View source for Pharmacology of ethanol

{{Short description|Pharmacodynamics and pharmacokinetics of ethanol}}
{{About|pharmacodynamics and pharmacokinetics of ethanol|ethanol as a psychoactive drug|alcohol (drug)|alcohols used in medicine|alcohols (medicine)|the substance in general|Ethanol}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| drug_name = Ethanol
| image = Ethanol-2D-skeletal.svg
| width = 175px
| alt = Skeletal formula of ethanol
| imageL = Ethanol-3D-balls.png
| widthL = 125px
| altL = Ball-and-stick model of ethanol
| imageR = Ethanol-3D-vdW.png
| widthR = 125px
| altR = Space-filling model of ethanol
| routes_of_administration = ''Common'': [[By mouth]]<br /> ''Uncommon'': [[Alcohol enema|suppository]], [[Alcohol inhalation|inhalation]], [[Vodka eyeballing|ophthalmic]], [[Alcohol powder|insufflation]], [[injection (medicine)|injection]]<ref>{{cite journal | vauthors = Gilman JM, Ramchandani VA, Crouss T, Hommer DW | title = Subjective and neural responses to intravenous alcohol in young adults with light and heavy drinking patterns | journal = Neuropsychopharmacology | volume = 37 | issue = 2 | pages = 467–477 | date = January 2012 | pmid = 21956438 | pmc = 3242308 | doi = 10.1038/npp.2011.206 | doi-access = free }}</ref>
| class = [[Analgesic]]; [[Anaphrodisiac]]; [[Anxiolytic]]; [[Depressant]]; [[Euphoriant]]; [[General anesthetic]]; [[Sedative]]
<!-- Pharmacokinetic data -->| bioavailability = 80%+<ref name="AcademicPress2013">{{cite book|title=Principles of Addiction: Comprehensive Addictive Behaviors and Disorders|url=https://books.google.com/books?id=5gRNl3oIwWEC&pg=PA162|date=17 May 2013|publisher=Academic Press|isbn=978-0-12-398361-9|pages=162–}}</ref><ref name="pmid3319346">{{cite journal | vauthors = Holford NH | title = Clinical pharmacokinetics of ethanol | journal = Clinical Pharmacokinetics | volume = 13 | issue = 5 | pages = 273–292 | date = November 1987 | pmid = 3319346 | doi = 10.2165/00003088-198713050-00001 | s2cid = 19723995 }}</ref>
| protein_bound = Weakly or not at all<ref name="AcademicPress2013" /><ref name="pmid3319346" />
| metabolism = [[Liver]] (90%):<ref name="pmid3279433">{{cite journal | vauthors = Pohorecky LA, Brick J | title = Pharmacology of ethanol | journal = Pharmacology & Therapeutics | volume = 36 | issue = 2–3 | pages = 335–427 | year = 1988 | pmid = 3279433 | doi = 10.1016/0163-7258(88)90109-x }}</ref><ref name="Levine2003">{{cite book | vauthors = Levine B |title=Principles of Forensic Toxicology|url=https://books.google.com/books?id=k7BInEQ-iqgC&pg=PA161|year=2003|publisher=Amer. Assoc. for Clinical Chemistry|isbn=978-1-890883-87-4|pages=161–}}</ref><br />• [[Alcohol dehydrogenase]]<br />• {{abbr|MEOS|microsomal ethanol-oxidizing system}} ([[CYP2E1]])
| metabolites = [[Acetaldehyde]]; [[Acetic acid]]; [[Acetyl-CoA]]; [[Carbon dioxide]]; [[Ethyl glucuronide]]; [[Ethyl sulfate]]; [[Properties of water|Water]]
| onset = [[Cmax (pharmacology)|Peak concentrations]]:<ref name="pmid3279433" /><ref name="AcademicPress2013" /><br />• Range: 30–90 minutes<br />• Mean: 45–60 minutes<br />• [[Fasting]]: 30 minutes
| elimination_half-life = [[Zero-order kinetics|Constant-rate elimination]] at typical concentrations:<ref name="PMID 5457514"/><ref name="Levine2003" /><ref name="pmid3279433" /><br />• Range: 10–34&nbsp;mg/dL/hour<br />• Mean (men): 15&nbsp;mg/dL/hour<br />• Mean (women): 18&nbsp;mg/dL/hr<br />At very high concentrations (t<sub>1/2</sub>): 4.0–4.5&nbsp;hours<ref name="pmid3319346" /><ref name="AcademicPress2013" />
| duration_of_action = 6–16 hours (amount of time that levels are detectable)<ref name="Iber1990">{{cite book | vauthors = Iber FL | title = Alcohol and Drug Abuse as Encountered in Office Practice|url=https://books.google.com/books?id=327L800dIGYC&pg=PA74|date=26 November 1990|publisher=CRC Press|isbn=978-0-8493-0166-7|pages=74–}}</ref>
| excretion = • Major: [[Ethanol metabolism|metabolism]] (into [[carbon dioxide]] and water)<ref name="AcademicPress2013" /><br />• Minor: [[urine]], [[breath]], [[sweat]] (5–10%)<ref name="pmid3279433" /><ref name="AcademicPress2013" />
| CAS_number = 64-17-5
| CAS_supplemental = 
| ATC_prefix = V03
| ATC_suffix = AZ01
| PubChem = 702
| IUPHAR_ligand = 2299
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00898
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 682
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 3K9958V90M
| KEGG = D00068
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 16236
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 545
| PDB_ligand = EOH

<!-- Chemical data -->| C = 2
| H = 6
| O = 1
| SMILES = CCO
| StdInChI = 1S/C2H6O/c1-2-3/h3H,2H2,1H3
| StdInChIKey = LFQSCWFLJHTTHZ-UHFFFAOYSA-N

<!-- Physical data -->| density = 0.7893
| density_notes = (at 20&nbsp;°C)<ref name="CRC2">{{RubberBible92nd|page=3.246}}</ref>
| melting_point = −114.14 ± 0.03
| melting_notes = <ref name="CRC2" />
| boiling_point = 78.24 ± 0.09
| boiling_notes = <ref name="CRC2" />
| solubility = Miscible
}}

The '''pharmacology of ethanol''' involves both pharmacodynamics (how it affects the body) and pharmacokinetics (how the body processes it). In the body, [[ethanol]] primarily affects the central nervous system, acting as a depressant and causing sedation, relaxation, and decreased anxiety. The complete list of mechanisms remains an area of research, but ethanol has been shown to affect ligand-gated ion channels, particularly the [[GABAA receptor|GABA<sub>A</sub> receptor]].

After oral ingestion, ethanol is absorbed via the stomach and intestines into the bloodstream. Ethanol is highly water-soluble and  diffuses passively throughout the entire body, including the brain. Soon after ingestion, it begins to be metabolized, 90% or more by the liver. One [[standard drink]] is sufficient to almost completely saturate the liver's capacity to metabolize alcohol.{{Citation needed|date=February 2025}} The main metabolite is acetaldehyde, a toxic carcinogen. Acetaldehyde is then further metabolized into ionic acetate by the enzyme aldehyde dehydrogenase (ALDH). [[Acetate]] is not carcinogenic and has low toxicity,<ref>{{cite web |title=Acetate, Ion chromatography standard solution, Safety Data Sheet |url=https://assets.thermofisher.com/DirectWebViewer/private/document.aspx?prd=ALFAA42563~~PDF~~MTR~~AGHS~~EN~~2024-04-01%2013:42:53~~Acetate%20%20Ion%20chromatography%20standard%20solution%20%20Specpure%c2%ae%20%20CH3CO2(1- |publisher=Thermo Fisher Scientific |page=4 |date=1 Apr 2024}}</ref> but has been implicated in causing [[hangovers]].<ref>{{cite journal | vauthors = Maxwell CR, Spangenberg RJ, Hoek JB, Silberstein SD, Oshinsky ML | title = Acetate causes alcohol hangover headache in rats | journal = PLOS ONE | volume = 5 | issue = 12 | pages = e15963 | date = December 2010 | pmid = 21209842 | pmc = 3013144 | doi = 10.1371/journal.pone.0015963 | bibcode = 2010PLoSO...515963M | doi-access = free }}</ref><ref>[https://www.newscientist.com/article/dn19942-is-coffee-the-real-cure-for-a-hangover.html 'Is coffee the real cure for a hangover?'] by Bob Holmes, [[New Scientist]], Jan. 15 2011, p. 17.</ref> Acetate is further broken down into carbon dioxide and water and eventually eliminated from the body through urine and breath. 5 to 10% of ethanol is excreted unchanged in the breath, urine, and sweat.

== History ==
[[File:(Five stages of inebriation, ca.1863-1868) - photographer Charles Percy Pickering (9610229733) (2).jpg|thumb|upright=0.9 |Stage Three of the Five stages of inebriation, {{circa}} 1863–1868, by Charles Percy Pickering]]
Beginning with the [[Gin Craze]], excessive drinking and drunkenness developed into a major problem for public health.<ref name="Jones2016">{{cite book | vauthors = Jones AW |chapter=Forensic Science Aspects of Ethanol Metabolism |title=Forensic Science Progress 5 |date=1991 |volume=5 |pages=31–89 |doi=10.1007/978-3-642-58233-2_2|isbn=978-3-540-53203-3 }}</ref><ref name="Jones2019">{{cite journal | vauthors = Jones AW |title=Alcohol, its absorption, distribution, metabolism, and excretion in the body and pharmacokinetic calculations |journal=WIREs Forensic Science |date=September 2019 |volume=1 |issue=5 |doi=10.1002/wfs2.1340|doi-access=free}}</ref> In 1874, [[Francis E. Anstie]]'s experiments showed that the amounts of alcohol eliminated unchanged in breath, urine, sweat, and feces were negligible compared to the amount ingested, suggesting it was oxidized within the body.<ref>{{cite book |title=The Practitioner |date=1874 |publisher=John Brigg |chapter-url=https://books.google.com/books?id=aLsvAQAAMAAJ&pg=PA28 |language=en| vauthors = Anstie FE |chapter=Final experiments on the elimination of alcohol from the body|pages=15–28|volume=13}}</ref> In 1902, Atwater and Benedict estimated that alcohol yielded 7.1 kcal of energy per gram consumed and 98% was metabolized.<ref>{{Citation| vauthors = Atwater WO, Benedict FG |author-link=Wilbur Olin Atwater| author2-link=Francis Gano Benedict|date=1902|title=An Experimental Inquiry Regarding the Nutritive Value of Alcohol|work=Sixth Memoir|series=Memoirs of the National Academy of Sciences|volume=VIII|publisher=US Government Printing Office|location=Washington|pages=231–397|id=[https://www.govinfo.gov/app/details/SERIALSET-04236_00_00-001-0233-0000 S. Doc. 57-233]|url=https://archive.org/details/experimentalinqu00atwa/page/232/mode/2up}}</ref> In 1922, Widmark published his method for analyzing the alcohol content of fingertip samples of blood.<ref>{{cite journal | vauthors = Widmark EM |title=Eine Mikromethode zur Bestimmung von Athylalkohol im Blut|language=de|trans-title=A micro-method for the determination of ethyl alcohol in the blood |journal=Biochemische Zeitschrift |date=1922 |volume=131 |pages=473–484 |hdl=2027/uc1.b3778068?urlappend=%3Bseq=499 |url=https://hdl.handle.net/2027/uc1.b3778068?urlappend=%3Bseq=499%3Bownerid=9007199257723309-553}}</ref>
Through the 1930s, Widmark conducted numerous studies and formulated the basic principles of ethanol pharmacokinetics for forensic purposes,<ref>{{cite journal |title=Die theoretischen Grundlagen und die praktische Verwendbarkeit der gerichtlich-medizinischen Alkoholbestimmung|trans-title=Principles and applications of medicolegal alcohol determination |journal=Journal of the American Medical Association |date=21 May 1932 |volume=98 |issue=21 |pages=1834 |doi=10.1001/jama.1932.02730470056035|type=book review}}</ref> including the eponymous Widmark equation. In 1980, Watson et al. proposed updated equations based on [[total body water]] instead of body weight.<ref>{{cite journal | vauthors = Watson PE, Watson ID, Batt RD | title = Prediction of blood alcohol concentrations in human subjects. Updating the Widmark Equation | journal = Journal of Studies on Alcohol | volume = 42 | issue = 7 | pages = 547–556 | date = July 1981 | pmid = 7289599 | doi = 10.15288/jsa.1981.42.547 }}</ref> The TBW equations have been found to be significantly more accurate due to rising levels of [[obesity]] worldwide.<ref>{{cite journal | vauthors = Maskell PD, Jones AW, Heymsfield SB, Shapses S, Johnston A | title = Total body water is the preferred method to use in forensic blood-alcohol calculations rather than ethanol's volume of distribution | journal = Forensic Science International | volume = 316 | pages = 110532 | date = November 2020 | pmid = 33099270 | doi = 10.1016/j.forsciint.2020.110532 }}</ref>

==Pharmacodynamics==
The principal [[mechanism of action]] for ethanol has proven elusive and remains not fully understood.<ref name="pmid18423561">{{cite journal | vauthors = Lobo IA, Harris RA | title = GABA(A) receptors and alcohol | journal = Pharmacology, Biochemistry, and Behavior | volume = 90 | issue = 1 | pages = 90–94 | date = July 2008 | pmid = 18423561 | pmc = 2574824 | doi = 10.1016/j.pbb.2008.03.006 }}</ref><ref name="pmid17591544">{{cite journal | vauthors = Santhakumar V, Wallner M, Otis TS | title = Ethanol acts directly on extrasynaptic subtypes of GABAA receptors to increase tonic inhibition | journal = Alcohol | volume = 41 | issue = 3 | pages = 211–221 | date = May 2007 | pmid = 17591544 | pmc = 2040048 | doi = 10.1016/j.alcohol.2007.04.011 }}</ref> Identifying [[molecular target]]s for ethanol is unusually difficult, in large part due to its unique biochemical properties.<ref name="pmid17591544" /> Specifically, ethanol is a very low [[molecular weight]] compound and is of exceptionally low [[potency (pharmacology)|potency]] in its actions, causing effects only at very high ([[millimolar]] ''mM'') concentrations.<ref name="pmid17591544" /><ref name="pmid19342616" /> For these reasons, it is not possible to employ traditional biochemical techniques to directly assess the binding of ethanol to [[receptor (biochemistry)|receptors]] or [[ion channel]]s.<ref name="pmid17591544" /><ref name="pmid19342616" /> Instead, researchers have had to rely on functional studies to elucidate the actions of ethanol.<ref name="pmid17591544" /> Even at present, no [[binding site]]s have been unambiguously identified and established for ethanol. Studies have published strong evidence for certain functions of ethanol in specific systems, but other laboratories have found that these findings do not replicate with different neuronal types and [[heterologous expression|heterologously expressed]] receptors.<ref>{{cite book | vauthors = Lovinger DM, Roberto M | title = Synaptic effects induced by alcohol | series = Current Topics in Behavioral Neurosciences| volume = 13 | pages = 31–86 | date = 2013 | pmid = 21786203 | pmc = 4791588 | doi = 10.1007/7854_2011_143 | isbn = 978-3-642-28719-0 }}</ref> Thus, there remains lingering doubt about the mechanisms of ethanol listed here, even for the GABA<sub>A</sub> receptor, the most-studied mechanism.<ref>{{cite journal | vauthors = Lovinger DM, Homanics GE | title = Tonic for what ails us? high-affinity GABAA receptors and alcohol | journal = Alcohol | volume = 41 | issue = 3 | pages = 139–143 | date = May 2007 | pmid = 17521844 | pmc = 2043151 | doi = 10.1016/j.alcohol.2007.03.008 }}</ref>

In the past, alcohol was believed to be a non-specific pharmacological agent affecting many [[neurotransmitter]] systems in the brain,<ref name="Vengeliene">{{cite journal | vauthors = Vengeliene V, Bilbao A, Molander A, Spanagel R | title = Neuropharmacology of alcohol addiction | journal = British Journal of Pharmacology | volume = 154 | issue = 2 | pages = 299–315 | date = May 2008 | pmid = 18311194 | pmc = 2442440 | doi = 10.1038/bjp.2008.30 }}</ref> but progress has been made over the last few decades.<ref name="pmid11391069">{{cite journal | vauthors = Narahashi T, Kuriyama K, Illes P, Wirkner K, Fischer W, Mühlberg K, Scheibler P, Allgaier C, Minami K, Lovinger D, Lallemand F, Ward RJ, DeWitte P, Itatsu T, Takei Y, Oide H, Hirose M, Wang XE, Watanabe S, Tateyama M, Ochi R, Sato N | title = Neuroreceptors and ion channels as targets of alcohol | journal = Alcoholism: Clinical and Experimental Research | volume = 25 | issue = 5 Suppl ISBRA | pages = 182S–188S | date = May 2001 | pmid = 11391069 | doi = 10.1097/00000374-200105051-00030 }}</ref><ref name="pmid17591544" /> It appears that it affects ion channels, in particular [[ligand-gated ion channel]]s, to mediate its effects in the CNS.<ref name="pmid18423561" /><ref name="pmid11391069" /><ref name="pmid24164436" /><ref name="pmid17591544" /> In some systems, these effects are facilitatory, and in others inhibitory. Moreover, although it has been established that ethanol modulates ion channels to mediate its effects,<ref name="pmid24164436">{{cite journal | vauthors = Olsen RW, Li GD, Wallner M, Trudell JR, Bertaccini EJ, Lindahl E, Miller KW, Alkana RL, Davies DL | title = Structural models of ligand-gated ion channels: sites of action for anesthetics and ethanol | journal = Alcoholism: Clinical and Experimental Research | volume = 38 | issue = 3 | pages = 595–603 | date = March 2014 | pmid = 24164436 | pmc = 3959612 | doi = 10.1111/acer.12283 }}</ref> ion channels are complex proteins, and their interactions and functions are complicated by diverse [[protein subunit|subunit]] compositions and regulation by conserved cellular signals (e.g. signaling lipids).<ref name="pmid18423561" /><ref name="pmid17591544" />

Alcohol is also converted into [[phosphatidylethanol]] (PEth, an unnatural lipid metabolite) by [[PLD2|phospholipase D2]]. This metabolite competes with [[Phosphatidylinositol 4,5-bisphosphate|PIP<sub>2</sub>]] agonist sites on [[lipid-gated ion channels]].<ref>{{cite journal | vauthors = Chung HW, Petersen EN, Cabanos C, Murphy KR, Pavel MA, Hansen AS, Ja WW, Hansen SB | title = A Molecular Target for an Alcohol Chain-Length Cutoff | journal = Journal of Molecular Biology | volume = 431 | issue = 2 | pages = 196–209 | date = January 2019 | pmid = 30529033 | pmc = 6360937 | doi = 10.1016/j.jmb.2018.11.028 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Robinson CV, Rohacs T, Hansen SB | title = Tools for Understanding Nanoscale Lipid Regulation of Ion Channels | journal = Trends in Biochemical Sciences | volume = 44 | issue = 9 | pages = 795–806 | date = September 2019 | pmid = 31060927 | pmc = 6729126 | doi = 10.1016/j.tibs.2019.04.001 }}</ref> The result of these direct effects is a wave of further indirect effects involving a variety of other [[neurotransmitter]] and [[neuropeptide]] systems.<ref name=Vengeliene /> This presents a novel indirect mechanism and suggests that a metabolite, not the ethanol itself, could cause the behavioural or symptomatic effects of alcohol intoxication. Many of the primary targets of ethanol are known to bind PIP<sub>2</sub> including GABA<sub>A</sub> receptors,<ref>{{cite journal | vauthors = Laverty D, Desai R, Uchański T, Masiulis S, Stec WJ, Malinauskas T, Zivanov J, Pardon E, Steyaert J, Miller KW, Aricescu AR | title = Cryo-EM structure of the human α1β3γ2 GABA<sub>A</sub> receptor in a lipid bilayer | journal = Nature | volume = 565 | issue = 7740 | pages = 516–520 | date = January 2019 | pmid = 30602789 | pmc = 6364807 | doi = 10.1038/s41586-018-0833-4 | bibcode = 2019Natur.565..516L }}</ref> but the role of PEth needs to be investigated further.

===List of known actions in the central nervous system===
Ethanol has been reported to possess the following actions in functional assays at varying concentrations:<ref name="pmid19342616">{{cite journal | vauthors = Spanagel R | title = Alcoholism: a systems approach from molecular physiology to addictive behavior | journal = Physiological Reviews | volume = 89 | issue = 2 | pages = 649–705 | date = April 2009 | pmid = 19342616 | doi = 10.1152/physrev.00013.2008 }}</ref>

* [[GABAA receptor|GABA<sub>A</sub> receptor]]: [[positive allosteric modulator]] (primarily of [[GABRD|δ subunit]]-containing receptors)<ref name="NHM-Ethanol" /><ref name="Mihic">{{cite journal | vauthors = Mihic SJ, Ye Q, Wick MJ, Koltchine VV, Krasowski MD, Finn SE, Mascia MP, Valenzuela CF, Hanson KK, Greenblatt EP, Harris RA, Harrison NL | title = Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors | journal = Nature | volume = 389 | issue = 6649 | pages = 385–389 | date = September 1997 | pmid = 9311780 | doi = 10.1038/38738 | bibcode = 1997Natur.389..385M | s2cid = 4393717 }}</ref>
* [[NMDA receptor]]: [[negative allosteric modulator]]<ref name="pmid22429661">{{cite journal |vauthors=Möykkynen T, Korpi ER |date=July 2012 |title=Acute effects of ethanol on glutamate receptors |journal=Basic & Clinical Pharmacology & Toxicology |volume=111 |issue=1 |pages=4–13 |doi=10.1111/j.1742-7843.2012.00879.x |pmid=22429661 |doi-access=free}}</ref><ref name="NHM-Ethanol" /><ref name=Lovinger />
* [[AMPA receptor]]: negative allosteric modulator<ref name="pmid22429661" />
* [[Kainate receptor]]: negative allosteric modulator<ref name="pmid22429661" />
* [[Glycine receptor]]: positive allosteric modulator<ref name="pmid28833225">{{cite journal | vauthors = Söderpalm B, Lidö HH, Ericson M | title = The Glycine Receptor-A Functionally Important Primary Brain Target of Ethanol | journal = Alcoholism: Clinical and Experimental Research | volume = 41 | issue = 11 | pages = 1816–1830 | date = November 2017 | pmid = 28833225 | doi = 10.1111/acer.13483 }}</ref>
* [[Serotonin receptor|Serotonin]] [[5-HT3 receptor|5-HT<sub>3</sub> receptor]]: positive allosteric modulator<ref name="pmid28833225" /><ref name="Lovinger">{{cite journal | vauthors = Lovinger DM | title = 5-HT3 receptors and the neural actions of alcohols: an increasingly exciting topic | journal = Neurochemistry International | volume = 35 | issue = 2 | pages = 125–130 | date = August 1999 | pmid = 10405996 | doi = 10.1016/S0197-0186(99)00054-6 | s2cid = 1391767 }}</ref>
* [[Opioid receptor]]: endogenous positive allosteric modulator<ref name="pmid22429661" />
* [[Muscarinic acetylcholine receptor]]: positive allosteric modulator.
* [[Nicotinic acetylcholine receptor]]: positive allosteric modulator<ref>{{cite journal | vauthors = Narahashi T, Aistrup GL, Marszalec W, Nagata K | title = Neuronal nicotinic acetylcholine receptors: a new target site of ethanol | journal = Neurochemistry International | volume = 35 | issue = 2 | pages = 131–141 | date = August 1999 | pmid = 10405997 | doi = 10.1016/S0197-0186(99)00055-8 | s2cid = 40991187 }}</ref><ref name="pmid24464050">{{cite journal | vauthors = Wu J, Gao M, Taylor DH | title = Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence | journal = Acta Pharmacologica Sinica | volume = 35 | issue = 3 | pages = 311–315 | date = March 2014 | pmid = 24464050 | pmc = 4647894 | doi = 10.1038/aps.2013.181 }}</ref><ref name="pmid28901722">{{cite journal | vauthors = Steffensen SC, Shin SI, Nelson AC, Pistorius SS, Williams SB, Woodward TJ, Park HJ, Friend L, Gao M, Gao F, Taylor DH, Foster Olive M, Edwards JG, Sudweeks SN, Buhlman LM, Michael McIntosh J, Wu J | title = α6 subunit-containing nicotinic receptors mediate low-dose ethanol effects on ventral tegmental area neurons and ethanol reward | journal = Addiction Biology | volume = 23 | issue = 5 | pages = 1079–1093 | date = September 2018 | pmid = 28901722 | pmc = 5849490 | doi = 10.1111/adb.12559 }}</ref>
* [[Glycine reuptake inhibitor]]<ref name="SitteFreissmuth2006">{{cite book| vauthors=Sitte H, Freissmuth M |date=2 August 2006 |title=Neurotransmitter Transporters |url={{google books |plainurl=y |id=CeZDAAAAQBAJ|page=472}} |publisher=Springer Science & Business Media |isbn=978-3-540-29784-0 |pages=472–}}</ref>
* [[Adenosine reuptake inhibitor]]<ref name="pmid19298329">{{cite journal | vauthors = Allen-Gipson DS, Jarrell JC, Bailey KL, Robinson JE, Kharbanda KK, Sisson JH, Wyatt TA | title = Ethanol blocks adenosine uptake via inhibiting the nucleoside transport system in bronchial epithelial cells | journal = Alcoholism: Clinical and Experimental Research | volume = 33 | issue = 5 | pages = 791–798 | date = May 2009 | pmid = 19298329 | pmc = 2940831 | doi = 10.1111/j.1530-0277.2009.00897.x }}</ref>
* [[L-type calcium channel]]: [[channel blocker]]
* [[G protein-coupled inwardly-rectifying potassium channel|GIRK]]: [[channel opener]]
* [[Voltage-gated calcium channel]]<ref name="pmid18423561" /><ref name="pmid11391069" /><ref name="pmid24164436" />
* [[dihydropyridine receptor|Dihydropyridine-sensitive L-type Ca2+ channels]]<ref name="Ethanol directly modulates gating o">{{cite journal | vauthors = Wang X, Wang G, Lemos JR, Treistman SN | title = Ethanol directly modulates gating of a dihydropyridine-sensitive Ca2+ channel in neurohypophysial terminals | journal = The Journal of Neuroscience | volume = 14 | issue = 9 | pages = 5453–5460 | date = September 1994 | pmid = 7521910 | pmc = 6577079 | doi = 10.1523/JNEUROSCI.14-09-05453.1994 }}</ref>
* [[BK channel]] modulation<ref name="pmid27238266">{{cite journal | vauthors = Dopico AM, Bukiya AN, Kuntamallappanavar G, Liu J | title = Modulation of BK Channels by Ethanol | journal = International Review of Neurobiology | volume = 128 | pages = 239–279 | year = 2016 | pmid = 27238266 | pmc = 5257281 | doi = 10.1016/bs.irn.2016.03.019 | isbn = 978-0-12-803619-8 }}</ref>
* [[G protein-coupled inwardly rectifying potassium channels|G-protein-activated inwardly rectifying K+ channels]]<ref>{{cite journal | vauthors = Kobayashi T, Ikeda K, Kojima H, Niki H, Yano R, Yoshioka T, Kumanishi T | title = Ethanol opens G-protein-activated inwardly rectifying K+ channels | journal = Nature Neuroscience | volume = 2 | issue = 12 | pages = 1091–1097 | date = December 1999 | pmid = 10570486 | doi = 10.1038/16019 | s2cid = 28730710 }}</ref>
* [[Medulla oblongata|Brain medulla]]: Decreased levels of [[nitric oxide]]<ref name="pmid29382335">{{cite journal | vauthors = Situmorang JH, Lin HH, Lo H, Lai CC | title = Role of neuronal nitric oxide synthase (nNOS) at medulla in tachycardia induced by repeated administration of ethanol in conscious rats | journal = Journal of Biomedical Science | volume = 25 | issue = 1 | pages = 8 | date = January 2018 | pmid = 29382335 | pmc = 5791364 | doi = 10.1186/s12929-018-0409-5 | doi-access = free }}</ref>
* [[Mesolimbic pathway]]: Increased levels of [[dopamine]] and [[endogenous]] [[opioid]]s, secondary to other actions<ref name="Mesolimbic dopamine release" /><ref name="NHM-Ethanol" />

Many of these actions have been found to occur only at very high concentrations that may not be pharmacologically significant at recreational doses of ethanol, and it is unclear how or to what extent each of the individual actions is involved in the effects of ethanol.<ref name="pmid17591544" /> Some of the actions of ethanol on ligand-gated ion channels, specifically the nicotinic acetylcholine receptors and the glycine receptor, are [[dose-dependent]], with potentiation ''or'' inhibition occurring dependent on ethanol concentration.<ref name="pmid19342616" /> This seems to be because the effects of ethanol on these channels are a summation of positive and negative allosteric modulatory actions.<ref name="pmid19342616" />

===GABA<sub>A</sub> receptors===
{{See also|GABAA#Ligands}}
[[File:Ethanol and GABA Receptor.png|thumb|Ethanol binding to GABA<sub>A</sub> receptor]]
Ethanol has been found to enhance GABA<sub>A</sub> receptor-mediated currents in functional assays.<ref name="pmid18423561" /><ref name="pmid17591544" /> Ethanol has long shown a similarity in its effects to [[positive allosteric modulator]]s of the GABA<sub>A</sub> receptor like [[benzodiazepine]]s, [[barbiturate]]s, and various [[general anesthetic]]s.<ref name="pmid18423561" /><ref name="pmid17591544" /> Some of these effects include [[anxiolytic]], [[anticonvulsant]], [[sedative]], and [[hypnotic]] effects, cognitive impairment, and motor incoordination.<ref name="first GABA">{{cite journal | vauthors = Kumar S, Porcu P, Werner DF, Matthews DB, Diaz-Granados JL, Helfand RS, Morrow AL | title = The role of GABA(A) receptors in the acute and chronic effects of ethanol: a decade of progress | journal = Psychopharmacology | volume = 205 | issue = 4 | pages = 529–564 | date = September 2009 | pmid = 19455309 | pmc = 2814770 | doi = 10.1007/s00213-009-1562-z }}</ref> In accordance, it was theorized and widely believed that the primary mechanism of action of ethanol is [[GABAA receptor positive allosteric modulator|GABA<sub>A</sub> receptor positive allosteric modulation]].<ref name="pmid18423561" /><ref name="pmid17591544" /> However, other ion channels are involved in its effects as well.<ref name="pmid11391069" /><ref name="pmid17591544" />  Although ethanol exhibits positive [[Allosteric regulation|allosteric binding]] properties to GABA<sub>A</sub> receptors, its effects are limited to pentamers containing the δ-subunit rather than the γ-subunit.<ref name="pmid17591544"/> Ethanol potentiates [[extrasynaptic]] [[GABRD|δ subunit]]-containing GABA<sub>A</sub> receptors at behaviorally relevant (as low as 3&nbsp;mM) concentrations,<ref name="pmid18423561" /><ref name="pmid17591544" /><ref name="pmid18278063">{{cite journal | vauthors = Wallner M, Olsen RW | title = Physiology and pharmacology of alcohol: the imidazobenzodiazepine alcohol antagonist site on subtypes of GABAA receptors as an opportunity for drug development? | journal = British Journal of Pharmacology | volume = 154 | issue = 2 | pages = 288–298 | date = May 2008 | pmid = 18278063 | pmc = 2442438 | doi = 10.1038/bjp.2008.32 }}</ref> but [[GABAA receptor#Subunits|γ subunit]] receptors are enhanced only at far higher concentrations (> 100&nbsp;mM) that are in excess of recreational concentrations (up to 50&nbsp;mM).<ref name="pmid18423561" /><ref name="pmid17591544" /><ref name="pmid28479395">{{cite journal | vauthors = Harrison NL, Skelly MJ, Grosserode EK, Lowes DC, Zeric T, Phister S, Salling MC | title = Effects of acute alcohol on excitability in the CNS | journal = Neuropharmacology | volume = 122 | pages = 36–45 | date = August 2017 | pmid = 28479395 | pmc = 5657304 | doi = 10.1016/j.neuropharm.2017.04.007 }}</ref>

GABA<sub>A</sub> receptors containing the δ-subunit have been shown to be located exterior to the synapse and are involved with tonic inhibition rather than its γ-subunit counterpart, which is involved in phasic inhibition.<ref name="first GABA" /> The δ-subunit has been shown to be able to form the allosteric binding site which makes GABA<sub>A</sub> receptors containing the δ-subunit more sensitive to ethanol concentrations, even to moderate social ethanol consumption levels (30mM).<ref>{{cite journal | vauthors = Wallner M, Hanchar HJ, Olsen RW | title = Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low concentrations known to affect humans | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 25 | pages = 15218–15223 | date = December 2003 | pmid = 14625373 | pmc = 299963 | doi = 10.1073/pnas.2435171100 | bibcode = 2003PNAS..10015218W | doi-access = free }}</ref> While it has been shown by Santhakumar et al. that GABA<sub>A</sub> receptors containing the δ-subunit are sensitive to ethanol modulation, depending on subunit combinations receptors could be more or less sensitive to ethanol.<ref name="third GABA">{{cite journal | vauthors = Baur R, Kaur KH, Sigel E | title = Structure of alpha6 beta3 delta GABA(A) receptors and their lack of ethanol sensitivity | journal = Journal of Neurochemistry | volume = 111 | issue = 5 | pages = 1172–1181 | date = December 2009 | pmid = 19765192 | doi = 10.1111/j.1471-4159.2009.06387.x | s2cid = 10577529 | doi-access = free }}</ref> It has been shown that GABA<sub>A</sub> receptors that contain both δ and β3-subunits display increased sensitivity to ethanol.<ref name="pmid17591544"/> One such receptor that exhibits ethanol insensitivity is α3-β6-δ GABA<sub>A</sub>.<ref name="third GABA" /> It has also been shown that subunit combination is not the only thing that contributes to ethanol sensitivity. Location of GABA<sub>A</sub> receptors within the synapse may also contribute to ethanol sensitivity.<ref name="first GABA" />

[[Ro15-4513]], a close [[structural analog|analogue]] of the benzodiazepine antagonist [[flumazenil]] (Ro15-1788), has been found to bind to the same site as ethanol and to competitively displace it in a saturable manner.<ref name="pmid17591544" /><ref name="pmid18278063" /> In addition, Ro15-4513 blocked the enhancement of δ subunit-containing GABA<sub>A</sub> receptor currents by ethanol ''[[in vitro]]''.<ref name="pmid17591544" /> In accordance, the drug has been found to reverse many of the behavioral effects of low-to-moderate doses of ethanol in rodents, including its effects on anxiety, memory, motor behavior, and self-administration.<ref name="pmid17591544" /><ref name="pmid18278063" /> Taken together, these findings suggest a binding site for ethanol on subpopulations of the GABA<sub>A</sub> receptor with specific subunit compositions via which it interacts with and potentiates the receptor.<ref name="pmid18423561" /><ref name="pmid17591544" /><ref name="pmid18278063" /><ref name="pmid27199667">{{cite journal | vauthors = Förstera B, Castro PA, Moraga-Cid G, Aguayo LG | title = Potentiation of Gamma Aminobutyric Acid Receptors (GABAAR) by Ethanol: How Are Inhibitory Receptors Affected? | journal = Frontiers in Cellular Neuroscience | volume = 10 | pages = 114 | year = 2016 | pmid = 27199667 | pmc = 4858537 | doi = 10.3389/fncel.2016.00114 | doi-access = free }}</ref>

===Calcium channel blocking===
{{See also|Calcium channel blocker#Ethanol}}
[[File:Ethanol blocks voltage gated calcium channel.png|thumb|upright=1.5|Ethanol blocks voltage-gated calcium channel]]

Research indicates [[alcohol (drug)|ethanol]] is involved in the inhibition of L-type calcium channels. One study showed the nature of ethanol binding to L-type calcium channels is according to first-order kinetics with a [[Hill coefficient]] around 1. This indicates ethanol binds independently to the channel, expressing [[cooperative binding|noncooperative binding]].<ref name="Ethanol directly modulates gating o"/> Early studies showed a link between calcium and the release of [[vasopressin]] by the [[secondary messenger system]].<ref name="first ethanol">{{cite journal | vauthors = Tobin V, Leng G, Ludwig M | title = The involvement of actin, calcium channels and exocytosis proteins in somato-dendritic oxytocin and vasopressin release | journal = Frontiers in Physiology | volume = 3 | pages = 261 | year = 2012 | pmid = 22934017 | pmc = 3429037 | doi = 10.3389/fphys.2012.00261 | doi-access = free }}</ref> Vasopressin levels are reduced after the ingestion of alcohol.<ref>{{cite journal | vauthors = Chiodera P, Coiro V | title = Inhibitory effect of ethanol on the arginine vasopressin response to insulin-induced hypoglycemia and the role of endogenous opioids | journal = Neuroendocrinology | volume = 51 | issue = 5 | pages = 501–504 | date = May 1990 | pmid = 2112727 | doi = 10.1159/000125383 }}</ref> The lower levels of vasopressin from the consumption of alcohol have been linked to ethanol acting as an antagonist to voltage-gated calcium channels (VGCCs). Studies conducted by Treistman et al. in the [[aplysia]] confirm inhibition of VGCC by ethanol. [[Voltage clamp]] recordings have been done on the aplysia neuron. VGCCs were isolated and calcium current was recorded using [[patch clamp]] technique having ethanol as a treatment. Recordings were replicated at varying concentrations (0, 10, 25, 50, and 100 mM) at a voltage clamp of +30 mV. Results showed calcium current decreased as concentration of ethanol increased.<ref>{{cite journal | vauthors = Treistman SN, Bayley H, Lemos JR, Wang XM, Nordmann JJ, Grant AJ | title = Effects of ethanol on calcium channels, potassium channels, and vasopressin release | journal = Annals of the New York Academy of Sciences | volume = 625 | issue = 1 | pages = 249–263 | year = 1991 | pmid = 1647726 | doi = 10.1111/j.1749-6632.1991.tb33844.x | s2cid = 28281696 | bibcode = 1991NYASA.625..249T }}</ref> Similar results have shown to be true in single-channel recordings from isolated nerve terminal of rats that ethanol does in fact block VGCCs.<ref>{{cite journal | vauthors = Walter HJ, Messing RO | title = Regulation of neuronal voltage-gated calcium channels by ethanol | journal = Neurochemistry International | volume = 35 | issue = 2 | pages = 95–101 | date = August 1999 | pmid = 10405992 | doi = 10.1016/s0197-0186(99)00050-9 | s2cid = 36172178 }}</ref>

Studies done by Katsura et al. in 2006 on mouse cerebral cortical neurons, show the effects of prolonged ethanol exposure. Neurons were exposed to sustained ethanol concentrations of 50 mM for 3 days ''in vitro''. [[Western blot]] and protein analysis were conducted to determine the relative amounts of VGCC subunit expression. α1C, α1D, and α2/δ1 subunits showed an increase of expression after sustained ethanol exposure. However, the β4 subunit showed a decrease. Furthermore, α1A, α1B, and α1F subunits did not alter in their relative expression. Thus, sustained ethanol exposure may participate in the development of ethanol dependence in neurons.<ref>{{cite journal | vauthors = Katsura M, Shibasaki M, Hayashida S, Torigoe F, Tsujimura A, Ohkuma S | title = Increase in expression of alpha1 and alpha2/delta1 subunits of L-type high voltage-gated calcium channels after sustained ethanol exposure in cerebral cortical neurons | journal = Journal of Pharmacological Sciences | volume = 102 | issue = 2 | pages = 221–230 | date = October 2006 | pmid = 17031067 | doi = 10.1254/jphs.fp0060781 | doi-access = free }}</ref>

Other experiments done by Malysz et al. have looked into ethanol effects on voltage-gated calcium channels on [[Detrusor urinae muscle|detrusor]] smooth muscle cells in guinea pigs. Perforated patch clamp technique was used having intracellular fluid inside the pipette and extracellular fluid in the bath with added 0.3% vol/vol (about 50-mM) ethanol. Ethanol decreased the {{chem|Ca|2+}} current in DSM cells and induced muscle relaxation. Ethanol inhibits VGCCs and is involved in alcohol-induced relaxation of the urinary bladder.<ref>{{cite journal | vauthors = Malysz J, Afeli SA, Provence A, Petkov GV | title = Ethanol-mediated relaxation of guinea pig urinary bladder smooth muscle: involvement of BK and L-type Ca2+ channels | journal = American Journal of Physiology. Cell Physiology | volume = 306 | issue = 1 | pages = C45–C58 | date = January 2014 | pmid = 24153429 | pmc = 3919972 | doi = 10.1152/ajpcell.00047.2013 }}</ref>

===Rewarding and reinforcing actions===
[[Image:D1 agonists.png|thumbnail|left|upright=1.6|Chemical structures of selective [[Dopamine receptor D1|dopamine receptor D<sub>1</sub>]] receptor agonists<ref name="pmid17154515">{{cite journal | vauthors = Cueva JP, Giorgioni G, Grubbs RA, Chemel BR, Watts VJ, Nichols DE | title = trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: synthesis, resolution, and preliminary pharmacological characterization of a new dopamine D1 receptor full agonist | journal = Journal of Medicinal Chemistry | volume = 49 | issue = 23 | pages = 6848–6857 | date = November 2006 | pmid = 17154515 | doi = 10.1021/jm0604979 }}</ref><ref name="pmid7658429">{{cite journal | vauthors = Michaelides MR, Hong Y, DiDomenico S, Asin KE, Britton DR, Lin CW, Williams M, Shiosaki K | title = (5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-azacyclopent-1- ena[c]-phenanthrene-9,10-diol (A-86929): a potent and selective dopamine D1 agonist that maintains behavioral efficacy following repeated administration and characterization of its diacetyl prodrug (ABT-431) | journal = Journal of Medicinal Chemistry | volume = 38 | issue = 18 | pages = 3445–3447 | date = September 1995 | pmid = 7658429 | doi = 10.1021/jm00018a002 }}</ref>]]

The reinforcing effects of alcohol consumption are mediated by acetaldehyde generated by [[catalase]] and other oxidizing enzymes such as [[CYP2E1|cytochrome P-4502E1]] in the brain.<ref>{{cite journal | vauthors = Karahanian E, Quintanilla ME, Tampier L, Rivera-Meza M, Bustamante D, Gonzalez-Lira V, Morales P, Herrera-Marschitz M, Israel Y | title = Ethanol as a prodrug: brain metabolism of ethanol mediates its reinforcing effects | journal = Alcoholism: Clinical and Experimental Research | volume = 35 | issue = 4 | pages = 606–612 | date = April 2011 | pmid = 21332529 | pmc = 3142559 | doi = 10.1111/j.1530-0277.2011.01439.x }}</ref> Although acetaldehyde has been associated with some of the adverse and toxic effects of ethanol, it appears to play a central role in the activation of the [[mesolimbic pathway|mesolimbic dopamine system]].<ref name="Mesolimbic dopamine release">{{cite journal | vauthors = Melis M, Enrico P, Peana AT, Diana M | title = Acetaldehyde mediates alcohol activation of the mesolimbic dopamine system | journal = The European Journal of Neuroscience | volume = 26 | issue = 10 | pages = 2824–2833 | date = November 2007 | pmid = 18001279 | doi = 10.1111/j.1460-9568.2007.05887.x | s2cid = 25110014 }}</ref>

Ethanol's rewarding and reinforcing (i.e., addictive) properties are mediated through its effects on [[dopamine]] neurons in the [[mesolimbic reward pathway]], which connects the [[ventral tegmental area]] to the [[nucleus accumbens]] (NAcc).<ref name="Alcoholism ΔFosB DB entry">{{cite web|title=Alcoholism – Homo sapiens (human) Database entry|url=http://www.genome.jp/dbget-bin/www_bget?hsa05034|website=KEGG Pathway|access-date=9 February 2015|date=29 October 2014}}</ref><ref name="Alcoholism ΔFosB">{{cite web |title=Alcoholism – Homo sapiens (human) |url=http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354 |work=KEGG Pathway |access-date=31 October 2014 |author=Kanehisa Laboratories |date=29 October 2014}}</ref> One of ethanol's primary effects is the allosteric inhibition of NMDA receptors and facilitation of GABA<sub>A</sub> receptors (e.g., enhanced GABA<sub>A</sub> receptor-mediated [[chloride]] flux through [[allosteric regulation]] of the receptor).<ref name="NHM-Ethanol">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |year=2009 |publisher=McGraw-Hill Medical |location=New York |isbn=978-0-07-148127-4 |page=372 |edition=2nd |chapter=Chapter 15: Reinforcement and Addictive Disorders}}</ref> At high doses, ethanol inhibits most [[ligand-gated ion channel]]s and [[voltage-gated ion channel]]s in neurons as well.<ref name="NHM-Ethanol" />

With acute alcohol consumption, dopamine is released in the [[chemical synapse|synapses]] of the mesolimbic pathway, in turn heightening activation of postsynaptic [[dopamine receptor D1|D<sub>1</sub> receptors]].<ref name="Alcoholism ΔFosB DB entry" /><ref name="Alcoholism ΔFosB" /> The activation of these receptors triggers postsynaptic internal signaling events through [[protein kinase A]], which ultimately [[phosphorylate]] [[cAMP response element binding protein]] (CREB), inducing CREB-mediated changes in [[gene expression]].<ref name="Alcoholism ΔFosB DB entry" /><ref name="Alcoholism ΔFosB" />

With chronic alcohol intake, consumption of ethanol similarly induces CREB phosphorylation through the D<sub>1</sub> receptor pathway, but it also alters NMDA receptor function through phosphorylation mechanisms;<ref name="Alcoholism ΔFosB DB entry" /><ref name="Alcoholism ΔFosB" /> an adaptive [[downregulation and upregulation|downregulation]] of the D<sub>1</sub> receptor pathway and CREB function occurs as well.<ref name="Alcoholism ΔFosB DB entry" /><ref name="Alcoholism ΔFosB" /> Chronic consumption is also associated with an effect on CREB phosphorylation and function via postsynaptic NMDA receptor signaling cascades through a [[MAPK/ERK pathway]] and [[CAMK]]-mediated pathway.<ref name="Alcoholism ΔFosB" /> These modifications to CREB function in the mesolimbic pathway [[inducible gene|induce expression]] (i.e., increase gene expression) of ΔFosB in the {{abbr|NAcc|nucleus accumbens}},<ref name="Alcoholism ΔFosB" /> where ΔFosB is the "master control protein" that, when overexpressed in the NAcc, is [[necessary and sufficient]] for the development and maintenance of an addictive state (i.e., its overexpression in the nucleus accumbens produces and then directly modulates compulsive alcohol consumption).<ref name="Alcoholism ΔFosB" /><ref name="What the ΔFosB?">{{cite journal | vauthors = Ruffle JK | title = Molecular neurobiology of addiction: what's all the (Δ)FosB about? | journal = The American Journal of Drug and Alcohol Abuse | volume = 40 | issue = 6 | pages = 428–437 | date = November 2014 | pmid = 25083822 | doi = 10.3109/00952990.2014.933840 | s2cid = 19157711 }}</ref><ref name="Cellular basis">{{cite journal | vauthors = Nestler EJ | title = Cellular basis of memory for addiction | journal = Dialogues in Clinical Neuroscience | volume = 15 | issue = 4 | pages = 431–443 | date = December 2013 | pmid = 24459410 | pmc = 3898681 | doi = 10.31887/DCNS.2013.15.4/enestler | quote = Despite the Importance of Numerous Psychosocial Factors, at its Core, Drug Addiction Involves a Biological Process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction.&nbsp;... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement }}</ref><ref name="Nestler">{{cite journal | vauthors = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nature Reviews. Neuroscience | volume = 12 | issue = 11 | pages = 623–637 | date = October 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 }}</ref>

===Relationship between concentrations and effects===
{{Main|Short-term effects of alcohol consumption}}
{| class="wikitable floatright" width=33%
|+ Blood alcohol levels and effects<ref name="Pohorecky & Brick">{{cite journal | vauthors = Pohorecky LA, Brick J | title = Pharmacology of ethanol | journal = Pharmacology & Therapeutics | volume = 36 | issue = 2–3 | pages = 335–427 | year = 1988 | pmid = 3279433 | doi = 10.1016/0163-7258(88)90109-X }}</ref>
! mg/dL || mM || % v/v || Effects
|-
| 50 || 11 || 0.05% || Euphoria, talkativeness, relaxation, happiness, gladness, pleasure, joyfulness.
|-
| 100 || 22 || 0.1% || Central nervous system depression, anxiety suppression, stress suppression, sedation, nausea, possible vomiting. Impaired motor, memory, cognition and sensory function.
|-
| >140 || 30 || >0.14% || Decreased blood flow to brain, slurred speech, double or blurry vision. 
|-
| 300 || 65 || 0.3% || Stupefaction, confusion, numbness, dizziness, loss of consciousness.
|-
| 400 || 87 || 0.4% || Ethylic intoxication, drunkenness, inebriation, alcohol poisoning or possible death.
|-
| 500 || 109 || >0.55% || Unconsciousness, coma and death.
|}

Recreational concentrations of ethanol are typically in the range of 1 to 50&nbsp;mM.<ref name="pmid28479395" /><ref name="pmid18423561" /> Very low concentrations of 1 to 2&nbsp;mM ethanol produce zero or undetectable effects except in alcohol-naive individuals.<ref name="pmid28479395" /> Slightly higher levels of 5 to 10&nbsp;mM, which are associated with light social drinking, produce measurable effects including changes in visual acuity, decreased anxiety, and modest behavioral disinhibition.<ref name="pmid28479395" /> Further higher levels of 15 to 20&nbsp;mM result in a degree of sedation and motor incoordination that is contraindicated with the operation of motor vehicles.<ref name="pmid28479395" /> In jurisdictions in the U.S., maximum blood alcohol levels for legal driving are about 17 to 22&nbsp;mM.<ref name="LiuHunt2012">{{cite book| vauthors = Liu Y, Hunt WA |title=The "Drunken" Synapse: Studies of Alcohol-Related Disorders|url=https://books.google.com/books?id=OPfpBwAAQBAJ&pg=PA40|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4615-4739-6|pages=40–}}</ref><ref name="RubinStrayer2008">{{cite book | vauthors = Rubin R, Strayer DS, Rubin E, McDonald JM |title=Rubin's Pathology: Clinicopathologic Foundations of Medicine|url=https://books.google.com/books?id=kD9VZ267wDEC&pg=PA257|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-9516-6|pages=257–}}</ref> In the upper range of recreational ethanol concentrations of 20 to 50&nbsp;mM, depression of the central nervous system is more marked, with effects including complete drunkenness, profound sedation, amnesia, emesis, hypnosis, and eventually unconsciousness.<ref name="pmid28479395" /><ref name="LiuHunt2012" /> Levels of ethanol above 50&nbsp;mM are not typically experienced by normal individuals and hence are not usually physiologically relevant; however, such levels – ranging from 50 to 100&nbsp;mM – may be experienced by alcoholics with high tolerance to ethanol.<ref name="pmid28479395" /> Concentrations above this range, specifically in the range of 100 to 200&nbsp;mM, would cause death in all people except alcoholics.<ref name="pmid28479395" />

As drinking increases, people become sleepy or fall into a [[stupor]]. After a very high level of consumption{{vague|date=January 2022}}, the respiratory system becomes depressed and the person will stop breathing. Comatose patients may aspirate their vomit (resulting in vomitus in the lungs, which may cause "drowning" and later [[pneumonia]] if survived). CNS depression and impaired motor coordination along with poor judgment increase the likelihood of accidental injury occurring. It is estimated that about one-third of alcohol-related deaths are due to accidents and another 14% are from intentional injury.<ref>The World Health Organization (2007) Alcohol and Injury in Emergency Departments</ref>

In addition to respiratory failure and accidents caused by its effects on the central nervous system, alcohol causes significant metabolic derangements. [[Hypoglycaemia]] occurs due to ethanol's inhibition of [[gluconeogenesis]], especially in children, and may cause [[lactic acidosis]], [[ketoacidosis]], and [[acute kidney injury]]. Metabolic acidosis is compounded by respiratory failure. Patients may also present with hypothermia.

==Pharmacokinetics==

The [[pharmacokinetic]]s of ethanol are well characterized by the [[ADME]] acronym (absorption, distribution, metabolism, excretion). Besides the dose ingested, factors such as the person's [[total body water]], speed of drinking, the drink's nutritional content, and the contents of the stomach all influence the profile of [[blood alcohol content]] (BAC) over time. Breath alcohol content (BrAC) and BAC have similar profile shapes, so most forensic pharmacokinetic calculations can be done with either. Relatively few studies directly compare BrAC and BAC within subjects and characterize the difference in pharmacokinetic parameters. Comparing arterial and venous BAC, arterial BAC is higher during the absorption phase and lower in the postabsorptive declining phase.<ref name="Jones2019"/>

===Endogenous production===
{{Further|Auto-brewery syndrome}}
[[File:Ethanol fermentation.jpg|thumb|Ethanol fermentation cycle]]

All organisms produce alcohol in small amounts by several pathways, primarily through [[fatty acid synthesis]],<ref>{{cite web|url=http://www.genome.jp/dbget-bin/show_pathway?hsa00071+125|title=Fatty Acid Synthesis}}</ref> [[glycerolipid]] metabolism,<ref>{{cite web|url=http://www.genome.jp/dbget-bin/show_pathway?hsa00561+125|title=Glycerolipid Metabolism}}</ref> and [[bile acid biosynthesis]] pathways.<ref>{{cite web|url=http://www.genome.jp/dbget-bin/show_pathway?hsa00120+125|title=Bile Acid Biosynthesis}}</ref> 
[[Fermentation]] is a biochemical process during which yeast and certain bacteria convert sugars to ethanol, carbon dioxide, as well as other metabolic byproducts.<ref name=":0">{{cite book | vauthors = Fath BD, Jørgensen SE |title=Encyclopedia of dcology|date = 23 August 2018|isbn=978-0-444-64130-4|edition=Second|publisher=Elsevier|location=Amsterdam, Netherlands|oclc=1054599976}}</ref><ref>{{cite book | vauthors = Mendez ML |title=Electronic noses and tongues in food science|date=2016|publisher=Academic Press |isbn=978-0-12-800402-9|location=London|oclc=940961460}}</ref> The average human digestive system produces approximately 3{{nbsp}}g of ethanol per day through fermentation of its contents.<ref>{{cite thesis | vauthors = Tillonen J | title = Ethanol, acetaldehyde and gastrointestinal flora  | degree = Ph.D. | publisher = Helsingin Yliopisto | url = https://helda.helsinki.fi/bitstream/handle/10138/22713/ethanola.pdf?sequence=}}</ref> Such production generally does not have any forensic significance because the ethanol is broken down before significant intoxication ensues. These trace amounts of alcohol range from 0.1 to {{val|0.3|u=ug/mL}} in the blood of healthy humans, with some measurements as high as {{cvt|1.6|ug/mL|g/L|sigfig=1}}.<ref>{{cite journal | title = Endogenous ethanol--its metabolic, behavioral and biomedical significance | journal = Alcohol | volume = 3 | issue = 4 | pages = 239–247 | date = July 1986 | pmid = 3530279 | doi = 10.1016/0741-8329(86)90032-7 | vauthors = Ostrovsky Y }}</ref>

[[Auto-brewery syndrome]] is a condition characterized by significant fermentation of ingested carbohydrates within the body. In rare cases, intoxicating quantities of ethanol may be produced, especially after eating meals. Claims of endogenous fermentation have been attempted as a defense against drunk driving charges, some of which have been successful, but the condition is under-researched.<ref name=":2">{{cite journal | vauthors = Logan BK, Jones AW | title = Endogenous ethanol 'auto-brewery syndrome' as a drunk-driving defence challenge | journal = Medicine, Science, and the Law | volume = 40 | issue = 3 | pages = 206–215 | date = July 2000 | pmid = 10976182 | doi = 10.1177/002580240004000304 | s2cid = 6926029 }}</ref>

===Absorption===
[[File:Fröccs.jpg|thumb|People drinking [[spritzer]]s at a festival in Hungary. Carbonated alcoholic drinks seem to be absorbed faster.]]
Ethanol is most commonly ingested by mouth,<ref name="AcademicPress2013">{{cite book|title=Principles of Addiction: Comprehensive Addictive Behaviors and Disorders|url=https://books.google.com/books?id=5gRNl3oIwWEC&pg=PA162|date=17 May 2013|publisher=Academic Press|isbn=978-0-12-398361-9|pages=162–}}</ref> but other [[Route of administration|routes of administration]] are possible, such as [[Alcohol inhalation|inhalation]], [[Alcohol enema|enema]], or by [[intravenous injection]].<ref name="pmid3279433">{{cite journal | vauthors = Pohorecky LA, Brick J | title = Pharmacology of ethanol | journal = Pharmacology & Therapeutics | volume = 36 | issue = 2–3 | pages = 335–427 | year = 1988 | pmid = 3279433 | doi = 10.1016/0163-7258(88)90109-x }}</ref><ref name="BegleiterKissin1996" /> With [[oral administration]], the ethanol is absorbed into the portal venous blood through the mucosa of the gastrointestinal tract, such as in the oral cavity, stomach, duodenum, and jejunum.<ref name="Jones2019"/> The oral [[bioavailability]] of ethanol is quite high, with estimates ranging from 80% at a minimum<ref name="AcademicPress2013" /><ref name="pmid3319346" /> to 94%-96%.<ref name="Busker2023"/> The ethanol molecule is small and uncharged, and easily crosses biological membranes by passive diffusion.<ref>{{cite journal | vauthors = Berggren SM, Goldberg L |title=The Absorption of Ethyl Alcohol from the Gastro-Intestinal Tract as a Diffusion Process |journal=Acta Physiologica Scandinavica |date=March 1940 |volume=1 |issue=3 |pages=246–270 |doi=10.1111/j.1748-1716.1940.tb00272.x}}</ref> The absorption rate of ethanol is typically modeled as a first-order kinetic process depending on the concentration gradient and specific membrane. The rate of absorption is fastest in the duodenum and jejunum, owing to the larger absorption surface area provided by the villi and microvilli of the small intestines. [[Gastric emptying]] is therefore an important consideration when estimating the overall rate of absorption in most scenarios;<ref name="Jones2019"/> the presence of a meal in the stomach delays gastric emptying,<ref name="pmid3279433" /><ref name="BegleiterKissin1996" /> and absorption of ethanol into the blood is consequently slower.<ref name=ARFs/> Due to irregular gastric emptying patterns, the rate of absorption of ethanol is unpredictable, varying significantly even between drinking occasions.<ref name="Jones2019"/> In experiments, aqueous ethanol solutions have been given intravenously or rectally to avoid this variation.<ref name="Jones2019"/> The delay in ethanol absorption caused by food is similar regardless of whether food is consumed just before, at the same time, or just after ingestion of ethanol.<ref name="pmid3279433" /> The type of food, whether [[fat]], [[carbohydrate]]s, or [[protein]], also is of little importance.<ref name="BegleiterKissin1996" /> Not only does food slow the absorption of ethanol, but it also reduces the bioavailability of ethanol, resulting in lower circulating concentrations.<ref name="pmid3279433" />

Regarding inhalation, early experiments with animals showed that it was possible to produce significant BAC levels comparable to those obtained by injection, by forcing the animal to breathe alcohol vapor.<ref>{{cite journal | vauthors = Gréhant N |title=Absorption par les poumons de vapeur d'alcool mélangée avec l'air|trans-title=Absorption by the lungs of alcohol vapor mixed with air|language=fr|journal=Bulletin du Muséum d'histoire naturelle |date=1897 |volume=3 |issue=1 |pages=28–29 |url=https://www.biodiversitylibrary.org/part/327828}}</ref> In humans, concentrations of ethanol in air above 10&nbsp;mg/L caused initial coughing and smarting of the eyes and nose, which went away after adaptation. 20&nbsp;mg/L was just barely tolerable. Concentrations above 30&nbsp;mg/L caused continuous coughing and tears, and concentrations above 40&nbsp;mg/L were described as intolerable, suffocating, and impossible to bear for even short periods. Breathing air with concentration of 15&nbsp;mg/L ethanol for 3 hours resulted in BACs from 0.2 to 4.5 g/L, depending on breathing rate.<ref>{{cite journal | vauthors = Lester D, Greenberg LA | title = The inhalation of ethyl alcohol by man. I. Industrial hygiene and medicolegal aspects. II. Individuals treated with tetraethylthiuram disulfide | journal = Quarterly Journal of Studies on Alcohol | volume = 12 | issue = 2 | pages = 168–178 | date = June 1951 | doi = 10.15288/qjsa.1951.12.167 | pmid = 14844643 | url = http://www.whilesciencesleeps.com/pdf/409.pdf }}</ref> It is not a particularly efficient or enjoyable method of becoming intoxicated.<ref name="pmid3279433"/>

Ethanol is not absorbed significantly through intact skin. The steady state flux is {{val|0.08|u=μmol/cm<sup>2</sup>/hr}}.<ref>{{cite journal | vauthors = Scheuplein RJ, Blank IH | title = Mechanism of percutaneous absorption. IV. Penetration of nonelectrolytes (alcohols) from aqueous solutions and from pure liquids | journal = The Journal of Investigative Dermatology | volume = 60 | issue = 5 | pages = 286–296 | date = May 1973 | pmid = 4758734 | doi = 10.1111/1523-1747.ep12723090 }}</ref> Applying a 70% ethanol solution to a skin area of {{val|1000|u=cm2}} for 1 hr would result in approximately {{val|0.1|u=g}} of ethanol being absorbed.<ref>{{cite book| vauthors = Schaefer H, Redelmeier TE |title=Skin Barrier: Principles of Percutaneous Absorption |date=26 September 1996 |doi=10.1159/000425546|page=247}}</ref> The substantially increased levels of ethanol in the blood reported for some experiments are likely due to inadvertent inhalation.<ref name="pmid3279433" /> A study that did not prevent respiratory uptake found that applying 200 mL of hand disinfectant containing 95% w/w ethanol (150 g ethanol total) over the course of 80 minutes in a 3-minutes-on 5-minutes-off pattern resulted in the median BAC among volunteers peaking 30 minutes after the last application at 17.5&nbsp;mg/L (0.00175%). This BAC roughly corresponds to drinking one gram of pure ethanol.<ref>{{cite journal | vauthors = Kramer A, Below H, Bieber N, Kampf G, Toma CD, Huebner NO, Assadian O | title = Quantity of ethanol absorption after excessive hand disinfection using three commercially available hand rubs is minimal and below toxic levels for humans | journal = BMC Infectious Diseases | volume = 7 | issue = 1 | pages = 117 | date = October 2007 | pmid = 17927841 | pmc = 2089071 | doi = 10.1186/1471-2334-7-117 | doi-access = free }}</ref> Ethanol is rapidly absorbed through cut or damaged skin, with reports of ethanol intoxication and fatal poisoning.<ref>{{cite journal | vauthors = Lachenmeier DW | title = Safety evaluation of topical applications of ethanol on the skin and inside the oral cavity | journal = Journal of Occupational Medicine and Toxicology | volume = 3 | pages = 26 | date = November 2008 | pmid = 19014531 | pmc = 2596158 | doi = 10.1186/1745-6673-3-26 | doi-access = free }}</ref>

The timing of peak blood concentration varies depends on the type of alcoholic drink:<ref>{{cite journal | vauthors = Mitchell MC, Teigen EL, Ramchandani VA | title = Absorption and peak blood alcohol concentration after drinking beer, wine, or spirits | journal = Alcoholism: Clinical and Experimental Research | volume = 38 | issue = 5 | pages = 1200–1204 | date = May 2014 | pmid = 24655007 | pmc = 4112772 | doi = 10.1111/acer.12355 }}</ref>
* [[Vodka tonic]]: 36 ± 10 minutes after consumption
* Wine: 54 ± 14 minutes
* Beer: 62 ± 23 minutes

Also, carbonated alcoholic drinks seem to have a shorter onset compare to flat drinks in the same volume. One theory is that carbon dioxide in the bubbles somehow speeds the flow of alcohol into the intestines.<ref>{{cite web |title=Champagne does get you drunk faster |url=https://www.newscientist.com/article/dn1717-champagne-does-get-you-drunk-faster/ |website=New Scientist}}</ref>

Absorption is reduced by a large meal. Stress speeds up absorption.<ref name=ARFs>{{cite web |url=http://www.bhs.umn.edu/alcohol-drugs/absorption-rate-factors.htm |title=Absorption Rate Factors |website=BHS.UMN.edu |archive-date=18 January 2013 |url-status=dead |archive-url=https://web.archive.org/web/20130118020512/http://www.bhs.umn.edu/alcohol-drugs/absorption-rate-factors.htm |quote=When food is ingested, the pyloric valve at the bottom of the stomach will close in order to hold food in the stomach for digestion and thus keep the alcohol from reaching the small intestine. The larger the meal and closer in time to drinking, the lower the peak of alcohol concentration; some studies indicate up to a 20% reduction in peak blood alcohol level.<br />Stress causes the stomach to empty directly into the small intestine, where alcohol is absorbed even faster.<br />Liquor mixed with soda or other bubbly drinks speeds up the passage of alcohol from the stomach to the small intestine, which increases the speed of absorption. |access-date=6 March 2018 }}</ref>

===Distribution===
After absorption, the alcohol goes through the [[portal vein]] to the liver, then through the [[hepatic veins]] to the heart, then the [[pulmonary arteries]] to the lungs, then the [[pulmonary vein]]s to the heart again, and then enters [[systemic circulation]].<ref name="Jones2019"/><ref name="Wiley">{{cite book|title=Handbook of alcoholic beverages : technical, analytical and nutritional aspects|year=2011|publisher=Wiley|location=Chichester|isbn=978-0-470-97665-4|url=https://books.google.com/books?id=gNc34oNpg0AC&pg=PT219|editor=Alan J.Buglass|access-date=6 July 2013}}</ref> Once in systematic circulation, ethanol [[distribution (pharmacology)|distributes]] throughout the body, [[passive diffusion|diffusing passively]] and crossing all [[biological membrane]]s including the [[blood-brain barrier]].<ref name="AcademicPress2013" /><ref name="BegleiterKissin1996">{{cite book | vauthors = Henri B, Kissin B |title=The Pharmacology of Alcohol and Alcohol Dependence |url=https://archive.org/details/pharmacologyofal00begl| url-access = registration |year=1996|publisher=Oxford University Press|isbn=978-0-19-510094-5|pages=[https://archive.org/details/pharmacologyofal00begl/page/18 18]–}}</ref> At equilibrium, ethanol is present in all body fluids and tissues in proportion to their water content. Ethanol does not [[plasma protein binding|bind to plasma proteins]] or other biomolecules.<ref name="Jones2019"/><ref name="AcademicPress2013" /><ref name="pmid3319346">{{cite journal | vauthors = Holford NH | title = Clinical pharmacokinetics of ethanol | journal = Clinical Pharmacokinetics | volume = 13 | issue = 5 | pages = 273–292 | date = November 1987 | pmid = 3319346 | doi = 10.2165/00003088-198713050-00001 | s2cid = 19723995 }}</ref> The rate of distribution depends on blood supply,<ref name="pmid3279433" /> specifically the cross-sectional area of the local capillary bed and the blood flow per gram of tissue.<ref name="Jones2019"/> As such, ethanol rapidly affects the brain, liver, and [[kidney]]s, which have high blood flow.<ref name="AcademicPress2013" /> Other tissues with lower circulation, such as skeletal muscles and [[bone tissue|bone]], require more time for ethanol to distribute into.<ref name="pmid3279433" /><ref name="Jones2019"/> In rats, it takes around 10–15 minutes for tissue and venous blood to reach equilibrium.<ref>{{cite journal | vauthors = Sunahara GI, Kalant H, Schofield M, Grupp L | title = Regional distribution of ethanol in the rat brain | journal = Canadian Journal of Physiology and Pharmacology | volume = 56 | issue = 6 | pages = 988–992 | date = December 1978 | pmid = 743637 | doi = 10.1139/y78-157 }}</ref> [[Cmax (pharmacology)|Peak circulating levels]] of ethanol are usually reached within a range of 30 to 90&nbsp;minutes of ingestion, with an average of 45 to 60&nbsp;minutes.<ref name="pmid3279433" /><ref name="AcademicPress2013" /> People who have fasted overnight have been found to reach peak ethanol concentrations more rapidly, at within 30&nbsp;minutes of ingestion.<ref name="pmid3279433" />

The [[volume of distribution]] {{mvar|V<sub>d</sub>}} contributes about 15% of the uncertainty to Widmark's equation<ref name="MaskellMass">{{cite journal | vauthors = Maskell PD, Cooper GA | title = The Contribution of Body Mass and Volume of Distribution to the Estimated Uncertainty Associated with the Widmark Equation | journal = Journal of Forensic Sciences | volume = 65 | issue = 5 | pages = 1676–1684 | date = September 2020 | pmid = 32421216 | doi = 10.1111/1556-4029.14447 | s2cid = 218677989 }}</ref> and has been the subject of much research. Widmark originally used units of mass (g/kg) for EBAC, thus he calculated the apparent {{em|mass}} of distribution {{mvar|M<sub>d</sub>}} or mass of blood in kilograms. He fitted an equation <math>M_d=\rho_m W</math> of the body weight {{mvar|W}} in kg, finding an average rho-factor of 0.68 for men and 0.55 for women. This {{mvar|ρ<sub>m</sub>}} has units of dose per body weight (g/kg) divided by concentration (g/kg) and is therefore dimensionless. However, modern calculations use weight/volume concentrations (g/L) for EBAC, so Widmark's rho-factors must be adjusted for the density of blood, 1.055 g/mL. This <math>\rho_v = V_d / W</math> has units of dose per body weight (g/kg) divided by concentration (g/L blood) - calculation gives values of 0.64 L/kg for men and 0.52 L/kg for women, lower than the original.<ref name="Jones2011"/> Newer studies have updated these values to population-average {{mvar|ρ<sub>v</sub>}} of 0.71 L/kg for men and 0.58 L/kg for women. But individual {{mvar|V<sub>d</sub>}} values may vary significantly - the 95% range for {{mvar|ρ<sub>v</sub>}} is 0.58-0.83 L/kg for males and 0.43-0.73 L/kg for females.<ref name="MaskellVd">{{cite journal | vauthors = Maskell PD, Heymsfield SB, Shapses S, Limoges JF | title = Population ranges for the volume of distribution (V<sub>d</sub> ) of alcohol for use in forensic alcohol calculations | journal = Journal of Forensic Sciences | volume = 68 | issue = 5 | pages = 1843–1845 | date = September 2023 | pmid = 37345356 | doi = 10.1111/1556-4029.15317 | doi-access = free }}</ref> A more accurate method for calculating {{mvar|V<sub>d</sub>}} is to use [[total body water]] (TBW) - experiments have confirmed that alcohol distributes almost exactly in proportion to TBW within the Widmark model.<ref>{{cite journal | vauthors = Endres HG, Grüner O | title = Comparison of D2O and ethanol dilutions in total body water measurements in humans | journal = The Clinical Investigator | volume = 72 | issue = 11 | pages = 830–837 | date = November 1994 | pmid = 7894207 | doi = 10.1007/BF00190736 }}</ref> TBW may be calculated using [[body composition]] analysis or estimated using anthropometric formulas based on age, height, and weight. {{mvar|V<sub>d</sub>}} is then given by <math>TBW_\text{kg} / F_{\text{water}}</math>, where <math>F_{\text{water}}</math> is the water content of blood, approximately 0.825 w/v for men and 0.838 w/v for women.<ref>{{cite journal | vauthors = Maskell PD, Jones AW, Heymsfield SB, Shapses S, Johnston A | title = Total body water is the preferred method to use in forensic blood-alcohol calculations rather than ethanol's volume of distribution | journal = Forensic Science International | volume = 316 | pages = 110532 | date = November 2020 | pmid = 33099270 | doi = 10.1016/j.forsciint.2020.110532 | s2cid = 224966411 }}</ref>

These calculations assume Widmark's zero-order model for the effects of metabolization, and assume that TBW is almost exactly the volume of distribution of ethanol. Using a more complex model that accounts for non-linear metabolism, Norberg found that V<sub>d</sub> was only 84-87% of TBW.<ref name="Norberg2001">{{cite journal | vauthors = Norberg A, Sandhagen B, Bratteby LE, Gabrielsson J, Jones AW, Fan H, Hahn RG | title = Do ethanol and deuterium oxide distribute into the same water space in healthy volunteers? | journal = Alcoholism: Clinical and Experimental Research | volume = 25 | issue = 10 | pages = 1423–1430 | date = October 2001 | pmid = 11696661 | doi = 10.1111/j.1530-0277.2001.tb02143.x }}</ref> This finding was not reproduced in a newer study which found volumes of distribution similar to those in the literature.<ref name="Busker2023"/>

===Metabolism===
[[Image:AlcoholDehydrogenase-1A4U.png|thumb|right|Alcohol dehydrogenase]]

Several [[metabolic pathway]]s exist:

* One pathway involves [[alcohol dehydrogenase]], particularly the IB (class I), beta polypeptide (ADH1B, EC 1.1.1.1) enzyme. The reaction uses NAD<sup>+</sup> to convert the ethanol into [[acetaldehyde]] (a toxic carcinogen). The enzyme [[acetaldehyde dehydrogenase]] ([[aldehyde dehydrogenase]] 2 family [[ALDH2]], EC 1.2.1.3) then converts the acetaldehyde into the non-toxic acetate ion (commonly found in [[acetic acid]] or vinegar).<ref name="pmid3279433" /><ref name="Levine2003"/> This ion is in turn is broken down into [[carbon dioxide]] and [[water]].<ref name="pmid3279433" /> Specifically, acetate combines with [[coenzyme A]] (acetyl-CoA synthetase) to form [[acetyl-CoA]], via the enzymes acyl-CoA synthetase short-chain family member 2 [[ACSS2]] (EC 6.2.1.1) and acetyl-CoA synthase 2 ([[ACSS1]]). acetyl-CoA then participates in the [[citric acid cycle]].<ref name="AcademicPress2013" /><ref name="Smith2005">Smith, C., Marks, Allan D., Lieberman, Michael, 2005, ''Marks' Basic Medical Biochemistry: A Clinical Approach'', 2nd ed., Lippincott Williams & Wilkins, USA, p. 458</ref> At even low physiological concentrations, ethanol completely saturates alcohol dehydrogenase.<ref name="pmid3279433" /> This is because ethanol has high affinity for the enzyme and very high concentrations of ethanol occur when it is used as a recreational substance.<ref name="pmid3279433" />
* The [[microsomal ethanol-oxidizing system]] (MEOS), specifically mediated by the [[cytochrome P450]] enzyme [[CYP2E1]], is another major route of ethanol metabolism.<ref name="pmid3279433" /><ref name="Levine2003" /> CYP2E1 is predominantly active at higher concentrations.<ref name="AcademicPress2013" /> Repeated or chronic use of ethanol increases the activity of CYP2E1.<ref name="pmid3279433" /><ref name="Levine2003" /> 
* The activity of ADH and CYP2E1 alone does not appear sufficient to fully explain the increase in ethanol metabolism rate. There may be one or more additional pathways that metabolize as much as 25 to 35% of ethanol at typical concentrations.<ref name="pmid3319346" />
* A small amount of ethanol undergoes [[conjugation (biochemistry)|conjugation]] to form [[ethyl glucuronide]] and [[ethyl sulfate]].<ref name="AcademicPress2013" />

==== Detailed ADH pathway ====

The reaction from ethanol to [[carbon dioxide]] and [[water]] proceeds in at least 11 steps in humans. C<sub>2</sub>H<sub>6</sub>O (ethanol) is converted to C<sub>2</sub>H<sub>4</sub>O ([[acetaldehyde]]), then to C<sub>2</sub>H<sub>4</sub>O<sub>2</sub> ([[acetic acid]]), then to [[acetyl-CoA]]. Once acetyl-CoA is formed, it is free to enter directly into the [[citric acid cycle]] (TCA) and is converted to 2 CO<sub>2</sub> molecules in 8 reactions. The equations:

:C<sub>2</sub>H<sub>6</sub>O(ethanol) + [[NADH|NAD]]<sup>+</sup> → C<sub>2</sub>H<sub>4</sub>O(acetaldehyde) + [[NADH]] + H<sup>+</sup>
:C<sub>2</sub>H<sub>4</sub>O(acetaldehyde) + [[NADH|NAD]]<sup>+</sup> + H<sub>2</sub>O → C<sub>2</sub>H<sub>4</sub>O<sub>2</sub>(acetic acid) + [[NADH]] + H<sup>+</sup>
:C<sub>2</sub>H<sub>4</sub>O<sub>2</sub>(acetic acid) + CoA + ATP → Acetyl-CoA + AMP + PP<sub>i</sub>

The [[Gibbs free energy]] is simply calculated from the free energy of formation of the product and reactants.<ref>CRC Handbook of Chemistry and Physics, 81st Edition, 2000</ref><ref>{{Cite web|url=https://biocyc.org/META/NEW-IMAGE?type=REACTION&object=ACETATE--COA-LIGASE-RXN|title=MetaCyc EC 6.2.1.1}}</ref> If catabolism of alcohol goes all the way to completion, then there is a very exothermic event yielding some {{val|1325|u=kJ/mol}} of energy. If the reaction stops part way through the metabolic pathways, which happens because acetic acid is excreted in the urine after drinking, then not nearly as much energy can be derived from alcohol, indeed, only {{val|215.1|u=kJ/mol}}. At the very least, the theoretical limits on energy yield are determined to be {{val|-215.1|u=kJ/mol}} to {{val|-1325.6|u=kJ/mol}}. The first with NADH is endothermic, requiring {{val|47.2|u=kJ/mol}} of alcohol, or about 3 molecules of [[adenosine triphosphate]] (ATP) per molecule of ethanol.{{Original research inline|date=June 2024}}

==== Variation ====
{{Further|Alcohol flush reaction}}

Variations in genes influence alcohol metabolism and drinking behavior.<ref>{{cite journal | vauthors = Agarwal DP | title = Genetic polymorphisms of alcohol metabolizing enzymes | journal = Pathologie-Biologie | volume = 49 | issue = 9 | pages = 703–709 | date = November 2001 | pmid = 11762132 | doi = 10.1016/s0369-8114(01)00242-5 }}</ref> Certain amino acid sequences in the enzymes used to oxidize ethanol are conserved (unchanged) going back to the last common ancestor over 3.5{{nbsp}}bya.<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?ascbin=8&maxaln=10&seltype=3&uid=pfam00107&querygi=34577061&aln=12,1,15,46,49,61,57,106,139,51,157,191,53,210,245,16,227,261,10,237,273,39,277,312,15,292,329,11,304,340,11,316,351,16,333,367,8|title=NCBI CDD Conserved Protein Domain ADH_zinc_N | vauthors = ((NIH/NLM/NCBI/IEB/CDD)) |website=www.ncbi.nlm.nih.gov|language=en|access-date=2018-04-28}}</ref> Evidence suggests that [[human]]s evolved the ability to metabolize dietary ethanol between 7 and 21 million years ago, in a common ancestor shared with [[chimpanzee]]s and [[gorilla]]s but not [[orangutan]]s.<ref>{{cite journal | vauthors = Carrigan MA, Uryasev O, Frye CB, Eckman BL, Myers CR, Hurley TD, Benner SA | title = Hominids adapted to metabolize ethanol long before human-directed fermentation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 2 | pages = 458–463 | date = January 2015 | pmid = 25453080 | pmc = 4299227 | doi = 10.1073/pnas.1404167111 | doi-access = free | bibcode = 2015PNAS..112..458C }}</ref> Gene variation in these enzymes can lead to variation in catalytic efficiency between individuals. Some individuals have less effective metabolizing enzymes of ethanol, and can experience more marked symptoms from ethanol consumption than others.<ref name="pmid1302043">{{cite journal | vauthors = Agarwal DP, Goedde HW | title = Pharmacogenetics of alcohol metabolism and alcoholism | journal = Pharmacogenetics | volume = 2 | issue = 2 | pages = 48–62 | date = April 1992 | pmid = 1302043 | doi = 10.1097/00008571-199204000-00002 }}</ref> However, those having acquired [[alcohol tolerance]] have a greater quantity of these enzymes, and metabolize ethanol more rapidly. Specifically, ethanol has been observed to be cleared more quickly by regular drinkers than non-drinkers.<ref name="pmid1302043" />

Falsely high BAC readings may be seen in patients with kidney or liver disease or failure. Such persons also have impaired acetaldehyde dehydrogenase, which causes acetaldehyde levels to peak higher, producing more severe [[hangover]]s and other effects such as flushing and tachycardia.  Conversely, members of certain ethnicities that traditionally did not use alcoholic beverages have lower levels of alcohol dehydrogenases and thus "sober up" very slowly but reach lower aldehyde concentrations and have milder hangovers.  The rate of detoxification of alcohol can also be slowed by certain drugs which interfere with the action of alcohol dehydrogenases, notably [[aspirin]], [[furfural]] (which may be found in [[fusel alcohol]]), fumes of [[trichloroethylene|certain solvents]], many [[Heavy metal (chemistry)|heavy metals]], and some [[pyrazole]] compounds. Also suspected of having this effect are [[cimetidine]], [[ranitidine]], and [[paracetamol|acetaminophen]] (paracetamol).{{Citation needed|date=June 2021}}

An "abnormal" liver with conditions such as [[hepatitis]], [[cirrhosis]], [[gall bladder]] disease, and [[Liver cancer|cancer]] is likely to result in a slower rate of metabolism. People under 25 and women may process alcohol more slowly.<ref>{{cite book |doi=10.1007/0-306-47138-8_9 |chapter=Gender Differences in Alcohol Metabolism |year=2002 | vauthors = Thomasson HR |title=Recent Developments in Alcoholism |isbn=978-0-306-44921-5 |volume=12 |pages=[https://archive.org/details/recentdevelopment12gala/page/163 163–72] |publisher=Plenum Press |pmid=7624539 |chapter-url-access=registration |chapter-url=https://archive.org/details/recentdevelopment12gala/page/163 }}</ref>

Food such as [[fructose]] can increase the rate of alcohol metabolism. The effect can vary significantly from person to person, but a 100&nbsp;g dose of fructose has been shown to increase alcohol metabolism by an average of 80%. In people with proteinuria and hematuria, fructose can cause falsely high BAC readings, due to kidney-liver metabolism.<ref name="#">Fructose & ethanol{{synthesis inline|date=March 2019}}
* {{cite journal | vauthors = Carpenter TM, Lee RC |title=The effect of fructose on the metabolism of ethyl alcohol in man |journal=Journal of Pharmacology and Experimental Therapeutics |date=1937 |volume=60 |issue=3 |url=http://jpet.aspetjournals.org/content/60/3/286.short |access-date=23 June 2016}}
* {{cite journal | vauthors = Tygstrup N, Winkler K, Lundquist F | title = The Mechanism of the Fructose Effect on the Ethanol Metabolism of the Human Liver | journal = The Journal of Clinical Investigation | volume = 44 | issue = 5 | pages = 817–830 | date = May 1965 | pmid = 14276139 | pmc = 292558 | doi = 10.1172/JCI105194 }}
* {{cite journal | vauthors = Patel AR, Paton AM, Rowan T, Lawson DH, Linton AL | title = Clinical studies on the effect of laevulose on the rate of metabolism of ethyl alcohol | journal = Scottish Medical Journal | volume = 14 | issue = 8 | pages = 268–271 | date = August 1969 | pmid = 5812044 | doi = 10.1177/003693306901400803 | s2cid = 3067691 }}
* {{cite journal | vauthors = Lowenstein LM, Simone R, Boulter P, Nathan P | title = Effect of fructose on alcohol concentrations in the blood in man | journal = JAMA | volume = 213 | issue = 11 | pages = 1899–1901 | date = September 1970 | pmid = 4318655 | doi = 10.1001/jama.1970.03170370083021 }}
* {{cite journal | vauthors = Pawan GL | title = Metabolism of alcohol (ethanol) in man | journal = The Proceedings of the Nutrition Society | volume = 31 | issue = 2 | pages = 83–89 | date = September 1972 | pmid = 4563296 | doi = 10.1079/pns19720020 | doi-access = free }}
* {{cite journal | vauthors = Thieden HI, Grunnet N, Damgaard SE, Sestoft L | title = Effect of fructose and glyceraldehyde on ethanol metabolism in human liver and in rat liver | journal = European Journal of Biochemistry | volume = 30 | issue = 2 | pages = 250–261 | date = October 1972 | pmid = 4145889 | doi = 10.1111/j.1432-1033.1972.tb02093.x | doi-access = free }}
* {{cite journal | vauthors = Soterakis J, Iber FL | title = Increased rate of alcohol removal from blood with oral fructose and sucrose | journal = The American Journal of Clinical Nutrition | volume = 28 | issue = 3 | pages = 254–257 | date = March 1975 | pmid = 1119423 | doi = 10.1093/ajcn/28.3.254 }}
* {{cite journal | vauthors = Rawat AK | title = Effects of fructose and other substances on ethanol and acetaldehyde metabolism in man | journal = Research Communications in Chemical Pathology and Pharmacology | volume = 16 | issue = 2 | pages = 281–290 | date = February 1977 | pmid = 847286 }}
* {{cite journal | vauthors = Iber FL | title = The effect of fructose on alcohol metabolism | journal = Archives of Internal Medicine | volume = 137 | issue = 9 | pages = 1121 | date = September 1977 | pmid = 901079 | doi = 10.1001/archinte.137.9.1121 }}
* {{cite journal | vauthors = Bode JC, Bode C, Thiele D | title = Alcohol metabolism in man: effect of intravenous fructose infusion on blood ethanol elimination rate following stimulation by phenobarbital treatment or chronic alcohol consumption | journal = Klinische Wochenschrift | volume = 57 | issue = 3 | pages = 125–130 | date = February 1979 | pmid = 439778 | doi = 10.1007/bf01476052 | s2cid = 8813046 }}
* {{cite journal | vauthors = Sprandel U, Tröger HD, Liebhardt EW, Zöllner N | title = Acceleration of ethanol elimination with fructose in man | journal = Nutrition and Metabolism | volume = 24 | issue = 5 | pages = 324–330 | date = 1980 | pmid = 7443107 | doi = 10.1159/000176278 }}
* {{cite journal | vauthors = Meyer BH, Müller FO, Hundt HK | title = The effect of fructose on blood alcohol levels in man | journal = South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde | volume = 62 | issue = 20 | pages = 719–721 | date = November 1982 | pmid = 6753183 }}
* {{cite journal | vauthors = Crownover BP, La Dine J, Bradford B, Glassman E, Forman D, Schneider H, Thurman RG | title = Activation of ethanol metabolism in humans by fructose: importance of experimental design | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 236 | issue = 3 | pages = 574–579 | date = March 1986 | doi = 10.1016/S0022-3565(25)38987-1 | pmid = 3950864 }}
* {{cite journal | vauthors = Mascord D, Smith J, Starmer GA, Whitfield JB | title = The effect of fructose on alcohol metabolism and on the [lactate]/[pyruvate] ratio in man | journal = Alcohol and Alcoholism | volume = 26 | issue = 1 | pages = 53–59 | date = 1991 | pmid = 1854373 }}
* {{cite journal | vauthors = Onyesom I, Anosike EO | title = Oral fructose-induced changes in blood ethanol oxidokinetic data among healthy Nigerians | journal = The Southeast Asian Journal of Tropical Medicine and Public Health | volume = 35 | issue = 2 | pages = 476–480 | date = June 2004 | pmid = 15691159 }}
* {{cite journal | vauthors = Uzuegbu UE, Onyesom I | title = Fructose-induced increase in ethanol metabolism and the risk of Syndrome X in man | journal = Comptes Rendus Biologies | volume = 332 | issue = 6 | pages = 534–538 | date = June 2009 | pmid = 19520316 | doi = 10.1016/j.crvi.2009.01.007 | url = https://comptes-rendus.academie-sciences.fr/biologies/articles/10.1016/j.crvi.2009.01.007/ }}
</ref>

==== First-pass metabolism ====

During a typical drinking session, approximately 90% of the metabolism of ethanol occurs in the liver.<ref name="pmid3279433" /><ref name="Levine2003">{{cite book | vauthors = Levine B |title=Principles of Forensic Toxicology|url=https://books.google.com/books?id=k7BInEQ-iqgC&pg=PA161|year=2003|publisher=Amer. Assoc. for Clinical Chemistry|isbn=978-1-890883-87-4|pages=161–}}</ref> Alcohol dehydrogenase and aldehyde dehydrogenase are present at their highest concentrations (in liver mitochondria).<ref name="Smith2005"/><ref>{{cite journal | vauthors = Tanaka F, Shiratori Y, Yokosuka O, Imazeki F, Tsukada Y, Omata M | title = Polymorphism of alcohol-metabolizing genes affects drinking behavior and alcoholic liver disease in Japanese men | journal = Alcoholism: Clinical and Experimental Research | volume = 21 | issue = 4 | pages = 596–601 | date = June 1997 | pmid = 9194910 | doi = 10.1111/j.1530-0277.1997.tb03808.x }}</ref> But these enzymes are widely expressed throughout the body, such as in the [[stomach]] and [[small intestine]].<ref name="AcademicPress2013" /> Some alcohol undergoes a first pass of metabolism in these areas, before it ever enters the bloodstream.<ref name="Wiley"/>

==== In alcoholics ====
Under alcoholic conditions, the citric acid cycle is stalled by the oversupply of NADH derived from ethanol oxidation.  The resulting backup of acetate shifts the reaction equilibrium for [[acetaldehyde dehydrogenase]] back towards acetaldehyde.  Acetaldehyde subsequently accumulates and begins to form covalent bonds with cellular macromolecules, forming toxic adducts that, eventually, lead to death of the cell.
This same excess of NADH from ethanol oxidation causes the liver to move away from fatty acid oxidation, which produces NADH, towards fatty acid synthesis, which consumes NADH.  This consequent [[lipogenesis]] is believed to account largely for the pathogenesis of [[alcoholic fatty liver disease]].

==== In human fetuses ====

In human embryos and fetuses, ethanol is not metabolized via ADH as ADH enzymes are not yet expressed to any significant quantity in human fetal liver (the induction of ADH only starts after birth, and requires years to reach adult levels).<ref name="auto">Ernst van Faassen and Onni Niemelä, Biochemistry of prenatal alcohol exposure, NOVA Science Publishers, New York 2011.{{page needed|date=January 2020}}</ref> Accordingly, the fetal liver cannot metabolize ethanol or other low molecular weight xenobiotics. In fetuses, ethanol is instead metabolized at much slower rates by different enzymes from the cytochrome P-450 superfamily (CYP), in particular by CYP2E1. The low fetal rate of ethanol clearance is responsible for the important observation that the fetal compartment retains high levels of ethanol long after ethanol has been cleared from the maternal circulation by the adult ADH activity in the maternal liver.<ref>{{cite journal | vauthors = Nava-Ocampo AA, Velázquez-Armenta Y, Brien JF, Koren G | title = Elimination kinetics of ethanol in pregnant women | journal = Reproductive Toxicology | volume = 18 | issue = 4 | pages = 613–617 | date = June 2004 | pmid = 15135856 | doi = 10.1016/j.reprotox.2004.02.012 | bibcode = 2004RepTx..18..613N }}</ref> CYP2E1 expression and activity have been detected in various human fetal tissues after the onset of organogenesis (ca 50 days of gestation).<ref>{{cite journal | vauthors = Brzezinski MR, Boutelet-Bochan H, Person RE, Fantel AG, Juchau MR | title = Catalytic activity and quantitation of cytochrome P-450 2E1 in prenatal human brain | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 289 | issue = 3 | pages = 1648–1653 | date = June 1999 | doi = 10.1016/S0022-3565(24)38317-X | pmid = 10336564 | url = http://jpet.aspetjournals.org/content/289/3/1648.long }}</ref> Exposure to ethanol is known to promote further induction of this enzyme in fetal and adult tissues. CYP2E1 is a major contributor to the so-called [[Microsomal ethanol oxidizing system|Microsomal Ethanol Oxidizing System]] (MEOS)<ref>{{cite journal | vauthors = Lieber CS | title = The discovery of the microsomal ethanol oxidizing system and its physiologic and pathologic role | journal = Drug Metabolism Reviews | volume = 36 | issue = 3–4 | pages = 511–529 | date = October 2004 | pmid = 15554233 | doi = 10.1081/dmr-200033441 | s2cid = 27992318 }}</ref> and its activity in fetal tissues is thought to contribute significantly to the toxicity of maternal ethanol consumption.<ref name="auto"/><ref>Pregnancy and Alcohol Consumption, ed. J.D. Hoffmann, NOVA Science Publishers, New York 2011.{{page needed|date=January 2020}}</ref> In presence of ethanol and oxygen, CYP2E1 is known{{by whom|date=January 2020}} to release superoxide radicals and induce the oxidation of polyunsaturated fatty acids to toxic aldehyde products like 4-hydroxynonenal (HNE).{{citation needed|date=January 2020}}

The concentration of alcohol in breast milk produced during lactation is closely correlated to the individual's blood alcohol content.<ref>{{cite journal | vauthors = Haastrup MB, Pottegård A, Damkier P | title = Alcohol and breastfeeding | journal = Basic & Clinical Pharmacology & Toxicology | volume = 114 | issue = 2 | pages = 168–173 | date = February 2014 | pmid = 24118767 | doi = 10.1111/bcpt.12149 }}</ref>

===Elimination===
Alcohol is removed from the bloodstream by a combination of metabolism, excretion, and evaporation. 90-98% of ingested ethanol is metabolized into carbon dioxide and water.<ref name="pmid3279433" /> Around 5 to 10% of ethanol that is ingested is excreted unchanged in [[urine]], [[breath]], and [[sweat]].<ref name="AcademicPress2013" /> Transdermal alcohol that diffuses through the skin as insensible perspiration or is exuded as sweat (sensible perspiration) can be detected using wearable sensor technology<ref>{{cite journal | vauthors = Lansdorp B, Ramsay W, Hamidand R, Strenk E | title = Wearable Enzymatic Alcohol Biosensor | journal = Sensors | volume = 19 | issue = 10 | pages = 2380 | date = May 2019 | pmid = 31137611 | pmc = 6566815 | doi = 10.3390/s19102380 | doi-access = free | bibcode = 2019Senso..19.2380L }}</ref> such as SCRAM ankle bracelet<ref>{{Cite web |title=SCRAM CAM® Bracelet Alcohol Ankle Monitor |url=https://www.scramsystems.com/monitoring/scram-continuous-alcohol-monitoring/ |access-date=2022-03-19 |website=SCRAM Systems |language=en-US}}</ref> or the more discreet ION Wearable.<ref>{{Cite web |title=ION Wearable |url=https://www.ionwearable.com/ |access-date=2022-03-19 |website=ION Wearable |language=en}}</ref> Ethanol or its metabolites may be detectable in urine for up to 96&nbsp;hours (3–5 days) after ingestion.<ref name="AcademicPress2013" />

Unlike most physiologically active materials, in typical recreational use, ethanol is removed from the bloodstream at an approximately constant rate (linear decay or [[zero-order kinetics]]), rather than at a rate proportional to the current concentration ([[exponential decay]] with a characteristic [[elimination half-life]]).<ref name="Levine2003" /><ref name="PMID 5457514">{{cite journal | vauthors = Becker CE | title = The clinical pharmacology of alcohol | journal = California Medicine | volume = 113 | issue = 3 | pages = 37–45 | date = September 1970 | pmid = 5457514 | pmc = 1501558 }}</ref> This is because typical doses of alcohol saturate the enzymes' capacity.  In Widmark's model, the elimination rate from the blood, {{mvar|β}}, contributes 60% of the uncertainty.<ref name="MaskellMass"/> Similarly to {{mvar|ρ}}, its value depends on the units used for blood.<ref name="Jones2011"/> {{mvar|β}} varies 58% by occasion and 42% between subjects; it is thus difficult to determine {{mvar|β}} precisely, and more practical to use a mean and a range of values. Typical elimination rates range from 10 to 34&nbsp;mg/dL per hour,<ref name="Levine2003" /><ref name="pmid3279433" /> with Jones recommending the range 0.10 - 0.25 g/L/h for forensic purposes, for all subjects.<ref name="JonesElimSurvey">{{cite journal | vauthors = Jones AW | title = Evidence-based survey of the elimination rates of ethanol from blood with applications in forensic casework | journal = Forensic Science International | volume = 200 | issue = 1–3 | pages = 1–20 | date = July 2010 | pmid = 20304569 | doi = 10.1016/j.forsciint.2010.02.021 }}</ref> Earlier studies found mean elimination rates of 15&nbsp;mg/dL per hour for men and 18&nbsp;mg/dL per hour for women,<ref name="Levine2003" /><ref name="pmid3279433" /> but Jones found 0.148 g/L/h and 0.156 g/L/h respectively. Although the difference between sexes is statistically significant, it is small compared to the overall uncertainty, so Jones recommends using the value 0.15 for the mean for all subjects.<ref name="JonesElimSurvey"/> This mean rate is very roughly 8 grams of pure [[ethanol]] per hour (one British [[Unit of alcohol|unit]]).<ref>{{cite web |date=26 June 2018 |title=How long does alcohol stay in your blood? |url=https://www.nhs.uk/chq/Pages/853.aspx |publisher=NHS Choices |access-date=12 April 2024 |archive-date=31 December 2017 |archive-url=https://web.archive.org/web/20171231134001/https://www.nhs.uk/chq/pages/853.aspx |url-status=dead }}</ref> Explanations for the gender difference are quite varied and include liver size, secondary effects of the volume of distribution, and sex-specific hormones.<ref>{{cite journal | vauthors = Dettling A, Skopp G, Graw M, Haffner HT | title = The influence of sex hormones on the elimination kinetics of ethanol | journal = Forensic Science International | volume = 177 | issue = 2–3 | pages = 85–89 | date = May 2008 | pmid = 18079079 | doi = 10.1016/j.forsciint.2007.11.002 }}</ref>  A 2023 study using a more complex two-compartment model with M-M elimination kinetics, with data from 60 men and 12 women, found statistically small effects of gender on maximal elimination rate and excluded them from the final model.<ref name="Busker2023">{{cite journal | vauthors = Büsker S, Jones AW, Hahn RG, Taubert M, Klotz U, Schwab M, Fuhr U | title = Population Pharmacokinetics as a Tool to Reevaluate the Complex Disposition of Ethanol in the Fed and Fasted States | journal = Journal of Clinical Pharmacology | volume = 63 | issue = 6 | pages = 681–694 | date = June 2023 | pmid = 36688276 | doi = 10.1002/jcph.2205 | doi-access = free }}</ref>

At concentrations below 0.15-0.20 g/L, alcohol is eliminated more slowly and the elimination rate more closely follows first-order kinetics. The overall behavior of the elimination rate is described well by [[Michaelis–Menten kinetics]]. This change in behavior was not noticed by Widmark because he could not analyze low BAC levels.<ref name="Jones2011"/> The rate of elimination of ethanol is also increased at very high concentrations, such as in overdose, again more closely following [[first-order kinetics]], with an elimination half-life of about 4 or 4.5&nbsp;hours (a clearance rate of approximately 6&nbsp;L/hour/70&nbsp;kg). This is thought to be due to increased activity of CYP2E1.<ref name="pmid3319346" /><ref name="AcademicPress2013" />

Eating food in proximity to drinking increases elimination rate significantly, mainly due to increased metabolism.<ref name="Busker2023"/>

===Modeling===

In fasting volunteers, blood levels of ethanol increase proportionally with the dose of ethanol administered.<ref name="BegleiterKissin1996" /> Peak blood alcohol concentrations may be estimated by dividing the amount of ethanol ingested by the [[body weight]] of the individual and correcting for water dilution.<ref name="pmid3279433" /> For time-dependent calculations, Swedish professor Erik Widmark developed a model of alcohol pharmacokinetics in the 1920s.<ref name=Ed>{{cite web | vauthors = Kuwatch E |title=Fast Eddie's 8/10 Method of Hand Calculating Blood Alcohol Concentration: A Simple Method For Using Widmark's Formula |url=http://www.dui-law.com/810art.htm|archive-url=https://web.archive.org/web/20031202155933/http://www.dui-law.com/810art.htm |archive-date=2003-12-02 }}</ref> The model corresponds to a single-compartment model with instantaneous absorption and [[zero-order kinetics]] for elimination. The model is most accurate when used to estimate BAC a few hours after drinking a single dose of alcohol in a fasted state, and can be within 20% [[Coefficient of variation|CV]] of the true value.<ref>{{cite conference | vauthors = Zuba D, Piekoszewski W |title=Uncertainty in Theoretical Calculations of Alcohol Concentration |book-title=Proc. 17th Internat. Conf. on Alcohol, Drugs and Traffic Safety |date=2004 |url=https://www.researchgate.net/publication/255499090}}</ref><ref>{{cite journal | vauthors = Gullberg RG | title = Estimating the uncertainty associated with Widmark's equation as commonly applied in forensic toxicology | journal = Forensic Science International | volume = 172 | issue = 1 | pages = 33–39 | date = October 2007 | pmid = 17210238 | doi = 10.1016/j.forsciint.2006.11.010 }}</ref> It is less accurate for BAC levels below 0.2 g/L (alcohol is not eliminated as quickly as predicted) and consumption with food (overestimating the peak BAC and time to return to zero).<ref>{{cite journal | vauthors = Searle J | title = Alcohol calculations and their uncertainty | journal = Medicine, Science, and the Law | volume = 55 | issue = 1 | pages = 58–64 | date = January 2015 | pmid = 24644224 | pmc = 4361698 | doi = 10.1177/0025802414524385 }}</ref><ref name="Jones2011">{{cite journal | vauthors = Jones AW | title = Pharmacokinetics of Ethanol - Issues of Forensic Importance | journal = Forensic Science Review | volume = 23 | issue = 2 | pages = 91–136 | date = July 2011 | pmid = 26231237 | url = https://www.researchgate.net/publication/280602837 }}</ref>

== See also ==
* [[Subjective response to alcohol]]

== References ==
{{Reflist}}

{{Acetylcholine receptor modulators}}
{{Ancient anaesthesia}}
{{GABAA receptor positive modulators}}
{{Glycine receptor modulators}}
{{Ion channel modulators}}
{{Ionotropic glutamate receptor modulators}}
{{Nicotinic acetylcholine receptor modulators}}
{{Purine receptor modulators}}
{{Serotonin receptor modulators}}

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