Substance Use Disorders

Genetic and biological (non-modifiable)

• Family history: a first-degree relative with a substance use disorder is the single most consistently tested risk factor; heritability operates through reward-pathway signaling rather than through any single gene.
• Protective and permissive metabolic variants: the *ALDH2\*2* allele common in East Asian populations causes acetaldehyde accumulation with flushing, nausea, and tachycardia after alcohol — a pharmacologic disulfiram-like effect that lowers alcohol use disorder risk. Rapid nicotine metabolizers (CYP2A6) smoke more heavily.
• Male sex: higher prevalence of most SUDs, though women progress from first use to dependence more rapidly (telescoping).
• Adolescent exposure: the prefrontal cortex matures last, so use before age 15 acts on a brain with immature executive control and markedly raises lifetime risk.

Psychiatric mechanisms (partly modifiable)

• Comorbid mental illness: mood, anxiety, PTSD, ADHD, and psychotic disorders all raise risk; self-medication of negative affect couples relief to use, reinforcing the loop. Untreated ADHD and conduct disorder are classic stem details.
• Impulsivity and externalizing traits: predict earlier onset and polysubstance use.

Environmental and social (modifiable)

• Adverse childhood experiences: abuse, neglect, and parental substance use produce chronic stress-axis activation that potentiates drug reinforcement.
• Peer use, availability, and low-cost access: proximal drivers of initiation.
• Social determinants: unstable housing, unemployment, incarceration, and limited treatment access sustain use.

Iatrogenic and exposure-related (modifiable)

• Prescription opioid exposure: high-dose or prolonged therapy after surgery or injury is the classic gateway in opioid use disorder stems; the CDC 2022 Clinical Practice Guideline for Prescribing Opioids for Pain urges lowest effective dose, avoidance of concurrent benzodiazepines, and reassessment before continuing.
• Chronic pain syndromes and benzodiazepine or stimulant prescribing without monitoring.
• Occupational access: health professionals with drug access (propofol, fentanyl) are a favored stem device.

• Dopamine dysregulation in reward circuitry: Addictive substances increase dopamine in the nucleus accumbens and ventral tegmental area (VTA), creating powerful reinforcement mechanisms; chronic use leads to dopamine receptor downregulation (decreased D2 receptor expression) and tolerance, requiring escalating doses to achieve the same effect

• Neuroadaptation and allostatic load: Repeated substance exposure causes homeostatic adjustments in receptor density, intracellular signaling cascades (cAMP, protein kinase A), and neurotransmitter systems; the brain adapts to counteract drug-induced changes, creating a new "set point" that requires continued use to maintain baseline function

• Limbic system sensitization: The amygdala and hippocampus become hypersensitive to drug-related cues, creating powerful conditioned responses and craving; simultaneously, prefrontal cortex function diminishes, reducing impulse control and decision-making capacity

• Glutamatergic and GABAergic changes: Chronic substance use alters excitatory (glutamate) and inhibitory (GABA) neurotransmission; withdrawal states result from loss of compensatory inhibition, manifesting as hyperexcitability and autonomic dysregulation

• Genetic predisposition: Heritability accounts for 40-60% of SUD risk; variations in genes encoding dopamine receptors (DRD2), catechol-O-methyltransferase (COMT), and opioid receptors (OPRM1) influence vulnerability

• Prefrontal cortex dysfunction: Addiction involves decreased gray matter in the dorsolateral prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex, impairing executive function, decision-making, and impulse inhibition even during abstinence

• Tolerance and withdrawal: Patients require escalating doses to achieve desired effects; characteristic withdrawal syndromes vary by substance class (opioid withdrawal causes mydriasis, rhinorrhea, and GI symptoms; alcohol withdrawal causes tremor, autonomic hyperactivity, and seizures)

• Loss of control and continued use despite consequences: Classic presentation includes failed attempts to cut down, continued use despite knowing problems it causes (job loss, relationship deterioration, legal issues), and progressive neglect of other activities

• Cravings and compulsive drug-seeking behavior: Intense psychological urges to use, especially triggered by environmental cues, social situations, or emotional distress; patients often describe an inability to resist despite strong intentions to abstain

• Behavioral and personality changes: Mood instability, irritability, anxiety, depression, social withdrawal, and neglect of hygiene and appearance; financial problems, legal troubles, and deception about substance use patterns

• Physical examination findings vary by substance:
• Opioids: miosis (pinpoint pupils), shallow respirations, track marks, abscesses
• Stimulants: tachycardia, hypertension, mydriasis, nasal septal perforation (cocaine), dental decay ("meth mouth")
• Alcohol: hepatomegaly, asterixis, neuropathy, gynecomastia
• Cannabis: conjunctival injection, amotivational syndrome

• Intoxication vs. withdrawal presentations: Intoxication (acute drug effect) differs markedly from withdrawal (absence of substance); recognizing both is critical as they present opposite clinical pictures (e.g., opioid intoxication causes sedation and miosis, while withdrawal causes agitation and mydriasis)

• DSM-5 Criteria: Diagnosis requires ≥2 of 11 criteria within 12 months, including tolerance, withdrawal, using more than intended, persistent desire to cut down, excessive time obtaining/using substance, failure to fulfill obligations, continued use despite consequences, risky use, social/occupational impairment, tolerance, and withdrawal; severity rated as mild (2-3), moderate (4-5), or severe (6+)

• Substance-specific screening tools:
• AUDIT (Alcohol Use Disorders Identification Test): 10-item screening for alcohol use; score ≥8 suggests hazardous drinking
• DAST-10 (Drug Abuse Screening Test): Validated 10-item tool for non-alcohol substance use
• CAGE questionnaire (Cut down, Annoyed, Guilty, Eye-opener): Quick 4-item screen for alcohol use disorder, though less specific than AUDIT

• Urine drug screens (UDS): Detects recent use of common substances; standard panels include opioids, cocaine, amphetamines, cannabinoids, benzodiazepines; immunoassay followed by confirmation with gas chromatography-mass spectrometry (GC-MS) for positive results; limitations include variable detection windows (THC weeks, stimulants 2-3 days) and false positives/negatives

• Laboratory markers for alcohol use:
• Elevated liver enzymes (AST, ALT, GGT) and elevated mean corpuscular volume (MCV) suggest chronic use
• Carbohydrate-deficient transferrin (CDT) and phosphatidylethanol (PEth) are more specific biomarkers with longer detection windows
• Elevated AST/ALT ratio (typically >2:1) is classic for alcoholic liver disease

• Clinical presentation and collateral history: Often diagnosis relies on clinical judgment; collateral information from family, employers, or previous medical records is invaluable; observe for stigmata of chronic use and comorbid conditions

• Assessment of withdrawal risk: Detailed history of previous withdrawals, seizures, or delirium tremens; vital signs, mental status exam, and use of CIWA-Ar (Clinical Institute Withdrawal Assessment for Alcohol Scale) help quantify alcohol withdrawal severity

General Principles

• Comprehensive biopsychosocial approach addressing medical, psychiatric, social, and spiritual needs
• Motivational interviewing and evidence-based psychotherapy as foundation
• Pharmacotherapy when indicated, combined with behavioral interventions

First-Line Treatments by Substance Class

Alcohol Use Disorder

• Naltrexone (50 mg daily or 380 mg IM monthly): Opioid antagonist reducing reward; reduces cravings and heavy drinking days; contraindicated in acute hepatitis or opioid use
• Acamprosate (666 mg three times daily): Restores glutamatergic-GABAergic balance; particularly effective for maintaining abstinence; safe in liver disease
• Disulfiram (250 mg daily): Produces aversive reaction with alcohol (flushing, nausea, chest pain, hypotension); requires motivation and monitoring; monitor LFTs

Opioid Use Disorder (OUD)

• Methadone (titrated to 60-120 mg daily): Full mu-opioid agonist; excellent retention rates; requires daily observed dosing at licensed clinics; long half-life prevents withdrawal
• Buprenorphine (8-24 mg daily, often combined with naloxone): Partial mu-opioid agonist with lower overdose risk; can be prescribed in office-based settings; ceiling effect on respiratory depression makes it safer than full agonists
• Naltrexone extended-release (380 mg IM monthly): Opioid antagonist for highly motivated patients; prevents relapse but requires complete detoxification first

Stimulant Use Disorder (cocaine/methamphetamine)

• No FDA-approved pharmacotherapy with proven efficacy; treatment relies on psychotherapy and behavioral interventions
• Contingency management: Incentivizing abstinence with vouchers or rewards; highly effective for stimulant use
• Consider bupropion or **moda

Withdrawal emergencies

• Delirium tremens (EMERGENCY): unopposed glutamatergic hyperexcitability after abrupt cessation in a physiologically dependent drinker; onset typically 2–4 days after the last drink with clouded sensorium, hallucinations, fever, and severe autonomic instability. Untreated mortality is substantial. Treat with escalating benzodiazepines guided by CIWA-Ar or a symptom-triggered protocol, per the ASAM Clinical Practice Guideline on Alcohol Withdrawal Management; phenobarbital or ICU-level dexmedetomidine adjuncts for benzodiazepine-refractory cases.
• Withdrawal seizures (EMERGENCY): generalized tonic–clonic, usually within the first ~2 days; phenytoin does not prevent them — benzodiazepines do.
• Sedative-hypnotic/barbiturate withdrawal carries the same lethal potential. Opioid withdrawal is miserable but not lethal in adults; it is dangerous in the fetus and in neonates (neonatal opioid withdrawal syndrome).

Complications of the substance itself

• Wernicke encephalopathy → Korsakoff syndrome (EMERGENCY): thiamine-dependent transketolase failure; confusion, ophthalmoplegia, ataxia progressing to irreversible anterograde amnesia with confabulation.
• Hepatic and GI: alcohol-associated hepatitis, cirrhosis with variceal bleeding and encephalopathy (AASLD), pancreatitis, Mallory–Weiss tears.
• Infectious (injection drug use): right-sided tricuspid endocarditis, epidural abscess, osteomyelitis, HIV, hepatitis C.
• Cardiopulmonary: dilated cardiomyopathy and atrial fibrillation (holiday heart) with alcohol; cocaine-induced coronary vasospasm, aortic dissection, and hypertensive emergency; stimulant hyperthermia and rhabdomyolysis.
• Opioid overdose (EMERGENCY): mu-receptor suppression of brainstem chemoreceptor drive → bradypnea, miosis, coma; naloxone reverses it.

Treatment-related complications

• Precipitated withdrawal: buprenorphine (high-affinity partial agonist) or naltrexone displacing a full agonist causes abrupt severe withdrawal — dose buprenorphine only in objective withdrawal (COWS-guided), and require an opioid-free interval before extended-release naltrexone (ASAM National Practice Guideline for the Treatment of Opioid Use Disorder).
• Methadone: QT prolongation and torsades; respiratory depression during induction because full analgesic effect precedes peak plasma levels.
• Disulfiram–ethanol reaction: acetaldehyde accumulation with flushing, vomiting, hypotension — can be severe.
• Naltrexone: hepatotoxicity risk and blocked analgesia in emergencies.
• Loss of tolerance after detox or incarceration markedly raises fatal overdose risk on relapse.

• Timeline is the diagnosis in alcohol withdrawal: tremor/anxiety within hours, alcoholic hallucinosis with an intact sensorium around day 1, seizures in the first ~2 days, and delirium tremens with clouded sensorium and autonomic storm around days 2–4. Hallucinations with a clear sensorium are not DTs — a favorite distractor.
• Symptom-triggered benzodiazepines beat fixed-schedule dosing (ASAM alcohol withdrawal guideline) and reduce total drug exposure. In cirrhosis or advanced liver disease, choose agents without oxidative hepatic metabolism — lorazepam, oxazepam, temazepam (the "LOT" drugs).
• Thiamine before glucose. Giving dextrose first to a malnourished drinker can precipitate Wernicke encephalopathy by consuming residual thiamine.
• Single best next step in suspected opioid overdose: support ventilation and give naloxone; the triad is miosis, bradypnea, and depressed consciousness. Naloxone's half-life is shorter than that of methadone or long-acting opioids, so re-sedation and repeat dosing/infusion are expected.
• Buprenorphine induction requires objective withdrawal (COWS-guided) — its high receptor affinity and partial agonism will otherwise displace a full agonist and precipitate withdrawal. The ceiling on respiratory depression makes it the safer office-based option; methadone remains restricted to opioid treatment programs.
• Pregnancy: buprenorphine or methadone are the standard of care for opioid use disorder (ACOG and SAMHSA); medically supervised withdrawal is discouraged because relapse and fetal risk are high. Expect neonatal opioid withdrawal syndrome and manage it — do not withhold maternal treatment to prevent it.
• Co-prescribe naloxone to patients on opioids at elevated overdose risk (CDC 2022 opioid prescribing guideline), and remember that post-detox or post-incarceration loss of tolerance is when overdose deaths cluster.
• Distractors to avoid: phenytoin for withdrawal seizures, flumazenil in a benzodiazepine-dependent patient (can precipitate refractory seizures), beta blockers as monotherapy for cocaine chest pain (benzodiazepines plus nitrates first), and naltrexone in anyone still using opioids.