Pharmacology of Drugs of Abuse and Addiction

Introduction/Overview

The pharmacology of drugs of abuse encompasses the study of substances that are used non-medically for their psychoactive effects, leading to a high potential for dependence and addiction. This field integrates principles of neuropharmacology, pharmacokinetics, and clinical medicine to understand how these substances alter brain function and behavior. Substance use disorders represent a significant global public health challenge, contributing to substantial morbidity, mortality, and socioeconomic burden. A thorough understanding of their pharmacology is essential for healthcare professionals to effectively diagnose, manage, and counsel patients.

The clinical relevance of this topic is paramount. Patients with substance use disorders frequently present across all healthcare settings, often with co-morbid medical and psychiatric conditions. Knowledge of the specific pharmacodynamic actions and pharmacokinetic profiles of abused substances informs clinical decisions regarding acute intoxication management, withdrawal syndrome treatment, relapse prevention, and harm reduction strategies. Furthermore, several drugs with high abuse potential retain important therapeutic roles when used under strict medical supervision, necessitating a nuanced understanding of their risk-benefit profile.

Learning Objectives

• Classify major drugs of abuse according to their primary pharmacological action and chemical structure.
• Explain the neurobiological mechanisms underlying reinforcement, tolerance, dependence, and addiction, with emphasis on the mesolimbic dopamine pathway and associated neural circuits.
• Compare and contrast the pharmacokinetic properties, including routes of administration, metabolism, and elimination, of major drug classes.
• Describe the acute and chronic clinical effects, adverse reaction profiles, and principles for managing intoxication and withdrawal for each drug class.
• Identify special population considerations and major drug interactions relevant to substances of abuse.

Classification

Drugs of abuse can be classified according to their primary pharmacological effect, chemical structure, or legal status. A pharmacologically-based classification is most useful for understanding clinical effects and mechanisms. The following categorization is widely utilized.

Central Nervous System Depressants

These agents produce sedation, anxiolysis, and, at higher doses, general anesthesia or coma. Their use is characterized by the development of tolerance and a potentially life-threatening withdrawal syndrome.

• Ethanol: A simple alcohol (ethyl alcohol).
• Barbiturates: e.g., phenobarbital, secobarbital. Derivatives of barbituric acid.
• Benzodiazepines: e.g., diazepam, alprazolam, clonazepam. Characterized by a benzene ring fused to a diazepine ring.
• Non-Benzodiazepine Sedative-Hypnotics (“Z-drugs”): e.g., zolpidem, zaleplon. Structurally distinct but share a similar mechanism.
• Gamma-Hydroxybutyrate (GHB): A short-chain fatty acid.

Central Nervous System Stimulants

These drugs increase alertness, arousal, and motor activity, often producing euphoria. They are associated with strong reinforcing properties and psychological dependence.

• Amphetamines: e.g., dextroamphetamine, methamphetamine. Phenethylamine derivatives.
• Cocaine: A tropane alkaloid ester derived from the coca plant.
• Synthetic Cathinones (“Bath Salts”): e.g., mephedrone, methylone. Structurally related to cathinone from the khat plant.
• Nicotine: A pyridine alkaloid.
• Caffeine: A methylxanthine alkaloid.

Opioids

This class includes natural, semi-synthetic, and fully synthetic agents that produce analgesia and euphoria by acting at opioid receptors. They are associated with high rates of physical dependence and overdose mortality.

• Natural Opiates: e.g., morphine, codeine (derived from the opium poppy).
• Semi-synthetic Opioids: e.g., heroin (diacetylmorphine), oxycodone, hydrocodone.
• Fully Synthetic Opioids: e.g., fentanyl, methadone, tramadol.

Hallucinogens

These substances alter perception, thought, and emotion, often inducing visual or auditory distortions. Their potential for producing classic physical dependence is generally lower, though psychological dependence can occur.

• Classical Hallucinogens (5-HT_2A agonists): e.g., lysergic acid diethylamide (LSD), psilocybin, mescaline.
• Dissociative Anesthetics: e.g., phencyclidine (PCP), ketamine. Primarily NMDA receptor antagonists.
• Salvinorin A: The active component of Salvia divinorum, a kappa-opioid receptor agonist.

Cannabinoids

Agents that act on the endocannabinoid system, producing a mixture of depressant, hallucinogenic, and stimulant-like effects.

• Phytocannabinoids: e.g., Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD) from Cannabis sativa.
• Synthetic Cannabinoids: e.g., JWH-018, Spice. Often full agonists with higher potency and toxicity.

Other Substances

This category includes inhalants, anabolic steroids, and other agents with abuse potential that do not fit neatly into the above classes.

• Inhalants: e.g., toluene (paint thinner), nitrous oxide, volatile nitrites (“poppers”).
• Anabolic-Androgenic Steroids: e.g., testosterone, nandrolone.

Mechanism of Action

The reinforcing and addictive properties of drugs of abuse are primarily mediated through their ability to hijack the brain’s natural reward circuitry. The mesolimbic dopamine pathway, projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), is a central component of this system. While initial drug use may be driven by various factors, repeated administration leads to neuroadaptations in this and connected circuits (prefrontal cortex, amygdala, hippocampus) that underlie the transition to compulsive use, characterized by impaired control, craving, and chronic relapse susceptibility.

Neurobiology of Reward and Addiction

Natural rewards (e.g., food, social interaction) cause a transient increase in dopamine release in the NAc, reinforcing the associated behavior. Drugs of abuse produce a much larger and more sustained dopamine surge. Chronic exposure leads to adaptive changes, including downregulation of dopamine D₂ receptors in the striatum and altered glutamate signaling, which are thought to contribute to diminished reward sensitivity to natural stimuli and enhanced salience of drug-related cues. The transition to addiction involves a shift from impulsive to compulsive drug use, mediated by a progression from ventral (reward, NAc) to dorsal (habit, dorsal striatum) striatal control and dysregulation of prefrontal cortical circuits responsible for executive function and inhibitory control.

Mechanisms by Drug Class

Central Nervous System Depressants: These agents generally facilitate the action of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Ethanol modulates GABA_A, glycine, NMDA, and other receptors. Benzodiazepines and barbiturates bind to distinct sites on the GABA_A receptor complex, increasing the frequency or duration of chloride channel opening, respectively, leading to neuronal hyperpolarization. GHB acts as an agonist at its own receptors and is also a weak agonist at GABA_B receptors.

Central Nervous System Stimulants: Cocaine binds to and inhibits the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), blocking reuptake and increasing synaptic concentrations of these monoamines. Amphetamines are substrates for these transporters; they are taken up into the presynaptic neuron and induce reverse transport, causing a massive efflux of monoamines from vesicular stores into the synapse. Nicotine is an agonist at nicotinic acetylcholine receptors (nAChRs), particularly the α4β2 subtype, leading to dopamine release in the NAc.

Opioids: These drugs are agonists at mu (μ), delta (δ), and kappa (κ) opioid receptors, which are G_i/o-protein coupled receptors. The reinforcing and euphoric effects are primarily mediated by μ-opioid receptors in the VTA and NAc. Activation of these receptors inhibits GABAergic interneurons in the VTA, leading to disinhibition of dopaminergic neurons and increased dopamine release in the NAc.

Hallucinogens: Classical hallucinogens like LSD and psilocybin (metabolized to psilocin) are partial agonists at serotonin 5-HT_2A receptors, particularly in cortical layer V pyramidal neurons. Dissociative agents like PCP and ketamine are non-competitive antagonists at the NMDA subtype of glutamate receptor, leading to a state of dissociation and altered sensory processing.

Cannabinoids: The primary psychoactive component, THC, is a partial agonist at cannabinoid CB₁ receptors, which are predominantly located presynaptically in the central nervous system. CB₁ activation inhibits the release of various neurotransmitters, including GABA and glutamate. CB₁ receptors on GABAergic terminals in the VTA mediate the disinhibition of dopamine neurons, contributing to reward.

Pharmacokinetics

The pharmacokinetic properties of drugs of abuse significantly influence their abuse liability, pattern of use, and acute toxicity. The route of administration is a critical determinant of the speed of onset and intensity of effect, with faster delivery to the brain generally correlating with higher reinforcing potential.

Absorption and Routes of Administration

Oral Ingestion: A common route for ethanol, benzodiazepines, prescription opioids, and hallucinogens like psilocybin. Onset is relatively slow (30-90 minutes) and bioavailability can be variable due to first-pass metabolism. For example, morphine undergoes significant hepatic first-pass effect, whereas its prodrug, heroin, is more lipophilic and crosses the blood-brain barrier more readily before being deacetylated to active metabolites.

Inhalation/Smoking: Provides rapid delivery (onset in seconds) due to the large surface area of the pulmonary alveoli. This route is used for nicotine (cigarettes), cocaine (crack cocaine), methamphetamine, THC (cannabis), and heroin. The rapid peak brain concentration contributes to high abuse liability.

Intranasal Insufflation (“Snorting”): Provides a moderate onset of action (3-5 minutes) as drugs are absorbed through the nasal mucosa, bypassing first-pass metabolism. Common for powdered cocaine, amphetamines, and heroin.

Intravenous Injection: Produces the most rapid and intense effect, with onset in 15-30 seconds. This route carries the highest risk of overdose and infectious complications (e.g., HIV, hepatitis C, endocarditis). Used for heroin, cocaine, and methamphetamine.

Other Routes: Subcutaneous or intramuscular injection (e.g., anabolic steroids), transdermal (e.g., fentanyl patches), and rectal administration are also encountered.

Distribution

Most drugs of abuse are lipophilic, facilitating rapid distribution across the blood-brain barrier. Volume of distribution (V_d) is often large. For instance, THC is highly lipophilic and accumulates in adipose tissue, leading to a prolonged elimination phase. Ethanol, in contrast, is hydrophilic and distributes into total body water.

Metabolism and Elimination

Hepatic metabolism is the primary route of elimination for most drugs of abuse, often involving cytochrome P450 (CYP) enzymes and conjugation reactions.

• Ethanol: Primarily metabolized by alcohol dehydrogenase (ADH) to acetaldehyde, which is then oxidized by aldehyde dehydrogenase (ALDH). A minor pathway involves CYP2E1, which is inducible by chronic use.
• Benzodiazepines: Metabolized extensively by CYP3A4 and other CYPs, and by glucuronidation. Some (e.g., diazepam) have active metabolites with long half-lives.
• Cocaine: Rapidly hydrolyzed by plasma and hepatic esterases to inactive metabolites (benzoylecgonine, ecgonine methyl ester). Its short half-life (≈1 hour) contributes to frequent re-dosing.
• Amphetamines: Metabolized by various CYP isoforms (e.g., CYP2D6) and undergo renal excretion, which is pH-dependent. Acidification of urine increases elimination.
• Opioids: Morphine is glucuronidated to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active). Codeine is a prodrug demethylated to morphine by CYP2D6. Methadone is metabolized by CYP3A4 and CYP2B6 and has a long, variable half-life (15-60 hours).
• THC: Metabolized by CYP2C9 and CYP3A4 to 11-hydroxy-THC (active) and then to 11-nor-9-carboxy-THC (inactive, the primary urinary metabolite).

Elimination half-lives vary widely, from minutes (crack cocaine, nitrous oxide) to days (some benzodiazepine metabolites, THC stored in fat). Renal excretion of parent drug or metabolites is common, though many are extensively metabolized.

Therapeutic Uses/Clinical Applications

Several drugs with high abuse potential have well-established therapeutic roles when used under medical supervision. The risk of misuse and diversion must be carefully weighed against clinical benefit.

Approved Medical Indications

Opioids: Remain the cornerstone for management of moderate to severe acute pain (e.g., post-surgical) and cancer-related pain. Specific agents like methadone and buprenorphine are also approved for the treatment of opioid use disorder (OUD) itself, as medications for opioid use disorder (MOUD).

Central Nervous System Stimulants: Amphetamines (e.g., mixed amphetamine salts) and methylphenidate are first-line pharmacotherapies for attention-deficit/hyperactivity disorder (ADHD). Modafinil and armodafinil are approved for narcolepsy and shift work sleep disorder.

Benzodiazepines and Sedative-Hypnotics: Indicated for the short-term management of anxiety disorders, insomnia, muscle spasms, alcohol withdrawal, and as pre-anesthetic medications.

Cannabinoids: Dronabinol (synthetic THC) and nabilone are approved for chemotherapy-induced nausea and vomiting and for appetite stimulation in AIDS-associated anorexia. Cannabidiol (Epidiolex®) is approved for certain severe childhood epilepsies (Lennox-Gastaut syndrome, Dravet syndrome).

Ketamine: A racemic mixture is used as a general anesthetic. Esketamine, the S-enantiomer, is approved as a nasal spray for treatment-resistant depression.

Off-Label and Investigational Uses

Psychedelic-assisted psychotherapy using psilocybin or MDMA (3,4-methylenedioxymethamphetamine, an amphetamine derivative with hallucinogenic properties) is under active investigation for conditions such as treatment-resistant depression, post-traumatic stress disorder, and end-of-life anxiety. Ibogaine, a plant-derived alkaloid, has been explored for the treatment of opioid and other substance use disorders, though significant safety concerns exist.

Adverse Effects

Adverse effects range from acute, dose-related toxicity to chronic organ damage and psychiatric sequelae. The pattern of effects is specific to each drug class.

Acute Toxicity and Overdose

Opioid Overdose: Presents as the classic triad of respiratory depression (due to μ-opioid receptor agonism in the brainstem), pinpoint pupils (miosis), and depressed level of consciousness (coma). Death results from hypoxic respiratory arrest. Pulmonary edema may occur.

Stimulant Overdose: Manifests as a hyperadrenergic crisis: hypertension, tachycardia, hyperthermia, arrhythmias, seizures, and intracerebral hemorrhage. Psychosis, agitation, and paranoia are common. Chronic use can lead to cardiomyopathy and aortic dissection.

Depressant Overdose: Ethanol, benzodiazepine, or barbiturate overdose causes progressive CNS depression: slurred speech, ataxia, stupor, coma, and respiratory depression. The combination of multiple depressants (e.g., ethanol and benzodiazepines) produces synergistic toxicity. GHB overdose is characterized by sudden onset of coma, often with bradycardia and myoclonus.

Cannabinoid: Acute adverse effects include anxiety, panic, paranoia, and psychosis in susceptible individuals. Impaired motor coordination increases accident risk.

Hallucinogens: “Bad trips” involve severe anxiety, paranoia, and frightening hallucinations. LSD can cause persistent perceptual disturbances (Hallucinogen Persisting Perception Disorder). PCP intoxication can lead to violent behavior, nystagmus, hypertension, and seizures.

Chronic Adverse Effects

• Ethanol: Liver disease (steatosis, hepatitis, cirrhosis), pancreatitis, cardiomyopathy, peripheral neuropathy, Wernicke-Korsakoff syndrome (thiamine deficiency), fetal alcohol spectrum disorders, and increased cancer risk.
• Stimulants (e.g., Methamphetamine): “Meth mouth” (severe dental caries), weight loss, skin lesions from picking, neurotoxicity leading to cognitive deficits, and anhedonia.
• Inhalants: Leukencephalopathy (toluene), peripheral neuropathy, cardiomyopathy (“sudden sniffing death”), and bone marrow suppression.
• Anabolic Steroids: Hepatotoxicity, dyslipidemia, hypertension, cardiomyopathy, testicular atrophy, gynecomastia, virilization in women, and aggressive behavior (“roid rage”).
• Nicotine/Tobacco: Cardiovascular disease, chronic obstructive pulmonary disease, and numerous cancers (lung, head and neck, bladder).

Withdrawal Syndromes

Physical dependence, revealed upon cessation of drug use, produces characteristic withdrawal syndromes that are often opposite to the drug’s acute effects.

Opioid Withdrawal: Although extremely distressing, it is rarely life-threatening in healthy adults. Symptoms include lacrimation, rhinorrhea, yawning, diaphoresis, piloerection (“gooseflesh”), mydriasis, nausea/vomiting, diarrhea, abdominal cramps, myalgia, and anxiety. Onset and duration depend on the half-life of the opioid.

Alcohol/Sedative-Hypnotic Withdrawal: This can be life-threatening. Symptoms progress from tremor, anxiety, and autonomic hyperactivity to seizures (rum fits) and delirium tremens (DTs). DTs are characterized by profound confusion, hallucinations, agitation, and autonomic instability (fever, tachycardia, hypertension), with mortality up to 5% if untreated.

Stimulant Withdrawal (“Crash”): Primarily psychological and not life-threatening. Features dysphoria, anhedonia, fatigue, increased appetite, hypersomnia or insomnia, and intense drug craving.

Drug Interactions

Drug interactions are common in populations using substances of abuse, often due to polypharmacy, self-medication, or unintentional co-ingestion. Interactions can be pharmacodynamic or pharmacokinetic.

Major Pharmacodynamic Interactions

• Additive CNS Depression: The combination of ethanol with benzodiazepines, barbiturates, opioids, or GHB produces synergistic depression of the respiratory and central nervous systems, dramatically increasing overdose risk.
• Cardiovascular Stimulation: Combining stimulants (e.g., cocaine and amphetamine) or using stimulants in patients with underlying cardiovascular disease can precipitate hypertensive crisis, arrhythmia, or myocardial infarction.
• Serotonin Syndrome: A potentially fatal condition caused by excessive serotonergic activity. Risk is increased when serotonergic drugs of abuse (e.g., MDMA, amphetamines) are combined with therapeutic serotonergic agents like selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), or certain opioids (tramadol, meperidine). Symptoms include hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes.

Major Pharmacokinetic Interactions

• Enzyme Induction: Chronic ethanol use induces CYP2E1, increasing the metabolism of drugs like acetaminophen, potentially leading to toxic metabolite accumulation. Chronic use of barbiturates or cannabis induces CYP3A4 and other enzymes, reducing plasma levels of substrates such as warfarin, antiepileptics, and antiretrovirals.
• Enzyme Inhibition: Acute ethanol intake competitively inhibits its own metabolism and can inhibit the metabolism of other drugs. Some synthetic cannabinoids and other novel psychoactive substances are potent inhibitors of CYP enzymes, but their profiles are often unknown.
• Opioid Metabolism: Methadone metabolism by CYP3A4 can be inhibited by agents like fluconazole, erythromycin, and some antiretrovirals (e.g., ritonavir), leading to toxic accumulation. Conversely, inducers like rifampin, carbamazepine, and phenytoin can precipitate withdrawal.

Contraindications

Absolute contraindications are often related to severe adverse reactions. For example, meperidine is contraindicated in patients taking MAOIs due to risk of serotonin syndrome or excitatory reactions. Relative contraindications abound, such as prescribing benzodiazepines to individuals with a history of substance use disorder or prescribing stimulants to patients with uncontrolled hypertension, arrhythmias, or severe anxiety.

Special Considerations

Pregnancy and Lactation

Substance use during pregnancy poses significant risks to both the mother and fetus. Management requires a careful balance between treating maternal addiction and minimizing fetal harm, often in consultation with specialists.

• Opioids: Untreated OUD in pregnancy carries high risk of poor prenatal care, overdose, and infectious diseases. Medically supervised opioid maintenance therapy with methadone or buprenorphine is the standard of care, as it stabilizes the mother and improves outcomes compared to illicit use. However, neonates will experience Neonatal Opioid Withdrawal Syndrome (NOWS), which requires monitoring and treatment. Opioids are excreted in breast milk; methadone and buprenorphine are generally considered compatible with breastfeeding if maternal dose is stable and the infant is observed for sedation.
• Ethanol: Contraindicated. No safe level of consumption has been established. Fetal Alcohol Spectrum Disorders (FASD) are a leading preventable cause of intellectual disability.
• Stimulants: Cocaine and methamphetamine use are associated with placental abruption, preterm birth, low birth weight, and potential neurodevelopmental effects. Use is contraindicated.
• Benzodiazepines: Use in the first trimester may be associated with a small increased risk of oral clefts. Use in the third trimester can cause fetal sedation and a neonatal withdrawal syndrome. Use should be avoided if possible, or limited to the lowest effective dose for the shortest duration.
• Cannabis: Data are evolving but suggest associations with low birth weight and potential effects on neurodevelopment. Use is not recommended.

Pediatric and Geriatric Considerations

Pediatric: Accidental ingestion is a major concern. Children are more susceptible to the toxic effects of many substances (e.g., a small amount of ethanol can cause hypoglycemia and coma). Adolescent brain development, particularly the prefrontal cortex, is vulnerable to the neurotoxic effects of substances like ethanol and cannabis, potentially impacting cognitive function and increasing the risk of developing a substance use disorder.

Geriatric: Age-related changes in pharmacokinetics (decreased hepatic metabolism, renal clearance, increased body fat) and pharmacodynamics (increased CNS sensitivity) make older adults more susceptible to adverse effects of drugs of abuse, as well as prescription medications with abuse potential (e.g., benzodiazepines, opioids). Falls, cognitive impairment, and drug interactions are significant risks.

Renal and Hepatic Impairment

Hepatic Impairment: For drugs extensively metabolized by the liver (most opioids, benzodiazepines, stimulants), impairment can lead to decreased clearance, prolonged half-life, and accumulation, increasing the risk of toxicity and overdose. Dose reduction is often necessary. Agents like morphine and oxycodone, which have active metabolites cleared renally, require extra caution as these metabolites may also accumulate.

Renal Impairment: Drugs or active metabolites excreted renally (e.g., morphine-6-glucuronide, amphetamines) will accumulate. This is particularly critical for methadone, whose metabolites are renally excreted and may contribute to toxicity in renal failure. Dose adjustment and careful monitoring are essential.

Summary/Key Points

• Drugs of abuse are classified pharmacologically as CNS depressants, stimulants, opioids, hallucinogens, and cannabinoids, each with distinct mechanisms of action primarily involving the mesolimbic dopamine reward pathway.
• The abuse liability of a substance is influenced by its pharmacokinetics, particularly the speed of onset of effect, which is determined by the route of administration (intravenous/inhalation > intranasal > oral).
• Chronic drug use induces neuroadaptations in reward, stress, and executive control circuits, leading to the compulsive drug-seeking behavior that characterizes addiction.
• Acute toxicity is class-specific: opioids cause respiratory depression; stimulants cause hyperadrenergic crisis; and depressants cause progressive CNS depression. Withdrawal from alcohol and sedative-hypnotics can be life-threatening.
• Several drugs of abuse have vital therapeutic roles (e.g., opioids for pain, stimulants for ADHD, benzodiazepines for anxiety), necessitating a risk-benefit analysis and vigilant monitoring for misuse.
• Management of substance use disorders involves a comprehensive approach including acute medical care, treatment of withdrawal, long-term maintenance pharmacotherapy (for opioid and alcohol use disorders), behavioral interventions, and harm reduction strategies.

Clinical Pearls

• Naloxone, a competitive μ-opioid receptor antagonist, is the specific antidote for opioid overdose and should be made available to patients and their families. Its duration of action is shorter than that of many opioids, necessitating repeated dosing or continuous infusion.
• Benzodiazepines (typically lorazepam, diazepam, or chlordiazepoxide) are the cornerstone for preventing and treating seizures and delirium tremens in alcohol withdrawal, often using a symptom-triggered or fixed-dose taper protocol.
• Medications for Opioid Use Disorder (MOUD)—methadone, buprenorphine, and naltrexone—are evidence-based treatments that reduce mortality, illicit opioid use, and infectious complications. They should be considered standard of care.
• Polysubstance use is common and dramatically increases the risk of fatal overdose, particularly the combination of opioids with benzodiazepines or ethanol.
• A non-judgmental, patient-centered approach that screens for substance use, assesses for use disorders, and offers treatment resources is a critical competency for all healthcare providers.

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