Intranasal Oxytocin Shows Early Promise for Cocaine Dependence

Batya Swift Yasgur, MA, LSW

January 31, 2022

Intranasal oxytocin (INOT) is showing early promise as a treatment for cocaine dependence, new research suggests.

Results of a small 6-week randomized, placebo-controlled trial in patients with cocaine use disorder showed a high level of abstinence in those who received INOT beginning 2 weeks after treatment initiation.

"In this population of cocaine-dependent individuals in a community clinic setting, we found the use of intranasal oxytocin to be safe and feasible, with no adverse events, and a high level of abstinence after 6 weeks, compared to placebo," lead author Wilfrid Noel Raby, PhD, MD, a Teaneck, New Jersey–based psychiatrist, told Medscape Medical News.

On the other hand, "the findings were paradoxical because there was a greater dropout rate in the intranasal oxytocin group after week 1, suggesting that oxytocin might have a biphasic effect, which should be addressed in future studies," added Raby, who was an adjunct clinical professor of psychiatry, Division on Substance Abuse, Montefiore Medical Center, Albert Einstein College of Medicine, New York City, when the trial was conducted.

The study was published in the March issue of Drug and Alcohol Dependence Reports.

"Crying Need"

"Focus on stress reactivity in addiction and on the loss of social norms among drug users has generated interest in oxytocin, due to its purported role in these traits and regulation of stress," the authors write.

Oxytocin is a neuropeptide that regulates autonomic functions. Previous research in cannabis users suggests it may have a role in treating addiction by reportedly reducing cravings. In addition, earlier research also suggests it cuts stress reactivity and state anger in cocaine users.

A previous trial of INOT showed it decreased cocaine craving, and additional research has revealed recurrent cocaine use results in lower endogenous oxytocin levels and depleted oxytocin in the hypothalamus and amygdala.

"The bias of my work is to look for simple, nonaddictive medicinal approaches that can be used in the community settings, because that's where the greatest crying need lies and where most problems from drug addiction occur," said Raby.

"There has been long-standing interest in how the brain adaptive systems, or so-called 'stress systems,' adjust in the face of drug dependence in general, and the main focus of the study has been to understand this response and use the insight from these adaptations to develop medicinal treatments for drug abuse, particularly cocaine dependence," he added.

To investigate the potential for INOT to promote abstinence from cocaine, the researchers randomized 26 patients with cocaine use disorder (73% male, mean [SD] age, 50.2 [5.4] years). Most participants had been using cocaine on a regular basis for about 25 years, and baseline average days of cocaine use was 11.1 (5.7) during the 30 days prior to study entry.

At a baseline, the researchers collected participants' medical history and conducted a physical examination, urine toxicology, electrocardiogram, comprehensive metabolic panel, and complete blood count. They used the MINI International Neuropsychiatric Interview to confirm the diagnosis of cocaine dependence.

The study began with a 7-day inpatient abstinence induction stage, after which participants were randomized to receive either INOT 24 IU or intranasal placebo (n = 15 and n = 11, respectively).

Patients attended the clinic three times per week. At each visit, they completed the cocaine craving scale, the Perceived Stress Scale, and the Clinician Global Inventory (all self-reports), as well as the Time Line Follow Back (TLFB) to document cocaine use.

Participants were trained to self-administer an intranasal solution at home, with compliance monitored in two ways ― staff observed self-administration of the randomized medication at the time of clinic visits and weighed the "at home bottle."

Cocaine use was determined using urine toxicology and TLFB self-report.

Threshold Period

INOT did not induce ≥3 weeks of continuous abstinence. However, beginning with week 3, the odds of weekly abstinence increased dramatically in the INOT group, from 4.61 (95% CI,1.05, 20.3) to 15.0 (1.18, 190.2) by week 6 (t = 2.12, P = .037).

The overall medication group by time interaction across all 6 weeks was not significant (F1,69 = 1.73, P = .19); but when the interaction was removed, the difference between the overall effect of medication (INOT vs placebo) over all 6 weeks "reached trend-level significance" (F1,70) = 3.42, P = .07).

The subjective rating outcomes (cravings, perceived stress, cocaine dependence, and depression) "did not show a significant medication group by time interaction effect," the authors report, although stress-induced cravings did tend toward a significant difference between the groups.

Half of the patients did not complete the full 6 weeks. Of those who discontinued, 85% came from the INOT group and 15% from the placebo group. Of the 11 who dropped out from the treatment group, seven were abstinent at the time of discontinuation for ≥1 week.

There were no significant differences in rates of reported side effects between the two groups.

"This study highlights some promise that perhaps there is a threshold period of time you need to cross, after which time oxytocin could really be really helpful as acute or maintenance medication," said Raby. The short study duration might have been a disadvantage. "We might have seen better results if the study had been 8 or 12 weeks in duration."

Using motivational approaches during the early phase — eg, psychotherapy or a voucher system — might increase adherence, and then "after this initial lag, we might see a more therapeutic effect," he suggested.

Raby noted that his group studied stress hormone secretions in the cocaine-dependent study participants during the 7-day induction period and that the findings, when published, could shed light on this latency period. "Cocaine dependence creates adaptations in the stress system," he said.

"Nice First Step"

Commenting on the study for Medscape Medical News, Jane Joseph, PhD, professor, Department of Neurosciences, and director of the neuroimaging division, Medical University of South Carolina, Charleston, said it is "nice to see a clinical trial using oxytocin in cocaine dependence [because] preclinical research has shown fairly convincing effects of oxytocin in reducing craving or stress in the context of cocaine seeking, but findings are rather mixed in human studies."

Joseph, who was not involved with the study, said her group's research showed oxytocin to be the most helpful for men with cocaine use disorder who reported childhood trauma, while for women, oxytocin "seemed to worsen their reactivity to cocaine cues."

She said the current study is a "nice first step" and suggested that future research should include larger sample sizes to "address some of the individual variability in the response to oxytocin by examining sex differences or trauma history."

The study was supported by an award from the National Institute of Drug Abuse. Raby and co-authors and Joseph have disclosed no relevant financial relationships.

Drug Alcohol Depend. March 2022, 100016. Full text

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