Ketamine for the treatment of addiction: Evidence and potential mechanisms

Addiction is framed as a chronic, relapsing disorder defined by craving, habitual drug-seeking and an aversive abstinence state, and it remains a major public-health and economic burden worldwide. Existing pharmacotherapies are limited: some serve as substitutes (for example methadone) while others modestly support abstinence, but several dependencies (notably stimulants and cannabis) lack convincing drug treatments and relapse rates for current therapies remain high (40%–80% at one year). Against this background, novel approaches are urgently required. Ezquerra-Romano and colleagues set out to review preclinical and clinical evidence for ketamine as a treatment for addiction and to examine plausible mechanisms by which it might reduce drug use and relapse. The review considers historical and pharmacological context, animal studies, clinical trials and uncontrolled clinical programmes, and discusses candidate mechanisms including neuroplasticity, network-level effects, antidepressant action, memory reconsolidation, the subjective psychedelic/mystical experience, and facilitation of psychotherapy.

The extracted text does not provide a specific Methods section describing search strategy, inclusion criteria, databases searched or formal systematic-review procedures. The paper is presented as a narrative review that synthesises preclinical and clinical studies, historical accounts (including Ketamine Psychedelic Therapy, KPT), mechanistic laboratory work, and human experimental and clinical findings. Where individual studies are discussed, the review reports design features of those studies (for example randomised or non-randomised trials, crossover designs, doses and routes used, and follow-up durations) but it does not appear from the extracted text to apply a formal meta-analytic methodology or risk-of-bias assessment. Consequently, the review aggregates evidence qualitatively, emphasising effect sizes and methodological limitations of the primary studies it describes.

Preclinical findings Animal evidence is limited but suggestive. One study in alcohol-preferring rats found that intraperitoneal ketamine at 20 mg/kg reduced ethanol self-administration by 33.3% without affecting motor activity or water intake; co-administration of rapamycin blocked this reduction. Another rodent experiment reported that 60 mg/kg ketamine given after re-exposure to a morphine-conditioned context reduced morphine conditioned place preference and that this suppression persisted after a morphine priming injection, which the authors interpreted as disruption of memory reconsolidation. Clinical and experimental human studies Historical clinical programmes and early non-randomised work: Ketamine Psychedelic Therapy (KPT), developed and deployed in the former Soviet Union from the mid-1980s, combined preparatory psychotherapy, intramuscular ketamine sessions (typically 2.5 mg/kg in the alcohol studies) with therapist guidance, exposure to alcohol-related cues during peak experience, and post-session group integration. In a non-randomised report comparing KPT (n=111) with treatment-as-usual controls (n=100) in recently detoxified alcohol-dependent patients, one-year abstinence was 66% in the KPT group versus 24% in controls (p<0.01). The extract notes this lacked randomisation, blinding and matched control therapies. Randomised and partially blinded trials in opioid dependence: A randomized, double-blind trial in 70 detoxified heroin-dependent patients compared two intramuscular ketamine doses (0.2 mg/kg, considered an ‘‘active placebo,’’ versus 2.0 mg/kg). After two years the higher dose group had greater abstinence (17% vs 2%, p<0.05), larger changes in nonverbal emotional attitudes, and longer-lasting reductions in craving. A later study from Krupitsky’s group randomised patients who had already received one KPT session to receive either two further monthly KPT sessions (total three sessions, n=26) or two monthly counselling sessions (single KPT group continued, n=27). At one year, 50% of the three-session KPT group remained abstinent versus 22% in the single-session group (p<0.05). Cocaine studies in non-treatment-seeking users: In a double-blind, crossover laboratory study of eight cocaine-dependent males, three infusions (0.41 mg/kg, 0.71 mg/kg ketamine and 2 mg lorazepam as active control) showed that 0.4 mg/kg increased motivation to quit and reduced cue-induced craving relative to lorazepam (both p=0.012); the higher ketamine dose produced greater mystical-type experiences, and mystical experiences mediated increased motivation to quit. In a larger randomised crossover study of 20 cocaine-dependent participants, intravenous ketamine (0.71 mg/kg over 52 minutes) was compared with midazolam (0.025 mg/kg). Ketamine produced a 67% reduction in laboratory cocaine choice relative to baseline, significantly fewer cocaine choices than midazolam (p<0.0001), and significant reductions in craving (p<0.01) and cue reactivity (p<0.05) lasting up to 48 hours. Real-world cocaine use was reduced in the first 3 days after ketamine versus midazolam (p<0.05), and some participants remained abstinent for the two-week follow-up. Mechanistic findings and biomarkers Synaptogenesis, mTOR and BDNF: The review highlights a putative molecular cascade by which NMDAR antagonism leads to increased synaptogenesis via mTOR signalling and AMPA receptor insertion. Evidence cited includes blockade of ketamine’s effects by rapamycin (an mTOR antagonist), and studies implicating ketamine metabolites (including certain HNK isomers) in mTOR activation. However, the authors also report conflicting data: some HNK stereoisomers produce antidepressant-like effects without NMDA activity or changes in mTOR, and human studies of peripheral BDNF after ketamine have shown mixed results and possible age-dependence. Functional network disruption: Neuroimaging studies of classic serotonergic psychedelics and of ketamine show reduced integrity of canonical resting-state networks, notably decreases in connectivity within the Default Mode Network (for example mPFC–posterior cingulate) and altered salience and visual networks. Vollenweider’s PET work is reported to show acute increases in activity in prefrontal cortex, anterior cingulate and insula after ketamine and psilocybin; the authors link these network changes to potential therapeutic effects on depression and addiction. Rapid antidepressant effects: The review summarises the sizeable literature demonstrating ketamine’s rapid antidepressant efficacy. Early trials used 0.5 mg/kg intravenous infusions and reported rapid, short-lived symptom relief lasting days. A systematic review and meta-analysis of seven randomised, double-blind, placebo-controlled trials is cited as showing higher remission and response rates with ketamine at 24 hours, 3 days and 7 days compared to saline or midazolam; overall response rates of 65%–70% within 24 hours are presented as substantially higher and faster than conventional antidepressants. Given high comorbidity between addiction and depression, the authors argue this antidepressant action could mediate anti-relapse effects. Reconsolidation and memory disruption: Preclinical data suggest NMDAR antagonists can disrupt reconsolidation of reward memories, and a preclinical meta-analysis is referenced indicating NMDAR antagonists may be more effective than adrenergic antagonists at targeting reward memory reconsolidation. Human data are limited: a memantine trial for smoking cessation showed no benefit, but memantine lacks ketamine’s psychological effects. Subjective psychedelic/mystical experiences and therapy enhancement: Several clinical reports associate the intensity of ketamine-induced mystical or cathartic experiences with better outcomes, including longer remission and increased motivation to quit. The review emphasises that mystical-type effects (rather than dissociation per se) mediated increased motivation in a cocaine study. The authors also describe theoretical and preliminary support for ketamine enhancing uptake of psychological therapies via transient openness, synaptogenesis-facilitated learning, and enriched therapeutic processing. Safety, limitations and administration: Across studies discussed, no major complications specific to therapeutic use in addiction were reported. The review notes that cognitive effects after single exposure typically resolve within days and that addiction risk appears low with limited, infrequent therapeutic dosing, whereas complications like ulcerative cystitis are associated with heavy daily recreational use. Most clinical studies used intramuscular or intravenous routes; intranasal administration is highlighted as a promising, practical alternative and small intranasal depression trials have shown benefit.

Ezquerra-Romano and colleagues interpret the assembled evidence as promising but preliminary. They argue that ketamine has produced substantial and clinically meaningful effects in several domains: increased one-year abstinence in detoxified alcoholics in KPT reports, dose-dependent improvements in heroin dependence including randomized data, and large short-term reductions in cocaine craving and self-administration in laboratory and small clinical studies. The authors propose multiple, potentially convergent mechanisms—enhanced synaptogenesis/neurogenesis (mTOR/BDNF-related), acute disruption and reorganisation of large-scale brain networks, rapid relief of depressive symptoms, disruption of reconsolidation of drug-cue memories, induction of mystical-type experiences that support psychological change, and facilitation of psychotherapy uptake. At the same time, the review stresses important limitations that constrain confidence in clinical efficacy. A recurring concern is the paucity of high-quality randomised controlled trials with adequate blinding and inactive placebo comparators; several influential studies lacked randomisation or used active but not inert comparators, and many samples were small or non-treatment-seeking. The authors also note the surprising scarcity of preclinical self-administration studies that would systematically test ketamine across addictions and probe mechanisms. Mixed findings regarding the role of particular metabolites (HNK stereoisomers) and inconsistent BDNF results underscore mechanistic uncertainty. From a safety and implementation perspective, the investigators contend that risks appear manageable in carefully selected patients given that therapeutic administrations are intermittent rather than daily, but they acknowledge potential adverse outcomes reported with heavy recreational use. Practical considerations discussed include developing feasible administration routes (intranasal is favoured) and combining ketamine with structured psychological therapies. The authors call urgently for well-designed randomised trials, mechanistic studies (both preclinical and human), and systematic evaluation of combined ketamine-plus-psychotherapy protocols to determine optimal dosing, timing and patient selection.

Ketamine is presented as a promising candidate treatment for multiple substance use disorders: the review summarises evidence of one-year abstinence benefits in alcohol dependence, dose-dependent improvements in heroin dependence, and substantial short-term reductions in cocaine craving and self-administration. Nevertheless, the authors conclude that the field requires higher-quality controlled clinical trials and mechanistic research to confirm efficacy, clarify how ketamine works in addiction, and identify the best ways to combine the drug with psychological therapies. If the initial findings are replicated in rigorous studies, the authors suggest ketamine could become an important new direction in addiction treatment.