The Therapeutic Potential of Psychedelics in Treating Substance Use Disorders: A Review of Clinical Trials

This paper presents a systematic review focused on experimental research aimed at exploring the effects of psychedelics on human subjects with different addictions. The goal was to identify and analyze the latest studies within the past decade (2013–2023), following the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocols [20].

For the literature search, electronic methods were employed to find articles pertinent to the research, and a manual review of references in the chosen publications was conducted. The authors reviewed the findings' titles and abstracts to assess their relevance based on the inclusion criteria.

Articles were searched using PubMed, Google Scholar, and the AI tool Consensus for the following principal expression: ["psychedelics-assisted therapy in addiction"]. Our research aimed to analyze the latest research on PAT, restricting our search period from 1 January 2013 to 31 December 2023. Two authors reviewed the search results, specifically the titles and abstracts. Each publication deemed potentially relevant during the search was scrutinized for its suitability for this review, with a thorough assessment based on predefined inclusion and exclusion criteria. Eight thousand, seven hundred and thirty-four articles were excluded from the review primarily because they did not align with the study's focus, such as addressing PAT in contexts other than addiction, or because they were identified as reviews, meta-analyses, non-experimental studies, book chapters, or research protocols.

Our investigation focused on clinical trials and randomized controlled trials conducted between 2013 and 2023 and published in English. We specifically chose studies that involved psychedelic substances such as LSD, psilocybin, MDMA, and ayahuasca/DMT for treating various addictions, including alcohol, tobacco, and other drugs. We excluded naturalistic and correlational studies, book chapters, review articles, and case reports. The research needed to present unique datasets. We did not include studies on healthy subjects, animal research, reviews, or meta-analyses.

Several key details were gathered from the studies, including the lead author, publication year, study location, study design, number of participants, the patients' types of addiction, the psychedelics used, the dosages given, the target condition, outcome measures, and details of the administration and treatment program setting. In the end, each study's principal findings and conclusions were documented.

A total of 10,325 papers were found by searching through databases like PubMed, Google Scholar, and Consensus AI. After eliminating 40 duplicate entries and excluding 8734 articles not aligned with the study's focus, 1551 articles were selected for further screening. Upon closer examination, an additional 876 articles were excluded, primarily because they addressed PAT in the context of psychiatric disorders other than addiction. We removed articles identified as reviews, meta-analyses, non-experimental studies, book chapters, or research protocols, in line with our inclusion criteria. Ultimately, 16 essential articles from the last decade, consisting of clinical trials and randomized controlled trials specifically investigating the use of PAT in treating addiction, were included in our review. The PRISMA flowchart in Figure 1 illustrates the detailed selection process, ensuring a systematic approach to identifying the most relevant and high-quality studies for our analysis.

The articles included in the study had several key features: year of publication, study design, number of participants, type of addiction studied, psychedelic substance and dosage used, target condition, outcome measures, setting, primary findings, and treatment program details (Table 1). These characteristics were selected to ensure a comprehensive understanding of how PAT is applied in treating SUD.

We focused on the year of publication to analyze recent trends, as research on psychedelics has gained momentum in the last decade. Knowledge of the study design, such as randomized controlled trials (RCTs) or open-label studies, helps assess the quality and reliability of the findings. The number of participants is important for understanding the statistical power of each study. The type of addiction and psychedelic substance used provide insights into which substances are being studied for specific disorders.

Outcome measures, such as changes in substance use and psychological effects, help gauge the treatment's efficacy. Additionally, setting details (clinical or community-based) provide context on how these therapies are administered. The main findings highlight the effectiveness of the treatment, while treatment program details allow for the comparison of different therapeutic approaches.

This systematic approach helped ensure that only relevant, high-quality studies were included in the analysis of PAT for addiction. In this study, a summary of research exploring the use of psychedelics in addiction treatment is provided. The Table 1 highlights key details, including the first author, publication year, DOI, study design, number of participants, type of dependency studied, psychedelic used (including dosage), and the target condition (Table 1).

We began by performing a descriptive analysis of the articles in this review, closely examining the features of recent studies on psychedelic therapy for SUD patients. There were no restrictions regarding the patients' countries of origin or where the studies were conducted. Between 2013 and 2023, 11 relevant articles met the research methodology's inclusion criteria. The median publication year was 2016, highlighting the growing importance and interest in this field within the scientific community. In terms of study designs, the review included four randomized controlled trials [21,22,24,29], three open-label pilot studies [23,26,28], one cross-sectional study [30], two qualitative studies [25,31], and one prospective experimental study [27]. When categorizing by addiction type, the studies covered alcohol dependence (four) [21,22,23,25] and tobacco users trying to quit smoking (four) [26,28,30,31], with one study on illicit drug users [24], one on cocaine addiction [29], and one focusing on mixed dependencies (alcohol, tobacco, and cocaine) [27]. The study sample sizes ranged from 10 to 358 patients, with an average of 55.18 participants, a median of 15, and a standard deviation of 98.58. The studies used various psychedelics, mainly psilocybin, ibogaine, and ayahuasca. Psilocybin was often administered at 25 mg/70 kg, though some studies did not specify amounts [21,22,23,24,26,28,29,31]. Ayahuasca was given in traditional doses without exact measurements [25,27]. One study used noribogaine in increasing concentrations [24]. One study used ketamine at 0.71 mg/kg [29], and another combined psilocybin and LSD without stating dosages [30]. Overall, dosage varied across studies, showing different approaches.

Each study had a different focus, but most evaluated substance use (alcohol, smoking, or cocaine), cravings, and psychological effects. O'Donnell and Bogenschutz [21,23], both from the University of New Mexico, centered on alcohol use, cravings, and psychological impacts. Agin-Liebes explored self-compassion and emotional regulation [22], while Garcia-Romeu and Johnson examined smoking cessation biomarkers and mystical experiences [26,28]. Dakwar assessed cocaine self-administration alongside mystical experiences, while Thomas and Loizaga-Velder concentrated on mindfulness, empowerment, and personal transformation, particularly in culturally integrated settings [25,27].

The settings varied from clinical environments to community-based retreats. O'Donnell, Agin-Liebes, and Bogenschutz conducted studies at the University of New Mexico [22,23] using structured environments conducive to psychotherapy. Glue evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of noribogaine in opioid-dependent patients seeking to discontinue methadone treatment, highlighting findings related to dose-dependent effects on QTc interval, opioid withdrawal symptoms, and adverse events [24]. Loizaga-Velder's work was set in a traditional ayahuasca retreat in Mexico, emphasizing spiritual transformation, while Thomas conducted his research in a First Nations community with traditional ceremonies [25,27]. Garcia-Romeu and Johnson worked at Johns Hopkins University, and Dakwar operated out of Columbia University, focusing on cocaine addiction with ketamine [26,28,29,30].

These studies demonstrated that psychedelics have the potential to reduce substance use and enhance psychological well-being. O'Donnell and Bogenschutz found that psilocybin significantly reduced alcohol cravings [21,23]. Agin-Liebes reported that psilocybin helped with emotional release and improved coping, resulting in decreased alcohol consumption [22]. Garcia-Romeu and Johnson's studies on smoking cessation showed long-term success, with up to 67% abstinence at 12 months [26,28,30]. Thomas and Loizaga-Velder reported positive effects on mindfulness and empowerment from ayahuasca therapy [25,27]. Dakwar's research revealed that mystical experiences with ketamine reduced cocaine use, highlighting the role of subjective experiences in treatment [29].

The treatment approaches varied widely. O'Donnell and Bogenschutz combined manualized psychotherapy with psilocybin sessions, with O'Donnell using a 12-week program and scheduled psilocybin doses [21,23]. Agin-Liebes offered 8 h psilocybin sessions, while Garcia-Romeu and Johnson integrated psilocybin with cognitive behavioral therapy (CBT) and mindfulness techniques for smoking cessation [22,26]. Thomas and Loizaga-Velder used ayahuasca group therapy with a solid cultural emphasis [25,27]. Dakwar's study was distinctive in using ketamine without psychotherapy, relying solely on the mystical experience for cocaine reduction [29].

Clinical settings like those used by O'Donnell, Agin-Liebes, and Bogenschutz emphasized structured environments with monitored psilocybin sessions and psychotherapy, showing evident reductions in alcohol use [21,22,23]. Garcia-Romeu and Johnson's studies highlighted psilocybin's effectiveness when combined with CBT for smoking cessation. In contrast, Thomas and Loizaga-Velder's naturalistic, culturally embedded studies emphasized the spiritual and transformative potential of psychedelics [25,26,27,28,30]. Dakwar's ketamine study, which lacked psychotherapy, demonstrated that psychedelic experiences alone can influence substance use outcomes, mainly through mystical experiences [29] (Table 2).

Our systematic review found five relevant studies in the previous ten years that investigated the effect of psychedelics on patients with alcohol dependence using different substances (psilocybin and ayahuasca brew).

Psilocybin has a relatively short duration of consciousness-altering effects (4–6 h) and a well-established safety profile, especially in clinical settings [21,23]. It has been shown to promote neuroplasticity, which may help with sustained behavior change, and its therapeutic effects are often tied to the intensity of the psychedelic experience, including mystical-type experiences that shift participants' values and self-identity [22].

These newest studies emphasize that these substances have the potential to catalyze behavioral and psychological changes, particularly by addressing emotional trauma and increasing self-awareness [21,23,25]. Especially, Bogenschutz et al.'s studies have demonstrated reductions in heavy drinking days and improved self-efficacy in managing alcohol cravings. Importantly, psilocybin's ability to induce "quantum" change experiences—sudden, profound shifts in the psychological state—is critical to its effectiveness [23]. These studies support earlier discoveries from the peak period of psychedelic research, which suggest that psilocybin can significantly reduce alcohol consumption and cravings, improve mental health, and promote overall well-being [10,34,55,72,73]. Key results include long-term reductions in alcohol use and enhanced psychological outcomes. Despite these promising findings, psilocybin is not widely implemented in practice due to regulatory challenges, a lack of large-scale clinical trials, and more research to establish its long-term safety and effectiveness. Furthermore, societal stigma and legal obstacles around psychedelics limit their adoption in mainstream medical treatments.

Across the studies, participants commonly reported improved self-compassion and emotional regulation. Both psilocybin and ayahuasca are believed to help individuals confront past trauma, negative emotions, and self-critical thoughts, which are often associated with addiction [21,25,74]. Psilocybin-treated participants had about 41% fewer heavy drinking days compared to those receiving a placebo [22]. On the other hand, Thomas et al. report statistically significant improvements in mindfulness and emotional regulation, and reductions in problematic substance use (e.g., cocaine) in people who use ayahuasca as a therapy. However, some studies report varying effects on different substances, with reductions in alcohol and cocaine use, but not in cannabis or opiates [31,75].

All alcohol dependence studies included highlight the importance of set and setting—whether through guided therapy sessions in clinical settings or through the ritualized use of substances like ayahuasca in culturally traditional settings [25,27]. The supportive context, whether religious or therapeutic, enhances the effectiveness of the psychedelics. The follow-up periods in these studies often extended to several months, and participants continued to show reductions in heavy drinking days.

Looking for studies about smoking cessation and tobacco dependence, we discovered, in the last ten years, four original papers that studied the effect of psychedelics in the process of quitting smoking. Specifically, psilocybin was frequently used in the treatment of tobacco dependence with promising results, revealing both common patterns and critical differences in the outcomes and methodologies.

Across the studies analyzed, psilocybin demonstrated a substantial capacity to promote smoking cessation. In an open-label pilot study, Johnson et al. in 2014 reported that 80% of participants (12 out of 15) achieved biologically confirmed smoking abstinence at six months post-treatment [26,28]. This high success rate far exceeds the 35% success rates typically observed with other pharmacological and behavioral interventions for smoking cessation [28,30]. Similar results were observed in long-term follow-ups, where 60% of participants remained abstinent after 30 months (Noorani et al.) in 2018 [31].

These findings consistently highlight the potential of psilocybin as an effective adjunct to CBT in smoking cessation treatments [76,77]. In all studies, the psychedelic experience was framed within a structured therapeutic program that included preparatory counseling, mindfulness training, and post-session integration discussions [26,31]. This combination of psilocybin with CBT appears to be essential in sustaining therapeutic gains, as participants were encouraged to process their psychedelic experiences in ways that supported long-term abstinence from smoking. These studies consistently report that the preparatory sessions helped participants frame their motivations for quitting, while the follow-up sessions reinforced their abstinence [28,31].

Differences across studies include the variability in the dosage and number of psilocybin sessions administered. In some studies, participants received two doses of psilocybin (20 mg/70 kg and 30 mg/70 kg) spaced two weeks apart, with an optional third high-dose session [26,28]. In others, the dose and the number of sessions were modified based on participants' smoking behaviors post-treatment [30]. While all participants underwent at least one high-dose session (typically 30 mg/70 kg), additional doses were tailored to individual needs, particularly for those who struggled to maintain abstinence. This flexible dosing strategy may contribute to the success rates observed across different follow-up periods. The duration of follow-up also varied between studies. While most studies conducted follow-ups at six months, some extended their follow-up periods to over 30 months, revealing that the effects of psilocybin on smoking cessation could persist for years [28]. Interestingly, while the success rate at six months was higher (80%), it decreased slightly over time, with 60% of participants remaining abstinent at long-term follow-up [30]. This decrease suggests that while psilocybin facilitates significant initial behavior change, maintaining long-term abstinence may require additional support or booster sessions.

Psilocybin's ability to evoke profound changes in self-concept and emotional processing appears to be crucial in promoting smoking cessation. Participants across all studies reported that their psilocybin sessions provided vivid insights into their reasons for smoking, which often resulted in a re-evaluation of their identity and behavior [26,30,31]. A common theme reported by participants was the realization that smoking no longer made sense in the context of their newly discovered sense of self. This shift in perspective, coupled with the supportive therapeutic framework, allowed participants to break free from their addiction to cigarettes. Additionally, in concordance with older studies, many participants noted that the acute effects of psilocybin, including heightened emotional awareness and introspection, overshadowed any withdrawal symptoms they might have experienced, making it easier to abstain from smoking [77,78].

The precise psychological and neurobiological mechanisms by which psilocybin facilitates smoking cessation remain unclear. While mystical experiences are consistently associated with successful outcomes, more research is needed to determine how these experiences translate into lasting behavior change. Neuroimaging studies and longitudinal assessments of cognitive and emotional changes following psilocybin treatment could provide valuable insights into the underlying mechanisms of action.

A 2016 New Zealand study investigated the safety and efficacy of noribogaine, a metabolite of ibogaine, in opioid-dependent patients undergoing methadone detoxification. The study found that noribogaine was generally well tolerated but caused a dose-dependent prolongation of the QTc interval, a measure of heart rhythm. There was a non-statistically significant trend toward reduced opioid withdrawal symptoms, particularly at the 120 mg dose. Still, the time to resumption of opioid substitution therapy (OST) was not significantly different between the placebo and treatment groups [24].

Looking to the future, the clinical trial NCT04003948, titled "Preliminary Efficacy and Safety of Ibogaine in the Treatment of Methadone Detoxification", is a Phase 2 study designed to evaluate the safety and efficacy of ibogaine hydrochloride in facilitating methadone detoxification. Similarly, the clinical trial NCT03380728, titled "Ibogaine in the Treatment of Alcoholism: a Randomized, Double-blind, Placebo-controlled, Escalating-dose, Phase 2 Trial", aims to assess the safety and efficacy of ibogaine hydrochloride in treating alcohol dependence.

While the New Zealand study provides preliminary insights into the potential of noribogaine for opioid detoxification, the ongoing clinical trials NCT04003948 and NCT03380728 are expected to offer more comprehensive data on the safety and efficacy of ibogaine hydrochloride in treating substance dependence. The outcomes of these trials will be crucial in determining the therapeutic viability of ibogaine and its derivatives for addiction treatment.

The treatment of illicit drug dependence has seen growing interest in the integration of psychedelics and psychoactive substances, such as ayahuasca, ketamine, and psilocybin. Each study emphasizes the importance of the psychoactive effects of the substances used—whether through mystical-type experiences induced by ketamine or psilocybin or the visionary and emotional effects produced by ayahuasca. For instance, the ketamine study by Dakwar et al. demonstrated that the mystical-type experiences generated by ketamine were significantly associated with improvements in cocaine dependence [27,29,79].

Across the studies, there were substantial reductions in the use of substances following psychedelic or psychoactive treatment. In the ayahuasca-assisted therapy studies, participants reported reductions in or the complete cessation of problematic substance use, including cocaine, alcohol, and tobacco [27,79]. Likewise, in the ketamine study, which did not involve a cultural or spiritual context, participants demonstrated marked reductions in cocaine self-administration and cravings following treatment. However, ketamine's ability to induce sustained behavior change appears to be more dependent on the intensity of the mystical-type experience, and the long-term effectiveness of ketamine without ongoing therapy or additional doses remains less understood compared to ayahuasca's results [29].

The future of psychedelic therapy in research and clinical practice for addictive use disorders holds significant promise, yet it necessitates rigorous investigation and cautious implementation. Recent studies have demonstrated that psychedelics such as psilocybin, ketamine, and ayahuasca may effectively reduce substance use, prolong periods of abstinence, and decrease the frequency of heavy usage days among individuals with SUD. These substances are believed to enhance neural plasticity, potentially reorganizing the disordered neural pathways involved in addiction. Additionally, psychedelics may attenuate maladaptive signaling in the mesolimbic reward pathway, offering a novel mechanism for treating SUD [80,81].

However, the existing research is limited by small sample sizes, methodological constraints, expectancy biases, and challenges with blinding procedures. The therapeutic effects observed are often partial and temporary, suggesting that repeated administrations and integration with psychotherapy might be necessary for enduring benefits. The combination of psychedelic treatment with psychotherapy appears to be more effective than either approach alone, highlighting the importance of a comprehensive therapeutic framework.

In research and therapeutic environments, administering classic hallucinogens requires careful safety measures to reduce risks. Participants must be screened thoroughly, excluding individuals with psychotic or bipolar disorders. A physician should be available during sessions, although the need for emergency interventions is rare. Psychological difficulties are typically addressed through reassurance from staff. Building a solid rapport between volunteers and staff before sessions helps alleviate anxiety and prepares individuals for the drug's powerful effects. Volunteers are constantly monitored closely and never left alone during the experience. Afterward, follow-up meetings allow participants to reflect on their emotional or spiritual experiences and receive further care if necessary.

Future research should focus on conducting high-quality, controlled studies with more extensive and diverse populations to confirm the efficacy and safety of PAT. Longitudinal studies are required to determine the longevity of therapeutic effects, and neuroimaging research could elucidate the neural correlates of long-term changes induced by psychedelics.

Regulatory challenges persist, as many psychedelics are constrained by restrictive schedules that limit their medical use. A shift in regulatory status, along with the development of accredited training programs for clinicians, would be essential for integrating psychedelic therapies into mainstream clinical practice. Addressing these hurdles could pave the way for psychedelics to become a valuable addition to the repertoire of treatments for SUD, particularly for patients who have not responded to conventional interventions. Ultimately, while psychedelic therapy offers a promising avenue for the treatment of addictive use disorders, its future relies on thorough research, ethical considerations, and careful implementation to ensure safe and effective outcomes for patients.