MENDOZA, ARGENTINA – Two promising pharmacotherapies are currently in clinical trials for treatment of cocaine dependence: disulfiram and a vaccine consisting of a cocaine-cholera toxin complex, Dr. Thomas Kosten said at the Sixth World Congress of Depressive Disorders.
Cocaine blocks the reuptake of dopamine, and after chronic abuse it causes a reduction in the number of postsynaptic dopamine receptors and eventually leads to damage of dopamine-responsive cells in the brain, said Dr. Kosten, professor of psychiatry and neuroscience at Baylor College of Medicine, Houston.
Neuroimaging studies show visible changes in the brain after abuse of amphetamines or cocaine, with a noticeable decrease in the number of dopamine-responding cells. Changes persist even after cocaine use has stopped.
“We have done these imaging studies out to 18 months after stopping cocaine and have shown no restoration in function,” he said. “It appears that these may be very long-term and relatively irreversible changes.”
Disulfiram (Antabuse) may improve this dopamine-deficient state, particularly in people with genetically low levels of the enzyme dopamine beta-hydroxylase, which converts dopamine to norepinephrine. Norepinephrine is associated with withdrawal symptoms, and dopamine is associated with reward from normal activities as well as from drug abuse. Disulfiram inhibits dopamine beta-hydroxylase, causing cells to release dopamine rather than norepinephrine. In seven placebo-controlled, double-blind studies involving more than 700 patients, disulfiram produced considerably better results than did placebo: up to 55% of urine samples were cocaine free in the disulfiram group, compared with about 40% in the placebo group.
“This is an effect size equivalent to what's seen in antidepressants for treating depression or standard antipsychotic agents for treating schizophrenia,” Dr. Kosten said.
The increased amount of dopamine appears to change the acute effects induced by cocaine. Ordinarily, someone smoking cocaine will get euphoria followed by increased craving for cocaine, but disulfiram markedly reduces the craving induced after cocaine is given.
Several minutes after the euphoria abates, the individual is likely to experience cocaine-induced dysphoria, with feelings of nervousness and paranoia that may last for more than an hour. Disulfiram has the dual effect of diminishing the craving and enhancing the negative feelings associated with cocaine use, he said.
Some people experience significantly more nervousness and paranoia when taking disulfiram with cocaine. Genetic mapping has suggested that people who experience disulfiram-induced dysphoria have a dominant mutation in a gene leading to the synthesis of dopamine beta-hydroxylase, a mutation that results in abnormally low enzyme levels. Thus, the dual action of disulfiram has therapeutic implications, particularly in abusers with abnormally low levels of dopamine beta-hydroxylase, who showed the best response to disulfiram treatment, Dr. Kosten said.
The vaccine approach targets the drug itself rather than the receptor. The cocaine molecule is too small to provoke an immunologic response on its own, so the vaccine consists of a complex of cocaine attached to the cholera toxin molecule. Antibodies generated to the cocaine-cholera toxin complex bind to cocaine, trapping it in the bloodstream and preventing its entry into the brain.
Several clinical trials have been conducted, and the vaccine appears to be safe and well tolerated. The most effective dosage is a high dose of the vaccine given five times over a period of 3 months. High levels of antibodies are necessary for a therapeutic effect. The vaccine blockade can be overridden, but three- to fourfold higher levels of cocaine are required for the drug user to feel the “normal” response to cocaine, Dr. Kosten said.
In clinical trials, about 75% of subjects appeared to have an effective antibody response. Subjects who received the vaccine had a significantly higher proportion of cocaine-free urines, compared with baseline, than did subjects who received placebo.
“We will move into phase III [Food and Drug Administration] approval studies in the next year or so, with the hope that this vaccine might be available in 2 or 3 years,” he said.
Dr. Kosten reported no conflicts of interest. He does not hold stock in Celtic Pharma, the company developing the vaccine. His studies have been supported by the National Institute on Drug Abuse.
Celtic Pharma has supplied vaccine and has conducted independent monitoring of the clinical trials for potential FDA submission.