Chemistry:Cocaethylene

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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 in small amounts when cocaine and ethanol coexist in the blood.[1] Cocaethylene was first synthesized in 1885;[2][3] its side effects were identified in 1989.[4]

Metabolic production from cocaine

Cocaethylene is the byproduct of concurrent consumption of alcohol and cocaine as they are metabolized by the liver. Normally, the hepatic enzyme carboxylesterase catalyzes the hydrolysis of cocaine in the liver, producing two primarily biologically inactive metabolites—benzoylecgonine and ecgonine methyl ester. If ethanol is also present in the liver, a portion of the cocaine undergoes transesterification with ethanol rather than hydrolysis with water, producing cocaethylene.[1]

cocaine + H2O → benzoylecgonine + methanol (with liver carboxylesterase 1)[5]
benzoylecgonine + ethanol → cocaethylene + H2O
cocaine + ethanol → cocaethylene + methanol (with liver carboxylesterase 1)[6]

Physiological effects

Cocaethylene increases the levels of serotonergic, noradrenergic, and dopaminergic neurotransmission in the brain and has a higher affinity for the dopamine transporter than cocaine, but has a lower affinity for the serotonin and norepinephrine transporters.[7][8] These pharmacological properties make cocaethylene a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI; also known as a "triple reuptake inhibitor").[9]

Although it cannot be bought, cocaethylene is largely considered recreational in and of itself, with stimulant, euphoriant, anorectic, sympathomimetic, and local anesthetic properties with a longer duration of action than cocaine.[10][11] A 2000 study by Hart et al. on the effects of intravenous cocaethylene in humans found that "cocaethylene has pharmacological properties in common with cocaine, but is less potent," consistent with prior research.[10]

Risks

While cocaethylene is more dangerous when administered alone, research suggests that the increase in risk from combining cocaine and ethanol is "thought to be due to alcohol decreasing the metabolism of cocaine and, therefore, increasing [...] cocaine concentrations with only a minimal (if any) contribution to an increased risk from the formation of cocaethylene".[12]

Use in research about combined use of cocaine and alcohol

Some studies[13][14] suggest that consuming alcohol in combination with cocaine may be more cardiotoxic than cocaine and "also carries an 18 to 25 fold increase over cocaine alone in risk of immediate death".[11]

Cocaethylene has been used as a biomarker for simultaneous alcohol and cocaine consumption. A 2021 study used this technique to show that people who consume alcohol and cocaine together have a higher risk of liver fibrosis.[15]

See also

References

  1. ↑ 1.0 1.1 "Cocaethylene metabolism and interaction with cocaine and ethanol: role of carboxylesterases". Drug Metabolism and Disposition 31 (1): 16–20. January 2003. doi:10.1124/dmd.31.1.16. PMID 12485948. 
  2. ↑ "Forensic Drug Profile: Cocaethylene". Journal of Analytical Toxicology 43 (3): 155–160. April 2019. doi:10.1093/jat/bkz007. PMID 30796807. 
  3. ↑ O'Neil, Maryadele J., ed (2001). The Merck index: an encyclopedia of chemicals, drugs, and biologicals (13 ed.). Whitehouse Station, N.J: Merck. ISBN 978-0-911910-13-1. 
  4. ↑ * "Warning of extra heart dangers from mixing cocaine and alcohol". The Guardian. 8 November 2009. https://www.theguardian.com/society/2009/nov/08/cocaine-alcohol-mixture-health-risks. 
  5. ↑ "MetaCyc Reaction: 3.1.1.". http://biocyc.org/META/NEW-IMAGE?type=REACTION&object=RXN-13424. 
  6. ↑ "MetaCyc Reaction: [no EC number assigned"]. http://biocyc.org/META/NEW-IMAGE?type=REACTION&object=RXN-13425. 
  7. ↑ "Alcohol plus cocaine: the whole is more than the sum of its parts". Therapeutic Drug Monitoring 18 (4): 460–464. August 1996. doi:10.1097/00007691-199608000-00026. PMID 8857569. 
  8. ↑ "Comparison in humans of the potency and pharmacokinetics of intravenously injected cocaethylene and cocaine". Psychopharmacology 116 (4): 428–432. December 1994. doi:10.1007/bf02247473. PMID 7701044. 
  9. ↑ "Triple Reuptake Inhibitors: The Next Generation of Antidepressants". Current Neuropharmacology 6 (4): 338–343. December 2008. doi:10.2174/157015908787386078. PMID 19587855. 
  10. ↑ 10.0 10.1 "Comparison of intravenous cocaethylene and cocaine in humans". Psychopharmacology 149 (2): 153–162. April 2000. doi:10.1007/s002139900363. PMID 10805610. 
  11. ↑ 11.0 11.1 "Cocaethylene toxicity". Journal of Addictive Diseases 16 (3): 75–84. 1997. doi:10.1300/J069v16n03_08. PMID 9243342. 
  12. ↑ "Cocaine Powder: Review of the evidence of prevalence and patterns of use, harms, and implications". UK Advisory Council on the Misuse of Drugs. https://assets.publishing.service.gov.uk/media/5a805ff3ed915d74e622e166/acmd_final_report_12_03_2015.pdf. 
  13. ↑ "Cocaine, ethanol, and cocaethylene cardiotoxity in an animal model of cocaine and ethanol abuse". Academic Emergency Medicine 8 (3): 211–222. March 2001. doi:10.1111/j.1553-2712.2001.tb01296.x. PMID 11229942. 
  14. ↑ "Alcohol and cocaine interactions in humans". The Journal of Pharmacology and Experimental Therapeutics 266 (3): 1364–1373. September 1993. doi:10.1016/S0022-3565(25)39392-4. PMID 8371143. 
  15. ↑ Tamargo, J. A., Sherman, K. E., Sékaly, R. P., Bordi, R., Schlatzer, D., Lai, S., Khalsa, J. H., Mandler, R. N., Ehman, R. L., & Baum, M. K. (2022). Cocaethylene, simultaneous alcohol and cocaine use, and liver fibrosis in people living with and without HIV. Drug and alcohol dependence, 232, 109273. https://doi.org/10.1016/j.drugalcdep.2022.109273

Further reading



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