What it is:A chronic, relapsing brain disease built on a triad: the right patient (genetic risk), the right substance, exposed at the right (wrong) time. Nobody knows the exact etiology, but once the reward circuitry gets hijacked, the illness is defined by loss of control over use despite consequences.
The core problem:Every substance in this chapter (except opioids, covered elsewhere) either depresses the CNS (alcohol, benzodiazepines, other sedative-hypnotics) or stimulates it (nicotine, cocaine, methamphetamine, MDMA), plus a grab-bag of "other" substances (cannabis, LSD, bath salts, inhalants). Each drug class has its own intoxication and withdrawal syndrome, and only a handful have FDA-approved medications for the use disorder itself.
What you do about it:Split every substance into two separate clinical problems. (1) What's happening to this patient right now, intoxication or withdrawal, and does it need emergent treatment? (2) What keeps them from using again long-term? The tools for each are completely different, and mixing them up is the most common way to get a board question wrong.
This chapter has a brutal asymmetry: alcohol, nicotine, and benzodiazepines have real pharmacotherapyfor both withdrawal and the chronic use disorder. Cocaine, methamphetamine, MDMA, cannabis, LSD, and inhalants have none.For those, you treat agitation or psychosis symptomatically and lean entirely on behavioral therapy. Less than 2% of people with alcohol use disorder ever receive pharmacotherapy at all, despite three approved drugs existing, so the gap here isn't the science, it's access and stigma.
Two classification systems matter here, and they answer different questions.
| System | Answers | Categories |
|---|---|---|
| DSM-5 severity | How bad is the use disorder itself? | Mild 2–3 criteria · Moderate 4–5 · Severe 6 or more (of 11 total) |
| CNS effect | What is the substance doing to the brain acutely? | Depressant (alcohol, benzos, sedative-hypnotics) · Stimulant (nicotine, cocaine, methamphetamine, MDMA) · Other (cannabis, LSD, cathinones, inhalants) |
DSM-5 substance use disorder is diagnosed the same way regardless of drug: 2 or more of 11 criteria in a 12-month period(impaired control, social impairment, risky use, and the pharmacologic criteria of tolerance and withdrawal). The substancechanges the clinical picture and the treatment, but the diagnostic framework never changes. Don't go looking for a separate diagnostic checklist per drug, there isn't one.
The true cause of SUD is unknown, but nearly every mechanism in this chapter traces back to one circuit: the mesolimbic dopamine pathway, projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). Every reinforcing substance, no matter how it works pharmacologically, ultimately dumps dopamine into the NAc. Drugs that block dopamine there produce dysphoria, and animals and humans reliably will not self-administer something that feels bad. That single fact explains why reward is universal but mechanism varies so widely between drug classes.
| Phase | Brain region | What drives it |
|---|---|---|
| Binge / Intoxication | Basal ganglia (mesolimbic reward) | Positive reinforcement, the substance simply feels good |
| Withdrawal / Negative affect | Extended amygdala | Negative reinforcement, using to escape a dysphoric internal state rather than to chase euphoria |
| Preoccupation / Anticipation | Prefrontal cortex | Craving triggered by conditioned cues (a street corner, a smell); executive dysfunction makes resisting harder |
Early in the disease, dopamine release is tied to the drug itself. With repeated use, dopamine release shifts to the cues that predict the drug, a street corner, a lighter, a specific bar stool, not the drug itself. That's why cue-driven craving persists years into recovery and why avoiding triggers is a real clinical recommendation, not just common sense. It's also why a patient who says they drink to escape "darkness" or anxiety rather than for a buzz is telling you they've moved into the withdrawal/negative-affect phase, driven by negative reinforcement, not the binge phase.
Chronic alcohol (and benzodiazepine) exposure causes the brain to compensate: GABA receptors downregulate and glutamate (NMDA) signaling upregulatesto counteract the constant depressant effect. Pull the depressant away suddenly and that adaptation is left unopposed, leaving a hyperexcitable brain. That's the entire reason benzodiazepines (which boost GABA) are the treatment for alcohol withdrawal, and why acamprosate (which dampens glutamate and modulates GABA) helps sustain abstinence afterward.
Alcohol.One standard drink, 14 g of ethanol (12 oz beer, 5 oz wine, or 1.5 oz of 80-proof liquor), raises BAC by roughly 20–25 mg/dL in a healthy 70-kg adult. Absorption starts in the stomach within 5–10 minutes; peak concentration hits 30–90 minutes after the last drink. Metabolism runs through alcohol dehydrogenase to acetaldehyde, then aldehyde dehydrogenase to CO₂ and water (this pathway is exactly what disulfiram blocks).
| BAC (%) | Impairment | Effects |
|---|---|---|
| 0.0–0.05 | Mild | Mild speech/memory/coordination impairment, relaxation, sleepiness |
| 0.06–0.15 | Increased | Impaired coordination, aggression risk, significantly impaired driving, moderate memory impairment |
| 0.16–0.30 | Severe | Dangerously impaired judgment and driving, blackouts, vomiting, signs of alcohol poisoning, loss of consciousness |
| 0.31–0.45 | Life-threatening | Loss of consciousness, significant risk of death |
Death generally occurs at BAC >400–500 mg/dL(0.40–0.50%). A BAC of 150 mg/dL on a clinical lab report equals 0.15% on a legal report equals 34 mmol/L, three different units for the same number, and a favorite way to write a confusing exam question.
Benzodiazepines and other sedative-hypnotics.Intoxication looks like alcohol intoxication: slurred speech, poor coordination, swaying, drowsiness, hypotension, nystagmus, confusion. Withdrawal severity tracks dose and duration of use, and mirrors alcohol withdrawal. Short-acting agents (oxazepam, lorazepam, alprazolam) start withdrawing within 12–24 hours of the last dose. Long-half-life agents (diazepam, chlordiazepoxide, clorazepate, or their active metabolites, 24 to over 100 hours) can delay withdrawal onset up to 7 days.
Flunitrazepam (Rohypnol)is the classic "date rape" drug, given without the victim's knowledge to lower inhibitions. Zolpidemhas low reported dependence liability, but tolerance and withdrawal do occur. Carisoprodol(a muscle relaxant metabolized to meprobamate) overdoses and misuse present just like alcohol.
Nicotineis a ganglionic nicotinic-receptor agonist with dose-dependent effects: low doses sharpen alertness and cognition, higher doses hit the reward center. It also drives catecholamine release, vasoconstriction, and increased heart rate, blood pressure, and oxygen consumption. Cigarette smoking remains the leading cause of preventable death in the US. Abrupt cessation triggers withdrawal within 24 hours: anxiety, craving, poor concentration, irritability, hostility, insomnia, restlessness.
Cocainemay be the single most behaviorally reinforcing substance covered here, about 10% of "recreational" users progress to heavy use. It blocks reuptake of dopamine, norepinephrine, and serotonin (a "non-transported inhibitor," unlike amphetamines which are actively transported substrates that trigger reverse efflux of neurotransmitter). Intoxication: agitation, euphoria, talkativeness, diaphoresis or chills, nausea, tachycardia, arrhythmias, respiratory depression, mydriasis, blood pressure swings, seizures, nasal septum damage with chronic snorting. Withdrawal starts within hours and lasts days: fatigue, sleep disturbance, nightmares, depression, craving, appetite change, bradyarrhythmias, even MI.
Mixing cocaine with alcohol produces cocaethylene, a longer-acting metabolite with a greaterrisk of death than cocaine alone. Snorted cocaine's high lasts 15–30 minutes; smoked crack/rock is absorbed almost instantly and peaks in 5–10 minutes. Cocaine's own elimination half-life is only about 1 hour, tolerance to the high builds fast.
Methamphetaminelasts longer than cocaine and can be taken orally, rectally, intranasally, IV, or smoked; IV/inhaled routes give an intense rush within minutes. It's synthesized from pseudoephedrine/ephedrine, which is why those products sit behind the pharmacy counter with ID requirements. Intoxication: wakefulness, hyperactivity, decreased appetite, dental caries, hyperthermia, euphoria, irritability, insomnia, paranoia, aggression, seizures, stroke, death. Withdrawal (2 days to several months) brings depression, cognitive impairment, craving, and fatigue, usually without acute distress; if delirium shows up, suspect withdrawal from a differentsubstance like alcohol instead.
MDMA (Ecstasy/Molly)is usually swallowed as a tablet or capsule with 4–6 hour effects, though it can be smoked, snorted, or injected. It stimulates the CNS with euphoria, relaxation, and a mild hallucinogenic quality, but also muscle tension, nausea, impaired memory/attention, chills, sweating, panic, and paranoid thinking. It raises heart rate and BP and is neurotoxic to serotonin neurons.
Cannabis(THC is psychoactive, CBD is not) is usually smoked, with effects in about 10 minutes; oral ingestion peaks around 2 hours because both compounds are poorly bioavailable. Single-use terminal half-life is 24 hours, but chronic use elongates this dramatically from fat-tissue accumulation, THC stays detectable on screening for 4–5 weeks after a chronic user stops. Acute effects: tachycardia, dilated bronchi, bloodshot eyes, euphoria, dry mouth, hunger, tremor, anxiety, panic, poor recall, disinhibition, and possible toxic psychosis; adolescent brains appear especially vulnerable to neurotoxic effects. Heavy users who stop abruptly get a real withdrawal syndrome: irritability, anger, anxiety, depressed mood, sleep trouble, decreased appetite.
Cyclical, severe vomiting in habitual cannabis users that resolves only with discontinuation. Classic history: chronic heavy user, cyclical vomiting, and relief with hot showers or baths. Treat symptoms (antiemetics, haloperidol, topical capsaicin) but the actual fix is stopping cannabis.
LSDcan act as either agonist or antagonist at 5-HT receptors. Intoxication mixes physical signs (mydriasis, tachycardia, diaphoresis, tremor, incoordination) with psychiatric ones (perceptual intensification, depersonalization, derealization, psychosis, flashbacks). It produces tolerance but is not physically addictive and has no withdrawal syndrome, a classic distractor against the sedative/stimulant classes that do withdraw.
Synthetic cathinones ("bath salts")are Schedule I sympathomimetic designer drugs related to khat. Effects include tachycardia, hypertension, DKA, paranoid psychosis, hyperthermia, agitation, hyponatremia, and suicide risk. Flakka is a particularly potent example.
Inhaled organic solvents(gasoline, glue, aerosols, nitrites, cleaning products) contain nitrous oxide, toluene, benzene, and similar chemicals. Effects: CNS depression, headache, nausea, anxiety, hallucinations; chronic use is toxic to nearly every organ system, and death can come from arrhythmia or suffocation.
DSM-5 defines substance use disorder as a "problematic pattern of substance use leading to clinically significant impairment or distress," manifested by 2 or more of 11 criteria within a 12-month period. The criteria cluster into impaired control, social impairment, risky use, and pharmacologic effects (tolerance and withdrawal are only 2 of the 11, so a patient can meet criteria without ever having physical withdrawal).
| Tool | Substance | Notes |
|---|---|---|
| CAGE | Alcohol / sedative-hypnotics | 4-question screen (Cut down, Annoyed, Guilty, Eye-opener); a modified version exists for smoking behavior |
| AUDIT / USAUDIT | Alcohol | Alcohol Use Disorders Identification Test; the US-adapted version (USAUDIT) is likely more accurate for detecting unhealthy use in American populations |
| DAST-10 | General drug use | Screening only, not diagnostic; higher scores push toward outpatient or higher levels of intervention rather than "no action" |
| SBIRT | Alcohol / general substance use | Screening, Brief Intervention, Referral to Treatment; the framework most primary care and ED screening is built on |
| Amphetamine Withdrawal Questionnaire | Stimulants | Used alongside DAST-10 and modified CAGE for stimulant-specific screening |
Dual diagnosis (a co-occurring psychiatric condition alongside the SUD) is the norm, not the exception. The recommended framing shift is from "why did you do that?"to "what happened to you?"The goal is understanding drivers, building a trusting environment, and avoiding re-traumatization, not confrontation. It takes a team: therapists, counselors, the addiction medicine physician, and the pharmacist.
Withdrawal management always takes priority over long-term use-disorder treatment.You can't start a craving-reduction medication on a patient who's about to seize.
Symptom-triggered treatment is the standard of care.Give benzodiazepines when the patient has symptoms anda CIWA-AR score ≥8. Reassess hourly while dosing continues; once the patient looks stable with scores <8, stretch reassessment to every 4–8 hours. If CIWA-AR is ≥19, switch to front-loading: a long-acting benzodiazepine (diazepam 10–20 mg or chlordiazepoxide 100 mg) repeated every 1–2 hours until sedated. Underdosing is a far more common error than overdosing.
Lorazepam is favored when route flexibility matters (it works IV, IM, or oral with predictable kinetics) or in significant hepatic impairment, since it's metabolized by glucuronidation rather than oxidation. Fluid, electrolyte, and vitamin deficiencies need correcting alongside benzodiazepine therapy. Seizures don't automatically need antiseizure drugs, treat with more benzodiazepine (higher dose, slower taper, or a single injection) unless the patient progresses to status epilepticus or has an underlying seizure disorder.
| Nutritional / supportive | ||
| Multivitamin | 1 tablet, oral/IV | Until eating a balanced diet at caloric goal |
| Thiamine | 100 mg, oral/IV | Empiric 5 days minimum; longer if deficient |
| Crystalloid fluids | 50–100 mL/h (NS or D5-0.45NS + 20 mEq KCl/L) | Until intake/output stabilizes |
| Autonomic / agitation adjuncts | ||
| Clonidine | 0.05–0.3 mg oral or TTS-1 to TTS-3 transdermal | 3 days or less (oral); 1 week or less (patch) |
| Haloperidol | 2.5–5 mg every 2–4 h, oral/IV | For agitation or hallucinations unresponsive to benzodiazepines; watch the ECG |
| Quetiapine / Aripiprazole | 25–200 mg / 5–15 mg | 2nd-gen antipsychotic option, added to scheduled benzodiazepine |
| Dexmedetomidine | 0.2 mcg/kg/h IV, titrate | 5 days or less; adjunct for autonomic hyperactivity |
| Phenobarbital | 30–260 mg oral/IV | 5 days or less; promotes GABA-A binding as a BZD adjunct |
| Benzodiazepines (the backbone of treatment) | ||
| Lorazepam (Ativan) | 0.5–8 mg oral/IV/IM | Dose to CIWA-AR; underdosing more common than overdosing |
| Chlordiazepoxide (Librium) | 25–300 mg oral | Long-acting, self-tapering |
| Diazepam (Valium) | 5–40 mg oral/IV/IM | Long-acting; used for front-loading |
| Oxazepam (Serax) | 15–30 mg oral | Short-acting; consider in significant hepatic impairment |
Three agents are FDA-approved. Duration of therapy depends on response, tolerability, patient preference, relapse history, and severity, there's no fixed endpoint.
Aldehyde dehydrogenase inhibitor. Drinking on it causes a genuinely aversive reaction.
Opioid antagonist. "Takes the fun out of drinking" by blocking mu-receptor-mediated reward.
Glutamate modulator. Smooths over the post-withdrawal GABA/glutamate imbalance and reduces craving.
Blocking aldehyde dehydrogenase lets acetaldehyde accumulate: flushing, vomiting, headache, palpitations, tachycardia, fever, hypotension. Severe reactions include respiratory depression, arrhythmia, MI, seizures, and death. The enzyme stays inhibited for up to 2 weeksafter the last dose, so the risk doesn't end when the pill stops. Get baseline LFTs, repeat at 2 weeks, 3 months, 6 months, then twice yearly, and wait at least 24 hours after the last drink before starting. Disulfiram takes a highly motivated patient with a strong support system, it works through fear of the reaction, not a neurobiological anti-craving effect.
Never give to a patient currently taking opioids, it precipitates severe, immediate opioid withdrawal. It's hepatotoxic and contraindicated with hepatitis, liver failure, or transaminases >5x normal, get baseline LFTs and repeat at 1–3 months then annually. Use cautiously with moderate-to-severe renal impairment. Common adverse effects: nausea, headache, dizziness, nervousness, insomnia, somnolence.
These pairs are exactly how exams test this section. Elevated LFTs / hepatic disease→ avoid naltrexone (hepatotoxic) → acamprosateis the answer (renally cleared, not hepatically). Significant renal impairment (e.g., CrCl <30)→ avoid acamprosate (renal elimination, needs dose adjustment or avoidance) → naltrexoneor disulfiram becomes the fallback. Patient wants to cut down, not quit entirely→ naltrexone is the only one of the three studied for reducing heavy drinking days rather than requiring full abstinence. Patient wants a hard deterrent for a specific event(a wedding, a trigger environment) → disulfiram.
| FDA-approved | ||
| Disulfiram (Antabuse) | 125–500 mg/day; caution in hepatic disease | Facial flushing on exposure, liver enzymes |
| Acamprosate (Campral) | 999–1998 mg/day and higher (333 mg tabs); adjust in renal impairment | Patient-reported craving, renal function; most common AE is diarrhea |
| Naltrexone oral (ReVia) | 50–100 mg/day; adjust in renal/hepatic impairment | Patient-reported craving |
| Naltrexone depot (Vivitrol) | 380 mg IM every 4 weeks | Craving, liver enzymes, injection-site reactions |
| Off-label, craving-directed | ||
| Antiseizure meds(topiramate, carbamazepine, valproic acid, gabapentin, oxcarbazepine) | Standard seizure-disorder doses | Craving, plasma drug levels |
| Antidepressants(fluoxetine, amitriptyline, citalopram, sertraline) | Standard depression doses | Craving, depression, anxiety symptoms |
GLP-1 receptor agonists (semaglutide, liraglutide) act on receptors in the hypothalamus andthe mesolimbic reward pathway (VTA/NAc), dampening hedonic drive. Preclinical and early clinical signals suggest reduced craving and heavy drinking days, plus possible benefit across nicotine, cannabis, and opioid use. This is not yet a guideline-directed AUD therapy, evidence is preliminary, cost and access are real barriers, and GI effects (nausea, vomiting, diarrhea), pancreatitis, and sarcopenia (muscle loss, particularly relevant in patients with nutritional deficits from heavy drinking) all need monitoring. Know it as a "why is this emerging" concept, not a first-line answer.
The USPSTF/AHRQ framework is the 5 A's: Ask about tobacco use, Advise to quit with a clear individualized message, Assess willingness to quit, Assist in quitting, Arrange follow-up. Even a <3-minute contact using the 5 A's beats no intervention. The USPSTF goal is at least 4 in-person counseling sessions totaling 90–300 minutes; motivational interviewing adds moderate benefit on top of other approaches. Counseling plus pharmacotherapy outperforms either alone.
First-line:NRT, bupropion SR, and varenicline, alone or combined if a single agent fails. Second-line(used if first-line fails): clonidine and nortriptyline.
| Nicotine Replacement Therapy (all OTC except inhaler and nasal spray, which are Rx) | ||
| Patch | >10 cigs/day: 21 mg × 6 wk → 14 mg × 2 wk → 7 mg × 2 wk. <10 cigs/day: start at 14 mg | 8–10 weeks; highest adherence of all NRT; remove at night if it disrupts sleep, or use the 16-hour patch |
| Gum | 4 mg if first cigarette ≤30 min after waking, 2 mg if >30 min. Taper frequency over 12 weeks. Max 24 pieces/day | 12 weeks; chew until peppery/minty, then "park" in the cheek; 4 mg more effective in heavy smokers |
| Lozenge | Same 4 mg / 2 mg split by time-to-first-cigarette. Max 5 in 6 hours or 20/day | 12 weeks; dissolve over 20–30 min, don't chew or swallow |
| Oral inhaler (Nicotrol) | 6–16 cartridges/day (10 mg nicotine each, ~2 mg absorbed), taper after 6 weeks | Up to 6 months; not studied beyond that; caution in reactive airway disease |
| Nasal spray (Nicotrol NS) | 1–2 sprays/nostril hourly as needed, max 10 sprays/hour (80/day); ≥16 sprays/day for best results | 3–6 months; more than doubles long-term abstinence vs. placebo; Pregnancy Category D |
| Non-nicotine, first-line | ||
| Bupropion SR (Zyban) | 150 mg daily × 3 days, then 150 mg BID (>8 h apart); max 300 mg/day | 3–6 months; start 1–2 weeks before quit day; no taper needed to stop |
| Varenicline (Chantix) | 0.5 mg daily × 3 days → 0.5 mg BID × 4 days → 1 mg BID from week 2 | 12 weeks (may extend another 12); take with food/full glass of water; adjust for CrCl ≤30 |
| Second-line (after first-line failure) | ||
| Clonidine | 0.15–0.75 mg/day oral, or 0.1–0.2 mg/day transdermal | Monitor BP; abrupt stop can rebound HTN, agitation, tremor |
| Nortriptyline | Start 25 mg/day, up-titrate to 75–100 mg/day; start 10–28 days before quit date | Commonly used ~12 weeks; sedation, dry mouth, blurred vision, urinary retention |
Absolute: current or past seizure disorder, current or prior bulimia/anorexia nervosa, and an MAOI within the last 14 days. Be careful stacking with anything else that lowers seizure threshold. Neuropsychiatric black-box language (depression, agitation, suicidal thoughts) was downgraded to a standard warning in 2016 for both bupropion and varenicline, but the warning to screen for psychiatric history and monitor for mood/behavior change is still current practice.
It's a partial agonistat α4β2 nicotinic receptors: enough activation to blunt withdrawal and craving, but with higher receptor affinity than nicotine itself, so if the patient smokes anyway, nicotine can't fully bind and the reward is blunted too. It may outperform bupropion and single-agent NRT, and combining either bupropion or varenicline with NRT can boost efficacy further, at the cost of more adverse effects. Most common varenicline AEs: nausea, sleep problems, constipation, gas, vomiting; consider a dose reduction for insomnia.
Evidence for tobacco pharmacotherapy in pregnancy is currently insufficient to weigh benefit against harm per USPSTF. Electronic nicotine delivery systems (vapes/e-cigarettes)remain controversial with limited long-term safety data; EVALI (e-cigarette or vaping-associated lung injury) has been linked mostly to THC-containing vape products.
There is currently no FDA-approved medicationfor cocaine, methamphetamine, or MDMA use disorder. Management is supportive: active monitoring of vital organ function during acute toxicity, and ongoing psychosocial/educational support for the chronic disorder. This is a straightforward, high-yield fact and a common "trick" answer choice (don't invent a drug that doesn't exist here).
Cannabis use disorderis notoriously hard to treat, marked by repeated failed quit attempts. Nonpharmacologic therapy is the backbone: cognitive behavioral therapy and motivational enhancement therapy, which work synergistically together. There's no approved medication, but a few agents have shown some success for withdrawal symptoms specifically, and more research is needed for all of them:
Tolerance develops fast, and cross-tolerance extends to other serotonergic hallucinogens (psilocybin, mescaline) but not to drugs acting on different systems (marijuana, amphetamines, PCP). Critically: no withdrawal syndrome exists for LSD.If a question describes a withdrawal picture, the answer isn't LSD.
For synthetic cathinones and inhalant toxicity, management is the same principle as stimulants and other CNS toxidromes: supportive care, monitor vital organ function, no substance-specific antidote or approved use-disorder medication.
| Parameter | When | Watching for |
|---|---|---|
| CIWA-AR score | Hourly during active alcohol withdrawal treatment; stretch to q4–8h once stable and <8 | Escalating symptoms needing more benzodiazepine, or safe taper |
| LFTs | Baseline, then 2 wk/3 mo/6 mo/twice yearly on disulfiram; baseline then 1–3 mo then annually on naltrexone | Hepatotoxicity, disulfiram-alcohol reaction severity |
| Renal function | Baseline and periodically on acamprosate, naltrexone | Need for dose adjustment or avoidance |
| Vital signs / ECG | During any withdrawal (alcohol, benzo) and stimulant intoxication | Autonomic instability, arrhythmia, hypertensive urgency |
| Patient-reported craving | Every visit on any AUD medication | Treatment response, need to adjust or switch agent |
| Weight / nutrition | Ongoing, especially early in alcohol treatment | Thiamine/vitamin deficiency, refeeding needs |
| Mood / suicidality | Each visit on bupropion, varenicline, or during any withdrawal | Neuropsychiatric adverse effects, dual-diagnosis decompensation |
| Smoking status / quit date adherence | Every visit during cessation pharmacotherapy | Slips, breakthrough cravings, need to combine agents |