Ketamine Promising in Cocaine Addiction

Batya Swift Yasgur, MA, LSW

July 05, 2019

A single ketamine infusion combined with mindfulness-based relapse prevention therapy (MBRP) improves abstinence and cuts cravings in cocaine-dependent adults, new research suggests.

Results of a randomized control trial show that rates of abstinence were significiantly higher in patients who received ketamine plus MBRP compared to control patients.

Moreover, those in the group that received ketamine were significantly less likely to experience relapse compared to control persons, and cravings were also significantly lower in the ketamine group throughout the trial.

"In individuals receiving MBRP, a single ketamine infusion led to significantly greater odds of abstinence and delayed the time to first use or dropout, suggesting that a single ketamine infusion promoted engagement with the behavioral treatment and led to better treatment outcomes," study investigator Elias Dakwar, MD, associate professor of psychiatry, Columbia University Medical Center, New York City, told Medscape Medical News.

"Behavioral modification for substance use disorders may benefit from certain medications, even when they are administered once," he added.

The study was published online June 24 in the American Journal of Psychiatry.

No Approved Medications

Currently, no medications are approved by the US Food and Drug Administration (FDA) for the treatment of cocaine use disorder, the authors note.

A "promising" line of research focuses on modulating glutamate neurotransmission.

The N-methyl-D-aspartate receptor (NMDAR) is the predominant glutamate receptor involved in learned behavior. In animal studies, NMDAR modulators have been shown to disrupt reinforcing effects of cocaine, but such modulators have not shown similar efficacy in human beings.

Ketamine modulates NMDAR but may have additional downstream effects on other neurotransmitter systems, as well as prefrontal synaptogenesis, mechanisms that may be relevant to the treatment of cocaine use disorder.

Successful treatment of cocaine use disorder has been undermined by craving, low motivation, and high behavioral reactivity, the authors note.

"Efforts at behavioral modifications are challenging for cocaine use disorder, with precarious motivation, craving, reactivity, and fixed perspectives impacting on the ability for people to benefit from behavioral, interventions," said Dakwar.

"Ketamine may improve many of these vulnerabilities. Further, it may serve as an experiential stepping stone for mindfulness training specifically," he added.

Addiction-Related Vulnerabilities

To investigate this hypothesis, the researchers randomly assigned 55 individuals who were seeking treatment for cocaine dependence to receive either a 40-minute intravenous infusion of ketamine (0.5 mg/kg) or midazolam (multiple brands) (0.025 mg/kg) in a 5-week trial.

Participants were hospitalized in a psychiatric research unit for 5 days. They received an infusion on day 2 and MBRP sessions daily from day 2 to day 5.

After trial completion, participants were referred to other treatments and were interviewed by telephone at 6 months.

The MBRP focused on cultivating mindfulness, integrating mindfulness into daily life, and promoting application of mindfulness to "addiction-related vulnerabilities" (eg, reactivity in high-risk situations).

During the follow-up clinic visits, which were conducted weekly during weeks 2 through 5, participants completed measurement tools related to vulnerabilities associated with cocaine (eg, craving), mindfulness (using the Five-Facet Mindfulness Questionnaire), and stress sensitivity (the Perceived Stress Scale).

Additionally, urine toxicology was performed, and participants were asked to report drug use, using a timeline follow-back method.

The primary outcome was 2 weeks of end-of-study abstinence (confirmed by urine toxicology).

Secondary outcomes were weekly cocaine use (during weeks 2–5) and weekly craving scores (during weeks 1–5).

No Adverse Effects

Treatment with ketamine was significantly associated with higher ratings of acute dissociation on the Clinician-Administered Dissociative States Scale (median score, 22 in the ketamine group [interquartile range (IQR) = 13–34]; and 7 in the midazolam group [IQR = 4–10]; χ2 = 6.25; df = 1; P < .001).

Participants experienced psychoactive effects during infusion, which resolved within 30 minutes.

There was no persistent dissociation in either the ketamine or the midazolam group; however, systolic blood pressure increased significantly during infusions of ketamine compared with midazolam (median change, 19.5 mmHg [IQR = 17.0–30.0] and 8.0 mmHg [IQR = 4.0–12.5], respectively; χ2 = 20.14; df = 1; P < .001).

The only reported adverse effect was mild sedation, which lasted ≤12 hours. There were no instances in either group of persistent psychiatric disturbances, clinical worsening, increased drug use, or emergence of new misuse of drugs.

The rate of urine test–confirmed abstinence during the last 2 weeks of the trial was much higher in the ketamine group than in the midazolam group (48.2% vs 10.7%, respectively).

After controlling for route of use, the researchers found that the odds of abstinence in the ketamine group at end of study were 6 times that of the midazolam group (odds ratio [OR] = 5.7; 95% confidence interval [CI] = 1.3–25.1; χ2 = 5.34; df = 1; P = .02).

The final main effects model showed even higher odds. After controlling for route of use, the odds of cocaine use in the midazolam group was 7.8 times the odds in the ketamine group (OR, 7.8; 95% CI = 1.5–39.9; t = 2.50; df = 164; P = .01).

Almost all the participants in the midazolam group (92.9%) went on to use cocaine or drop out. By contrast, a little more than half of the participants in the ketamine group (57.7%) did so.

There was no change in drug use over time in either group (t = 20.29; df = 164; P = .77), "suggesting that participants in the ketamine group maintained their early improvements over the course of the trial," the authors state.

The final main-effects model found that craving scores were 58.1% lower in the ketamine group compared to the midazolam group (t = 22.57; df = 100; P = .01; 95% CI = 18.6–78.6), after controlling for route of use.

At the 6-month telephone follow-up interview, none of the participants in the midazolam group were abstinent. By contrast, 44% of the participants in the ketamine group reported abstinence.

"Mindfulness training may be easier to pursue with certain capacities, such as nonreactivity — some experiential precedent for what mindfulness involves and motivation for engaging in it," Dakwar commented.

"These results suggest that ketamine may promote all these," he added.

Credible Mechanism

Commenting on the study for Medscape Medical News, Dan V. Iosifescu, MD, director of clinical research, Nathan Kline Institute, and associate professor of psychiatry, New York University School of Medicine, New York City, who was not involved with the study, called it "fairly innovative."

Most studies of ketamine have excluded participants who had substance abuse disorders, because ketamine itself is "a substance of abuse, and there are places where it is used as a party drug, under the name Special K, so this is one of only a few studies where it was used as treatment specifically for people with substance abuse," he said.

"Another interesting aspect of the study is that ketamine was paired with psychotherapy — specifically, mindfulness-based relapse prevention — a therapy that has previously been shown to have some effects in cocaine abusers, substance abusers in general, but is not very efficacious."

He noted that no psychotherapies for substance abuse "work very well — they all kind of help, but not dramatically so."

These psychotherapies are "essentially based on people learning some skills, strategies to better deal with their impulse to use drugs," he said.

Ketamine and other medications that modulate glutamate systems, such as memantine, which is a weaker glutamate modulator that iws FDA-approved for Alzheimer disease — have some effect on cognitive enhancement, Iosifescu explained.

Some research has "postulated that ketamine may be helpful by improving the patient's ability to attend to psychotherapy," he said.

He added that "the study was not clear whether ketamine has an effect by itself or whether it has an effect by improving the patient's ability to attend, understand, and retain the information they are supposed to learn in MBRP therapy."

But this hypothesis suggests a "legitimate and credible mechanism by which this latter effect would be possible," he said.

Too Soon to Recommend

Also commenting on the study for Medscape Medical News, Ashwin A. Patkar, MD, professor of psychiatry and community health and medical director, Duke Addictions Program, Duke University Medical Center, Durham, North Carolina, who was not involved with the study, said that clinicians "should be aware that intravenous infusion of a single dose of ketamine, along with intensive mindfulness-based behavioral intervention, appears to hold promise for cocaine use disorder."

However, "clinicians should be cautious in recommending intravenous ketamine for cocaine-addicted individuals, based on results of a single trial with a modest sample size," he warned.

"Further studies with larger sample sizes and more rigorous evaluation of abuse potential in substance-using population are necessary before implementing ketamine in clinical practice," Patkar said.

The authors agree.

"Further research is needed to replicate these results in a larger sample, as well as to clarify mechanisms, examine more rigorously the hypothesis of synergy between ketamine and behavioral treatments, and evaluate emerging pharmacotherapies comparable to ketamine," they write.

The study was supported by a grant from the National Institute on Drug Abuse. Dakwar has disclosed no relevant financial relationships. The other authors' disclosures are listed on the original article. Iosifescu reports no relevant financial relationships. Patkar is on the advisory board of the Centers for Psychiatric Excellence (COPE) and the speakers' bureau of Janssen Pharmaceuticals. Patkar's spouse is a shareholder in COPE.

Am J Psychiatry. Published online June 24, 2019. Abstract

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