Cocaine and Cannabis Dependence: What Works?

Michael T. Compton, MD, MPH

Editor’s Note:

As the first in a 3-part series on highlights from the 2011 annual meeting of the American Psychiatric Association (APA) in sunny Honolulu, Hawaii, Michael T. Compton, MD, MPH, Associate Professor, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, discusses the management of cocaine and cannabis dependence.

Cocaine Dependence: The Latest in Treatment

The annual meeting of the APA offered a remarkable breadth of sessions, just a few of which are highlighted in this series.

In Symposium 5[1] on Saturday, May 14, titled “Choosing the Right Treatment for Substance Abuse,” Dr. Herbert D. Kleber (Professor of Psychiatry and Director of the Division of Substance Abuse at the Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY), discussed treatments for cocaine dependence in a talk titled “The Elusive Goal of Psychostimulant Dependence Pharmacotherapy.” As a brief introduction to the central effects of cocaine and amphetamines, Dr. Kleber noted that when administered acutely, these drugs increase synaptic levels of the monoamines dopamine, norepinephrine, and serotonin. Agonist approaches to treatment may restore monoaminergic function and reverse deficits contributing to ongoing use while reducing craving through substitution. Despite worries about abuse, diversion, and induction of craving, clinical evidence to date does not support these concerns about potential agonist approaches. However, there are possible adverse cardiovascular effects. Agonist agents that have received some research attention include d-methamphetamine, methylphenidate-sustained release, and d-amphetamine-sustained release. There is some evidence that the use of such agonists enhances retention in psychostimulant abuse treatment. Dr. Kleber also mentioned the potential utility of disulfiram, well known in the armamentarium of treating alcohol dependence, which is known to also increase the ratio of dopamine to norepinephrine by blocking dopamine beta hydroxylase. He noted that 7 studies, including a total of more than 300 patients, have assessed effects of disulfiram in treating psychostimulant abuse.

Several other agents are worth considering. Dr. Kleber noted that the effects of modafinil are less clear. That agent, which requires further study, is well tolerated, has no stimulant effects, and has not been associated with indications of abuse/misuse. However, studies to date have had problems with retention (ie, high dropout rates). Bupropion, a dopamine and norepinephrine reuptake inhibitor, reduces subjective effects of psychostimulants and decreases craving in initial laboratory studies.

Do Antagonist Approaches Work?

Antagonist approaches are generally less effective because they require a high level of motivation. Active vaccines — combinations of a cocaine analog and a carrier protein — are being studied. They appear to slow entry of cocaine into the brain (cocaine metabolism is not changed), thereby decreasing euphoric effects or the apparent potency. No serious safety concerns have been uncovered in initial trials of active vaccines, although mild side effects such as site reactions may occur. Clinically sufficient levels of antibodies may not be achieved, however, in a substantial portion of patients receiving the active vaccine. Naltrexone decreases dopaminergic effects of stimulants via decreasing opioidergic activity. Indirect antagonists that have been studied, but without unequivocal results, include topiramate, gabapentin, and vigabatrin. Some research has suggested that when pharmacologic agents, such as desipramine, levodopa, and bupropion, are used in combination with contingency management strategies, better results are demonstrated.

Future Treatment Strategies

Future medications may be developed to target changes in brain function that occur in response to repeated psychostimulant administration, which are responsible for maintenance of use and relapse. Dr. Kleber noted that “we have a number of promising agents; we hope that in the future — when we present next year — we will have more data on the vaccines and some of the other agents discussed here.” At the end of his presentation, a question from the audience pertained to any potential treatments for methamphetamine addiction, which appears to be a growing problem in the United States. Dr. Kleber noted that, unfortunately, none have been shown in controlled trials to be effective.

Background on Cannabis Dependence?

In the same Symposium,[1] Frances R. Levin, MD (Kennedy-Leavy Professor of Clinical Psychiatry at the Columbia University College of Physicians and Surgeons), discussed “Choosing Treatments for Cannabis Dependence: What Are the Best Options?” She began by noting that although there has been some work on psychotherapies for cannabis use disorders, very little research has been conducted on potential pharmacotherapies. She pointed out, “However, I would predict that within the next 5 years, the problems associated with cannabis use will continue to grow as use continues to increase.”

Cannabis is the most widely used illicit drug in both the United States and worldwide. Although it has a lower abuse potential than some other illicit drugs, the sheer numbers of people who try it result in a  much higher number developing dependence, “and it certainly is a growing problem,” Dr. Levin noted. Additionally, adolescents comprise 40% of substance abuse treatment admissions for cannabis addiction.

In a brief overview of the central effects of cannabis, she noted that delta-9-tetrahydrocannabinol is the key active agent but that hundreds of other compounds are present. After briefly discussing cannabinoid receptors and the endocannabinoids, Dr. Levin noted that the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition lacks a cannabis withdrawal diagnostic category despite the fact that there is clearly a withdrawal syndrome experienced by chronic, heavy users. “Because of this withdrawal syndrome, it can be quite difficult for people who do want to quit,” she noted. Common withdrawal symptoms include decreased appetite, irritability, nervousness/anxiety, restlessness, sleep problems, anger/aggression, and craving.

So What Works?

In terms of psychotherapeutic approaches for cannabis dependence, some research suggests benefits of motivational interviewing, cognitive-behavioral therapy, family structural therapy (used primarily for adolescents and their families), and contingency management strategies. Treatment leads to a decreased amount and frequency of use, but no one treatment approach appears to be superior. Some studies suggest that the combination of contingency management and cognitive-behavioral therapy might work best. In terms of new psychosocial approaches, a very small nonrandomized trial of aerobic  exercise resulted in a reduction in cannabis use, and there is early evidence of potentially using computer-delivered therapy.

Although minimally studied to date, potential pharmacologic treatments for cannabis dependence may include various agonists, antagonists, partial agonists, agents that alleviate withdrawal symptoms, and medicines used to treat comorbid conditions such as attention-deficit/hyperactivity disorder in adolescents. Most pharmacologic studies to date have been done in the laboratory setting, at a study phase between preclinical and clinical trials. There has been some research on divalproex; bupropion; nefazodone; mirtazapine; quetiapine; baclofen, of which high doses appeared to reduce cannabis craving; and naltrexone, which actually appeared to enhance the subjective effects of cannabis while not affecting withdrawal symptoms. Dr. Levin noted that while although laboratory studies give us signals, they are only a first step toward finding agents that can be used in the clinical setting. Other studies have examined oral tetrahydrocannabinol and rimonabant, which was previously reviewed by the US Food and Drug Administration for obesity but did not get approval, in part due to adverse effects including dysphoria and suicidal ideation. The combination of dronabinol and lofexidine showed some initial effects, which are now a focus of study in the clinical setting.

Cannabis Conclusions

In summary, the findings have not been robust to date; as yet, there is no clear consensus on which agents show promise for cannabis dependence, or exactly which outcomes should ideally be targeted. The treatment of comorbid conditions such as depression, anxiety, attention-deficit/hyperactivity disorder, and bipolar disorder is clearly indicated, although the medications used to treat these disorders are usually helpful for the psychiatric condition but not necessarily for the comorbid cannabis use disorder. Thus, for such dually diagnosed patients, quitting can be quite difficult. A summary of the limited research to date indicates that treatment of some sort is better than no treatment, and that combined treatment approaches may be the most effective. “Clearly, there is a need for more effective pharmacologic interventions,” Dr. Levin concluded.