Safety, tolerability and efficacy of levodopa-carbidopa treatment for cocaine dependence: two double-blind, randomized, clinical trials

Abstract

Rationale: The role of dopamine in cocaine abuse has been long recognized. Cocaine use can profoundly alter dopaminergic functioning through depletion of this monoamine and changes in receptor functioning. Based on these facts, levodopa (L-dopa) pharmacotherapy may be helpful in reducing or abolishing cocaine use.

Objective: The current studies sought to evaluate the safety, tolerability and efficacy of L-dopa as a treatment for cocaine dependence.

Methods: In Study 1, 67 cocaine-dependent subjects were randomized in a 5-week, double-blind, placebo-controlled safety trial. Subjects received either placebo, or 400 mg L-dopa plus 100 mg of the peripheral decarboxylase inhibitor, carbidopa, in a sustained-release preparation (Sinemet CR). In Study 2, 122 cocaine-dependent subjects were enrolled in a 9-week, randomized, double-blind, placebo-controlled trial to compare placebo to 400/100 mg and 800/200 mg L-dopa/carbidopa treatments. Placebo or L-dopa were administered twice daily in both studies.

Results: L-dopa was well tolerated with similar retention and medication adherence rates compared to placebo. Only two side effects occurred more often in L-dopa-treated patients: nausea and dizziness. L-dopa lowered diastolic blood pressure in a dose-dependent fashion. In these trials, L-dopa had no effect on cocaine use, cocaine craving, or mood.

Conclusion: These two studies demonstrate the safety and tolerability of L-dopa pharmacotherapy in cocaine-dependent patients. No evidence for greater efficacy of L-dopa compared to placebo was observed. The possibility of enhancing treatment effects by combining L-dopa with other behavioral or pharmacological interventions is discussed.

Figure 1

Participant enrollment and retention figure for Study 1. Protocol violations indicate high absenteeism or failure to provide self-report or biological data.

Figure 2

Participant enrollment and retention figure for Study 2. Protocol violations indicate high absenteeism or failure to provide self-report or biological data.

Figure 3

Designs of two randomized, placebo-controlled, double-blind trials of L-dopa/carbidopa for cocaine dependence. Participants completed a 3-10 day intake evaluation phase prior to randomization to a treatment condition. Following randomization, participants underwent 7 (Study 2) or 14 day (Study 1) stabilization phase that involved a dose run-up (Study 1). Subsequently, participants began either a 28 day (Study 1) or 64 day (Study 2) treatment phase. After the treatment phase, those in Study 1 discontinued medication while those in Study 2 were switched to placebo for a 1-week run-down.

Figure 4

Participant retention for Study 1 (Plot A) or Study 2 (Plot B). No significant differences in retention seen between groups in either study.

Figure 4

Participant retention for Study 1 (Plot A) or Study 2 (Plot B). No significant differences in retention seen between groups in either study.

Figure 5

Cocaine-use proportions for Study 1 (Plot A) or Study 2 (Plot B) during respective 4- and 8-week dosing periods. A significant medication × time effect was seen in Study 1 while no treatment effects were observed in Study 2.

Figure 5

Cocaine-use proportions for Study 1 (Plot A) or Study 2 (Plot B) during respective 4- and 8-week dosing periods. A significant medication × time effect was seen in Study 1 while no treatment effects were observed in Study 2.