10.1 Pharmacology and epidemiology of substances

Alcohol pharmacology and epidemiology

Absorption and distribution

• Absorption is slow in the stomach, where gastric alcohol dehydrogenase gives first-pass metabolism, and fast in the small intestine.

• Gastric surgery that speeds alcohol into the small bowel raises the peak blood alcohol concentration (BAC).

• Ethanol distributes through body water, so women and older people often reach a higher BAC from the same dose.

Metabolism

• Elimination is roughly zero order, with BAC falling by about 10 to 20 mg/100 ml per hour.

• Reduced ALDH2 activity, common in some East Asian populations, causes acetaldehyde to build up, with flushing, tachycardia and nausea.

• Disulfiram permanently blocks aldehyde dehydrogenase, so acetaldehyde builds up after any alcohol and deters drinking.

• Metronidazole causes a disulfiram-like reaction, so people should avoid alcohol during the course and for 48 hours after it.

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Receptor actions and withdrawal

Alcohol potentiates gamma-aminobutyric acid (GABA-A) receptors and inhibits N-methyl-D-aspartate (NMDA) glutamate receptors at the same time.

• Tolerance develops as receptors adapt to chronic drinking by reducing inhibition and increasing excitation, so abrupt withdrawal brings tremor, seizures or delirium tremens.

• Benzodiazepines treat withdrawal by enhancing GABA-A inhibition, replacing the inhibitory tone lost when receptors adapted to chronic alcohol.

Units and guidance

• A UK unit is 8 g or 10 ml of ethanol: units = volume in ml x percentage alcohol by volume / 1000.

• Low-risk guidance is no more than 14 units a week for either sex.

• Binge drinking in UK surveys means more than 8 units in one session for men or 6 for women.

Epidemiology

• The alcohol harm paradox is greater harm in deprived groups despite similar or lower average consumption.

• UK alcohol-specific deaths in 2024 ran at 14.8 per 100,000, with 20.2 in men and 9.7 in women.

Synthetic cathinones

• Mephedrone, a synthetic cathinone, can be recognised by a distinctive fishy body odour in the user's sweat.

Cannabis pharmacology and epidemiology

Cannabinoids and receptors

• Delta-9-tetrahydrocannabinol (THC) is the plant cannabinoid that produces the intoxicating effects of cannabis, as a partial agonist at CB1 receptors.

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• Anandamide and 2-arachidonoylglycerol are the endogenous ligands, which regulate transmitter release by retrograde signalling.

• THC is highly lipid-soluble and slowly eliminated, so its inactive urinary metabolite (THC-COOH) stays detectable for days after occasional use and weeks after frequent use.

• A positive urine test shows exposure, not current intoxication.

Intoxication

• Intoxication gives relaxed euphoria, giggling, altered time sense and increased appetite.

• The physical signs are conjunctival injection, dry mouth, tachycardia and normal pupils.

• Memory, attention and coordination are impaired, and higher doses can cause panic, paranoia, depersonalisation or psychotic symptoms.

Dependence and withdrawal

• Withdrawal gives effects roughly opposite to intoxication: reduced appetite, insomnia with vivid dreams, irritability, anxiety and restlessness.

• Symptoms start within 1 to 3 days, peak at 2 to 6 days and settle over 1 to 2 weeks, though sleep disturbance may last longer.

• Older cohorts put dependence at about 9% of ever-users, one sixth of adolescent starters and a quarter to a half of daily users.

Long-term effects

• Amotivational syndrome is apathy, passivity, loss of drive and poor persistence with long-term goals, classically linked to chronic heavy use.

• Its status as a separate syndrome is disputed, because slowly eliminated THC causes continuing intoxication and mood disorder may coexist.

• Cannabis smoking carries tobacco-associated lung cancer risk, because it is usually rolled with tobacco and inhaled deeply with the breath held.

• Cannabinoid hyperemesis is recurrent severe vomiting in long-term frequent users; hot bathing may relieve it, and stopping cannabis prevents recurrence.

Epidemiology

• Cannabis has the highest lifetime prevalence of any illicit drug in Europe, at a little under 30% of adults aged 15 to 64.

• About 8% of all adults and about 15% of young adults used it in the last year, against about 5% or less for the next most used drugs.

Cannabis and psychosis

• Regular use raises the risk of schizophrenia roughly two- to fourfold compared with non-use.

• In the Dunedin birth cohort, use begun by age 15 raised the risk of schizophrenia-like psychosis at 26 about fourfold over never-users, more than use begun in late adolescence.

• Cannabis users develop psychosis about 2.7 years earlier than non-users (Large et al., 2011 meta-analysis).

• Risk rises with frequency and potency, but shared genetic liability, adversity, other drugs and self-medication of prodromal symptoms complicate causal inference.

• Cannabis contributes to psychosis without being necessary or sufficient, and a population odds ratio is not an individual's probability.

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Stimulants pharmacology and epidemiology

Agents and sources

• Amphetamine-type stimulants include amfetamine, dexamfetamine and methamphetamine. Cocaine is used as powder or as crack.

• Cocaine is the alkaloid of the South American (Andean) coca shrub, Erythroxylum coca.

• Cathinone is the principal psychoactive alkaloid of khat (Catha edulis). It is potent but unstable, and degrades to the weaker cathine.

• Mephedrone is a synthetic cathinone.

• Prescribed stimulants treat attention deficit hyperactivity disorder and narcolepsy.

How stimulants act

• Amphetamine also disrupts vesicular storage through vesicular monoamine transporter 2, and heavy use can deplete stores.

• Cocaine also blocks noradrenaline and serotonin reuptake and voltage-gated sodium channels, which gives it local anaesthetic action and cardiac conduction toxicity.

• Khat is an amphetamine-type stimulant because cathinone, like amphetamine, releases monoamines, mainly dopamine and noradrenaline.

• Mephedrone both releases and blocks reuptake of dopamine, noradrenaline and serotonin, so its profile is closest to MDMA (methylenedioxymethamphetamine): a stimulant and empathogen.

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Route, onset and duration

Cocaine's euphoria is intense but short-lived, and the route sets how fast it comes and how long it lasts.

• Smoked cocaine (crack) gives the most immediate high, lasting only about 5 to 10 minutes.

• Snorted cocaine acts within minutes and lasts about 15 to 30 minutes.

• Oral cocaine has a slower onset.

• Amphetamine effects last hours, about 4 to 6 hours or longer when taken orally.

• Alcohol and cocaine together form cocaethylene, an active, longer-lasting metabolite that adds cardiac risk.

Intoxication

Cocaine and amphetamine-type stimulants both cause a sympathomimetic toxidrome: agitation, paranoia, sweating, tachycardia, hypertension, hyperthermia, dilated pupils and seizures.

• Amphetamine intoxication can produce a paranoid, hallucinatory state in clear consciousness.

• Cocaine causes arrhythmia, cardiac ischaemia and seizures during intoxication, often within one to two hours and disproportionately after a first exposure.

• With repeated use, tolerance develops to euphoria and appetite suppression, while sensitisation (reverse tolerance) increases psychotic and repetitive motor effects.

Physical harms of cocaine

• Stroke: vasoconstriction and acute hypertension make cocaine the misused substance most likely to precipitate stroke, ischaemic or haemorrhagic.

• Nasal septum: snorting causes ischaemic necrosis and perforation, a long-term harm built up over months of use.

• Heart: cocaine causes ischaemia through vasoconstriction, thrombosis and raised oxygen demand, and severe hypertension can cause aortic dissection.

Withdrawal: the crash

Cocaine or amphetamine withdrawal is a crash whose core feature is dysphoric mood.

• Other features are fatigue, hypersomnia, craving and vivid unpleasant dreams from rapid eye movement sleep rebound.

• Appetite increases, the reverse of the appetite loss during use.

• Vital signs stay normal.

• The danger is severe depression and suicide, so assess suicide risk.

• The cocaine crash may last a day or two and amphetamine withdrawal several days, but low mood, poor sleep and craving can persist longer.

Urine screening

• Amphetamines are detectable in urine for about 48 to 72 hours after use.

• A drug structurally resembling amphetamine can give a false-positive amphetamine immunoassay, so a positive screen needs confirmation by mass spectrometry.

Epidemiology

• In the Crime Survey for England and Wales for the year ending March 2025, 2.1% of 16 to 59-year-olds and 2.3% of 16 to 24-year-olds had used powder cocaine in the past year.

• Past-year amphetamine use stayed below 1%.

• Household surveys miss many marginalised people who use crack.

• Worldwide 2017 estimates show stimulant dependence adds to deaths from suicide, homicide, accidental injury and cardiovascular disease.

• Amphetamine dependence carries a larger share of these deaths than cocaine dependence for every cause, and cardiovascular disease is the smallest share.

• Chemsex is drug use to facilitate or prolong sex, particularly among some men who have sex with men, often combining methamphetamine or mephedrone with gamma-hydroxybutyrate or gamma-butyrolactone.

Hallucinogens pharmacology and epidemiology

Three families

Classic serotonergic hallucinogens

• Psilocybin, LSD and mescaline form one group with closely similar effects and cross-tolerance.

• Psilocybin is converted to the active drug psilocin.

• DMT taken by mouth is broken down by monoamine oxidase (MAO). In ayahuasca, harmala alkaloids inhibit MAO A, so it becomes active orally.

Intoxication

• Users see intensified colours and patterns, have synaesthesia and an altered body image, lose their sense of time, and feel euphoria or anxiety.

• The physical signs listed in ICD-11 are a mild sympathomimetic picture: tachycardia, raised blood pressure, pupillary dilatation, sweating and tremor.

• The user's expectations (set) and surroundings (setting) shape the experience.

Tolerance and dependence

• Tolerance develops rapidly and clears within days of stopping.

• There is no physiological dependence and no withdrawal syndrome, and compulsive use is rare, so classic hallucinogens have the lowest dependence potential of commonly used drugs.

Adverse effects

• Brief flashbacks that do not impair are not HPPD, and neurological, visual and psychiatric causes must be excluded.

• NBOMe compounds are potent 5-HT2A agonists sold on blotter as LSD, and they cause seizures, hyperthermia and deaths.

Ketamine

• Ketamine intoxication is a dissociative anaesthetic picture: dissociation and perceptual change with ataxia, nystagmus and raised muscle tone.

• Ketamine is detectable in urine for about 2 days, and its hepatic metabolite norketamine for about 14 days.

• Unlike classic hallucinogens, ketamine causes dependence, with craving and withdrawal symptoms such as anxiety, dysphoria, poor sleep, sweating and tremor.

Ketamine uropathy

• Ketamine uropathy is an ulcerative cystitis caused by direct toxicity to the urothelium in chronic users.

• Patients have frequency, urgency, suprapubic pain and haematuria with sterile urine.

• It progresses to a scarred, shrunken, contracted bladder and can obstruct the upper tract and impair renal function.

• Stopping early improves recovery, but established damage may persist or need surgery.

Phencyclidine

• PCP is an NMDA channel blocker whose effects last hours, occasionally days.

• Intoxication gives agitation, analgesia, vertical and other nystagmus, ataxia, dysarthria, muscle rigidity and raised blood pressure.

• Psychomotor retardation is not a feature; PCP intoxication is agitated.

• Seizures are uncommon and mainly occur at high doses.

Anticholinergic hallucinogens

These cause delirium with dry flushed skin, dilated pupils, tachycardia, hyperthermia and urinary retention. Classic hallucinogens also dilate the pupils, but cause sweating rather than dry skin.

Epidemiology and risk

• Classic hallucinogen use is less common than cannabis use and concentrated in younger adults.

• Nitrous oxide became a Class C drug in the UK on 8 November 2023.

• Psychosis vulnerability, unstable mood, anxiety, unfamiliar surroundings and uncertain dose raise the risk.

• Ayahuasca is dangerous with serotonergic medicines or MDMA, and ketamine with opioids or alcohol increases respiratory danger.

Solvents and nitrites pharmacology and epidemiology

Agents and actions

Solvent intoxication

• Solvent intoxication is a brief depressant state of the central nervous system, with disinhibition, slurred speech, ataxia, nystagmus and drowsiness.

• A perioral and perinasal rash, a chemical smell on the breath and irritated eyes, nose and throat point to recent sniffing or bagging.

• Hydrocarbons sensitise the myocardium to catecholamines, so fright or a chase can trigger a fatal arrhythmia.

• Suffocation in bags, aspiration and burns also kill, and butane features most in UK deaths.

Chronic solvent harm

Nitrous oxide and vitamin B12

• Nitrous oxide inactivates vitamin B12, causing a functional deficiency with raised homocysteine even when serum B12 is normal.

• The result is subacute combined degeneration of the cord: dorsal column signs (sensory ataxia, positive Romberg sign) and corticospinal signs (weakness, extensor plantars).

• It can present with psychosis, and anaemia may be absent.

• Treat promptly with B12 and stop nitrous oxide; supplements do not protect someone who keeps using.

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Alkyl nitrites

• Nitrites cause flushing, headache, a brief rush, hypotension and reflex tachycardia, and dependence is uncommon.

• Methaemoglobinaemia shows as disproportionate cyanosis, chocolate-brown blood, normal arterial oxygen tension and oximetry near 85%; co-oximetry confirms it.

• Nitrites taken with sildenafil, tadalafil or vardenafil cause profound hypotension, so the combination is contraindicated.

• Poppers can damage foveal photoreceptors, causing lasting central visual loss.

Law and epidemiology

• Nitrous oxide became Class C on 8 November 2023, but solvents and nitrites are not controlled under the Misuse of Drugs Act.

• Solvent use often starts in early adolescence because products are easy to obtain.

• Past-year nitrous oxide use among 16 to 24-year-olds fell from 8.7% in 2019/20 to 1.3% in 2024/25, and the fall began before reclassification.

• Poppers are used more by gay and bisexual men, especially in sexualised settings.

MDMA and related substances

Action and effects

• MDMA (3,4-methylenedioxymethamphetamine) is a substituted amphetamine that combines amphetamine-like stimulant effects with LSD-like hallucinogenic effects in one dose.

• It enters neurons through monoamine transporters and reverses them. This releases mainly serotonin, with noradrenaline and dopamine.

• Its empathogenic effects are warmth, emotional openness and reduced social threat.

Related compounds

MDMA itself is Class A and Schedule 1. PMA sold as ecstasy is dangerous because its delayed onset encourages people to take more.

Kinetics

• Effects begin in 30 to 60 minutes, peak at around two hours and last 3 to 5 hours, but the half-life is 8 to 9 hours.

• CYP2D6 metabolises MDMA, and MDMA inhibits its own metabolism, so a repeated dose raises exposure disproportionately.

Acute toxicity

Hyperthermia and hyponatraemia both cause collapse, confusion or seizures, but giving more hypotonic fluid worsens hyponatraemia.

• Serotonin toxicity is likeliest with MAO inhibitors such as moclobemide or linezolid, and clonus with hyperreflexia supports the diagnosis.

• Low mood, fatigue and poor sleep may follow use for several days.

Benzodiazepines and barbiturates

Action at the GABA-A receptor

Both classes enhance the chloride channel of the gamma-aminobutyric acid A (GABA-A) receptor, but at different sites and in different ways.

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Half-life and interdose withdrawal

• Interdose withdrawal occurs with drugs of short elimination half-life and no long-lived active metabolites, such as lorazepam, because plasma levels fall between regular doses.

• Diazepam and chlordiazepoxide do not cause it, because they produce desmethyldiazepam, whose half-life of 36 to 200 hours keeps levels steady and causes delayed sedation.

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Acute effects and overdose

• Common adverse effects are the dose-related triad of drowsiness, dizziness and ataxia, all from GABA-A-mediated central depression.

• Overdose of a benzodiazepine alone is relatively safe; fatal cases usually involve alcohol, opioids or other sedatives, and death comes from central respiratory depression.

• Flunitrazepam is the benzodiazepine most linked to drug-facilitated sexual assault: it is highly potent, tasteless in solution, and causes rapid sedation and anterograde amnesia.

Flumazenil

• Flumazenil is a competitive antagonist at the benzodiazepine site of the GABA-A receptor and acts nowhere else, so it does not reverse barbiturates or alcohol.

• It reverses benzodiazepine sedation but is not licensed in the UK for benzodiazepine overdose.

• It can provoke seizures or withdrawal, especially in dependent patients or after a proconvulsant co-ingestion, so airway and ventilatory support remain the mainstay.

Dependence

The risk of dependence rises with the length of continuous use.

• Physical dependence can develop at therapeutic doses and is distinct from addiction.

• Courses for anxiety or insomnia are usually 2 to 4 weeks.

Withdrawal

Withdrawal is a hyperexcitable rebound state: after adapting to the drug, the brain has too little inhibition and too much excitation when it stops.

• Kinaesthetic hallucinations are false perceptions of movement or body position; vestibular hallucinations also occur.

• People who are dependent should taper gradually and never stop abruptly.

Barbiturates in current use

Phenobarbital strongly induces liver enzymes and has a long half-life, so it causes interactions and delayed, severe withdrawal.

Urine screening

• Sertraline can give a false-positive benzodiazepine result on urine immunoassay.

Opioids pharmacology and epidemiology

Receptors

• Mu, kappa and delta receptors all inhibit signalling through G proteins.

• Mu receptors mediate much analgesia, reward and respiratory depression, while kappa activation often causes dysphoria.

• Mu activation suppresses inhibitory interneurons, which frees ventral tegmental dopamine neurons and raises mesolimbic dopamine.

Classification

Opioids are classed on two axes: intrinsic efficacy at the mu receptor (full agonist, partial agonist or antagonist) and duration of action (short or long).

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• Buprenorphine displaces full agonists and so precipitates withdrawal, which is why induction waits until withdrawal is clear.

• Codeine gives poor CYP2D6 metabolisers little analgesia and puts ultra-rapid metabolisers at risk of morphine toxicity.

Acute effects and tolerance

Opioids cause analgesia, euphoria, sedation, nausea, respiratory depression and miosis, and they slow the gut, causing constipation, delayed gastric emptying and dry mouth.

Tolerance develops unevenly.

• Loss of tolerance during abstinence means a return to the old dose after prison, detoxification or rehabilitation can be fatal.

Overdose

• Opioid overdose gives coma, respiratory depression and pinpoint pupils, all reversed by naloxone.

• Other sedatives cause coma without miosis, although absent miosis does not rule out opioid poisoning.

• Agitation after naloxone is precipitated withdrawal.

• Naloxone often wears off before the opioid, so toxicity can recur and repeated doses may be needed.

• Alcohol, benzodiazepines and gabapentinoids add to opioid respiratory depression.

Dependence and withdrawal

• Physical dependence can develop after about five days of continuous use, and the drug's half-life then sets withdrawal onset and duration.

• Opioid withdrawal is a physical, noradrenergic syndrome of yawning, lacrimation, rhinorrhoea, mydriasis, piloerection, cramps and diarrhoea, unlike the largely psychological withdrawal from stimulants and cannabis.

• Withdrawal signs mirror opioid effects: the pupils dilate in withdrawal and constrict with use or overdose.

• Diarrhoea comes from rebound gut hypermotility, the opposite of opioid constipation.

• The physical signs arise from rebound hyperactivity of the noradrenergic locus coeruleus once chronic opioid inhibition is lifted.

• The ventral tegmental area and nucleus accumbens mediate euphoria and reinforcement, not withdrawal signs.

• Cold turkey is the colloquial name for opioid withdrawal, taken from its gooseflesh (piloerection).

• Withdrawal is usually not life-threatening in a healthy adult.

Withdrawal features appear in order:

1. Anxiety and restlessness come first, followed by mucosal signs, sweating and autonomic arousal.

2. Gastrointestinal features and piloerection appear next.

3. The most advanced stage comes later still.

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Epidemiology

• Heroin, not any synthetic or prescription opioid, accounts for most illicit opioid use across Europe, including the UK.

• Dependent users usually take about 0.25 to 2 g of street heroin a day.

• Nitazenes are synthetic benzimidazole opioids of widely varying, sometimes extreme potency that adulterate or replace heroin; deaths involving them in England and Wales rose from 52 in 2023 to 195 in 2024.