L1 Psych Med Vertical Drug and alcohol use disorders 1

Overview

This lecture covers what counts as a drug, how substance use disorders are diagnosed and what tolerance, dependence and withdrawal mean, the factors and the common dopaminergic mechanism that drive dependence, drug use trends and prevalence in New Zealand, and how drugs rank by measured harm. It then works through the major classes in turn, with alcohol treated in most depth (pharmacokinetics, metabolism, BAC, intoxication, harms, withdrawal and its kindling basis, foetal alcohol syndrome, screening, population-level price and availability policy, and treatment), followed by cannabis, nicotine, stimulants, opioids and hallucinogens. Examinable material is flagged as: substance use disorder criteria, alcohol harms including the withdrawal syndrome, alcohol’s role in other disease states, the CAGE and AUDIT screening instruments, and treatment interventions including community agencies and brief interventions. Linked resource: HIC Unit 6, Alcohol and Drugs.

What a drug is, and drug classes

WHO definition of a drug: a chemical entity used non-medically, self-administered for its psychoactive effect.

Classes with examples given:

• CNS depressants: alcohol, benzodiazepines, barbiturates
• CNS stimulants: amphetamines, MDMA, BZP
• Opioids: oxycodone, morphine, codeine, methadone, homebake
• Hallucinogens: LSD, psilocybin, ketamine
• Cannabinoids
• Solvents
• Others: steroids, nicotine, caffeine, anticholinergics, antihistamines

The Drugs Wheel is an alternative classification into 7 categories, with an outer ring of established substances and an inner ring of newer psychoactive substances:

• Stimulants: amphetamine, cocaine, methamphetamine, methylphenidate, khat, modafinil, pseudoephedrine, nicotine, caffeine (newer: ethylphenidate, alpha-PVP, MDPHP, mexedrone)
• Empathogens: MDA, MDMA (newer: methylone, 3-MMC, 5/6-APB, mCPP, MDAI)
• Psychedelics: LSD, psilocybin, mescaline, 5-MeO-DMT, DMT, 2C-B, 2C-I, DOM (newer: 1P-LSD, alpha-MT, 25x-NBOMe, 2C-B-FLY)
• Dissociatives: ketamine, PCP, DXM, nitrous oxide, salvia, ether (newer: 3-MeO-PCP, MXE, diphenidine)
• Depressants: alcohol, diazepam, temazepam, zopiclone, methaqualone, GHB/GBL, gabapentinoids, solvents and inhalants (newer: etizolam, pyrazolam, flualprazolam, clonazolam)
• Opioids: heroin, methadone, buprenorphine, oxycodone, dihydrocodeine, morphine, fentanyl, tramadol (newer: acetylfentanyl, brorphine, isotonitazene)
• Cannabinoids: cannabis, THC, CBD (newer synthetics: Delta-8-THC, JWH-018, 5F-ADB, HHC)

Diagnosing substance use disorder (DSM-V)

Eleven criteria across four areas, assessed over 12 months. Severity by criterion count: 2 to 3 = mild, 4 to 5 = moderate, 6 or more = severe.

1. Impaired control: (1) taking more or for longer than intended; (2) unsuccessful efforts to stop or cut down; (3) a great deal of time spent obtaining, using or recovering from use; (4) craving.
2. Social impairment: (5) failure to fulfil major obligations; (6) continued use despite problems caused or exacerbated by use; (7) important activities given up or reduced.
3. Risky use: (8) recurrent use in hazardous situations; (9) continued use despite physical or psychological problems caused or exacerbated by use.
4. Pharmacologic dependence: (10) tolerance; (11) withdrawal.

Dependence terminology

• Tolerance: reduction in response to a drug after repeated administration, via receptor and second messenger desensitisation or downregulation. Acute and chronic forms. May drive increased intake to obtain the desired effect.
• Dependence: compulsive drug-taking behaviour, loss of ability to control use, intrusion into normal activities, plus tolerance and withdrawal.
• Withdrawal: rebound physiological effects on cessation or reduction of intake. Symptoms are usually opposite to those the drug produces: insomnia and anxiety after benzodiazepines and alcohol; sedation and depression after cocaine and methamphetamine.

Factors associated with substance dependence

Environmental: family or peer group behaviour; availability of other reinforcers such as recreational resources; job and educational opportunities; conditioned stimuli (environmental cues paired with drug use); prior experience and expectations.

Host, genes: both protective and predisposing effects for alcohol. Defective ALDH genes in 40% of Eastern Asians. A reduced-sensitivity-to-alcohol phenotype in alcoholics. GWAS findings: Klotho-B (KLB gene) associated with alcohol intake (PNAS 2016); RGMA and opioid dependence (Biol Psych 2018).

Host, personality traits: antisocial or anxious traits, risk-taking.

Drug factors: ease of availability, price, purity and potency; route of administration (GI, intranasal, IV, inhalation); pharmacokinetic profile, meaning speed of onset and offset. IV dosing, smoking and snorting give rapid absorption and a high Cmax with intense euphoria; oral dosing such as methadone gives slow absorption, lower Cmax and lower-intensity psychological effects.

Multifactorial prediction: Whelan et al (Nature 2014) predicted teenage binge drinking from the IMAGEN longitudinal study of 692 adolescents. Model components were history (romantic or sexual relationship, smoking, prior deviant behaviour), personality (extravagance, excitability, disorganization) and brain (parenchymal volume), alongside genetics, cognitive and demographic variables. Prospective relevance: odds of adult alcohol dependence fall by 10% for each year that drinking onset is delayed in adolescence.

Common mechanism: dopamine in the nucleus accumbens

Dependence-inducing drugs have widely different primary pharmacologies: alcohol acts at GABA-A and GIRKs, opioids at mu-opioid receptors, nicotine at alpha4beta2 nicotinic cholinergic receptors, cocaine at the dopamine transporter. All of them release dopamine in the nucleus accumbens. The reward circuit runs from the VTA via the medial forebrain bundle to the nucleus accumbens, with connections to prefrontal cortex, septum and amygdala.

Can blocking central reward pathways treat addiction? For a single dose, yes (Arch Gen Psych 1999): 11 cocaine-dependent subjects, rising single dose with placebo insertion design, placebo plus ecopipam 10, 25 and 100 mg, then cocaine 30 mg IV two hours post-dose, with subjective effects on visual analogue scales plus BP, HR and adverse events. Ecopipam produced dose-dependent reductions in the subjective effects of cocaine, but the cardiovascular effects (raised BP and HR) were unaffected. For chronic dosing, no: rapid tolerance develops to the antagonist effects.

Trends, prevalence and epidemiology

Global trends per WHO, despite the war on drugs: increased use of illicit substances; lower age of initiation; growth in world supply; use of multiple substances; increasing levels of intoxication, alcoholic poisoning and drug overdoses; increased use by women.

NZ data sources. Community samples: Adolescent Health Research Group (2003); NZ Drug Trends Survey (Massey University, Chris Wilkins), a yearly anonymous online survey of drug market trends. Longitudinal research: Christchurch Health and Development Study; Dunedin Multidisciplinary Health and Development Study.

NZ Drug Trends Survey findings across 2017/18 to 2022/23: cocaine price trending toward stable or increasing; LSD availability shifting toward “very easy” with tab price falling from $36to$32; methamphetamine falling from $563to$406 per gram; cannabis availability shifting toward “very easy” with price falling from $368to$336 per ounce.

South Island ease and speed of purchase (methamphetamine and cannabis, 2018), reported as % “very easy” to buy and % able to buy in under 20 minutes, per region: Nelson and Marlborough 53%/16% very easy, 24%/17% under 20 min; West Coast and Southland 57%/17%, 39%/20%; Canterbury 50%/19%, 26%/16%; Otago 40%/12%, 16%/9%.

Warning

On the purchase-ease slide the two data columns per region are not explicitly labelled by substance, so which figure belongs to methamphetamine and which to cannabis cannot be read off the slide.

NZ Mental Health Survey 2006, 12-month prevalence (%), by total, age band (16 to 24, 25 to 44, 45 to 64, over 65) and sex:

Disorder	Total	16-24	25-44	45-64	>65	Male	Female
Alcohol abuse	2.6	7.1	3.2	0.8	<0.1	3.7	1.6
Alcohol dependence	1.3	3.0	1.7	0.4	<0.1	1.7	0.9
Drug abuse	1.2	3.8	1.2	0.2	<0.1	1.6	0.8
Drug dependence	0.7	2.1	0.9	0.1	<0.1	1.1	0.4
Marijuana abuse	0.9	3.2	0.9	0.2	<0.1	1.3	0.6
Marijuana dependence	0.5	1.5	0.6	<0.1	<0.1	0.8	0.2
Any substance use disorder	3.5	9.6	4.2	1.2	<0.1	5.0	2.2

Key points: prevalence is highest at 16 to 24 and falls steeply with age, abuse exceeds dependence for every substance, and male rates are roughly double female rates.

Relative harm of drugs

Nutt et al (Lancet 2010) used multicriteria decision analysis with an expert committee to score drugs commonly available in the UK. Overall harm splits into harm to users (physical: drug-specific mortality, drug-related mortality, drug-specific damage, drug-related damage; psychological: dependence, drug-specific and drug-related impairment of mental functioning; social: loss of tangibles, loss of relationships) and harm to others (physical and psychological injury; social: crime, environmental damage, family adversities, international damage, economic cost, community).

Overall harm scores (harm to users plus harm to others): alcohol 72 (46 of it to others, by far the largest), heroin 55, crack cocaine 54, metamfetamine 33, cocaine 27, tobacco 26, amfetamine 23, cannabis 20, GHB 19, benzodiazepines 15, ketamine 15, methadone 14, mephedrone 13, butane 11, anabolic steroids 10, khat 9, ecstasy 9, LSD 7, buprenorphine 7, mushrooms 6. On the harm-to-users versus harm-to-others plot, alcohol is the extreme outlier for harm to others (about 85) with mid-high harm to users; heroin and crack cocaine are high on both axes; cannabis sits at low to moderate values on both.

NZ equivalent (Croisin et al, J Psychopharm 2023), weighted harm to self plus harm to others: alcohol 88 (52 to others), methamphetamine 71, synthetic cannabinoids 50, tobacco products 49, non-prescription opioids 44, illegal fentanyls 42, opioid substitution products 42, prescription opioids 42, cannabis 32, solvents and fuels 29, benzodiazepines 19, amphetamine-type substances 18, cocaine 16, GHB/GBL 12, synthetic cathinones 10, ketamine 8, MDMA 7, PIEDs 7, nitrite-based inhalants 5, ENDs/vapes 4, hallucinogens 4, kava 4, nitrous oxide 3.

The conclusion drawn from both datasets: there is no clear relationship between legal scheduling and harm liability. Drug scheduling is not based on science but on social and political decisions. Historical framing offered: if alcohol had only just been discovered, would it be approved for sale?

Alcohol: pharmacokinetics and metabolism

Ethyl alcohol, ethanol, C2H5OH.

A standard drink is 10 g of pure alcohol. Equivalents: 330 mL can of beer at 4% = 1; 100 mL glass of table wine at 12.5% = 1; 335 mL RTD spirits at 8% = 2.1; 750 mL bottle of wine at 13% = 7.7; 1000 mL bottle of spirits at 47% = 37; 3 L cask of wine at 12.5% = 30.

Pharmacokinetics: rapid absorption, dose-proportional exposures, and zero order elimination. Peak blood alcohol occurs within about an hour, then declines roughly linearly; four drinks (40 g) takes about 7 hours to clear.

Metabolism: alcohol is converted by alcohol dehydrogenase and CYP2E1 to acetaldehyde, then by aldehyde dehydrogenase to acetic acid, then to water and CO2. Alcohol dehydrogenase is rate limiting at about 7.5 g/h, which is why elimination is zero order.

Factors affecting blood alcohol concentration (BAC):

• Amount consumed: more drinks, higher BAC
• Speed of consumption: rapid drinking (sculling, shotgunning) gives a higher peak BAC than slow drinking of the same amount
• Body weight: higher weight, lower BAC for the same intake
• Gender: women reach higher BACs than men matched for intake, weight and age, because of lower body water content
• Food: slows absorption and reduces peak BAC
• Age: older people reach higher BACs than younger people matched for intake, weight and gender, because of lower body water content
• Alcoholic content: dilute versus concentrated affects absorption, interacting with food intake
• Drug interactions: drugs that slow gastric emptying, such as opioids, reduce peak BAC

WHO 2018 Global Status Report, NZ data: recorded per capita consumption in 2016 was beer 38%, wine 33%, spirits 29%, other under 1%. Total recorded consumption rose from about 9 litres of pure alcohol in 1961 to a peak of about 13.5 around 1978, then fell back to about 9 by 2016; beer tracked the same shape at a lower level while wine and spirits rose gradually toward about 3 litres each. Globally (Lancet 2018), age-standardised current drinking prevalence in 2016 was highest (80 to 100%) in high-income Western countries, Russia and Australia/NZ for males, and lowest (0 to 19.9%) across much of Africa, the Middle East and South and Southeast Asia, with female prevalence below male prevalence everywhere.

Acute alcohol intoxication and driving

Clinical features by BAC (adapted from Vonghia et al, 2008). The drink-driving limit is 0.05.

• BAC <0.05%: impairment in some tasks requiring skill, increased talkativeness, relaxation, altered perception of the environment
• BAC >0.10%: ataxia, hyper-reflexia, impaired judgment, lack of coordination, mood, personality and behavioural changes, nystagmus, prolonged reaction time, slurred speech
• BAC >0.20%: amnesia, diplopia, dysarthria, hypothermia, nausea, vomiting
• BAC >0.40%: respiratory depression, coma, death

Driving performance by BAC: 0.02% (about 2 beers) loss of judgment and trouble doing two tasks at once; 0.05% (3 beers) reduced coordination and tracking of moving objects, difficulty steering; 0.08% (4 beers) trouble controlling speed, difficulty processing information and reasoning; 0.10% (5 beers) markedly slowed reaction time, difficulty staying in lane and braking; 0.15% (7 beers) serious difficulty controlling the car and focusing on driving. Relative crash risk rises steeply with BAC and rises fastest and highest in the youngest drivers (15 to 19 years) at any given BAC, compared with 20 to 29 and 30+ year olds.

Alcohol and harm to health

Harms of large consumption, by system:

• Brain: impaired development; Wernicke-Korsakoff syndrome with vision changes, ataxia and impaired memory; psychological effects including cravings, irritability, antisociality, depression, anxiety, panic, psychosis, hallucinations, delusions and sleep disorders
• Mouth, trachea, oesophagus: cancer
• Blood: anaemia
• Heart: alcoholic cardiomyopathy
• Liver: cirrhosis, hepatitis
• Stomach: chronic gastritis
• Pancreas: pancreatitis
• Peripheral tissues: increased risk of type 2 diabetes

Associations with small to moderate consumption: increased insulin sensitivity and lower risk of diabetes; reduced number of silent infarcts and decreased risk of dementia; increased HDL, decreased thrombosis, reduced fibrinogen, increased fibrinolysis, reduced artery spasm from stress and increased coronary blood flow; higher bone mineral density. Effects linked with both large and small to moderate consumption: reduced risk of rheumatoid arthritis (joints), reduced risk of gallstones (gallbladder), reduced risk of kidney stones (kidney).

Warning

The slide lists brain “atrophy” inside the small-to-moderate-consumption box but marks it as a harm, an apparent inconsistency on the slide itself.

Foetal alcohol syndrome (Lancet Neurology 2019): a neurodevelopmental disorder associated with heavy alcohol consumption in pregnancy, quantified as 1 to 3 standard drinks per day. Features are a characteristic pattern of facial anomalies (short palpebral fissures, indistinct philtrum, thin upper lip, with or without microcephaly and micrognathia), growth deficiencies, central nervous system abnormalities, and behavioural and cognitive impairments. Imaging contrasts structural and diffusion tractography scans of an affected child with an unexposed child, showing altered white-matter fibre tracts.

Types of alcoholism

Cloninger (Arch General Psychiatry 1981) divided alcoholism into two types.

	Type 1 (about 75%)	Type 2 (about 25%)
Genetics	Weaker	Stronger
Onset	Heavy drinking starts in response to setbacks, losses or outside circumstances	Onset under 25 years, drinking regardless of life circumstances, history of fights and arrests
Gender	M = F	M >> F
Personality	Anxious, shy, pessimistic, sentimental, emotionally dependent, rigid, reflective, slow to anger	Sensation- and novelty-seeking, impulsive, less socialised, usually no guilt, fear or loss of control
Dependence	Drinking manages strong emotions such as anxiety and depression	Polysubstance abuse common as part of an antisocial lifestyle

Alcohol withdrawal

Signs: elevated blood pressure, tachycardia, elevated body temperature, sweating, tremulousness of the body and increased hand tremor, dilated pupils, disorientation, hyperarousal, grand mal seizure.
Symptoms: anxiety, insomnia, illusions, hallucinations, paranoid ideas, nausea, irritability.

Time course: symptoms rise quickly and peak around day 1 to 2 in severe withdrawal, declining slowly over the following days; moderate withdrawal peaks lower and earlier and resolves faster. The seizure risk window sits near day 1.

What causes it? Isbell’s 1955 study, “An Experimental Study of the Etiology of Rum Fits and Delirium Tremens”, asked whether withdrawal symptoms are caused by chronic high alcohol levels or by the absence of alcohol. Ten prisoners, ex-morphine addicts, were given alcohol hourly from 6AM to midnight plus a 3AM dose for up to 3 months, at daily doses of 253 to 464 g (25 to 46 standard drinks). Subjects who drank for a short period (under 16 days, 34 days) had mild or no symptoms, with no hallucinations or convulsions. Subjects who drank for 48 to 83 days had markedly higher scores for tremor, sweating, hypertension, fever, and visual and auditory hallucinations, and convulsions occurred (one subject had 7). The duration of exposure, not the alcohol level itself, drove severity.

Kindling is offered as the basis of alcohol withdrawal: an electrophysiological sensitisation phenomenon described by Graham Goddard in 1969, in which repeated intermittent weak (subconvulsive) stimulation of discrete brain regions gradually produces stronger generalised behavioural responses and eventually seizures. Stimulation may be electrical or pharmacological. On this model, alcohol withdrawal symptoms develop as a response to repeated episodes of alcohol intoxication. Supporting data (Brown, Biol Psych 1988): among patients withdrawing, about 48% of those who had seizures had 5 or more prior detoxes, versus about 12% of those who did not.

Pharmacology (Glue and Nutt, Br J Psych 1990):

1. Acute alcohol increases inhibition (GABA-A, GIRKs) and decreases activation (NMDA), producing sedation, amnesia and incoordination.
2. Chronic alcohol produces adaptive decreased inhibition and increased activation, giving tolerance and, over a long period, withdrawal.
3. On stopping alcohol, inhibition is markedly reduced and activation markedly increased, producing autonomic overactivity, anxiety and seizures.

Treatment of alcohol withdrawal:

• Supportive care: hydration; nutritional support, especially thiamine; treat concurrent illnesses; monitor for Wernicke’s encephalopathy (confusion, ataxia, ophthalmoplegia). Severe cases, for example those with past seizures, require hospital admission; less severe cases can detox at home.
• Medication: not needed for mild cases with absent or mild withdrawal symptoms. Benzodiazepines otherwise: diazepam 10 mg hourly until withdrawal symptoms are controlled, then taper over the next 5 days. This works through cross-tolerance with alcohol at GABA-A receptors.

Screening instruments

CAGE, four yes/no questions scored 1 for yes:

• C: Have you ever felt you should Cut down on your drinking?
• A: Have people Annoyed you by criticising your drinking?
• G: Have you ever felt Guilty about your drinking?
• E: Have you ever had a drink first thing in the morning (Eye opener)?

Interpretation: 0 or 1 suggests low risk of problem drinking; 2 or 3 indicates high suspicion for alcoholism; 4 is virtually diagnostic.

AUDIT-C, three questions scored 0 to 4 each (a = 0 through e = 4), total 0 to 12:

1. How often do you have a drink containing alcohol? (never / monthly or less / 2 to 4 times a month / 2 to 3 times a week / 4+ times a week)
2. How many standard drinks do you have on a typical drinking day? (1 to 2 / 3 to 4 / 5 to 6 / 7 to 9 / 10+)
3. How often do you have six or more drinks on one occasion? (never / less than monthly / monthly / weekly / daily or almost daily)

Positive thresholds: men 4 or more, women 3 or more, which is optimal for identifying hazardous drinking or active alcohol use disorders.

Population-level alcohol policy: price and availability

UK data (Academy of Medical Sciences, 2004) show litres of alcohol per person aged 15+ rising steadily from 1960 to the 2000s while price relative to income fell steadily over the same period, an inverse relationship between price and consumption.

Natural experiments in altering price or availability:

Event	Change	Consumption	Harm
Denmark 1917	Large increase in spirits taxes, some increase in beer taxes	-76%	DTs cases -93%, alcohol deaths -83%
Sweden 1955	Abolition of alcohol rationing	+25%	DTs cases +438%
Finland 1969	Beer available in grocery stores, 20-fold increase in availability	+46%	Alcohol deaths +58%
Russia 1985-8	Reduced availability	-34%	Alcohol deaths -54%

The Ledermann distribution (1956) plots millions of drinkers against litres of alcohol per year as a right-skewed curve, peaking around 10 to 20 litres per year with a long tail out to 140 litres. Cheaper alcohol and greater availability shift the whole distribution to the right and flatten it, moving the population toward higher consumption. Dearer alcohol and less availability do the reverse, shifting the curve to a lower, narrower peak. The point is that population-level measures move everyone’s drinking, not just the heaviest drinkers’.

The 5+ solution for alcohol (Babor et al 2003, confirmed by Anderson et al 2009):

1. Raise alcohol prices: increase excise tax, and possibly a minimum price per standard drink
2. Raise the purchase age
3. Reduce alcohol accessibility
4. Reduce marketing and advertising
5. Increase drink-driving counter-measures
   Plus: increase treatment opportunities for heavy drinkers

Price per standard unit varies enormously, which is why a minimum unit price only affects cheap alcohol (a 2016 Ministry of Justice proposal was $1to$1.20 minimum): Yalumba Reserve 9.75 units, $134,$13.74 per unit; Speights 330 mL 1.32 units, $1.67,$1.26; Steinlager 330 mL 1.65 units, $1.83,$1.11; rum 1 L 40 units, $40,$1.00; Banrock Station 9 units, $7,$0.78; wine cask 33 units, $21,$0.64; methylated spirits 96 units, $6,$0.06.

Treatment of alcoholism

Options:

• Acute detox, in hospital or community
• Brief psychoeducational intervention
• CADS
• Peer support networks: AA (and NA), Alanon for spouses and family
• Community organisations: Bridge Programme, Odyssey House and others

Most benefit comes from psychological and social approaches; medication has only a small role.

Common components of a brief intervention:

• Expressed concern from the provider regarding unhealthy alcohol use
• Feedback linking the patient’s drinking to their health issues
• Education about recommended drinking limits
• Offer of explicit advice to cut down drinking or abstain
• Follow-up 2 to 4 weeks later to assess response
• Referral to specialty addictions treatment if indicated

Drug treatment of alcohol dependence, in three categories:

• Substitution treatment: none. Benzodiazepines should work but do not.
• Anti-craving medication: naltrexone (mu-opioid antagonist), acamprosate. Off label: topiramate and baclofen (GABA-B agonist) reduce craving and drinking days.
• Aversive medication: disulfiram (aldehyde dehydrogenase inhibitor).

Experimental neuromodulation for craving (Neurotherapeutics 2020): increased craving in alcoholics is associated with increased dorsal anterior cingulate cortex (dACC) beta activity, and switching this off with TMS reduces craving, prompting a trial of continuous stimulation. Two Lamitrode 44 electrodes were sutured back-to-back and placed between the two hemispheres on the dACC, with wires run subcutaneously to a pulse generator below the right clavicle, overnight observation in ICU, and double-blind activation of the generator at day 3 or day 17. At week 12 there was a 60.7% reduction in craving and an 80% reduction in alcohol consumption (n = 8): mean craving score fell from about 7.5 to about 3 (p = 0.0040) and mean standard drinks per day from about 25 to about 5 (p = 0.0006).

Cannabis

Main active component is THC.

Pharmacology: agonists at CB1 and CB2 receptors. CB1 receptors are G-protein-coupled, at high density in cortex and hippocampus, mainly expressed on GABA interneurons that express CCK, so the role is modulatory. Endogenous ligands are anandamide and 2AG, with extensive modulatory and developmental roles in multiple organ systems. CB1 is associated with the psychological and performance effects; CB2 with immune modulation.

Discovery timeline: 1964, Raphael Mechoulam reports the structure of THC; 1988, Allyn Howlett identifies specific THC binding sites in brain; 1990, Lisa Matsuda clones the CB1 receptor; 1993, Sean Munro clones CB2; 1992 to 1995, the first endogenous cannabinoid ligands (2AG, anandamide) are identified; 1996 to 2004, synthetic and degrading enzymes identified; 2005, rimonabant (a CB1 inverse agonist) approved in the EU for obesity.

Acute effects, dependent on dose and prior experience: the “high”; mellowing out; impaired psychomotor performance, memory and time perception; dizziness; hunger; paranoia or anxiety reactions; possible analgesia.

Tolerance: seen after 3 to 4 doses, and disappears rapidly on abstinence.

Dependence: lower risk of developing dependence than alcohol, cocaine or heroin. US data show the highest rates of hospitalisation in youth with a subsequent fall in adulthood, whereas alcohol admissions are highest in older age groups. Withdrawal syndrome of restlessness, irritability and insomnia, seen after abstinence in daily heavy users, though the transcript records this as uncertain. CB1 antagonists can precipitate withdrawal in animals dosed chronically with THC, but not in humans.

Treatment: no medications identified or relevant for dependence or withdrawal; benzodiazepines are used symptomatically for an acute anxiety reaction.

Acute harms: adverse reactions to intoxication; driving while intoxicated, since cannabis impairs aspects of cognitive performance such as manual dexterity and attention in continuous performance tasks, and use before driving probably increases crash risk, with estimates of 2.5% of motor vehicle accident deaths versus 29% for alcohol; pregnancy and prenatal exposure, associated with decreased cognitive performance at age 3 and behavioural problems at age 10.

Chronic harms:

• Dependence
• Respiratory and cardiovascular impairment: probable impaired respiratory function and an increase in cancers
• Psychosocial functioning: in the Christchurch birth cohort, cannabis use at ages 14 to 25 was associated with poorer educational outcomes, lower income, greater welfare dependence and unemployment, and lower relationship and life satisfaction (Drug Alcohol Rev 2012)
• Mental health: a modest association with schizophrenia. Odds ratios for psychosis (N = 34,653, USA, Schizophrenia Res 2013): lifetime cannabis use 1.27, lifetime cannabis abuse 1.79, lifetime cannabis dependence 3.69, so risk scales with severity of use.

Silins (Lancet Psychiatry 2014) followed about 3000 NZ and Australian adolescents prospectively to age 30. Those with daily cannabis use before age 17 were 60% less likely to complete high school and 60% less likely to attain a university degree, 18 times more likely to become cannabis dependent, 8 times more likely to use other illicit drugs, and about 7 times more likely to attempt suicide.

A Danish population-based cohort study (2005 to 2021, JAMA Psychiatry 2023) found higher risk of depression and bipolar disorder, both psychotic and non-psychotic, in people with cannabis use disorder (CUD). For unipolar depression of any type, the proportion diagnosed by age 75 reached about 40% in the CUD group versus about 10% without, HR 1.84 (95% CI 1.78 to 1.90). For bipolar disorder of any type, about 14% versus about 1.5%, HR 2.96 (95% CI 2.73 to 3.21).

Nicotine

Pharmacology: N-cholinergic agonist; activates dopamine release in the VTA; also has opioid and glucocorticoid effects.

Acute effects: combined stimulant (subjective alertness) and depressant (muscle relaxation) effects.

Tolerance: acute, so the first cigarette of the day has the greatest effect; and chronic, with loss of early tolerability symptoms such as nausea.

Dependence: probably the highest dependence liability of any drug, because of rapid brain entry, multiple daily reinforcements, and place conditioning (smoking paired with food, sex or situations). It has the lowest rates of successful quitting and rapid reinstatement of dependence after restarting.

Withdrawal: irritability, impatience, hostility, anxiety, dysphoria; difficulty concentrating, restlessness; decreased heart rate; increased appetite and weight gain.

Treatment:

• Detox with nicotine replacement (gum, spray, patch), which gives steady concentrations rather than peaks and troughs and therefore lower dependence liability. No formulation has an efficacy advantage. Abstinence rates of 15 to 20% are only marginally better than placebo at 5 to 10% at 6 and 12 months (JAMA 1993).
• Anti-craving medication: bupropion (Zyban).
• Nicotinic partial agonists (varenicline, cytisine, dianicline) at the alpha4beta2 subtype. Seven-week quit rates: 48% on varenicline 1 mg BID, 33% on Zyban, 16% on placebo.

Stimulants

Cocaine

• Pharmacology: inhibits the dopamine transporter, and also the noradrenaline and serotonin transporters, acutely raising synaptic monoamine levels. Very rapid elimination.
• Acute effects: increased alertness and vigilance; self-confidence, sense of wellbeing, euphoria; increased HR and BP; craving; involuntary movements; stereotyped behaviour, paranoia, anxiety; cardiovascular toxicity; acute psychosis.
• Tolerance: rapid for euphoria; none for cardiovascular effects or craving; possible sensitisation to certain toxic effects such as paranoia and psychotogenic effects.
• Dependence: extremely high liability.
• Withdrawal after chronic use: dysphoria and depression, sleepiness, fatigue, craving, bradycardia, improving over 1 to 3 weeks.
• Treatment: no approved or reliably effective drug treatments; psychosocial management is the mainstay.

Amphetamines

• Pharmacology: stimulate presynaptic release of dopamine, noradrenaline and serotonin.
• Acute effects: similar to cocaine when smoked or injected; after oral doses, increased alertness, decreased fatigue, mood elevation, increased self-confidence, increased motor and speech activity; acute paranoid psychosis.
• Tolerance: rapid to the anorexic effects of oral amphetamine, less rapid to mood and psychomotor performance effects, and absent for autonomic effects such as raised BP.
• Dependence: extremely high liability.
• Withdrawal after chronic use: dysphoria and depression, sleepiness, fatigue, craving, bradycardia, improving over 1 to 3 weeks. No effective drug treatments.

Opioids

Natural: opium, morphine. Synthetic: heroin, methadone and others.

Pharmacology: mu opioid agonism.

Acute effects: analgesia; euphoria, depending on route of administration; nausea, constipation, sedation, dizziness; respiratory depression; pruritus, hypotension.

Tolerance: rapid for euphoria, and slower for sedative, analgesic, respiratory depressant and nausea effects. Dose escalation occurs with injectable and smoked opioids, less so with oral and long half-life drugs.

Dependence: distinguish physical dependence, as in patients on opioids for cancer pain, from the full dependence syndrome of opioid addiction. Cancer patients tolerate slow down-titration and stopping without any desire to reinstate drug use.

Withdrawal: resembles a severe flu-like illness, unpleasant but not life threatening. Onset within 30 to 36 hours of the last methadone dose, peaking about 36 to 72 hours after that, with craving and risk of further use very high during this window, and it may persist as a milder state for weeks afterwards.

• Early withdrawal, 8 to 24 hours after last use: Grade 1: lacrimation, rhinorrhoea, diaphoresis, yawning, restlessness, insomnia. Grade 2: piloerection, muscle twitching, myalgia, arthralgia, abdominal pain.
• Fully developed withdrawal, 1 to 3 days after last use: Grade 3: tachycardia, hypertension, tachypnoea, fever, anorexia, nausea, extreme restlessness. Grade 4: diarrhoea, vomiting, dehydration, hyperglycaemia, hypotension, curled-up position.

Withdrawal treatment options: nothing (cold turkey); or medically managed withdrawal to abstinence using clonidine (alpha2-agonist, 0.15 mg BID, effective against autonomic symptoms) plus loperamide (peripheral opioid agonist, effective against GI symptoms). Sustained abstinence rates are very low.

Long term opioid substitution is the most successful strategy in managing opioid dependence. Rationale: the major complications of chronic opioid use are social and legal, and the physical complications are secondary to the illicit nature of use, so both can be avoided by providing pharmaceutical grade non-IV opioids. Once stabilised, patients do not generally escalate doses, and substitution facilitates involvement with psychological and social services. Regimens use full or partial mu agonists, all class B or C controlled drugs: methadone 20 to 80 mg/day orally, daily; Suboxone (buprenorphine/naloxone 4:1) 8/2 to 32/8 mg/day sublingually. Seven heroin substitution trials have been completed in the EU.

Hallucinogens

Indoleamines (LSD, DMT, psilocybin, mescaline)

• Pharmacology: 5HT2A receptor agonism, which correlates with hallucinatory potency
• Acute effects: highly variable changes in mood, perception and thought, with secondary autonomic changes; trips last 4 to 12 hours
• Tolerance: frequent repeated use is uncommon so tolerance is rare, but tolerance to behavioural effects occurs after 3 to 4 daily doses
• Dependence: may not occur
• Treatment: talking down; benzodiazepines are effective; antipsychotics may intensify hallucinatory symptoms

Phenethylamines (MDA, MDMA/ecstasy)

• Pharmacology: 5HT2A receptor agonism plus dopamine release
• Acute effects: changes in mood, perception and thought; euphoria; dose-dependent autonomic effects such as tachycardia, dry mouth, jaw clenching and hyperthermia
• Tolerance: to the positive or euphoric effects but not to the negative effects
• Dependence: some cases reported but probably rare; behavioural changes (impulsivity, memory impairment) after chronic use; no withdrawal syndrome described
• Treatment: may not be required, otherwise symptomatic, such as benzodiazepines for agitation

Important

Hyperthermia from MDMA (serotonin syndrome) is a medical emergency requiring inpatient supportive care.

NMDA antagonists (phencyclidine/PCP, ketamine)

• Pharmacology: antagonist at NMDA-type glutamate receptors
• Acute effects: emotional withdrawal; concrete thinking; hallucinations; hostile or aggressive behaviour; at higher doses anaesthesia, coma, rhabdomyolysis, hyperthermia
• Tolerance: seen in animals, not known whether it occurs in man
• Dependence: can produce dependence, with a possible withdrawal syndrome (tremor, sleepiness, diarrhoea, bruxism) seen in monkeys
• Treatment: diazepam for agitation or psychosis, avoiding anticholinergic antipsychotics; overdose needs life support as there is no specific antidote, and coma may last 7 to 10 days

Kappa-opioid agonists (salvinorin A, cyclazocine)

• Pharmacology: agonist at kappa opioid receptors
• Acute effects: intense hallucinations and perceptual distortions; analgesia; sedation; feelings of unreality; depersonalisation
• Tolerance: not known. Dependence: not known. Treatment: none established

Therapeutic use of hallucinogens: treatment-resistant depression, with ketamine (many studies) and psilocybin (Carhart-Harris); generalised and social anxiety, with ketamine (local studies); depression and anxiety in patients with terminal cancer, with psilocybin (Griffiths), LSD and MDMA (Wolfson, and a local study); PTSD, with MDMA-facilitated psychotherapy (Mithoefer, MAPS) and ketamine (local study).

Mechanism for durable effects: most psychedelics promote spinogenesis, synaptogenesis and functional plasticity (Cell Reports 2018). The process involves Trk-B and BDNF, with 5HT2A receptor involvement, and MDMA and LSD show this activity while d-amphetamine and serotonin do not. Microscopy of apical and basal dendrites shows significantly increased dendritic spine density after DMT, ketamine, DOI and LSD compared with vehicle.

Self-test

1. State the WHO definition of a drug and list the seven categories used by the Drugs Wheel.
2. List the four areas covered by the DSM-V substance use disorder criteria, giving the criteria within each, and state the severity thresholds.
3. Distinguish tolerance, dependence and withdrawal, and explain why withdrawal symptoms take the form they do.
4. Explain why route of administration and pharmacokinetic profile influence dependence liability.
5. Different dependence-inducing drugs act on different receptors. Explain what they nonetheless have in common, naming the primary target for alcohol, opioids, nicotine and cocaine.
6. The ecopipam study reduced the subjective effects of cocaine. Explain why this did not translate into a treatment for addiction, and state which cocaine effects were unaffected.
7. Describe the age and sex pattern of substance use disorders in the 2006 NZ Mental Health Survey, quoting the total and 16 to 24 prevalence for any substance use disorder.
8. Alcohol ranks first for overall harm in both the UK and NZ analyses. Explain which component of the harm score drives this, and state what the authors conclude about drug scheduling.
9. Describe the metabolic pathway of alcohol, naming the enzymes, and explain why alcohol shows zero-order elimination.
10. Predict how each of the following changes peak BAC for a fixed alcohol intake: drinking rapidly rather than slowly, being female rather than male, eating beforehand, and co-administration of an opioid. Give the reason in each case.
11. List the main clinical features of acute alcohol intoxication at BAC above 0.10%, above 0.20% and above 0.40%.
12. Distinguish Type 1 from Type 2 alcoholism on genetics, onset, gender ratio and personality.
13. Describe the signs and symptoms of alcohol withdrawal, separating signs from symptoms.
14. Explain the kindling hypothesis of alcohol withdrawal and give the two lines of evidence presented for it.
15. Describe the receptor-level changes with acute alcohol, chronic alcohol and alcohol cessation, and link each to its clinical consequence.
16. Outline the management of alcohol withdrawal, including when medication is needed and the benzodiazepine regimen with its pharmacological rationale.
17. State the four CAGE questions and the interpretation of each score band.
18. What are the positive AUDIT-C thresholds for men and women, and what do they identify?
19. Explain, using the Ledermann curve, why raising alcohol price affects the whole population rather than only heavy drinkers, and list the 5+ solution.
20. Name the three categories of drug treatment for alcohol dependence with an example of each, and state how large a role medication plays overall.
21. List the features of foetal alcohol syndrome and the level of maternal consumption associated with it.
22. Describe the pharmacology of CB1 and CB2 receptors, including location, the cells expressing CB1, and the endogenous ligands.
23. What happens to the odds of psychosis as cannabis use moves from use to abuse to dependence? Quote the odds ratios.
24. Why does nicotine have the highest dependence liability of the drugs discussed, and how do varenicline, bupropion and nicotine replacement compare in quit rates?
25. Distinguish the pharmacology of cocaine from that of amphetamines, and state which effects tolerance does and does not develop to for each.
26. Describe the time course and the four graded stages of opioid withdrawal.
27. A patient on long-term opioids for cancer pain is tapered off without difficulty. Explain what this distinguishes, and outline the rationale for opioid substitution treatment in dependence, naming two regimens with doses.
28. Compare indoleamine, phenethylamine and NMDA-antagonist hallucinogens on pharmacology and on the treatment of an acute presentation.
29. A 19-year-old is brought in agitated and hallucinating after taking a drug at a party, with tachycardia, jaw clenching and a temperature of 40 degrees. Which class does this suggest, and what is the priority?
30. Integrative: a 20-year-old man drinking heavily since age 15 presents in withdrawal with a seizure, after three previous detoxes. Using the lecture material, explain his seizure risk, classify his likely alcoholism type, name the screening tool you would use, and outline acute and longer-term management.

Answers

Reveal answers

1. A drug is a chemical entity used non-medically, self-administered for its psychoactive effect. Drugs Wheel categories: stimulants, empathogens, psychedelics, dissociatives, depressants, opioids, cannabinoids.
2. Impaired control (using more or longer than intended, unsuccessful efforts to cut down, great deal of time obtaining/using/recovering, craving); social impairment (failure to fulfil major obligations, continued use despite problems, important activities given up); risky use (recurrent use in hazardous situations, continued use despite physical or psychological problems); pharmacologic dependence (tolerance, withdrawal). Over 12 months: 2 to 3 mild, 4 to 5 moderate, 6 or more severe.
3. Tolerance is reduced response after repeated administration via receptor or second messenger desensitisation and downregulation. Dependence is compulsive drug-taking with loss of control and intrusion into normal activities, plus tolerance and withdrawal. Withdrawal is rebound physiological effect on cessation or reduction. Symptoms are usually opposite to the drug’s own effects, hence insomnia and anxiety after benzodiazepines and alcohol, sedation and depression after cocaine and methamphetamine.
4. IV, smoked and snorted routes give rapid absorption and a high Cmax, producing intense euphoria and psychological effects; oral dosing such as methadone gives slow absorption, lower Cmax and lower intensity effects. Speed of onset and offset is a listed drug factor in dependence.
5. They all release dopamine in the nucleus accumbens, via the VTA and medial forebrain bundle reward circuit. Alcohol acts at GABA-A and GIRKs, opioids at mu-opioid receptors, nicotine at alpha4beta2 nicotinic cholinergic receptors, cocaine at the dopamine transporter.
6. Ecopipam reduced cocaine’s subjective effects dose-dependently after a single dose, but with chronic dosing rapid tolerance develops to the antagonist effects, so the benefit is not sustained. Cocaine’s cardiovascular effects, raised BP and HR, were unaffected.
7. Prevalence is highest at 16 to 24 and falls steeply with age, and male rates are roughly double female rates. Any substance use disorder: total 3.5%, 16 to 24 years 9.6% (male 5.0%, female 2.2%).
8. Harm to others: alcohol scores 46 of 72 in the UK analysis and 52 of 88 in the NZ analysis, by far the largest such component of any drug. The authors conclude there is no clear relationship between scheduling and harm liability, so drug scheduling is not based on science but is a social and political decision.
9. Alcohol is converted by alcohol dehydrogenase and CYP2E1 to acetaldehyde, then by aldehyde dehydrogenase to acetic acid, then to water and CO2. Alcohol dehydrogenase is rate limiting at about 7.5 g/h, so elimination proceeds at a fixed rate independent of concentration, which is zero order.
10. Rapid drinking raises peak BAC compared with slow drinking of the same amount. Being female gives a higher BAC than a male matched for intake, weight and age, because of lower body water content. Food slows absorption and reduces peak BAC. An opioid slows gastric emptying and therefore reduces peak BAC.
11. Above 0.10%: ataxia, hyper-reflexia, impaired judgment, lack of coordination, mood, personality and behavioural changes, nystagmus, prolonged reaction time, slurred speech. Above 0.20%: amnesia, diplopia, dysarthria, hypothermia, nausea, vomiting. Above 0.40%: respiratory depression, coma, death.
12. Type 1 (about 75%): weaker genetic contribution; heavy drinking begins in response to setbacks, losses or circumstances; M = F; anxious, shy, pessimistic, sentimental, emotionally dependent, rigid, reflective, slow to anger. Type 2 (about 25%): stronger genetic contribution; onset under 25 regardless of circumstances with fights and arrests; M >> F; sensation- and novelty-seeking, impulsive, less socialised, usually without guilt, fear or loss of control.
13. Signs: elevated blood pressure, tachycardia, elevated body temperature, sweating, tremulousness and increased hand tremor, dilated pupils, disorientation, hyperarousal, grand mal seizure. Symptoms: anxiety, insomnia, illusions, hallucinations, paranoid ideas, nausea, irritability.
14. Kindling (Goddard 1969) is electrophysiological sensitisation in which repeated intermittent subconvulsive stimulation of discrete brain regions gradually produces stronger generalised responses and eventually seizures; applied to alcohol, withdrawal symptoms develop as a response to repeated episodes of intoxication. Evidence: Isbell’s 1955 study, where subjects drinking for 48 to 83 days had far more severe symptoms including hallucinations and convulsions than those drinking under 16 to 34 days; and Brown 1988, where about 48% of patients who seized in withdrawal had 5 or more prior detoxes versus about 12% of those who did not.
15. Acute alcohol increases inhibition (GABA-A, GIRKs) and decreases activation (NMDA), giving sedation, amnesia and incoordination. Chronic alcohol produces the opposite adaptation, decreased inhibition and increased activation, giving tolerance and eventually withdrawal. On stopping, inhibition is markedly reduced and activation markedly increased, giving autonomic overactivity, anxiety and seizures.
16. Supportive care: hydration, nutritional support especially thiamine, treat concurrent illness, and monitor for Wernicke’s encephalopathy (confusion, ataxia, ophthalmoplegia). Severe cases such as those with past seizures need hospital admission; less severe cases can detox at home. Medication is not needed for mild cases; otherwise diazepam 10 mg hourly until symptoms are controlled, then taper over 5 days, which works via cross-tolerance with alcohol at GABA-A receptors.
17. Cut down on your drinking; people Annoyed you by criticising your drinking; felt Guilty about your drinking; had a drink first thing in the morning (Eye opener). Score 0 or 1 is low risk, 2 or 3 is high suspicion of alcoholism, 4 is virtually diagnostic.
18. Men 4 or more, women 3 or more, which is optimal for identifying hazardous drinking or active alcohol use disorders.
19. The Ledermann curve is the whole population’s distribution of annual consumption; cheaper, more available alcohol shifts and flattens the entire curve to the right and dearer, less available alcohol shifts it back to a lower, narrower peak, so price moves everyone’s intake, not just that of the heaviest drinkers. The 5+ solution: raise alcohol prices (excise tax, possible minimum unit price), raise the purchase age, reduce accessibility, reduce marketing and advertising, increase drink-driving counter-measures, plus increase treatment opportunities for heavy drinkers.
20. Substitution: none, since benzodiazepines should work but do not. Anti-craving: naltrexone (mu-opioid antagonist) and acamprosate, with off-label topiramate and baclofen. Aversive: disulfiram (aldehyde dehydrogenase inhibitor). Most benefit comes from psychological and social approaches; medication has only a small role.
21. Characteristic facial anomalies (short palpebral fissures, indistinct philtrum, thin upper lip, with or without microcephaly and micrognathia), growth deficiencies, central nervous system abnormalities, and behavioural and cognitive impairments. Associated with heavy consumption in pregnancy, given as 1 to 3 standard drinks per day.
22. Both are G-protein-coupled receptors targeted by cannabinoid agonists. CB1 is at high density in cortex and hippocampus, mainly on CCK-expressing GABA interneurons, so its role is modulatory, and it mediates the psychological and performance effects. CB2 mediates immune modulation. Endogenous ligands are anandamide and 2AG, with extensive modulatory and developmental roles across organ systems.
23. The odds rise with severity: lifetime use 1.27, lifetime abuse 1.79, lifetime dependence 3.69.
24. Rapid brain entry, multiple daily reinforcements and place conditioning (smoking paired with food, sex or particular situations), giving the lowest rates of successful quitting and rapid reinstatement after restarting. Seven-week quit rates: varenicline 1 mg BID 48%, bupropion (Zyban) 33%, placebo 16%; nicotine replacement gives 15 to 20% abstinence versus 5 to 10% on placebo at 6 and 12 months, with no advantage for any formulation.
25. Cocaine inhibits the dopamine transporter and also the noradrenaline and serotonin transporters, acutely raising synaptic monoamines, and is eliminated very rapidly; amphetamines stimulate presynaptic release of dopamine, noradrenaline and serotonin. Cocaine: rapid tolerance to euphoria, none to cardiovascular effects or craving, possible sensitisation to paranoia and psychotogenic effects. Amphetamine: rapid tolerance to anorexic effects, less rapid to mood and psychomotor effects, none to autonomic effects such as raised BP.
26. Onset within 30 to 36 hours of the last methadone dose, peaking about 36 to 72 hours later, with very high craving and relapse risk, and a milder state persisting for weeks. Early withdrawal at 8 to 24 hours: Grade 1 lacrimation, rhinorrhoea, diaphoresis, yawning, restlessness, insomnia; Grade 2 piloerection, muscle twitching, myalgia, arthralgia, abdominal pain. Fully developed at 1 to 3 days: Grade 3 tachycardia, hypertension, tachypnoea, fever, anorexia, nausea, extreme restlessness; Grade 4 diarrhoea, vomiting, dehydration, hyperglycaemia, hypotension, curled-up position.
27. It distinguishes physical dependence from the full dependence syndrome: cancer pain patients tolerate slow down-titration and stopping without any desire to reinstate use. Substitution rationale: the major complications of chronic opioid use are social and legal and the physical complications are secondary to illicit use, so supplying pharmaceutical grade non-IV opioids avoids them; stabilised patients do not escalate doses, and it facilitates engagement with psychological and social services, making it the most successful strategy. Regimens: methadone 20 to 80 mg/day orally, daily; Suboxone (buprenorphine/naloxone 4:1) 8/2 to 32/8 mg/day sublingually.
28. Indoleamines (LSD, DMT, psilocybin, mescaline) are 5HT2A agonists; treat by talking down and with benzodiazepines, and avoid antipsychotics, which may intensify hallucinations. Phenethylamines (MDA, MDMA) are 5HT2A agonists plus dopamine releasers; treatment may not be required, otherwise symptomatic such as benzodiazepines for agitation, with hyperthermia a medical emergency. NMDA antagonists (PCP, ketamine) block NMDA-type glutamate receptors; use diazepam for agitation or psychosis, avoid anticholinergic antipsychotics, and in overdose provide life support as there is no antidote, with coma lasting 7 to 10 days.
29. A phenethylamine such as MDMA, given the euphoria, tachycardia, jaw clenching and hyperthermia. Hyperthermia (serotonin syndrome) is a medical emergency requiring inpatient supportive care; benzodiazepines can be used symptomatically for agitation.
30. Repeated prior detoxes are the risk factor for withdrawal seizures under the kindling model, with about 48% of patients who seize having had 5 or more prior detoxes versus about 12% of those who do not; his seizure risk peaks near day 1 of withdrawal. Onset of heavy drinking before 25 regardless of circumstances in a male fits Type 2 alcoholism. Screen with CAGE (2 or 3 high suspicion, 4 virtually diagnostic) or AUDIT-C (positive at 4 or more in men). Acutely, admit to hospital given the seizure, hydrate, give thiamine, treat concurrent illness, monitor for Wernicke’s encephalopathy, and give diazepam 10 mg hourly until symptoms are controlled then taper over 5 days. Longer term, use psychological and social approaches (brief intervention, CADS, AA, community organisations such as the Bridge Programme or Odyssey House) as the mainstay, with anti-craving naltrexone or acamprosate, or disulfiram, in a small supporting role.