Ethanol

Ethanol (ethyl alcohol) is the psychoactive constituent of alcoholic drinks and one of the most widely used recreational drugs in the world. Unlike most substances on this site it is a 'low-affinity, high-dose' drug: it does not bind any single receptor tightly but acts at millimolar concentrations: a 'legally drunk' blood level of 0.08% is roughly 17 mM: interacting weakly with many ion channels and receptors at once. This is why there is no meaningful nanomolar binding table for ethanol. Its pharmacology is best described by the systems it shifts rather than by a single high-affinity target. The net effect is CNS depression, produced mainly by tilting the brain's excitatory–inhibitory balance toward inhibition. Ethanol potentiates inhibitory GABA-A receptor signalling (with a notable role for extrasynaptic δ-subunit receptors) while inhibiting excitatory NMDA-type glutamate receptors. It also modulates glycine, nicotinic acetylcholine and serotonin 5-HT3 receptors and several potassium and calcium channels, and it drives reward by increasing dopamine release in the mesolimbic system and engaging endogenous opioid signalling: the rationale for anti-craving drugs such as naltrexone and acamprosate. With repeated heavy use the brain adapts in the opposite direction, down-regulating GABA-A and up-regulating NMDA/glutamate signalling, producing tolerance and physical dependence. When drinking stops this leaves the CNS in a hyperexcitable state: withdrawal ranges from tremor, anxiety and insomnia to, in severe cases, seizures and delirium tremens, which can be fatal and is a medical emergency. Repeated withdrawals sensitise the process ('kindling'). Alcohol is one of the few drugs whose withdrawal can itself kill, so heavily dependent drinkers should not stop abruptly without medical support. Ethanol is well absorbed from the gut and cleared mostly by hepatic oxidation: alcohol dehydrogenase (ADH) converts it to the toxic, reactive intermediate acetaldehyde, which aldehyde dehydrogenase (ALDH2) then converts to acetate, with the CYP2E1 pathway induced by chronic use. Elimination is essentially zero-order: a roughly fixed 0.10–0.15 g/L per hour regardless of blood level. Acetaldehyde build-up causes the flushing reaction seen with the common East-Asian ALDH2-deficient genotype and with disulfiram, and it contributes to hangover and to alcohol's carcinogenicity. Long-term harms include liver disease, cardiovascular disease, dependence and cancer. The IARC and WHO classify alcoholic beverages as a Group 1 human carcinogen with no established safe level.