Step 1 · Neurology & Psychiatry

Substance Use & Neuropharmacology of Abuse

Name: Substance Use & Neuropharmacology of Abuse
Creator: Veli Bakalov, MD

Which withdrawals can kill, which antidotes to reach for, and the dopamine that drives them all

Neurology & Psychiatry·Psychiatric Disorders·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Every drug of abuse raises dopamine in the mesolimbic reward pathway (ventral tegmental area → nucleus accumbens).
Alcohol and sedative-hypnotic withdrawal can be lethal (seizures, delirium tremens); opioid and stimulant withdrawal are miserable but not lethal.
Alcohol withdrawal: tremor at 6–24 h, seizures and hallucinosis at 12–48 h, delirium tremens at 48–96 h; treat all stages with benzodiazepines.
Wernicke (confusion, ophthalmoplegia, ataxia) is reversible, whereas Korsakoff (anterograde amnesia, confabulation, mammillary body damage) is not; give thiamine before glucose.
Opioid intoxication = miosis, respiratory depression and constipation (reverse with naloxone); withdrawal = mydriasis, lacrimation, yawning, piloerection and diarrhea (methadone, buprenorphine or clonidine).
Naloxone is the short-acting antagonist for acute reversal; naltrexone is the long-acting antagonist for maintenance in opioid and alcohol use disorder.
Benzodiazepines increase GABA-A channel opening frequency and barbiturates increase opening duration; flumazenil reverses benzodiazepines but can precipitate seizures.
Cocaine blocks dopamine, norepinephrine and serotonin reuptake and causes coronary vasospasm; treat with benzodiazepines, nitrates and aspirin, and avoid nonselective β-blockers.
PCP (NMDA antagonist): violence, multidirectional nystagmus and analgesia; cannabis: red eyes, increased appetite, and hyperemesis relieved by hot showers; varenicline is the most effective smoking-cessation aid.

Reward circuitry and the intoxication–withdrawal pattern

The final common pathway. Dopaminergic neurons in the ventral tegmental area (VTA) project to the nucleus accumbens, forming the mesolimbic reward circuit. Every drug of abuse ultimately raises dopamine release in the accumbens, and that surge reinforces further use.

Ventral tegmental areaDopaminergic cell bodies
Dopamine releaseEvery abused drug raises it, directly or indirectly
Nucleus accumbensReward and reinforcement

Withdrawal mirrors intoxication. Chronic exposure makes the brain adapt against the drug, so stopping it unmasks the opposite state. Depressants produce hyperexcitable withdrawal, and stimulants produce a crash. The key safety rule is that alcohol and sedative-hypnotic withdrawal can kill through seizures and delirium tremens. Opioid and stimulant withdrawal are miserable but not lethal.

Intoxication vs withdrawal by drug class

Drug	Mechanism	Intoxication	Withdrawal
Alcohol	Potentiates GABA-A, inhibits NMDA	Disinhibition, slurred speech, ataxia, nystagmus, then CNS and respiratory depression	Tremor, seizures, hallucinosis, delirium tremens; can be lethal
Benzodiazepines, barbiturates	Potentiate GABA-A	CNS and respiratory depression, worse with alcohol	Like alcohol, including seizures; can be lethal
Opioids	μ-opioid receptor agonists	Miosis, respiratory depression, decreased consciousness, constipation, bradycardia	Mydriasis, lacrimation, rhinorrhea, yawning, piloerection, diarrhea, myalgias; not lethal
Cocaine, amphetamines	Increase synaptic dopamine, norepinephrine and serotonin	Euphoria, mydriasis, hypertension, tachycardia, hyperthermia, agitation	Crash: hypersomnia, depression, hyperphagia, craving; not lethal
Cannabis	THC acts at CB1 receptors	Euphoria, red eyes, increased appetite, dry mouth, tachycardia	Mild: irritability, insomnia, decreased appetite
LSD	Serotonin 5-HT2A agonist	Perceptual distortions, visual hallucinations	No true physiologic withdrawal

Alcohol

GABA up, NMDA down. Alcohol potentiates GABA-A receptors and inhibits NMDA glutamate receptors. It causes disinhibition, slurred speech, ataxia and nystagmus at lower levels, then CNS and respiratory depression. Chronic use causes liver disease, pancreatitis and cardiomyopathy. Combined with thiamine deficiency, it also causes Wernicke-Korsakoff syndrome. With chronic use, GABA-A receptors downregulate and NMDA receptors upregulate. Sudden abstinence therefore leaves the brain hyperexcitable.

6–24 hoursTremor, anxiety, insomnia, diaphoresis
12–48 hoursWithdrawal seizures (generalized tonic-clonic)
12–48 hoursAlcoholic hallucinosis: usually visual, with a clear sensorium
48–96 hoursDelirium tremens: autonomic instability, confusion, hallucinations, high mortality

Treating withdrawal. Benzodiazepines are the treatment across the whole spectrum, including delirium tremens (e.g., lorazepam), because they replace the missing GABA-A tone and prevent seizures and death. Long-acting agents such as chlordiazepoxide or diazepam are common choices. Lorazepam or oxazepam is preferred in liver disease because neither has active metabolites.

Wernicke-Korsakoff. Wernicke encephalopathy comes from thiamine (vitamin B1) deficiency. It is the triad of confusion, ophthalmoplegia and ataxia, and it is reversible. Untreated, it progresses to Korsakoff syndrome, with irreversible anterograde amnesia, confabulation and damage to the mammillary bodies. Thiamine is a cofactor for pyruvate dehydrogenase, α-ketoglutarate dehydrogenase and transketolase. A glucose load uses up the little thiamine that remains.

Give thiamine before glucose. Glucose given first can precipitate or worsen Wernicke encephalopathy.

Maintenance for alcohol use disorder. Naltrexone reduces craving and relapse. Acamprosate (an NMDA modulator) and disulfiram (an aldehyde dehydrogenase inhibitor that makes drinking unpleasant) are the other classic options.

Opioids and sedative-hypnotics

Opioid intoxication: pinpoint and apneic. Opioids cause miosis (pinpoint pupils), respiratory depression, decreased consciousness, decreased bowel sounds with constipation, and bradycardia. Overdose kills through apnea and is reversed with naloxone. Tolerance develops to most effects, but not to miosis or constipation. Because naloxone is short-acting, a long-acting opioid such as methadone can re-sedate the patient after the dose wears off.

Opioid withdrawal: miserable, not lethal. Withdrawal causes mydriasis, lacrimation, rhinorrhea, yawning, piloerection ("cold turkey"), diarrhea, myalgias and flu-like symptoms. Manage it with the opioid agonists methadone or buprenorphine, or give clonidine for the autonomic symptoms.

Opioid-related agents

Agent	Action	Main use
Naloxone	Short-acting antagonist (IV, intranasal)	Acute overdose reversal; restores breathing quickly
Naltrexone	Long-acting antagonist (oral, IM)	Maintenance in opioid and alcohol use disorder; reduces craving and relapse
Methadone	Long-acting full μ agonist	Withdrawal management and maintenance
Buprenorphine	Partial μ agonist	Withdrawal management and maintenance
Clonidine	α2 agonist	Autonomic symptoms of withdrawal

Naltrexone, or buprenorphine given while a full agonist is still on board, can precipitate withdrawal in a dependent patient.

Sedative-hypnotics. Benzodiazepines increase how often the GABA-A chloride channel opens, whereas barbiturates prolong each opening. At high doses, barbiturates can open the channel directly. That is why they are especially lethal in overdose, and both classes are more dangerous combined with alcohol. Flumazenil reverses benzodiazepine overdose, but it can precipitate seizures in chronic users. As with alcohol, sedative withdrawal can cause seizures and is dangerous.

Stimulants and nicotine

Stimulants dilate and speed up. Cocaine and amphetamines cause euphoria, mydriasis, hypertension, tachycardia, hyperthermia and agitation, with a risk of MI, arrhythmia and seizure. Cocaine blocks the reuptake of dopamine, norepinephrine and serotonin. Amphetamines mainly drive catecholamine release. Stimulant withdrawal is a crash of fatigue, hypersomnia, depression, hyperphagia and craving. It is unpleasant but not life-threatening.

Cocaine-specific harms. Cocaine causes coronary vasospasm and MI, hypertension and nasal septum perforation, and it can trigger placental abruption. Treat agitation and cardiac symptoms with benzodiazepines. For chest pain, add nitrates and aspirin.

Classic teaching is to avoid nonselective β-blockers such as propranolol in cocaine toxicity, because unopposed α-adrenergic stimulation worsens coronary vasoconstriction.

Nicotine and caffeine. Nicotine acts at nicotinic acetylcholine receptors. Withdrawal brings irritability, anxiety, restlessness and intense craving. Cessation aids are varenicline (a partial nicotinic agonist and the most effective single agent), bupropion and nicotine replacement. Bupropion is avoided in seizure and eating disorders because it lowers the seizure threshold. Caffeine withdrawal causes headache and fatigue.

Cannabis and hallucinogens

Cannabis. THC acts at CB1 receptors to produce euphoria, conjunctival injection (red eyes), increased appetite, dry mouth, tachycardia, a slowed sense of time and impaired coordination. Withdrawal is mild, with irritability, insomnia and decreased appetite. Heavy chronic use can cause cannabinoid hyperemesis syndrome.

Cannabinoid hyperemesis syndrome is cyclic vomiting in a chronic user that is characteristically relieved by hot showers.

LSD. LSD causes perceptual distortions and visual hallucinations and has no true physiologic withdrawal.

PCP (phencyclidine). PCP is an NMDA-receptor antagonist. It causes violent, agitated behavior, nystagmus that can be vertical, horizontal or rotary, analgesia, hyperthermia and dissociation. Violence, multidirectional nystagmus and analgesia together point to PCP.