Disulfiram effects on responses to intravenous cocaine administration

Abstract

Disulfiram has been studied as a treatment for cocaine dependence. We report results of a randomized, double-blind, placebo-controlled, within-subject study to examine the interaction of disulfiram with intravenous cocaine.

Methods: Non-treatment-seeking, cocaine-dependent, volunteers participated in serial experiments in which they received disulfiram placebo, 62.5 or 250 mg/day on days 1-6. On days 4-6, participants received a morning disulfiram dose 2 h prior to a scheduled session in which they were administered intravenous cocaine placebo, 0.25 mg/kg (n=9) or 0.5 mg/kg (n=3) over 1 min. Blood, cardiovascular and subjective measures were collected. Seven days of washout occurred between disulfiram conditions.

Results: Following active disulfiram treatments and cocaine 0.25 mg/kg administration, plasma cocaine AUC (0-480 min) was increased (p=0.003 and 0.001) and cocaine clearance decreased (p<0.001). Disulfiram treatments also decreased cocaine clearance for the 0.5 mg/kg cocaine dose (p=0.002 and<0.001). Neither disulfiram dose with cocaine altered cardiovascular responses relative to cocaine alone. Following cocaine 0.25 mg/kg, 'any high' (p=0.021 and 0.019), 'cocaine high' (p=0.017 and 0.018) and 'rush' (p=0.013 and 0.047) significantly decreased with either disulfiram dose.

Conclusions: Disulfiram decreased cocaine clearance without toxicity. Cocaine 'high' and 'rush' were diminished. Disulfiram may be a promising pharmacotherapy in selected cocaine dependent individuals.

Fig. 1

(A) Mean plasma cocaine concentrations over time (min.) following cocaine (Coc) 0.25 mg/kg (i.v.) (n=9) administration during treatment with disulfiram (DS) placebo, 62.5 mg/d or 250 mg/d. (B) Mean plasma cocaine concentrations over time (min.) following cocaine 0.5 mg/kg (i.v.) (n=3) administration during treatment with disulfiram placebo, 62.5 mg/d or 250 mg/d.

Fig. 2

(A): Mean heart rate (beats/min) over time (min.) following cocaine0.25 mg/kg (i.v.) (n=9) administration during treatment with disulfiram placebo, 62.5 mg/d or 250 mg/d. (B) Mean heart rate (beats/min) over time (min.) following cocaine 0.5 mg/kg (i.v.) (n=3) administration during treatment with disulfiram placebo, 62.5 mg/d or 250 mg/d.

Fig 3

(A): Mean systolic blood pressure (mmHg) over time (min.) following cocaine 0.25 mg/kg (i.v.) (n=9) administration during treatment with disulfiram placebo, 62.5 mg/d or 250 mg/d. (B) Mean systolic blood pressure (mmHg) over time (min.) following cocaine 0.5 mg/kg (i.v.) (n=3) administration during treatment with disulfiram placebo, 62.5 mg/d or 250 mg/d.

Fig 4

(A): Mean diastolic blood pressure (mmHg) over time (min.) following cocaine 0.25 mg/kg (i.v.) (n=9) administration during treatment with disulfiram placebo, 62.5 mg/d or 250 mg/d. (B) Mean diastolic blood pressure (mmHg) over time (min.) following cocaine 0.5 mg/kg (i.v.) (n=3) administration during treatment with disulfiram placebo, 62.5 mg/d or 250 mg/d.

Fig. 5

(A) Mean cocaine ‘high’ over time (min.) following cocaine 0.25 mg/kg (i.v.) (n=9) administration during treatment with disulfiram placebo, 62.5 mg/d or 250 mg/day. (B) Mean ‘rush’ measurements over time (min.) following cocaine 0.25 mg/kg (i.v.) (n=9) administration during treatment with disulfiram placebo, 62.5 mg/d or 250 mg/day.