Drug-Drug Interactions of Cocaine



Cocaine abusers have reported that alcohol prolongs the euphoriant properties of cocaine, while ameliorating the acutely unpleasant physical and psychological sequelae, primarily paranoia and agitation. It may also lessen the dysphoria associated with acute cocaine abstinence. It has also been proposed that concurrent alcohol abuse may be an integral part of cocaine abuse. The combination of cocaine with alcohol can cause enhanced hepatotoxicity and enhanced cardiotoxicity. Trauma in patients who use cocaine plus alcohol has been reported. Those who use cocaine plus alcohol are 3-5 times more likely to have homicidal ideation and plans; this is particularly prominent in patients with antisocial personality disorder. A large high school survey by the Centers for Disease Control and Prevention showed that illicit substance abuse, prevalence of weapon carrying, and physical fighting were higher among the adolescents who reported recent use of cocaine, marijuana, alcohol, and corticosteroids. Among 215 female homicide offenders, 70% had been regular drug users at some time before imprisonment. Alcohol, crack, and powdered cocaine were the drugs most likely to be related to these homicides.

In a double-blind study, subjects meeting DSM-IV criteria for cocaine dependence and alcohol abuse participated in three drug administration sessions, involving intranasal cocaine with oral alcohol, cocaine with oral placebo alcohol, and cocaine placebo with oral alcohol. Cocaine plus alcohol produced greater euphoria and increased perception of well-being than cocaine alone. Heart rate was significantly higher with cocaine plus alcohol than with either alone. Cocaine concentrations were higher after cocaine plus alcohol than after cocaine alone. Metabolism of cocaine to cocaethylene was observed only during administration of cocaine plus alcohol. The authors concluded that enhanced psychological effects during abuse of cocaine plus alcohol may encourage the ingestion of larger amounts of these substances, placing users at increased risk of toxicity than with either drug alone.

The adverse effects of the combined use of alcohol and cocaine have been reviewed. There is little evidence that this combination acts synergistically or that either drug enhances the negative effects of the other. However, the combination leads to the formation of cocaethylene, which may potentiate cardiotoxic effects and the combination has a greater than additive effect on heart rate. Lastly, cocaine antagonizes the learning and psychomotor performance deficits and driving impairment caused by alcohol.

Reports of liver complications after cocaine use are infrequent. However, fulminant hepatitis with acute renal insufficiency requiring liver transplantation occurred after the use of cocaine and alcohol.

• A 33-year-old chronic alcoholic with hepatitis C developed acute liver and renal insufficiency with grade III encephalopathy. Hemodialysis was begun and emergency liver transplantation was performed. The explanted liver showed marked diffuse macrovesicular steatosis with massive coagulative-type necrosis. The postoperative course included a persistently raised gamma-glutamyltransferase, but he recovered fully after 60 days.

Macrovesicular steatosis can be attributed to alcohol or cocaine, but massive liver necrosis is more probably due to cocaine. The mechanisms of cocaine hepatotoxicity, such as increased lipid peroxidation, free radical activity, and impaired calcium sequestration, may be potentiated by alcohol.


Anticholinergic poisoning involving adulterated cocaine has been reported.

• A 39-year-old man who was a recreational user of alcohol and cocaine presented with agitation, hallucinations, and delirium. He had a dry flushed skin, tachycardia, dilated, minimally reactive pupils, urinary retention, and absent bowel sounds. He was treated with intravenous fluids and a sedative. There were cocaine metabolites in the urine. Reanalysis of a urine sample by thin layer chromatography confirmed the presence of the anticholinergic drug atropine.


An interaction of clozapine with cocaine has been reported. Eight male cocaine addicts underwent four oral challenges with increasing doses of clozapine (12.5, 25, and 50 mg) and placebo, followed 2 hours later by cocaine 2 mg/kg intranasally. Subjective and physiological responses, and serum cocaine concentrations were measured over 4 hours. Clozapine pretreat-ment increased cocaine concentrations during the study and significantly increased the peak serum cocaine concentrations dose-dependently. Despite this rise in blood concentrations, clozapine pretreatment significantly reduced subjective responses to cocaine, including “expected high,” “high,” and “rush” effects, notably at the 50 mg dose. There were also significant effects on “sleepiness,” “paranoia” and “nervousness.” Clozapine caused a significant near-syncopal episode in one subject, requiring withdrawal. Clozapine had no significant effect on baseline pulse rate or systolic blood pressure, but it attenuated the significant pressor effects of a single dose of intranasal cocaine. These data suggested a possible therapeutic role for clozapine in the treatment of cocaine addiction in humans, but also suggest caution due to the near-syncopal event and the increase in serum cocaine concentrations.


Chronic cocaine use sensitizes coronary arterial a-adre-noceptors to agonists.


Cocaine combined with indometacin in a 23-year-old pregnant woman at 34 weeks gestation may have caused fetal anuria and neonatal gastric hemorrhage.

Monoamine oxidase inhibitors

The combination of monoamine oxidase inhibitors with cocaine can cause hyperpyrexia.

Neuroleptic drugs

Cocaine-abusing psychiatric patients significantly more often develop neuroleptic drug-induced acute dystonia according to a 2-year study carried out on the island of Curacao, Antilles, where cocaine and cannabis are often abused. The sample consisted of 29 men with neuroleptic drug-induced acute dystonia aged 17-45 years who had received high potency neuroleptic drugs in the month before admission; nine were cocaine users and 20 non-users. Cocaine use was a major risk factor for neuroleptic drug-induced acute dystonia and should be added to the list of well-known risk factors, such as male sex, younger age, neuroleptic drug dosage and potency, and a history of neuroleptic drug-induced acute dystonia. The authors suggested that high-risk cocaine-using psychiatric patients who start to take neuroleptic drugs should be provided with an anticholinergic drug as a prophylactic measure to prevent neuroleptic drug-induced acute dystonia.


It has been suggested that calcium channel blockers can be used to treat cocaine dependence, and some studies have shown reductions in cocaine-induced subjective and cardiovascular responses with nifedipine and diltiazem. The cardiovascular and subjective responses to cocaine have been evaluated in a double-blind, placebo-controlled, crossover study in five subjects pretreated with two dosage of nimodipine. Nimodipine 60 mg attenuated the rise in systolic, but not diastolic, blood pressure after cocaine. In three subjects nimodipine 90 mg produced greater attenuation than 60 mg. The subjective effects of cocaine were not altered by either dose of nimodipine.


The combination of opiates and cocaine in drug overdose deaths has been examined retrospectively in a review of all accidental drug overdoses that resulted in death in New York City from 1990 to 1998. There were 7451 accidental overdose deaths, of which opiates played a role in 71%, cocaine in 70%, and alcohol in 40%; one of these drugs was identified in 98% of all overdose deaths. As evidence of higher poly drug mortality, 58% of the deaths were caused by more than one drug. The most common combination was opiates plus cocaine, which caused a peak death rate in 1994 of 44 per million person-years, compared with rates of 21 and 31 deaths per million person-years for opiates and cocaine alone respectively. Although it was retrospective, this study has elaborated and highlighted the dangers of polydrug abuse and has shown that the risk of overdose is significantly increased when opiates and cocaine are used together.

Rhabdomyolysis and ventricular fibrillation has been attributed to cocaine plus diamorphine (heroin) ingestion.

• A 28-year-old man went into cardiorespiratory arrest after using intravenous cocaine and diamorphine. He was intubated and ventilated and given adrenaline, naloxone, and sodium bicarbonate. During a thoracot-omy he developed ventricular fibrillation and was electrically converted to sinus rhythm. He had hyperkalemia and myoglobinuria. He developed acute renal insufficiency, disseminated intravascular coagulopathy, and a right leg compartment syndrome. There were cocaine metabolites and opioids in his urine. Hemodialysis and fasciotomy were performed, but he died 2 months later with a complicating bronch-opneumonia.

The authors discussed the possibility that naloxone, an effective opioid antidote, may have been harmful in this case.


In a single-blind, placebo-controlled, within-subject, non-randomized, crossover study in 12 cocaine-dependent subjects, intravenous cocaine (20 mg and 40 mg) was evaluated before and during transdermal selegiline (20 mg), a selective inhibitor of monoamine oxidase B. Selegiline attenuated the effects of cocaine on systolic blood pressure and heart rate and many of its subjective effects, including the desire to use cocaine. Selegiline did not alter the pharmacokinetics of cocaine or cocaine-induced changes in prolactin and growth hormone. These results provide further evidence that selegiline may be useful in the treatment of cocaine abuse and dependence and provide safety documentation important in justifying the need for larger-scale therapeutic trials.


Procaine and cocaine are esters that are hydrolysed by plasma cholinesterase and may therefore competitively enhance the action of suxamethonium (succinylcholine). Chloroprocaine may have a similar action. Lidocaine also interacts, although the mechanism is not clear unless very high doses are used.

Selections from the book: “Meyler’s Side Effects of Psychiatric Drugs” (2009)