Does co-ingestion of alcohol alter cocaine metabolism, producing cocaethylene?

Cocaine Metabolism Changes with Alcohol Co-Ingestion

Yes, when cocaine and alcohol are taken together, a unique active metabolite called cocaethylene is formed through hepatic transesterification—this is the only known instance where a new psychoactive substance is created entirely within the body. 1, 2

Mechanism of Cocaethylene Formation

The metabolic pathway involves hepatic transesterification of cocaine in the presence of ethanol, producing cocaethylene (the ethyl ester of benzoylecgonine) as a novel active metabolite. 1, 3

• This transesterification reaction occurs in the liver and represents a unique metabolic process distinct from typical cocaine metabolism 1
• The formation is dose-dependent and route-dependent, with oral cocaine administration producing significantly more cocaethylene (34% ± 20%) compared to smoked cocaine (18% ± 11%), due to first-pass hepatic metabolism 4
• Approximately 24% (± 11%) of intravenous cocaine is converted to cocaethylene when combined with alcohol 4

Pharmacological Properties of Cocaethylene

Cocaethylene has a pharmacological profile similar to cocaine but with important differences that increase toxicity risk:

• Cocaethylene is equipotent to cocaine at inhibiting dopamine reuptake at the dopamine transporter, which may account for enhanced euphoria with combined cocaine-alcohol use 1
• The metabolite has a longer half-life than cocaine, resulting in prolonged psychoactive effects and extended cardiovascular stress 2, 5
• Cocaethylene reaches significant blood concentrations—postmortem studies have detected concentrations equal to or exceeding those of cocaine itself 1
• The metabolite shares many neurochemical and behavioral properties with cocaine but differs in relative potency at dopamine versus serotonin transporters 3

Clinical Significance and Cardiovascular Impact

The combination of cocaine and alcohol produces greater cardiovascular toxicity than either substance alone, mediated through cocaethylene formation:

• Heart rate and rate-pressure product increases are significantly greater with the cocaine-ethanol combination compared to cocaine alone, across all routes of administration 4
• The American College of Cardiology notes that myocardial complications occur with both small and large cocaine doses, and cocaethylene may be more cardiotoxic than the parent drug 6, 2
• Subjects experience enhanced subjective euphoria and intoxication effects when cocaine and ethanol are combined, which explains the popularity and toxicity of this drug combination 4, 5
• The prevalence of concurrent cocaine-alcohol use exceeds 50% among cocaine users, making this a clinically relevant phenomenon 3

Important Clinical Caveats

• Most cardiac risk assessment tools do not ask about cocaine use, which can prevent optimal therapeutic decision-making when cocaethylene toxicity is present 2
• The longer duration of action from cocaethylene means that cardiovascular monitoring and management may need to be extended beyond typical cocaine intoxication timeframes 2, 5
• The American College of Cardiology recommends avoiding beta-blockers within 4-6 hours of cocaine exposure due to risk of unopposed alpha-adrenergic stimulation, and this caution applies equally to cocaethylene toxicity 6, 7