Dietary Supplement May Help Treat Cocaine Dependence

Miriam Davis, PhD

June 16, 2015

The dietary supplement citicoline shows promise in the treatment of cocaine dependence in patients with bipolar disorder (BD), but its benefits appear to decline over time, new research suggests.

The results of a 12-week randomized controlled trial comparing citicoline to placebo for patients with both cocaine dependence and BD showed that the supplement significantly reduces cocaine use in the initial weeks of treatment.

"Citicoline was well tolerated for treatment of cocaine dependence in patients with bipolar disorder. Cocaine use was significantly reduced with citicoline initially, although treatment effects diminished over time, suggesting the need for augmentation strategies to optimize long-term benefit," the investigators, led by E. Sherwood Brown, MD, PhD, University of Texas Southwestern Medical Center, in Dallas, write.

The findings were published online May 22 in the American Journal of Psychiatry.

Challenging Population

"Bipolar disorder has the highest rates of substance abuse of any axis I disorder, with lifetime prevalence reaching 61%. And very little is known about treatment of substance abuse with this condition," Dr Brown told Medscape Medical News.

A naturally occurring compound in the brain that acts through several neurotransmitter systems, citicoline was previously shown in a smaller 2007 clinical trial, conducted by the same research group, to prevent relapse in BD patients with cocaine dependence.

The investigators note that substance use in BD has several deleterious effects. Studies report higher rates of violence and aggression, higher rates of hospitalization, lower rates of recovery, and greater rates of medication nonadherence.

"Thus, patients with bipolar disorder and substance dependence are a large and challenging population and an important public health concern," they write.

To confirm the findings of their previous study, the investigators recruited 130 outpatients with BD and cocaine dependence who were then randomly assigned to receive citicoline or placebo.

Cocaine use was measured by thrice-weekly urine drug screens during the course of the 12-week trial. As a measure of conservatism, the protocol called for all missing urine screens to be automatically classified as a positive urine test result.

The citicoline group showed an almost immediate reduction in cocaine use. Nearly 80% of the placebo group had a positive drug screen in the first 2 weeks of the trial, compared with 65% in the citicoline group.

Nevertheless, cocaine use in the citicoline group gradually increased during the course of the trial. By week 12, cocaine-positive urine screens were found in 74% of the citicoline group vs 78% of the placebo group. Still, the results were statistically significant for a reduction in cocaine use.

Decline in Efficacy

The investigators were unsure why citicoline's effect diminished over time. Patients were given an initial dose of 500 mg/day, which was gradually increased by week 6 to a maximum of 2000 mg/day.

"One possibility for the decline in efficacy was that patients developed tolerance to the effects. The other possibility is that the higher doses were too high," said Dr Brown.

The investigators note that magnetic resonance spectroscopy data suggest that 500 mg/day is associated with a greater change in membrane phospholipids than the higher dose of 2000 mg/day.

There were no differences between the group receiving citicoline and the group receiving placebo in mood symptoms, which were measured using the Inventory of Depressive Symptomatology–Self Report, the Hamilton Depression Rating Scale, and the Young Mania Rating Scale.

There were also no differences in cocaine craving between the two study groups, as measured by the Cocaine Craving Questionnaire. This negative finding suggests that "the effects of citicoline on cocaine use are not mediated through a reduction in craving," the authors write.

"Two areas may be most important specifically for its use in cocaine dependence, its increase of acetylcholine levels in the brain, and its stabilization of cell membranes via its effects on phospholipid metabolism," said Dr Brown.

The investigators also found that citicoline was safe and well tolerated. There were no differences between groups on the Somatic Symptom Scale. Several prior studies of citicoline for indications other than cocaine dependence showed that adverse events were higher in the placebo groups than the citicoline groups.

Overall, the results suggest that citicoline alone may best be used in the acute phase of treatment and that other treatments should be considered for the long term. Dr Brown observed that citicoline may be "a useful addition to standard treatment in some patients."

Now that there are two controlled clinical trials showing beneficial effects for cocaine use in BD patients, Dr Brown would like to see citicoline trials in other mood disorders, cocaine dependence in general, and other addictive disorders.

Large Clinical Problem

Commenting on the findings for Medscape Medical News, Ihsan Salloum, MD, MPH, professor of psychiatry and chief of treatment and research in the Division of Alcohol and Drug Abuse, University of Miami School Miller School of Medicine, noted that substance abuse in BD is a "very big clinical problem."

"We see it often in clinical practice but don't have a lot to offer patients. This is the first study showing that a medication has an effect," he said.

Dr Salloum also noted that BD patients with cocaine dependence are difficult to study and are hard to recruit and retain in a clinical trial.

Further, he noted that the current trial was labor intensive because of the requirement for thrice-weekly urine screens.

"The fact that the authors still found a positive effect using a conservative methodology ― classifying a missing drug screen as positive ― is very important," said Dr Salloum.

Dr Salloum emphasized that the study findings are a significant advance because citicoline is available over the counter and does not interact with other medications.

However, before recommending citicoline's use in clinical practice, Dr Salloum said he would like to see confirmation of the findings in a multicenter clinical trial that examines the supplement's most effective dose.

The study was funded by the National Institutes of Health. Dr Brown and Dr Salloum report no relevant financial relationships.

Am J Psychiatry. Published online May 22, 2015. Abstract

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