Ketamine's potential role in treating substance use disorders

The first published study using ketamine to treat SUDs is from Russia in 1992. This randomized trial involved 186 men with alcoholism who failed aversive emetic therapy (administering nausea-inducing drugs during alcohol consumption), pharmacological treatment, and individual and group therapy for three months. They either continued treatment as usual or underwent treatment with ketamine. Eighty-six men were randomized to receive ketamine treatment in three stages: an explanation of the procedure, the ketamine administration itself, and group psychotherapy. Notably, during ketamine (3 mg/kg IM) administration, patients smelled and tasted alcohol during the curated, aversive psychedelic experience. At the 1-year follow-up, 60/86 (69.8%) of patients assigned to the ketamine treatment group reported abstinence from alcohol as compared to 24/100 (24%) of the control group. Ketamine treatment was more effective than all other forms of treatment at that time and there were no stated adverse reactions during ketamine administration [].

A 1997 prospective cohort study and review of underlying mechanisms of ketamine administration for the treatment of alcoholism expanded on these findings. Two hundred and eleven men with alcoholism were able to choose between ketamine treatment or conventional psychotherapy after 3 months of individual and group psychotherapy. In total, 111 chose ketamine treatment carried out in three stages: an explanation alongside treatment of psychiatric comorbidities, ketamine administration, and group psychotherapy. Ketamine (2.5 mg/kg IM) was administered alongside a curated, aversive experience. Measured by self-report, 73/111 (65.8%) of the ketamine treatment group attained one or more years of sobriety as compared to 24/100 (24%) of the control group. At the 2-year follow-up and 3-year follow-up for the ketamine group, 33/81 (40.7%) and 14/42 (33.3%), respectively, maintained sobriety []. The authors conclude by stating that they successfully carried out ketamine treatment on over 1000 patients without any complications including ketamine use disorder [].

Inspired by Krupitsky, Kolp et al. conducted a retrospectively reported case series in the U.S. of 70 adults with alcohol dependence treated with ketamine-enhanced psychotherapy, which is described as psychoanalytic therapy focusing on ketamine's ability to replicate near-death experiences. Based on their best recollection, they estimate up to 90% of patients had a comorbid SUD and 50% with a psychiatric comorbidity. Initially, ketamine-enhanced psychotherapy was offered as part of an outpatient weekly ten-session treatment program where ketamine (unknown dose) was administered on the seventh session and the transpersonal experience was subsequently integrated. This approach led to an approximately 25% abstinence rate at 1 year. In an attempt to replicate Krupitsky's 70% abstinence rate at one year, ketamine-enhanced psychotherapy went through four iterations and was ultimately a 3-week-long program with 90 h of psychotherapy weekly and two ketamine sessions. Within this context, patients achieved the 70% abstinence rate at 1 year [].

Das et al. conducted a single-blind randomized controlled trial of 90 non-treatment-seeking adults with hazardous/harmful drinking patterns without alcohol use disorder (AUD) to either receive (1) retrieval/destabilization of maladaptive alcohol memories (RET) and ketamine, (2) no RET (RET procedure for non-drinking memories) and ketamine, or (3) RET and placebo to test if ketamine can disrupt the reconsolidation of maladaptive reward memories (MRMs). RET or no RET was performed and 5 min later, an IV ketamine infusion (serum concentration 350 ng/mL for 30 min) or IV saline placebo infusion began. One week later, participants that received RET and ketamine had significantly decreased urges to drink, decreased enjoyment of alcohol, and decreased number of binges. None of these differences were observed in the control groups. Nine months later, RET and ketamine showed the greatest reduction in total alcohol consumption. There was a significant correlation between ketamine and metabolite levels during the period of memory instability after RET but not for no RET, suggesting that ketamine had a dose-dependent relationship to reconsolidation blockade. The authors conclude that ketamine can interfere with the reconsolidation of maladaptive alcohol memories and thus reduce drinking in this population [].

An open-label pilot study recruited five patients with major depressive disorder (MDD) and comorbid AUD to receive injectable naltrexone 2–6 days before the initiation of weekly ketamine infusions (0.5 mg/kg IV) for four weeks. All showed a 50% or higher improvement from baseline in the Montgomery–Asberg Depression Rating Scale by 4 weeks and 4/5 (80%) reported improvement in alcohol craving as measured by the Obsessive Compulsive Drinking Scale. The authors conclude that naltrexone did not interfere with the clinical response to ketamine and that ketamine treatment may enhance the treatment of comorbid AUD by decreasing cravings [].

A randomized, double-blind, active control, pilot trial explored the effects of a single ketamine infusion (0.71 mg/kg IV over 52 min) vs midazolam (0.025 mg/kg IV over 52 min) and motivational enhancement therapy (MET) for the treatment of AUD. Forty treatment-seeking adults with alcohol dependence either received ketamine (17/40) or midazolam (23/40) during the second week of a five-week outpatient trial. Both groups received a total of six MET sessions. Measured by self-report and urine toxicology, patients who received ketamine had a significantly higher proportion of alcohol-abstinent days during the last 3 weeks of the study. During this time, the proportion of heavy drinking days increased in the midazolam group but remained stable in the ketamine group and time to relapse was significantly higher in the ketamine group. At the 6-month follow-up, via telephone interviews, 6/8 (75%) of the ketamine group reported abstinence compared to 3/11 (27%) in the midazolam group. There were no persistent psychoactive effects or initiation of drug misuse in either study group [].

Secondary analysis of this study examined the mystical experience via the Hood Mysticism Scale (HMS) and the dissociative effects as measured by the Clinician Administered Dissociative States Scale (CADSS). Ketamine produced significantly higher scores on both scales as compared to midazolam. The HMS had a significant correlation with decreased heavy drinking days, but the CADSS did not. Similarly, increased HMS score was significantly correlated with longer time to relapse, but CADSS was not [].

Grabski et al. conducted a randomized, double-blind, placebo-controlled phase 2 clinical trial with 96 adults with moderate to severe AUD. These adults were randomized to one of four treatments: (1) ketamine and mindfulness-based relapse prevention therapy, (2) ketamine and alcohol education, (3) saline and therapy, or (4) saline and education in a 1:1:1:1 ratio. Ketamine (0.8 mg/kg IV over 40 min) or placebo (0.9% IV saline of equal volume) were administered at visits 2, 4, and 6. Therapy or education was given on visits 2–8. Using the Alcohol Timeline Follow Back self-report questionnaire at the 3- and 6-month follow-ups, there was a significantly greater percentage of days of abstinence in the ketamine and therapy group as compared to saline and education. However, there was no significant difference for odds of relapse within 6 months. Six participants reported using ketamine illicitly on a single occasion after receiving the infusions but all of them had previously used ketamine recreationally [].

Terasaki et al. conducted a three-arm, open-label randomized trial comparing the effect of (1) a single infusion of ketamine (0.5 mg/kg IV over 40 min) and linkage to an outpatient addiction clinic, (2) naltrexone (380 mg IM) and linkage, or (3) linkage alone on 30-day all-cause hospital readmission rates. Forty-four hospitalized adults with severe AUD and at least one alcohol-related hospitalization or emergency department visit within the past year were randomized. On the anticipated day of discharge, the intervention occurred without psychotherapy. The 30-day readmission rates were 2/13 (15.4%) for ketamine, 3/14 (21.4%) for naltrexone, and 7/17 (41.2%) for linkage alone. Clinic attendance was 8/13 (61.5%) for ketamine, 7/14 (50%) for naltrexone, and 7/17 (41.2%) for linkage alone. However, these outcomes were not statistically significant, which the authors assert is due to their small sample size. There were no serious adverse events or reported illicit ketamine use [].

Wong et al. looked at a retrospective cohort of 23 adults admitted to the ICU that received an adjunctive ketamine infusion (mean total infusion rate 0.20 mg/kg/h IV for approximately 56 h) for the management of alcohol withdrawal syndrome; usually delirium tremens. Comparing pre- and post-administration, they found ketamine may reduce benzodiazepines requirements without affecting sedation scores []. Pizon et al. conducted a retrospective cohort study of 63 adult patients admitted to ICU diagnosed with delirium tremens. As compared to those treated with solely symptom-triggered benzodiazepines and phenobarbital, ketamine infusion (mean 0.19 mg/kg/h for approximately 47 h) was associated with a significant decrease in the length of ICU stay, likelihood of intubation, and mean benzodiazepine dose received []. Shah et al. conducted a retrospective cohort study of 30 adults admitted to the ICU that received adjunctive ketamine (median 0.75 mg/kg/h for approximately 54 h) for lorazepam infusion-resistant alcohol withdrawal syndrome. Initial symptom control was achieved within 1 h for all patients alongside a significant reduction in benzodiazepine requirements []. Combining the above studies, the only adverse effect reported was oversedation in two patients.

Ketamine's treatment of opioid use disorder (OUD) is multifaceted. There are numerous studies demonstrating that ketamine can reduce both acute and chronic pain [,,] and reduce the respiratory suppression and hyperalgesia associated with opioid use []. Taken together, this evidence suggests ketamine may reduce the total amount of opioids required for adequate pain control, potentially decreasing the incidence of OUD from opioid exposure.

Ketamine can be used to treat OUD directly. A 2002 double-blind, randomized controlled trial in Russia compared the effects of a psychedelic dose of ketamine (2.0 mg/kg IM) with a non-psychedelic dose (0.2 mg/kg IM) in an inpatient setting. This included psychotherapy in preparation, during ketamine administration, and afterwards. Seventy detoxified heroin-addicted patients were randomly assigned in a 1:1 ratio. Measured by self-report, collateral information, and urine toxicology, the psychedelic dosing produced a significant increase in abstinence and lower cravings at 24 months. Both groups had decreased anhedonia, anxiety, and depression alongside improvements in internal locus of control, understanding meaning and purpose of one's life, spirituality, and attitude towards abstinence. There were no psychiatric complications including the development of ketamine use disorder and this intervention proved more effective than conventional treatments at the time [].

A follow-up randomized clinical trial by the same group in Russia compared three ketamine sessions with a single session. Each group received the same psychedelic dose of ketamine (2.0 mg/kg IM). Fifty-nine detoxified patients with heroin dependence were randomly assigned to each group. Like the prior study, patients received psychotherapy before, during, and after their first ketamine session. Both groups received monthly 1-h addiction counseling sessions with the three-session group having two additional ketamine sessions following counseling. At 1 year follow-up, the rate of abstinence in the three-session group was significantly higher, 13/26 (50%), as compared to 6/27 (22.2%). The additional improvements noted in their 2002 study were seen alongside no differences in cravings, anxiety, or depression [].

An open-label proof of concept study examined the combination of ketamine, rTMS, and trauma interventions using mindfulness-based extinction and reconsolidation of memories (TIMBER). This study included three patients with a diagnosis of OUD that underwent a single infusion of ketamine (0.75 mg/kg IV over 45 min) and, 1 week later, five sessions of rTMS to the right dorsolateral prefrontal cortex alongside five sessions of TIMBER over 1 to 2 weeks. There was a significant decrease in every patient's Opiate Craving Scale score [].

A randomized, double-blind, double-arm, active control study in Iran compared one treatment with ketamine (0.5 mg/kg over 40 min) or buprenorphine (16 mg sublingual) for anxiety and opioid cravings measured by the HAM-A and Opioid Cravings Scale for 64 inpatient adult participants with comorbid MDD and OUD. Both interventions led to significant decreases in anxiety and opioid craving at 2 h, 24 h, and 1 week post-intervention without differences between the two groups [].

A randomized, placebo-controlled, double-blind trial in Lithuania compared normal saline or a subanesthetic ketamine infusion (0.5 mg/kg/h IV) for management of opioid withdrawal during rapid opioid antagonist induction under general anesthesia. Fifty-eight patients with opiate dependence were admitted and stabilized on intramuscular morphine. On day 3, patients were put under general anesthesia and received naloxone and naltrexone. Of the 50 patients included in the final analysis, those that received the ketamine infusion had significant suppression of precipitated withdrawal as evidenced by an attenuated rise in cardiovascular, respiratory, and neuroendocrine response [].

Heeny et al. conducted a retrospective case series involving 10 patients with buprenorphine-precipitated withdrawal treated with ketamine. They were generally given a ketamine infusion (0.3 mg/kg IV over 15 min) followed by an addition infusion (0.3–1 mg/kg over 1 h). All of these patients had reported improvement in their clinical opioid withdrawal scale (COWS) []. Some other examples include Hailozian et al. who presents a case of a fentanyl-using patient with OUD who developed severe buprenorphine-precipitated withdrawal during an outpatient buprenorphine micro-induction that was successfully treated by a ketamine infusion (0.6 mg/kg IV over 1 h) []. Christian et al. present a case of a patient with OUD who developed severe buprenorphine precipitated withdrawal with a COWS > 36 after presenting to the emergency department and receiving buprenorphine. He was treated with ketamine (0.6 mg/kg IV over 75 min on two separate occasions) and withdrawal resolved []. Our own addiction psychiatry clinic has reported a case of a patient with OUD, MDD, OCD, and chronic pain who spontaneously (without medical recommendations) tapered down their buprenorphine/naloxone dosing from 16 mg to 8 mg a day without experiencing withdrawal or rebound craving during the early stages of esketamine treatment []. Within this context, sublingual, sub-dissociative dosed ketamine has been studied in a polit case series to transition patients from fentanyl and methadone to buprenorphine, with the majority of 37 patients reporting either significant improvement or resolution of precipitated withdrawal [].

A 2014 randomized, double-blind, lorazepam-controlled, crossover trial by Dakwar et al. examined the effects of three infusions, two different doses of ketamine (0.41 mg/kg IV and 0.71 mg/kg IV over 52 min) vs. lorazepam (2 mg IV over 52 min), on cue-induced cravings measured by the visual analog scale for cocaine craving and motivation to quit cocaine measured by the University of Rhode Island Change Assessment. Eight non-treatment-seeking patients with cocaine dependence received each infusion separated by 48 h and outcomes were assessed 24 h post-infusion while admitted to a research unit. Both doses increased motivation to quit and decreased cue-induced craving but the higher dose further reduced cue-induced craving. At 4 weeks, measured by Timeline Follow Back and urine toxicology, there was a significant decrease in the amount and frequency of cocaine use in the ketamine group. There were no adverse psychiatric effects and no initiation of ketamine or benzodiazepine misuse [].

Secondary analysis of this trial explored if the mystical experiences from ketamine infusions influenced the observed effects. Using a modified version of the HMS, ketamine led to significantly higher scores than the lorazepam infusion, with the higher dose of ketamine being the highest. They found that the intensity of the mystical experience mediated the motivation to quit cocaine at 24 h while CADSS did not [].

A follow-up randomized, double-blind, midazolam-controlled, crossover trial by the same group looked at the effect of a single ketamine infusion (0.71 mg/kg IV over 52 min) vs. midazolam (0.025 mg/kg IV over 52 min) on cocaine self-administration. Twenty non-depressed, non-treatment-seeking patients with cocaine dependence were admitted to a research unit for 6 days three times to analyze the effects of (1) normal saline, (2) ketamine, and (3) midazolam with normal saline first and randomly ketamine or midazolam second and third. A 70-min choice session consisting of five choices between cocaine and money was conducted 28 h post-infusion. Ketamine led to a significant reduction in cocaine choices (1.61/5) as compared to both saline baseline (almost 5/5) and midazolam (4.33/5). Notably, two patients entered remission from cocaine use after ketamine administration and were thus ineligible for the third hospitalization. There were no notable adverse effects [].

Secondary analysis of the above study explored the mystical experiences and if this mediated ketamine's observed effects. The CADSS, the HMS, and the Near-Death Experiences Scale (NDES) were assessed. Ketamine led to significantly higher psychoactive effects on all measures compared to midazolam. The decreases in cocaine self-administration and cravings were mediated by the HMS but not the CADSS or NDES. The authors noted the psychoactive effects were transient and well tolerated [].

These studies culminated in a randomized, double-blind, midazolam-controlled, clinical trial that compared one ketamine infusion (0.5 mg/kg IV over 40 min) to an infusion of midazolam (0.025 mg/kg IV over 40 min) with 5 days of mindfulness-based relapse prevention (MBRP) in the inpatient setting. Fifty-five treatment-seeking patients with cocaine dependence were randomized. All received MBRP daily on days 2–5 and their infusion occurred earlier on day 2. They then returned twice weekly for 4 additional weeks of MBRP. During the last 2 weeks of the trial, 13/27 (48.2%) of the ketamine group and 3/28 (10.7%) of the midazolam group had urine-test-confirmed abstinence from cocaine. At the 6-month follow-up, 12/27 (44%) of the ketamine group self-reported abstinence from cocaine compared to 0/28 (0%) of the midazolam group. Additionally, the ketamine group had lower levels of cocaine craving scores and a longer time to relapse. No adverse psychiatric effects or development of substance misuse were noted [].

A retrospective cohort study used artificial intelligence (AI) prediction and an expert panel to determine candidates for the treatment of cocaine use disorder and their potential mechanisms of action. The AI identified 35 drug candidates and ketamine was selected by the expert panel for further analysis. The AI compared patients with cocaine use disorder that were either exposed to ketamine as a general anesthetic or for the treatment of depression to controls. After analysis of over 90 million patients from the U.S., patients with ketamine exposure were more likely to achieve remission than controls (HR 1.98 for ketamine as a general anesthetic and 4.39 for ketamine as an antidepressant). It also identified that ketamine targets multiple genes of interest that are also implicated in AUD, stimulant use disorder, OUD, and nicotine use disorder [].

A single-medication-blind proof of concept study by Azhari et al. investigated subanesthetic ketamine combined with motivation enhancement therapy (MET) and MBRP for the treatment of cannabis use disorder over 6 weeks. Eight treatment-seeking patients with cannabis dependence received one ketamine infusion (0.71 mg/kg IV over 52 min) during week 2 after 24 h of abstinence and non-responders received a second infusion (1.41 mg/kg over 92 min) during week 4. Mindfulness-based exercises were used during each infusion. They also received MET on week 1, day 1, MET on the day before their first ketamine infusion, MET the afternoon after the infusion, and MBRP twice weekly on weeks 3 to 6. The non-responders, 3/8, as defined as continued use or intolerable cravings, received MET the day before the second infusion and the afternoon after. There was a significant decrease in the number of cannabis-using days measured by Timeline Follow Back starting 1 week after the first infusion and lasting through the end of the study. There was an increase in patients' confidence to abstain from using cannabis but no differences were found for craving. Overall, 6/8 participants achieved 3 or more weeks of abstinence confirmed by urine toxicology by the end of the study. No participants developed misuse of any other substance and no adverse psychiatric effects were noted [].

A small, randomized, single-blind, placebo-controlled pilot study by Chuang et al. investigated a single infusion of subanesthetic ketamine without psychotherapy for the treatment of tobacco use disorder over 8 days in a non-treatment-seeking sample. Ten participants were randomized and six received a single infusion of ketamine (0.5 mg/kg over 20 min) on day 1 in addition to completing a 7-day smoking diary pre- and post-infusion. The ketamine infusion was safe and well tolerated. There was a nonsignificant decrease in the Questionnaire of Smoking Urges, potentially indicating lower cravings, and there was a nonsignificant trend towards a decrease in the Minnesota Withdrawal Scale. There was no significant effect on self-reported cigarette use [].

We know of no published studies that examine ketamine for the treatment of methamphetamine use disorder, but this is an area of ongoing research (CTN-0132). However, a preclinical study demonstrated potential benefit. Sprague-Dawley rats were given methylazoxymethanol (MAM) acetate in accordance with the MAM rat model of schizophrenia or saline. Seven control rats and five MAM rats were allowed to self-administer methamphetamine (0.08 mg/kg/infusion IV) for a 14-day maintenance period followed by a 14-day abstinence period. Then, a 5-day relapse period to re-establish drug taking behavior with a saline intraperitoneal injection to assess the effect on methamphetamine self-administration. At least one day after this, ketamine (5 mg/kg IP) was administered. There was no significant change in self-administration of methamphetamine in MAM rats after ketamine administration. However, there was a significant decrease in the amount of methamphetamine self-administered in control rats [].