After years of minimal innovation in pharmacological treatment of addiction disorders, there has been recent substantial renewed interest and investment to assess the therapeutic potential of psychedelic compounds. Reference Gomez-Escolar, Folch-Sanchez, Stefaniuk, Swithenbank, Nisa and Braddick1 Although at the time of writing in 2024, no psychedelic had been approved by any regulatory mechanism for the treatment of an addiction disorder, widespread media coverage and significant advocacy have led to an increase in people seeking advice on their therapeutic utility. Reference Koslowski, Johnson, Gründer and Betzler2 Given that people may increasingly feel encouraged to seek out both sanctioned and unsanctioned supply of these substances, it is particularly vital that mental health professionals are aware of the extant evidence base, future research directions and controversies within the literature.
This editorial discusses the published evidence available from randomised trials that have used psychedelic compounds in the treatment of addiction disorders, with a focus on each study’s reported primary efficacy outcome. Reference Gomez-Escolar, Folch-Sanchez, Stefaniuk, Swithenbank, Nisa and Braddick1
Psychedelics
Psychedelics can be classified as either ‘typical serotonergic’ or ‘atypical’, with typical compounds including lysergic acid diethylamide (LSD), psilocybin (often referred to as ‘magic mushrooms’), dimethyltryptamine (a component of the traditional beverage ayahuasca) and mescaline (a component of the peyote cactus). Atypical psychedelics include dissociative anaesthetics such as ketamine, phencyclidine and dextromethorphan, along with the entactogen 3,4-methyl-enedioxy-methamphetamine (known as MDMA) and ibogaine and its analogues.
Alcohol use disorder
LSD
Six trials published between 1966 and 1970 randomised a total of 536 participants to either a single of dose of LSD (ranging between 3 μg/kg and 800 μg) (n = 325) or to a control condition of low-dose LSD (ranging between 25 and 50 μg), an active control (including d-amphetamine or ephedrine sulphate) or no drug (n = 211). Reference Krebs and Johansen3 When all outcomes were dichotomised into either ‘improved’ (defined as a self-reported ‘clear, substantial improvement in alcohol misuse’) or ‘not improved’ and pooled in a random-effects meta-analysis, there were significantly increased odds of improvement at the first reported follow-up (ranging between 2 and 6 months) in the LSD group compared with the control group (odds ratio = 1.96, 95% CI: 1.36–2.84; P = 0.0003).
Psilocybin
One trial published in 2022 randomised a total of 95 participants to either two administrations of psilocybin (25 mg/70 kg and 25–40 mg/70 kg) plus psychotherapy (n = 49) or an active control (diphenhydramine) plus psychotherapy (n = 46). Reference Bogenschutz, Ross, Bhatt, Baron, Forcehimes and Laska4 This reported a significantly lower number of self-reported heavy drinking days at 32 weeks in the psilocybin group compared with the diphenhydramine group (9.7 v. 23.6%, mean difference = 13.9%, 95% CI: 3.0–24.7; P = 0.01).
Ketamine
Two studies published in 2020 and 2022 randomised a total of 136 participants. Reference Gomez-Escolar, Folch-Sanchez, Stefaniuk, Swithenbank, Nisa and Braddick1 The first trial randomised a total of 40 participants to either a single intravenous infusion of ketamine at 0.71 mg/kg plus motivational enhancement therapy (MET) (n = 17) or an active control (midazolam) plus motivational enhancement therapy (n = 23). This reported a significantly increased number of self-reported days abstinent from alcohol at 21 days follow-up in the ketamine group compared with the control group. The second trial randomised a total of 96 participants to one of four arms: (a) three weekly intravenous ketamine infusions at 0.8 mg/kg plus psychological therapy (n = 24), (b) three placebo (saline) infusions plus psychological therapy (n = 23), (c) three intravenous ketamine infusions plus alcohol education (n = 24), or (d) three placebo infusions plus alcohol education (n = 25). This reported a significantly increased mean number of self-reported days abstinent from alcohol at 6 months follow-up in the ketamine arms compared with the placebo arms (79.2 v. 62.8%, mean difference = 10.1%, 95% CI: 1.1–19.0).
Opioid use disorder
LSD
One study published in 1973 randomised a total of 78 participants to either a single dose of LSD (ranging between 300 and 450 μg) and a 6-week residential programme followed by an out-patient programme with weekly psychotherapy (n = 37) or a control out-patient programme and weekly psychotherapy (n = 37). Reference Savage and McCabe5 This reported a significantly higher percentage of participants with abstinence (verified by urine drug screen) from opioid use at 12 months in the LSD group compared with the control group (25 v. 5%; P < 0.05).
Ketamine
Three studies published in 2002, 2006 and 2007 randomised a total of 181 participants. Reference Gomez-Escolar, Folch-Sanchez, Stefaniuk, Swithenbank, Nisa and Braddick1 The first trial randomised 70 participants to either a single high dose of intramuscular ketamine (2 mg/kg) plus psychotherapy (n = 35) or a control of a single low dose of intramuscular ketamine (0.2 mg/kg) plus psychotherapy (n = 35). A higher percentage of participants with abstinence from opioid use, verified by urine drug screen, at 2 years follow-up was reported in the high-dose ketamine group compared with the low-dose ketamine group (P < 0.5).
The second trial randomised 53 participants to either three doses of intramuscular ketamine at 2 mg/kg plus psychotherapy (n = 26) or a control group of a single dose of intramuscular ketamine at 2 mg/kg plus psychotherapy (n = 27). A significantly higher percentage of participants with abstinence from opioid use, verified by urine drug screen, was reported at 1 year follow-up in the three-dose ketamine group compared with the single dose ketamine group (50 v. 22.2%; P < 0.05).
The third trial randomised 58 participants to either an intravenous infusion of ketamine at 0.5 mg/kg (n = 22) or a matching placebo (saline) control (n = 28). There was no significant difference reported in the percentage of participants with abstinence from opioid use, verified by urine drug screen, at 4 months follow-up in the ketamine group compared with the control group (19 v. 17%; P > 0.05).
Noribogaine
One study published in 2016 randomised a total of 27 participants to noribogaine at a dose of either 60, 120 or 180 mg (n = 18) or a matching placebo control (n = 9). Reference Glue, Cape, Tunnicliff, Lockhart, Lam and Hung6 There was no significant difference reported in the total opioid withdrawal rating score in the noribogaine group compared with the placebo group.
Cocaine use disorder
Ketamine
Two studies published in 2014 and 2017 randomised a total of 28 participants. Reference Gomez-Escolar, Folch-Sanchez, Stefaniuk, Swithenbank, Nisa and Braddick1 The first trial randomised eight participants to either a single intravenous ketamine infusion at 0.71 mg/kg (n = 5) or an active control (lorazepam; n = 3). An increase was reported in the median change in University of Rhode Island Change Assessment score, a validated measure of readiness to change in people with cocaine use disorder, at 24 h post-infusion in the ketamine group compared with the control group (+3.6 v. +0.15; P = 0.012). The second trial randomised 20 participants to either a single intravenous infusion of ketamine at 0.71 mg/kg (n = 10) or an active control (midazolam; n = 10). A significant reduction was reported in the number of times individuals chose to self-administer cocaine, as opposed to receiving a monetary reward, at 28 h post-infusion in the ketamine group compared with the control group (1.61 v. 4.33; P < 0.0001).
Ibogaine
One study published in 2014 randomised a total of 20 participants to 1800 mg ibogaine (n = 10) or a placebo control (n = 10). Reference Prior and Prior7 A significantly lower number of urine drug-screen samples positive for cocaine use over 24 weeks were reported in the ibogaine group compared with the control group (P = 0.023).
Discussion
There is a significant body of published evidence from randomised studies in patients with substance use disorders (SUDs), with more than 1000 patients having been randomised since the inception of psychedelic research in the 1960s. Although the overwhelming majority of trials report positive results with respect to efficacy outcomes relating to substance reduction and abstinence, there have been consistent concerns regarding a number of methodological limitations.
The majority of studies have suffered from having small sample sizes without adequate statistical power and tend to have been conducted in highly selective populations that are non-representative of patients entering SUD treatment. Few studies have included patients with comorbid mental health conditions or comorbid addiction disorders, or those with moderate and severe degrees of SUD. Reference Gomez-Escolar, Folch-Sanchez, Stefaniuk, Swithenbank, Nisa and Braddick1 Psychotherapy components, where present, are often inadequately described, with significant heterogeneity in delivered psychotherapeutic interventions; this leads to difficulties in ascertaining the specific efficacy of the psychedelic experience compared with other intervention and contextual components. Lack of adequate blinding and choice of appropriate controls have also been criticisms within the literature, with intentional lack of blinding or the difficulties surrounding the choice of placebo potentially leading to unintentional participant unblinding.
A substantial number of larger-scale trials are currently recruiting across an increased range of both psychedelic compounds and SUDs with expanded discussion of their potential utility in behavioural addictions. Reference Romero, Czakó, van den Brink and Demetrovics8 However, concomitant levels of funding or research into both the harmful consequences of psychedelic use and the treatment of problematic psychedelic use itself are severely lacking. Several reports note recent observed increases in illicit psychedelic use, with an increase in the availability of unregulated psychedelic ‘retreats’. This increase in sanctioned and unsanctioned use of psychedelic substances, particularly among patients with common mental disorders who have increased vulnerabilities to developing comorbid addictions and serious mental illness, has the theoretical potential to lead to increased rates of psychedelic-related harm and to divert people from accessing mainstream addiction services. Professionals need be aware of the relative dearth of evidence available for the treatment of psychedelic-induced onset or worsening of these conditions, and the potential negative effects of psychedelic use on (mental) health should be clearly communicated when discussing any benefits in a therapeutic context. Reference Roberts, Sanderson and Guerrini9
There have been many touted ‘silver bullet’ pharmacological agents that have purported to ‘cure’ addiction disorders over the past century; however, it is a holistic treatment approach that includes pharmacotherapy in addition to psychological, emotional, employment and housing support that best helps individuals to recover and sustain positive change. At the time of writing, there has been a decade-long systematic underfunding of addiction treatment services within the UK, and with the potential advent of psychedelic therapy comes additional concerns that any additional funding required for psychedelic treatments could come from the same budgetary envelope, placing additional pressure on an already-stretched treatment delivery system which currently lacks the infrastructure or workforce to deliver a novel non-first-line therapy.
Every prescribing decision involves balancing the potential risks and benefits, and it is an overused cliché to end an article with the truism that ‘more research is needed’. However, in the case of the potential efficacy of psychedelic treatment in addiction disorders, this would appear the most apt conclusion. Reference Gomez-Escolar, Folch-Sanchez, Stefaniuk, Swithenbank, Nisa and Braddick1 The numerous available small-scale studies, however, do report consistent positive outcomes relating to abstinence maintenance across SUDs and across studied psychedelic compounds; in addition, unlike the situation in many other areas of addiction research, funding has been made available for larger-scale, more methodologically rigorous studies that aim to address some of these questions. However, there remains a substantial imbalance in both interest and funding for the treatment of problematic use of psychedelics compared with their use as potential therapeutic compounds. Although professionals should be aware that the available evidence base for psychedelics is limited, and that there are no current licensed indications for their use in addiction disorders, there remains a strong evidence base for many other interventions in the treatment of addiction. Even if the larger-scale psychedelic trials do not live up to the hype, when it comes to treating people with addiction disorders, there is always hope.
Funding
This work is supported by the author’s National Institute for Health and Care Research (NIHR) Advanced Fellowship (NIHR302215). The views presented here are those of the author and should not be attributed to the National Health Service, the NIHR, or the Department of Health and Social Care. The funders made no contribution to the study design; the collection, analysis and interpretation of data; the writing of the report; or the decision to submit the article for publication.
Declaration of interest
E.R. is a member of the BJPsych editorial board. He did not take part in the review or decision-making process for this paper.
Author biography
E.R. is a senior clinical lecturer in Addiction Psychiatry at King’s College London and a consultant addiction psychiatrist at the South London and Maudsley NHS Foundation Trust, London, UK.
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