AAAP 2008: COMT Inhibitor Shows Promise in Treating Marijuana Addiction

Marlene Busko

December 08, 2008

December 8, 2008 (Boca Raton, Florida) — The catechol-o-methyl-transferase (COMT) inhibitor entacapone, which increases dopamine in the synaptic cleft, shows promise in the treatment of marijuana dependence, a pilot study suggests.

Although marijuana is commonly perceived to be innocuous, new neurobiological findings show it has neurotoxic effects, lead study author Rahim Shafa, MD, from Boston University, in Massachusetts, told Medscape Psychiatry.

In addition, as a result of successful antitobacco public-health campaigns, marijuana is replacing tobacco as the "gateway" drug, or first drug used, among young people.

"This study is the first to look at a therapeutic intervention that addresses craving by marijuana users," said Dr. Shafa.

"We hypothesized that if we can manipulate COMT — the main enzyme in the synaptic cleft that destroys available dopamine — we might remove the desire to seek marijuana," he said.

"Our results suggest that COMT-inhibitor drugs may potentially play a significant role in treating marijuana dependence, and they support the need for a larger, double-blind, placebo-controlled follow-up study."

The study was presented at the American Academy of Addiction Psychiatry 19th Annual Meeting and Symposium.

Alarming Increase

The increase in marijuana use, particularly among young people, has been "alarming," said Dr. Shafa. A 2004 national survey found that an estimated 14.6 million Americans over the age of 12 years used marijuana, and a 2006 survey showed that 63% of new users were younger than 18 years.

As yet, however, no pharmacological treatment exists for individuals who become dependent on this drug.

To determine whether treatment with the COMT inhibitor entacapone would decrease marijuana craving, the investigators performed an open-label study in 36 patients who met the Diagnostic and Statistical Manual of Mental Disorders, 4th ed (DSM-IV) criteria for marijuana dependence. Most study subjects also abused other substances.

The researchers chose to administer entacapone rather than tolcapone — a similar drug which is also approved by the US Food and Drug Administration for adjunctive treatment in Parkinson's disease — since, although it does not penetrate the blood-brain barrier as readily, it has a better safety profile.

Patients received up to 2000 mg/day of entacapone and could also use it as needed.

"Natural High"

Efficacy of entacapone was defined as improvement on the Clinical Global Impression score, where scores of 1, 2, or 3 indicated 4, 8, or 12 weeks of abstinence from marijuana, respectively.

More than half of the patients (52.7%) achieved at least 4 weeks of abstinence.

The most common adverse effects were urine discoloration (all 36 subjects), somnolence (2), palpitation (1), sweating (1), and nausea (1).

The study was limited by its small size. However, according to the researchers, these early findings suggest that COMT inhibitors might decrease marijuana craving by correcting the dopamine imbalance across the synaptic cleft and allowing a natural surge of dopamine, or "natural high."

"People who seek drugs might be dopamine-deprived and looking for a way to increase dopamine, to get 'high.' If we can remove the need for this — for example, by manipulating COMT enzyme activity — perhaps we can remove their desire to seek drugs," said Dr. Shafa.

The study authors did not report any financial disclosures.

American Academy of Addiction Psychiatry (AAAP) 19th Annual Meeting and Symposium: Poster 3. Presented December 4, 2008.


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