Tripping up addiction: the use of psychedelic drugs in the treatment of problematic drug and alcohol use

Morgan and colleagues frame the paper around the apparent paradox that illicit psychedelic drugs might be used to treat the very addictions for which they are often controlled. They note historical and contemporary interest in several compounds — lysergic acid diethylamide (LSD), psilocybin, ibogaine, ayahuasca and ketamine — and argue that growing neurobiological understanding has renewed interest in their therapeutic potential for problematic alcohol and drug use. The review sets out to synthesise available clinical and observational evidence for these compounds in treating substance-use disorders, to discuss plausible mechanisms (including antidepressant effects, stimulation of neuroplasticity and profound subjective ‘‘mystical’’ experiences) and to highlight gaps in the evidence base, particularly the need for randomised controlled trials and careful safety evaluation.

The extracted text does not present a formal Methods section describing search strategy, inclusion/exclusion criteria or a systematic review protocol. Instead, the paper reads as a narrative review that integrates findings from historical literature, observational reports, early clinical trials and animal studies. Where specific quantitative syntheses are cited, the authors report them descriptively: for example, they reference a previously published meta-analysis combining six randomised controlled trials of LSD for alcoholism (536 participants). Much of the remainder of the evidence presented derives from small clinical studies, open-label trials, non-randomised comparisons and observational reports, together with preclinical mechanistic studies. The lack of a clearly reported search or selection methodology in the extracted text means the reader cannot assess study identification or risk-of-bias procedures from this extract.

Evidence for different compounds is summarised separately. LSD: The authors report that early clinical research (1950s–60s) investigated LSD for alcohol dependence. They cite a meta-analysis that pooled six randomised controlled trials (total n = 536). Across those trials, 59% of participants assigned to active LSD treatment versus 38% of controls showed reliable improvement at the first follow-up (1–2 months), and the differences remained at six months. There is also a single older study suggesting some effect in opioid addiction. Recent work includes the first acute human neuroimaging study of LSD. Psilocybin: Small, uncontrolled clinical studies are described. In a trial of 15 nicotine-dependent smokers given moderate and high doses of psilocybin alongside cognitive behavioural therapy, abstinence was observed in 12/15 at six months, 10/15 at 12 months and 9/15 at long-term follow-up (>16 months). Participants commonly rated the experience as highly meaningful. In a separate small sample of 10 volunteers with severe alcohol use disorder, psilocybin plus psychosocial intervention produced significant reductions in drinking relative to baseline. The authors emphasise that these studies lack control groups and that more rigorous trials are underway. Ibogaine: Ibogaine is reported to have attracted interest as an anti-craving and anti-withdrawal agent for opiate and cocaine dependence. No double-blind, placebo-controlled clinical trials are reported; evidence is primarily observational and from informal treatment centres. The authors state that over 3,000 people have taken ibogaine in treatment contexts and that it is licensed for use in New Zealand. They also note well-publicised fatalities associated with ibogaine, which contributed to early research programmes being halted; this raises safety concerns, particularly if administered during acute opioid withdrawal. Ayahuasca: Observational reports and ritual/religious use are described as being associated with reduced alcohol and drug problems. The authors cite a recent observational study of 12 people treated with ayahuasca that found reductions in alcohol, cocaine and tobacco use and improved subjective wellbeing, but evidence is limited in quantity and quality. Ketamine: As an N-methyl-D-aspartate receptor (NMDAR) antagonist, ketamine produces a transient psychedelic/dissociative state at sub-anaesthetic doses. The authors highlight an influential non-randomised study of ‘‘ketamine psychedelic therapy’’ in alcohol dependence in which 111 patients who received ketamine were compared with 100 control patients who received conventional treatment; abstinence at one year was 65.8% in the ketamine group versus 24% in controls, but participants self-selected treatment. Smaller case series report similar high abstinence proportions (e.g. 70% at one year in 15 patients). A randomised trial comparing high versus low (psychedelic versus non-psychedelic) ketamine doses in heroin addiction (n = 70) found greater long-term abstinence in the high-dose group (>15% abstinent at 24 months versus <5% in the low-dose group), but that trial had no inactive placebo. Laboratory studies also indicate that ketamine can reduce cocaine self-administration and craving 24 hours post-infusion, with the subjective intensity or mystical quality of the experience mediating motivation to quit. Mechanistic and adjunct findings: The authors present converging mechanistic data. Ketamine has established rapid antidepressant effects; a small open-label psilocybin trial in treatment-resistant depression is noted. Psychedelics may reduce depressive symptoms and disrupt ruminative neural circuits implicated in relapse. Preclinical data suggest both ketamine and classic hallucinogens stimulate neuroplasticity: ketamine increases brain-derived neurotrophic factor (BDNF) translation via eEF2 signalling, potentiates hippocampal synaptic responses, enhances synaptogenesis and long-term potentiation. Rodent studies of LSD and synthetic 5HT-2A agonists (e.g. DOI) show gene transcription changes and BDNF-related dendritic remodelling. Ibogaine's effects in rodents are linked to increased glial cell line-derived neurotrophic factor (GDNF) expression and reduced alcohol self-administration. Across clinical studies, the intensity and mystical character of subjective experience correlate with better substance-use outcomes, suggesting experiential effects may contribute to sustained change. Safety and limitations of evidence: The evidence base is heterogeneous in quality. For psilocybin, LSD and ketamine there are promising early clinical data but few rigorous RCTs; for ibogaine and ayahuasca evidence is largely observational. Safety concerns are specifically highlighted for ibogaine due to reported fatalities. The authors note that serotonergic hallucinogens have not been associated with later addiction, whereas ketamine has recognised abuse potential, albeit not commonly observed in therapeutic settings.

The authors interpret the assembled evidence as indicative of a resurgence in research on psychedelic-assisted interventions for substance-use disorders, with preliminary signals of efficacy for ketamine, LSD and psilocybin and more tentative, lower-quality evidence for ayahuasca and ibogaine. They emphasise that the field is at an early stage and that randomised controlled trials are required to establish efficacy and safety definitively. In contextualising the findings, the paper suggests multiple, non-mutually exclusive mechanisms that could explain sustained reductions in substance use: rapid antidepressant effects (noting the high prevalence of depressive symptoms in people with addiction), stimulation of neuroplasticity through BDNF- and related pathways, and long-term psychological changes following intense subjective or ‘‘mystical’’ experiences that may reframe life perspectives and motivation. Key limitations acknowledged include the predominance of small uncontrolled studies and observational reports for many compounds, the absence of double-blind placebo-controlled trials for some agents (notably ibogaine), and safety concerns that require systematic evaluation. The authors also point to regulatory constraints and historical stigma — for example Schedule 1 classifications — as impediments to conducting the large, definitive trials needed. Finally, they note that abuse potential appears low for classic serotonergic hallucinogens in therapeutic settings, while ketamine and dissociative anaesthetics have some potential for misuse that must be monitored.

Morgan and colleagues conclude that renewed research into psychedelic drugs for addiction is producing promising signals and that clearer evidence should emerge within a few years as controlled trials progress. They reiterate that ketamine, LSD and psilocybin show the strongest early evidence, ayahuasca and ibogaine are promising but supported mainly by lower-quality data, and that safety — particularly for ibogaine — must be addressed. The authors propose that antidepressant effects, induced neuroplasticity and psychologically meaningful experiences are plausible therapeutic mechanisms, and they caution that regulatory and social barriers will need to be overcome for these compounds to find a place in modern medicine.