Cocaethylene

Cocaethylene (ethylbenzoylecgonine) is the ethyl ester of benzoylecgonine. It is structurally similar to cocaine, which is the methyl ester of benzoylecgonine. Cocaethylene is formed by the liver when cocaine and ethanol coexist in the blood.[1] In 1885, cocaethylene was first synthesized (according to edition 13 of the Merck Index),[2] and in 1979, cocaethylene's side effects were discovered.[3]

Cocaethylene
Clinical data
Other namesbenzoylecgonine ethyl ester, ethylbenzoylecgonine,
Pregnancy
category
  • C
Routes of
administration		Produced from ingestion of cocaine and ethanol
ATC code
  • none
Legal status
Legal status
  • UK: Controlled Drug
  • US: Analogue to a Schedule I/II drug (possibly)
  • Not scheduled
Identifiers
IUPAC name
  • ethyl (2R,3S)-3-benzoyloxy-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.164.816
Chemical and physical data
FormulaC18H23NO4
Molar mass317.385 g·mol−1
3D model (JSmol)
SMILES
  • O=C(O[C@H]1C[C@H]2N(C)[C@@H]([C@H]1C(=O)OCC)CC2)c3ccccc3

Metabolic production from cocaine

Cocaethylene is the byproduct of concurrent consumption of alcohol and cocaine as metabolized by the liver. Normally, metabolism of cocaine produces two primarily biologically inactive metabolites—benzoylecgonine and ecgonine methyl ester. The hepatic enzyme carboxylesterase is an important part of cocaine's metabolism because it acts as a catalyst for the hydrolysis of cocaine in the liver, which produces these inactive metabolites. If ethanol is present during the metabolism of cocaine, a portion of the cocaine undergoes transesterification with ethanol, rather than undergoing hydrolysis with water, which results in the production of cocaethylene.[1]

cocaine + H2O → benzoylecgonine + methanol (with liver carboxylesterase 1)[4]
benzoylecgonine + ethanol → cocaethylene + H2O
cocaine + ethanol → cocaethylene + methanol (with liver carboxylesterase 1)[5]

Physiological effects

Cocaethylene is largely considered a recreational drug in and of itself, with stimulant, euphoriant, anorectic, sympathomimetic, and local anesthetic properties. The monoamine neurotransmitters serotonin, norepinephrine, and dopamine play important roles in cocaethylene's action in the brain. Cocaethylene increases the levels of serotonergic, noradrenergic, and dopaminergic neurotransmission in the brain by inhibiting the action of the serotonin transporter, norepinephrine transporter, and dopamine transporter. These pharmacological properties make cocaethylene a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI; also known as a "triple reuptake inhibitor").

In most users, cocaethylene produces euphoria and has a longer duration of action than cocaine.[6][7] Some studies[8][9] suggest that consuming alcohol in combination with cocaine may be more cardiotoxic than cocaine and "it also carries an 18 to 25 fold increase over cocaine alone in risk of immediate death".[7] Cocaethylene has a higher affinity for the dopamine transporter than does cocaine, but has a lower affinity for the serotonin and norepinephrine transporters.[10][11]

In McCance-Katz et alia's 1993 study cocaethylene "produced greater subjective ratings of 'High' in comparison with administration of cocaine or alcohol alone."[6]

See also

References
  1. Laizure SC, Mandrell T, Gades NM, Parker RB (January 2003). "Cocaethylene metabolism and interaction with cocaine and ethanol: role of carboxylesterases". Drug Metabolism and Disposition. 31 (1): 16–20. doi:10.1124/dmd.31.1.16. PMID 12485948.
  2. "Validate User".
  3. "Warning of extra heart dangers from mixing cocaine and alcohol". TheGuardian.com. 8 November 2009.
  4. "MetaCyc Reaction: 3.1.1". Retrieved 25 January 2016.
  5. "MetaCyc Reaction: [no EC number assigned]". Retrieved 25 January 2016.
  6. Hart, C. L.; Jatlow, P.; Sevarino, K. A.; McCance-Katz, E. F. (2000). "Comparison of intravenous cocaethylene and cocaine in humans". Psychopharmacology. 149 (2): 153–162. doi:10.1007/s002139900363. PMID 10805610. S2CID 25055492.
  7. Andrews P (1997). "Cocaethylene toxicity". Journal of Addictive Diseases. 16 (3): 75–84. doi:10.1300/J069v16n03_08. PMID 9243342.
  8. Wilson LD, Jeromin J, Garvey L, Dorbandt A (March 2001). "Cocaine, ethanol, and cocaethylene cardiotoxity in an animal model of cocaine and ethanol abuse". Academic Emergency Medicine. 8 (3): 211–22. doi:10.1111/j.1553-2712.2001.tb01296.x. PMID 11229942.
  9. Farré, M; de la Torre, R; Llorente, M; Lamas, X; Ugena, B; Segura, J; Camí, J (September 1993). "Alcohol and cocaine interactions in humans". Journal of Pharmacology and Experimental Therapeutics. 266 (3): 1364–73. PMID 8371143.
  10. Jatlow P, McCance EF, Bradberry CW, Elsworth JD, Taylor JR, Roth RH (August 1996). "Alcohol plus cocaine: the whole is more than the sum of its parts". Therapeutic Drug Monitoring. 18 (4): 460–4. doi:10.1097/00007691-199608000-00026. PMID 8857569.
  11. Perez-Reyes M, Jeffcoat AR, Myers M, Sihler K, Cook CE (December 1994). "Comparison in humans of the potency and pharmacokinetics of intravenously injected cocaethylene and cocaine". Psychopharmacology. 116 (4): 428–32. doi:10.1007/bf02247473. PMID 7701044. S2CID 6558411.

Further reading
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