Editing Cocaethylene

{{Short description|Chemical compound}}
{{Drugbox
| IUPAC_name         = ethyl (2''R'',3''S'')-3-benzoyloxy-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
| image              = Cocaethylene-2D-skeletal.png
| image_class        = skin-invert-image
| image2             = Cocaethylene-3D-balls.png

<!--Clinical data-->| tradename          = 
| pregnancy_category = C
| legal_AU           = 
| legal_CA           = 
| legal_UK           = CD
| legal_US           = Schedule II
| legal_US_comment   = 
| legal_status       = 
| routes_of_administration = Produced from ingestion of cocaine and ethanol

<!--Pharmacokinetic data-->| bioavailability    = 
| metabolism         = 
| elimination_half-life = 
| excretion          = <!--Identifiers-->
| CAS_number         = 529-38-4
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = FJO3071W5Y
| ATC_prefix         = none
| PubChem            = 65034
| ChEMBL             = 608806
| ChemSpiderID       = 559082

<!--Chemical data-->| C                  = 18
| H                  = 23
| N                  = 1
| O                  = 4
| smiles             = O=C(O[C@H]1C[C@H]2N(C)[C@@H]([C@H]1C(=O)OCC)CC2)c3ccccc3
| synonyms           = benzoylecgonine ethyl ester, ethylbenzoylecgonine,
| melting_point      = 
| solubility         = 
}}

'''Cocaethylene''' ('''ethylbenzoylecgonine''') is the [[ethyl group|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.<ref name="Laizure et al 2003">{{cite journal | vauthors = Laizure SC, Mandrell T, Gades NM, Parker RB | title = Cocaethylene metabolism and interaction with cocaine and ethanol: role of carboxylesterases | journal = Drug Metabolism and Disposition | volume = 31 | issue = 1 | pages = 16–20 | date = January 2003 | pmid = 12485948 | doi = 10.1124/dmd.31.1.16 }}</ref> In 1885, cocaethylene was first synthesized (according to edition 13 of the ''[[Merck Index]]''),<ref name="pmid30796807">{{cite journal | vauthors = Jones AW | title = Forensic Drug Profile: Cocaethylene | journal = Journal of Analytical Toxicology | volume = 43 | issue = 3 | pages = 155–160 | date = April 2019 | pmid = 30796807 | doi = 10.1093/jat/bkz007 | doi-access = free }}</ref> and in 1979, cocaethylene's side effects were discovered.<ref>* {{cite web | vauthors = Doward J | date = 8 November 2009 | url = https://www.theguardian.com/society/2009/nov/08/cocaine-alcohol-mixture-health-risks | title = Warning of extra heart dangers from mixing cocaine and alcohol | work = The Guardian }}
</ref>

==Metabolic production from cocaine==

Cocaethylene is the byproduct of concurrent consumption of [[Ethanol|alcohol]] and [[cocaine]] as metabolized by the liver. Normally, metabolism of cocaine produces two primarily [[biologically inactive]] [[metabolites]]—[[benzoylecgonine]] and [[ecgonine methyl ester]]. The [[liver|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.<ref name="Laizure et al 2003"/>

:cocaine + H<sub>2</sub>O → benzoylecgonine + [[methanol]] (with [[liver carboxylesterase 1]])<ref>{{cite web | url=http://biocyc.org/META/NEW-IMAGE?type=REACTION&object=RXN-13424 | title=MetaCyc Reaction: 3.1.1. | access-date=25 January 2016}}</ref>
:benzoylecgonine + ethanol → cocaethylene + H<sub>2</sub>O
:cocaine + ethanol → cocaethylene + [[methanol]] (with liver carboxylesterase 1)<ref>{{cite web | url=http://biocyc.org/META/NEW-IMAGE?type=REACTION&object=RXN-13425 | title=MetaCyc Reaction: [no EC number assigned] | access-date=25 January 2016}}</ref>

==Physiological effects==

Cocaethylene increases the levels of [[Serotonin|serotonergic]], [[noradrenergic]], and [[dopaminergic]] [[neurotransmission]] in the brain and has a higher [[Drug action#Affinity|affinity]] for the dopamine transporter than cocaine, but has a lower affinity for the serotonin and norepinephrine transporters.<ref>{{cite journal |vauthors=Jatlow P, McCance EF, Bradberry CW, Elsworth JD, Taylor JR, Roth RH |date=August 1996 |title=Alcohol plus cocaine: the whole is more than the sum of its parts |journal=Therapeutic Drug Monitoring |volume=18 |issue=4 |pages=460–464 |doi=10.1097/00007691-199608000-00026 |pmid=8857569}}</ref><ref>{{cite journal |vauthors=Perez-Reyes M, Jeffcoat AR, Myers M, Sihler K, Cook CE |date=December 1994 |title=Comparison in humans of the potency and pharmacokinetics of intravenously injected cocaethylene and cocaine |journal=Psychopharmacology |volume=116 |issue=4 |pages=428–432 |doi=10.1007/bf02247473 |pmid=7701044 |s2cid=6558411}}</ref> These pharmacological properties make cocaethylene a [[serotonin-norepinephrine-dopamine reuptake inhibitor]] (SNDRI; also known as a "triple reuptake inhibitor").<ref>{{cite journal | vauthors = Marks D, Pae C, Patkar A | title = Triple Reuptake Inhibitors: The Next Generation of Antidepressants | journal = Current Neuropharmacology | volume = 6 | issue = 4 | pages = 338–343 | date = December 2008 | pmid = 19587855 | doi = 10.2174/157015908787386078| pmc = 2701280 }}</ref>

Although it cannot be bought, cocaethylene is largely considered [[recreational drug|recreational]] in and of itself, with [[stimulant drug|stimulant]], [[euphoriant]], [[anorectic]], [[sympathomimetic drug|sympathomimetic]], and [[local anesthetic]] properties with a longer duration of action than cocaine.<ref name="Original_Investigation">{{cite journal |vauthors=Hart CL, Jatlow P, Sevarino KA, McCance-Katz EF |date=April 2000 |title=Comparison of intravenous cocaethylene and cocaine in humans |journal=Psychopharmacology |volume=149 |issue=2 |pages=153–162 |doi=10.1007/s002139900363 |pmid=10805610 |s2cid=25055492}}</ref><ref name="J_Addict_Dis">{{cite journal |vauthors=Andrews P |year=1997 |title=Cocaethylene toxicity |journal=Journal of Addictive Diseases |volume=16 |issue=3 |pages=75–84 |doi=10.1300/J069v16n03_08 |pmid=9243342}}</ref> 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.<ref name="Original_Investigation" />

=== 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".<ref name="ACMDReport">{{cite web |title=Cocaine Powder: Review of the evidence of prevalence and patterns of use, harms, and implications |url=https://assets.publishing.service.gov.uk/media/5a805ff3ed915d74e622e166/acmd_final_report_12_03_2015.pdf |access-date=14 March 2025 |publisher=UK Advisory Council on the Misuse of Drugs}}</ref> 

Some studies<ref>{{cite journal |vauthors=Wilson LD, Jeromin J, Garvey L, Dorbandt A |date=March 2001 |title=Cocaine, ethanol, and cocaethylene cardiotoxity in an animal model of cocaine and ethanol abuse |journal=Academic Emergency Medicine |volume=8 |issue=3 |pages=211–222 |doi=10.1111/j.1553-2712.2001.tb01296.x |pmid=11229942 |doi-access=}}</ref><ref name="Farre">{{cite journal |vauthors=Farré M, de la Torre R, Llorente M, Lamas X, Ugena B, Segura J, Camí J |date=September 1993 |title=Alcohol and cocaine interactions in humans |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=266 |issue=3 |pages=1364–1373 |doi=10.1016/S0022-3565(25)39392-4 |pmid=8371143}}</ref> suggest that consuming alcohol in combination with cocaine may be more [[cardiotoxicity|cardiotoxic]] than cocaine and "it also carries an 18 to 25 fold increase over cocaine alone in risk of immediate death".<ref name="J_Addict_Dis" />

Additionally, studies have determined that cocaethylene has a higher [[Hepatotoxicity|hepatoxicity]] than alcohol or cocaine and their respective metabolites alone, significantly increasing the risk of [[liver fibrosis]].<ref>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</ref>

== See also ==
* [[Ethylphenidate]]
* [[Euphoriants]]
* [[Methylvanillylecgonine]]
* [[Local anesthetics]]
* [[RTI-160]]
* [[Stimulants]]
* [[Tropanes]]
* [[Vin Mariani]]
* [[Pemberton's French Wine Coca]]

== References ==
{{Reflist|32em}}

=== Further reading ===
{{refbegin|33em}}
* {{cite web | vauthors =  Morris J | date = 19 April 2010 | url = http://www.alcoholpolicy.net/2010/04/cocaethylene-responding-to-combined-alcohol-and-cocaine-use.html | title = Cocaethylene: responding to combined alcohol and cocaine use | work = Alcohol Policy UK }}
* {{cite journal | vauthors = Landry MJ | title = An overview of cocaethylene, an alcohol-derived, psychoactive, cocaine metabolite | journal = Journal of Psychoactive Drugs | volume = 24 | issue = 3 | pages = 273–276 | year = 1992 | pmid = 1432406 | doi = 10.1080/02791072.1992.10471648 }}
* {{cite journal | vauthors = Hearn WL, Rose S, Wagner J, Ciarleglio A, Mash DC | title = Cocaethylene is more potent than cocaine in mediating lethality | journal = Pharmacology, Biochemistry, and Behavior | volume = 39 | issue = 2 | pages = 531–533 | date = June 1991 | pmid = 1946594 | doi = 10.1016/0091-3057(91)90222-N | s2cid = 36163843 }}
* {{cite journal | vauthors = Hearn WL, Flynn DD, Hime GW, Rose S, Cofino JC, Mantero-Atienza E, Wetli CV, Mash DC | display-authors = 6 | title = Cocaethylene: a unique cocaine metabolite displays high affinity for the dopamine transporter | journal = Journal of Neurochemistry | volume = 56 | issue = 2 | pages = 698–701 | date = February 1991 | pmid = 1988563 | doi = 10.1111/j.1471-4159.1991.tb08205.x | s2cid = 35719923 }}
{{refend}}

[[Category:Benzoate esters]]
[[Category:Carboxylate esters]]
[[Category:Tropanes]]
[[Category:Euphoriants]]
[[Category:Stimulants]]
[[Category:Local anesthetics]]
[[Category:Sympathomimetics]]
[[Category:Cocaine]]
[[Category:Serotonin–norepinephrine–dopamine reuptake inhibitors]]
[[Category:Human drug metabolites]]
[[Category:Recreational drug metabolites]]