A double-blind, placebo-controlled assessment of the safety of potential interactions between intravenous cocaine, ethanol, and oral disulfiram

Abstract

BACKGROUND A majority of cocaine addicts have a comorbid alcohol use disorder. Previous studies demonstrated efficacy of disulfiram in the treatment of cocaine dependence among patients with comorbid alcohol use disorder or opioid dependence. However, the cardiac risks of a disulfiram-ethanol reaction (DER) in individuals who drink, when coupled with the cardiac effects of cocaine, could result in significant toxicity or lethality due to the 3-way drug interaction. AIMS This study examined the safety of combining cocaine (30 mg i.v.) and ethanol (0.4 g/kg i.v.) in disulfiram-treated (0, 250, and 500 mg/d, p.o.) cocaine-dependent research volunteers. RESULTS The results showed that disulfiram did not enhance the cardiovascular effects of cocaine and may have reduced the subjective high from cocaine. In contrast, ethanol produced adverse ECG changes including QTc prolongation and a DER consisting of hypotension, tachycardia, nausea, and flushing in disulfiram-treated subjects. The severity of the DER was related to disulfiram dose and the trial with 500 mg/d was stopped prematurely due to safety concerns. The DER-related hypotension and tachycardia seen with ethanol infusion alone in disulfiram-treated subjects, was not exacerbated when combined with cocaine. In fact, cocaine tended to counteract the ethanol-related hypotension though it did exacerbate the tachycardia in two of seven subjects. CONCLUSIONS Though conclusions are limited by the moderate doses of cocaine, ethanol, and disulfiram tested, the data do suggest that the risks of the moderate use of cocaine and ethanol in individuals treated with moderate doses of disulfiram (≤250 mg/d) may not be as problematic as some may assume.

A randomized factorial trial of disulfiram and contingency management to enhance cognitive behavioral therapy for cocaine dependence

“…Furthermore, little to no ‘rebound’ after cessation of CM and/or medication was seen during the follow-up period. Finally, disulfiram appeared safe in this sample, with no significant difference in cardiovascular effects or hypertension across medication groups, concerns that have been raised regarding its use with cocaine abusers (Roache et al, 2011). There were some differences in reported frequency of nausea/vomiting, which may reflect some ‘testing’ of the disulfiram effect by participants.…”

Assessment of safety, cardiovascular and subjective effects after intravenous cocaine and lofexidine

“…The distribution half-life of cocaine from an IV dose is about 10 min and the elimination T-½ of cocaine is ~1 hour (50–80 min). Doses used for IV cocaine administration in this study have been successfully utilized in several laboratory-based clinical studies and have proven safe (Johnson et al 1998; Newton et al 2012; Newton et al 2005; Roache et al 2011; Walsh et al 1994). All subjects received cocaine infusions on five days: Days −1, 1, 2, 6, and 7 (as described above).…”

“…Decreasing central levels of NE appears to be responsible for disulfiram’s effects on cocaine use in humans. Although disulfiram has shown efficacy as a treatment for cocaine dependence, potentially dangerous interactions with alcohol preclude it from becoming a first-line pharmacotherapy (Roache et al 2011). …”

Altered methamphetamine place conditioning in mice vaccinated with a succinyl-methamphetamine-tetanus-toxoid vaccine

“…Potential pharmacotherapies are often complicated by serious drug interactions or poor medication side-effect profiles that decrease compliance and thus efficacy when assessed in clinical trials. [3][4][5] An alternative treatment approach for SUDs is immunotherapy that has better compliance since treatments may involve fewer adverse events and only a few injections instead of daily medication dosing. [6][7][8] A number of SUD vaccines are in preclinical development, and some have been tested in humans.…”