Can psychedelic compounds play a part in drug dependence therapy?

After a century of modern psychiatry, enduring remission from dependence on alcohol, opiates, stimulants and nicotine remains difficult to achieve. Although some pharmacological treatments exist, failure rates are substantial and consensus on the most efficacious approaches is lacking. Research into psychedelic drug-assisted therapy was substantial in the 1950s and 1960s but largely halted for sociopolitical reasons; interest has re-emerged and contemporary studies are now exploring psilocybin, ketamine, ibogaine and ayahuasca specifically for substance dependence. Harkins and colleagues set out to examine whether psychedelic compounds might contribute to drug-dependence therapy. The paper surveys historical and cross-cultural uses of psychedelics, outlines possible psychological and biological mechanisms, summarises contemporary clinical and observational findings, and discusses theoretical objections, practical limitations and regulatory barriers to clinical implementation. The aim is to make the case for renewed, rigorous research into psychedelic-assisted interventions for substance misuse.

The paper reviews substance-specific burdens and existing treatments to contextualise the potential role of psychedelics. For alcohol, the authors note that about one adult in 20 in the UK is alcohol dependent and one quarter of adults drink hazardously. A 2002 meta-analysis of 361 controlled trials identified 46 interventions, with brief interventions and motivational enhancement ranking highest and pharmacotherapies such as the GABAergic agent acamprosate and the opioid antagonist naltrexone ranking third and fourth; however, no single coherent best treatment has emerged. The societal cost of alcohol misuse in England is estimated at around £20 billion a year. Regarding opioids, the authors report over 123,000 people injecting heroin in the UK and a 12-fold increase in mortality among users compared with the general population. Methadone and buprenorphine improve retention and reduce misuse, mortality and criminality but carry medical risks and limitations, including dangers when combined with sedatives. For stimulants such as cocaine, no widely accepted substitution pharmacotherapy exists; psychosocial approaches (contingency management, cognitive–behavioural therapy, motivational interviewing) remain the mainstay. Tobacco causes more deaths than any other legal or illegal drug, with around 1.2 million deaths annually in Europe; varenicline, bupropion and nicotine replacement improve quit rates but most patients still relapse. The authors mention an ongoing open-label pilot in M.W.J.'s laboratory suggesting promising results for psilocybin combined with cognitive–behavioural therapy for smoking cessation, and an open-label psilocybin pilot for alcohol dependence registered at the University of New Mexico. Historically, clinicians such as Humphry Osmond and Abram Hoffer used LSD in the 1950s and 1960s for alcohol dependence, reporting high abstinence rates and suggesting that mystical or spiritual experiences—rather than drug-induced psychosis—were associated with successful outcomes. Cross-cultural reports are cited in which indigenous use of iboga (ibogaine), ayahuasca (DMT) and peyote (mescaline) has been associated with reductions in alcohol dependence. The authors discuss proposed therapeutic mechanisms. Psychedelic experiences have been linked to sustained changes in personality, attitudes and behaviour in observational studies, and to pronounced personal meaning and spiritual significance in volunteer trials with psilocybin. An ‘‘afterglow’’ period lasting several weeks was described in early research and proposed to confer emotional strength and reduced craving, supporting abstinence. A recent paper by Bogenschutz and Pommy is noted as further exploring psychological and biological mechanisms. Contemporary empirical work is summarised. A team in Russia during the 1990s conducted placebo-controlled ketamine studies in more than 1,000 patients with alcoholism, reporting total abstinence for more than a year in 66% of the ketamine group versus 24% in controls; nonetheless, the authors report that the Russian Federation now forbids further ketamine research. Observational studies of ibogaine-assisted therapy have been conducted in Mexico and New Zealand, and a Canadian study has investigated ayahuasca for dependence. The authors emphasise that most contemporary research remains early-stage, often open-label or observational, and that methods and efficacy need more rigorous evaluation.

The authors interpret the collected evidence as indicative of potential utility for psychedelic-assisted psychotherapy in substance dependence, while emphasising that the evidence base is nascent and constrained by methodological and legal limitations. They reiterate historical and cross-cultural signals of efficacy and highlight contemporary positive, though preliminary, findings (for example, the Russian ketamine trials and pilot psilocybin work), but caution that these do not yet establish standard clinical practice. Several practical and ethical limitations are acknowledged. Psychedelic-assisted sessions can be long and resource-intensive, raising cost and scalability concerns. Safety exclusions will prevent some patients from receiving these treatments. Legal restrictions are a major barrier: many candidate compounds are classified at Schedule I or Class A levels, which prohibits medical use outside tightly regulated research. The authors argue that a change in regulatory status and plans for approved manufacture would be necessary for clinical translation. They also address the objection that treating dependence with other psychoactive or potentially misused drugs is problematic, noting that maintenance pharmacotherapies already use controlled drugs and that several psychedelics (psilocybin, LSD) do not appear to support compulsive drug-seeking. Harkins and colleagues conclude that, given the high burden of substance dependence and the limitations of current treatments, there is an ethical imperative to investigate whether psychedelic drug-assisted psychotherapy can improve outcomes. They call for rigorous randomised trials, further mechanistic research and careful attention to safety, cost and regulatory pathways before these approaches could be recommended in routine clinical care.