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Systematic Review
The aim of this report is to summarize the evidence regarding the clinical and cost-effectiveness of ketamine for treating substance use disorders (SUDs) in adults. This report also aims to review the evidence-based guidelines regarding the use and administration of ketamine for adults with SUDs
The authors state:
"We identified a total of 493 citations from the literature search. Following screening of titles and abstracts, we excluded 470 citations and retrieved 23 potentially relevant reports from the electronic search for full-text review. We found 2 potentially relevant publications from the grey literature search. Of the 25 potentially relevant articles, we excluded 22 publications for various reasons and included 3 that met the inclusion criteria."
"Clinical Effectiveness of Ketamine versus Placebo or No Treatment for Adults with SUDs:
Abstinence:
In the SR by Kelson et al. (2023),16 a double-blind, placebo-controlled phase II clinical trial studied the effects of ketamine therapy in the treatment of AUD with relapse prevention-based psychological therapy. The 96 patients were randomly assigned to 1 of 4 groups: 3 weekly ketamine infusions (0.8 mg/kg) and psychotherapy, 3 weekly saline infusions and psychotherapy, 3 weekly ketamine infusions and alcohol education, or 3 weekly saline infusions and alcohol education. At 6-month follow-up, there was statistically significantly greater number of days of abstinence in the pooled ketamine group compared to placebo (mean difference [MD] = 10.1; 95% CI, 1.1 to 19). Compared with saline plus alcohol education group at 3-month follow-up, ketamine plus psychotherapy group had statistically significantly greater number of days of abstinence (MD = 15.9; 95% CI, 3.8 to 28.1).
Withdrawal:
The SR by Kelson et al. (2023)16 included 2 noncontrol studies evaluating the efficacy of ketamine for treatment of alcohol withdrawal.
• A single-group, retrospective cohort study examined the effectiveness of adjunctive ketamine therapy with a conventional withdrawal treatment protocol (benzodiazepine ± dexmedetomidine ± phenobarbital ± propofol ± antipsychotics ± clonidine ± intubation) in patients with alcohol withdrawing symptoms. The mean initial dose of ketamine was 0.21 mg/kg/h. Compared with baseline, there was no change in Withdrawal Assessment Scale scores (defined as a benzodiazepineequivalent requirement of 40 mg/h of diazepam for alcohol withdrawal management) in patients within 6 hours of ketamine initiation. Ketamine treatment correlated with no statistically significant change in median benzodiazepine requirements of –40.0 mg (IQR = –106.7 to 21.7; P = 0.11) and –13.3 mg (IQR = –86.7 to 50.0, P = 0.33) at 12- and 24-hours post-infusion, respectively.
• A retrospective cohort study investigated the use of adjunctive ketamine therapy for the reduction of lorazepam infusion requirements and symptom control in patients with benzodiazepine-resistant alcohol withdrawal. The median initial infusion dose of ketamine was 0.75 mg/kg/h. The results showed that 100% of patients achieved initial symptom control at 1 hour after ketamine infusion CADTH Health Technology Review Ketamine for Adults With Substance Use Disorders 17 compared to baseline. One day after ketamine infusion, lorazepam’s infusion requirements decreased by approximately 4 mg/h (P < 0.05). In the 48 hours following ketamine therapy, 48% of patients completely weaned off all lorazepam infusions.
Consumption:
The SR by Kelson et al. (2023)16 included a single-blind, placebo-controlled RCT examining the effects of ketamine on alcohol consumption. The study assigned patients to either the intervention (IV ketamine targeting a plasma concentration of 350 ng/dL after alcohol use) or placebo groups (IV ketamine with no alcohol consumption or IV saline after alcohol use). After 10 days of intervention, there was statistically significant reduction in drinking (days/week; binges/week) occurred in the ketamine group (P < 0.001), but not in the control group. From day 10 to 9 months of follow-up, mean weekly alcohol consumption in the ketamine group decreased from approximately 672 g to 328 g.
Clinical effectiveness of Ketamine versus alternative interventions for adults with SUD:
Abstinence:
The SR by Kelson et al. (2023)16 included 3 studies that appraised the effectiveness of ketamine compared with alternative interventions for the treatment of AUD.
• An RCT examined the effectiveness of “affective contra-attribution” method of alcohol dependent treatment, which consisted of introductory psychotherapy, ketamine psychedelic treatment (3 mg/ kg IM) in combination with aethimizol and bemegride, and group therapy. The aim of this method was to change patients’ attitudes toward alcohol consumption by creating a negative association with alcohol. The comparator group received conventional AUD treatment (aversive emetic therapy, pharmacologic treatment for cravings, and psychotherapy). The treatment duration was 3 months. At 1-year follow-up, 69.8% (60/86) of patients in the ketamine group reported sobriety compared to 24% (24/100) in the control group. The statistical significance of this finding was not reported.
• The same authors conducted a subsequent cohort study to analyze the effectiveness of ketamine psychedelic therapy (aethimizol, bemegride, ketamine [2.5 mg/kg IM], and psychotherapy) versus conventional AUD treatment. The ketamine psychedelic therapy focused more on existential and transpersonal psychology. The treatment duration was 3 months. At 1-year follow-up, 65.8% (73/111) of patients in the ketamine group reported complete sobriety compared to 24% (24/100) in the control group. The statistical significance of this finding was not reported.
• A randomized, midazolam-controlled pilot trial was conducted to study the effects of a single ketamine infusion (0.71 mg/kg) combined with motivational enhanced therapy (6 sessions) for the treatment of AUD. During 21 days after infusion, the proportion of patients with abstinence in the ketamine group remained stable, while it decreased substantially in the midazolam group. At 6 months, 75% (6/8) of patients in the ketamine group and 27% (3/11) in the control remained abstinent. The statistical significance of this finding was not reported
Consumption:
The SR by Kelson et al. (2023)16 included a randomized, midazolam-controlled trial examining the effects of a single ketamine infusion (0.71 mg/kg) combined with motivational enhanced therapy for the treatment of AUD. At 3-week follow-up after infusion, 47.1% (8/17) in the ketamine group and 59.1% (13/22) in the midazolam group used alcohol products. The statistical significance of this finding was not reported. There was statistically significant reduction with time in heavy drinking days in the ketamine group compared with midazolam group (P < 0.001)."
"This review included 2 SRs, and 1 RCT regarding the clinical effectiveness of ketamine for treating patients with AUD, and CUD and OUD.
Findings from the 2 included SRs suggested that a combination of ketamine and psychotherapy treatment may be effective in promoting abstinence and reducing alcohol and cocaine use. The results were mixed concerning withdrawal and craving. Findings from a single study included in the SR by Walsh et al. (2022) on the effect of ketamine for the treatment of OUD for consumption and withdrawal were inconclusive. The effect of ketamine on health care utilization in patients with severe AUD reported in the included RCT was also inconclusive due to small sample size. At subanesthetic dosing, ketamine treatment was associated with dissociative and psychotomimetic effects, and nondissociative effects. While these effects were mild and transient, the dissociative or psychomimetic characteristics and abuse potential of ketamine remains a concern in long-term treatments.
Further high-quality clinical trials with larger sample sizes, blinding, and low risk of bias would help to provide more accurate findings on clinical efficacy, dosing strategies, and safety profile of ketamine for the treatment of AUD, CUD and OUD. Studies on other substances of abuse (e.g., nicotine, amphetamines, and cannabis) may provide important insights to the overall efficacy of ketamine in the treatment of SUDs. Research on optimal dose, route and frequency of administration, and combination of psychotherapy will also be paramount to determine the optimal treatment protocol of ketamine for treating of each specific SUDs."