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Tuesday 11 April 2006

Anti-fungal agent that curbed cocaine use in rodents has opposite effect in humans

By: Yale University

Ketoconazole, an anti-fungal agent that helps curb cocaine use in laboratory rats, stimulates rather than reduces cocaine and heroin use in humans, according to a study by researchers at Yale School of Medicine.

"Contrary to the predicted effects, both heroin and cocaine use increased after patients were stabilized on methadone and ketoconazole," said Thomas Kosten, professor of psychiatry at Yale and lead author of the study published in the March issue of the journal Drug and Alcohol Dependence. "Depressive and withdrawal symptoms improved no more with ketoconazole than with placebo treatment, and side effects were greater on ketoconazole than placebo."

"We were hoping that the addicts would remain cocaine free, but our study showed that ketoconazole (kee-toe-caw-nah-zoll) didn't seem to make any difference," he said.

One of the side effects of ketoconazole is to suppress cortisol levels. Cortisol is a hormone whose production is stimulated by stress and is associated with relapse among heroin and cocaine addicts.

"Stress plays an important role in substance abuse problems," Kosten said. "In studies with rodents, stress induced reinstatement of opioid and cocaine self-administration and ketoconazole, a cortisol synthesis inhibitor, reduced cocaine self-administration in rodents."

He said the research team conducted the study to clarify conflicting results when the agent was administered to primates and humans as well as laboratory rats. In a 12-week double blind clinical trial, ketoconazole and a placebo were randomly administered to 39 male and female cocaine addicts who were taking methadone, which is known to reduce cortisol levels. The ketoconazole was administered in doses varying from 200 milligrams up to 900 milligrams daily.

"In agreement with the negative results from acute dosing studies in primates and humans, chronic ketoconazole treatment does not appear to reduce cocaine or opioid use in humans maintained on methadone," Kosten said.

In addition, morning cortisol levels were significantly lower than normal values throughout the clinical trial, but were not lower with ketoconazole than placebo treatment.

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