what form of psychotherapy is contributed to the interpretation of the results, critical revisions to the indicated, and whether higher and/or multiple dosages translate to drafts of the manuscript, and approved the final version. All authors a more favorable effect compared to lower and/or single dosages of contributed to the article and approved the submitted version. psilocybin are not addressed in the currently registered clinical trials. The results of ongoing and future studies assessing the efficacy of psychedelics in SUD will reveal their true potential. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be Conclusion construed as a potential conflict of interest. In this systematic review, we identified only one double-blind, placebo-controlled RCT, and three small clinical trials, of which three were conducted in the 21st century assessing the efficacy of psilocybin Publisher’s note in patients with alcohol and tobacco use disorder. All four studies combined psilocybin with some form of psychotherapy and showed All claims expressed in this article are solely those of the a beneficial effect of psilocybin-assisted therapy on SUD, but the risk authors and do not necessarily represent those of their affiliated of bias ranged from some concerns to critical. Future (double-blind, organizations, or those of the publisher, the editors and the reviewers. placebo-controlled) RCTs in patients with SUD need to evaluate Any product that may be evaluated in this article, or claim that may whether psilocybin-assisted therapy is effective in this population. be made by its manufacturer, is not guaranteed or endorsed by the publisher. Data availability statement Supplementary material The original contributions presented in this study are included in The Supplementary Material for this article can be found online the article/Supplementary material, further inquiries can be directed at: https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1134454/ to the corresponding author. full#supplementary-material References 1. Castaldelli-Maia J, Bhugra D. Analysis of global prevalence of mental and substance 9. Kelmendi B, Kaye A, Pittenger C, Kwan A. Psychedelics. Curr Biol. (2022) 32:R63–7. use disorders within countries: focus on sociodemographic characteristics and income doi: 10.1016/j.cub.2021.12.009 levels. Int Rev Psychiatry. (2022) 34:6–15. doi: 10.1080/09540261.2022.2040450 10. McClure-Begley T, Roth B. The promises and perils of psychedelic pharmacology for 2. Degenhardt L, Charlson F, Ferrari A, Santomauro D, Erskine H, Mantilla-Herrara A, psychiatry. Nat Rev Drug Discovery. 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