Do Hallucinogens Have a Role in the Treatment of Addictions? A Review of the Current Literature

The investigators conducted a narrative review using PubMed and Google Scholar, combining terms for psychedelics (for example, "psilocybin," "LSD," "ibogaine," "ayahuasca," "ketamine") with addiction-related terms (for example, "addiction," "alcoholism," "substance use disorder"). Searches included all articles published up to 1 July 2020. MDMA was excluded because the authors found insufficient literature on its use specifically for addictive disorders in their searches. Screening proceeded in stages: 392 articles were screened by title to find studies addressing hallucinogens and addiction, yielding 101 items taken forward for abstract screening. Twenty-five full texts underwent detailed review and 18 studies met the authors' inclusion criteria. Included studies were clinical trials, meta-analyses synthesising clinical trial data, or retrospective clinical assessments that directly evaluated a single hallucinogen for addiction-related outcomes. Excluded materials comprised animal studies, non-English reports with no translation, opinion pieces without original data, studies of disorders other than substance use (especially those with serious psychiatric comorbidity), and agents outside the stated scope. The reviewers also used prior review articles to cross-check references and to identify studies possibly missed by the initial searches. Methodological limitations of individual studies were assessed and noted in a summary table (referred to in the text).

Lysergic acid diethylamide (LSD): Historical clinical work on LSD and alcoholism from the mid-twentieth century is summarised. Early uncontrolled work in Saskatchewan treated 24 alcohol-dependent patients with a single 200–400 μg LSD session in the context of inpatient therapy, reporting a 50% response rate at 3 years (6 patients reduced use, 6 remained abstinent, 12 unchanged). Hollister et al. carried out a controlled study in 72 men comparing 600 μg LSD to 60 mg dextroamphetamine; blinded interviewers found significant improvement in drinking behaviour for the LSD group at 2 months but no significant difference at 6 months and attrition limited 12-month analyses. Bowen et al. and Pahnke et al. combined psychotherapy with LSD and reported short-term improvements up to 6 months, with Pahnke noting a correlation between intensity of the psychedelic experience and clinical response. A 2012 meta-analysis pooling six randomised trials (325 LSD-treated subjects versus 211 controls receiving dextroamphetamine, ephedrine or no active treatment) found significant benefits of LSD on alcohol misuse at short-term (2–3 months) and medium-term (6 months) follow-up but no significant effects at 12 months; similarly, short-term differences in abstinence rates were detected but not sustained. Psilocybin: Clinical research has focused on smoking cessation and alcohol dependence. A Johns Hopkins open-label feasibility study enrolled 15 treatment-seeking smokers in a 15-week programme with three psilocybin sessions (weeks 5, 7 and 13) plus cognitive–behavioural smoking cessation preparation. At 6 months, 12/15 participants showed sustained abstinence; at 12 months 10/15 (67%) were biologically confirmed abstinent. A longer-term follow-up reached 12 of the original 15 participants at a mean of 30 months post-treatment; nine participants (60%) were biologically confirmed abstinent, with seven reporting continuous abstinence since the initial quit date. Bogenschutz et al. conducted an open-label study in 10 alcohol-dependent individuals receiving a 12-week motivational enhancement therapy programme plus two open-label psilocybin sessions (0.3 mg/kg then 0.4 mg/kg). Both percent heavy drinking days and total drinking days decreased relative to baseline and to the pre-psilocybin period, with significant differences maintained up to 36 weeks except for one interval (heavy drinking days during weeks 9–12, p = 0.059). Ketamine: The review summarises several controlled and randomised trials. A controlled clinical trial in alcoholism (n = 211) reported that supplementing standard treatment with ketamine-assisted psychotherapy (KPT) yielded total abstinence at 1 year in 65.8% of the treatment group versus 24% of controls; the authors reported personality stabilisation and psychosocial changes post-treatment. In cocaine use disorder, a randomised study of 55 patients compared a single ketamine infusion with midazolam during a 5-day inpatient stay followed by a 5-week mindfulness relapse-prevention programme; 48.2% of the ketamine group maintained abstinence over the last 2 weeks of the programme versus 10.7% in the midazolam arm, and ketamine patients had lower relapse likelihood and craving scores. For heroin addiction, a double-blind RCT in 70 detoxified patients compared a hallucinogenic dose (2.0 mg/kg) with a non-hallucinogenic dose (0.2 mg/kg) plus existentially oriented therapy; KPT yielded significantly higher abstinence rates and prolonged craving reduction across most monthly time points over a 24-month follow-up. A subsequent trial randomised 59 detoxified heroin addicts to one versus two KPT sessions (one month apart); 1-year survival analysis showed 50% abstinence in the repeated-session group versus 22.2% in the single-session group. Ibogaine: The authors describe observational and open-label series targeting opioid dependence. Malcolm et al. enrolled 50 opioid-dependent participants in a week-long ibogaine-assisted detoxification with careful pre-treatment transition to short-acting opioids and periprocedural morphine management. Using the Clinical Opiate Withdrawal Scale (COWS) and Subjective Opiate Withdrawal Scale (SOWS), 48 hours after ibogaine administration 78% had no withdrawal signs by COWS, 20% had mild signs and 2% had moderate signs; SOWS ratings at 48 hours were 68% mild, 10% moderate and 22% severe. A large open-label series (n = 191) reported significant reductions in withdrawal and craving immediately and at 1 month post-detoxification. A separate cohort of 30 patients treated with a single therapeutic dose with booster doses as required was followed with the Addiction Severity Index Composite (ASIC) at 1, 3, 6, 9 and 12 months; significant improvements were reported across drug use, family/social and legal domains, with 50% opioid-free at 1 month and 33% opioid-free at 3 months. A subset (12/30, 40%) had favourable outcomes (>75% decrease in drug use) at 9 and 12 months. Ayahuasca: Evidence is largely observational. One study of 12 participants from a rural First Nations community combined a 4-day addiction retreat with two ayahuasca sessions and reported statistically significant improvements in several behavioural well-being measures; decreases in self-reported alcohol, tobacco and cocaine use were observed but only the reduction in cocaine use reached significance. A qualitative follow-up at 6 months (n = 11) emphasised participants' enhanced ability to recognise negative thought patterns sustaining addiction and reported reductions in substance use and craving, with eight participants noting cessation of at least one substance. Two comparative studies using the Addiction Severity Index over 1 year contrasted jungle-based ayahuasca users (n = 56) with rural controls (n = 56), and urban users (n = 71) with urban controls (n = 59). Jungle users scored significantly lower on the ASI alcohol use and psychiatric subscales and showed a larger time-dependent decrease in ASI drug use; comparable effects were not observed in the urban cohort, where family/social scores worsened. A retrospective comparison of adolescents in a Brazilian ayahuasca sect (Uniao do Vegetal, n = 41) with non-users (n = 43) found no significant differences in lifetime drug use; controls reported higher past-year alcohol consumption (74.4% v 46.3%) and higher recent 30-day alcohol use (65.1% v 32.5%).

Nigam and colleagues interpret the collated evidence as supportive but preliminary: hallucinogens may address addiction by combining pharmacological modulation of reward circuitry with profound, therapy-facilitated psychological experiences that enable insight and behavioural change. They highlight shared and divergent pharmacodynamic mechanisms: LSD and psilocybin act primarily as 5-HT2A receptor agonists (a receptor implicated in producing the altered states that appear therapeutically salient), ketamine is an NMDA receptor antagonist with complex downstream effects, ibogaine shows kappa-opioid agonism and NMDA antagonism (and unique effects on opioid withdrawal) and ayahuasca's DMT component stimulates multiple 5-HT receptor subtypes together with monoamine oxidase inhibition from beta-carbolines. The authors stress methodological limitations across the literature that limit clinical inference. Key deficits include a paucity of large, systematic, double-blind randomised controlled trials; small sample sizes; sampling bias; regulatory constraints around Schedule I substances that impede research; and difficulty in creating convincing placebos because of the overt subjective effects of these drugs. They also note likely publication bias against negative findings, inconsistent assessment and reporting of adverse effects, limited long-term safety data, non-representative participant demographics, and a lack of standardised therapeutic regimens (variability in preparatory and integration therapy, dosing and session frequency). With regard to efficacy durability, the authors observe mixed long-term results and attribute at least some of this heterogeneity to methodological differences in dosing, frequency and adjunctive psychotherapy rather than to definitive lack of effect. They recommend higher-powered trials, including studies of repeated dosing at scheduled intervals and better standardisation of therapy, safety monitoring and adverse-event assessment. Finally, the review notes that regulatory shifts—such as the FDA's designation of psilocybin as a Breakthrough Therapy for treatment-resistant depression—may facilitate more rigorous, large-scale trials for certain agents and that preliminary data justify further investigation rather than immediate clinical adoption.