Pharmacology of Drugs of Abuse and Addiction

Introduction/Overview

The pharmacology of drugs of abuse represents a critical intersection of neurobiology, pharmacokinetics, and clinical medicine. Substance use disorders constitute a major public health burden, characterized by a compulsive pattern of drug-seeking and use despite significant harmful consequences. Understanding the pharmacological principles underlying these agents is essential for healthcare professionals to manage intoxication, withdrawal, and long-term treatment strategies. The neurobiological substrates of addiction involve complex adaptations within brain reward, motivation, and executive control circuits, primarily mediated by the mesolimbic dopamine system and its connections.

Clinical Relevance and Importance

Substance use disorders are prevalent chronic medical conditions associated with significant morbidity, mortality, and societal cost. Clinicians across all specialties encounter patients affected by these disorders, either as a primary diagnosis or as a complicating factor in other medical and psychiatric conditions. A detailed pharmacological knowledge base enables rational clinical decision-making regarding acute overdose management, medication-assisted treatment, recognition of drug-drug interactions, and patient counseling. Furthermore, many drugs of abuse have legitimate medical applications, and their therapeutic use requires a precise understanding of their abuse potential and risk profiles.

Learning Objectives

• Classify major drugs of abuse based on their pharmacological properties and primary mechanisms of action on the central nervous system.
• Describe the neurobiological mechanisms underlying reinforcement, tolerance, dependence, and addiction, with emphasis on synaptic plasticity within reward pathways.
• Analyze the pharmacokinetic and pharmacodynamic profiles of major drug classes, including routes of administration, metabolism, and duration of action.
• Identify the acute and chronic clinical effects, adverse reactions, and toxidromes associated with different substances.
• Outline the pharmacological principles guiding current evidence-based treatments for substance use disorders, including agonist, antagonist, and partial agonist therapies.

Classification

Drugs of abuse are typically classified according to their primary pharmacological effect on the central nervous system, their chemical structure, or their legal status. A functional classification based on predominant clinical and neuropharmacological effects is most clinically useful.

Central Nervous System Depressants

This class comprises agents that reduce neuronal excitability and slow down brain function. Primary examples include ethanol (alcohol), benzodiazepines (e.g., diazepam, alprazolam), barbiturates (e.g., phenobarbital), gamma-hydroxybutyrate (GHB), and certain inhalants (e.g., toluene). They primarily potentiate inhibitory neurotransmission mediated by gamma-aminobutyric acid (GABA).

Opioids

Opioids are natural, semi-synthetic, or synthetic compounds that bind to opioid receptors. This class includes natural opiates like morphine and codeine, semi-synthetics like heroin and oxycodone, and full synthetics like fentanyl and methadone. They are classified as agonists, partial agonists, or antagonists at mu-, delta-, and kappa-opioid receptors.

Central Nervous System Stimulants

Stimulants increase alertness, attention, and energy by enhancing catecholaminergic transmission. Subcategories include:
Psychostimulants: Cocaine (a local anesthetic with stimulant properties), amphetamine, methamphetamine, and methylphenidate.
Entactogens/Empathogens: 3,4-Methylenedioxymethamphetamine (MDMA or “ecstasy”), which has mixed stimulant and psychedelic properties.
Nicotine: A stimulant acting primarily on nicotinic acetylcholine receptors.
Caffeine: A mild stimulant acting as an adenosine receptor antagonist.

Hallucinogens

These substances alter perception, thought, and emotion. They are divided into two broad groups:
Classic Hallucinogens: Act primarily as agonists or partial agonists at serotonin 5-HT_2A receptors. Examples include lysergic acid diethylamide (LSD), psilocybin (from mushrooms), and mescaline (from peyote cactus).
Dissociative Anesthetics: Act primarily as non-competitive antagonists at the N-methyl-D-aspartate (NMDA) glutamate receptor. Examples include phencyclidine (PCP) and ketamine.

Cannabinoids

The primary psychoactive component is delta-9-tetrahydrocannabinol (THC), a partial agonist at central cannabinoid CB₁ receptors. This class includes plant-derived cannabis (marijuana, hashish) and synthetic cannabinoids (e.g., “Spice” or “K2”).

Other Substances

This category includes anabolic-androgenic steroids, which are abused for their muscle-building effects, and novel psychoactive substances (“designer drugs”) that are continually synthesized to circumvent legal restrictions.

Mechanism of Action

The reinforcing and addictive properties of drugs of abuse are primarily mediated through their direct or indirect effects on the mesolimbic dopamine pathway, which projects from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and prefrontal cortex. Acute drug administration typically increases extracellular dopamine in the NAc, signaling reward and reinforcing drug-taking behavior. However, chronic use leads to neuroadaptive changes, including downregulation of reward circuitry and strengthening of glutamatergic pathways involved in habit formation and craving.

Neurobiology of Reinforcement and Addiction

The transition from voluntary use to compulsive addiction involves three primary stages: binge/intoxication, primarily involving the NAc and dorsal striatum; withdrawal/negative affect, involving the extended amygdala; and preoccupation/anticipation (craving), involving the prefrontal cortex, insula, and hippocampus. Chronic drug exposure induces long-term neuroplasticity, including changes in gene expression, dendritic spine morphology, and synaptic strength, which underlie tolerance, dependence, and the persistent risk of relapse.

Mechanisms by Drug Class

CNS Depressants: Ethanol and benzodiazepines allosterically modulate the GABA_A receptor, increasing chloride ion influx and neuronal hyperpolarization. Ethanol has additional actions on NMDA glutamate receptors, glycine receptors, and various ion channels. This global CNS depression produces the characteristic effects of anxiolysis, sedation, and motor incoordination.

Opioids: Exogenous opioid agonists, such as heroin or morphine, primarily activate mu-opioid receptors (MORs). In the VTA, MOR activation disinhibits dopamine neurons by reducing GABAergic input, leading to increased dopamine release in the NAc. Opioids also produce analgesia and euphoria via actions in the periaqueductal gray and other brain regions.

Stimulants: Cocaine binds to the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), blocking reuptake and causing a rapid increase in synaptic monoamine levels. Amphetamines are substrates for these transporters; they are taken up into the presynaptic neuron and induce reverse transport of monoamines out of synaptic vesicles into the synapse. Nicotine acts as an agonist at nicotinic acetylcholine receptors, particularly the α4β2 subtype, leading to dopamine release in the NAc.

Hallucinogens: Classic hallucinogens like LSD are potent partial agonists at cortical 5-HT_2A receptors. Activation of these receptors on pyramidal neurons and GABAergic interneurons disrupts normal thalamic gating and cortical information processing, leading to altered perception. Dissociatives like ketamine block the NMDA receptor, disrupting glutamate signaling and producing feelings of detachment and altered sensory perception.

Cannabinoids: THC, the main psychoactive cannabinoid, is a partial agonist at presynaptic CB₁ receptors, which are G_i/o-protein coupled. Their activation inhibits the release of various neurotransmitters, including GABA and glutamate. In the VTA, this can disinhibit dopamine neurons, contributing to reward. Endocannabinoids like anandamide act as retrograde messengers.

Pharmacokinetics

The pharmacokinetic profile of a drug of abuse significantly influences its abuse liability, pattern of use, and associated harms. Factors such as speed of onset, peak effect, and duration of action are critical determinants of reinforcement.

Absorption and Routes of Administration

The route of administration dramatically affects the rate and extent of absorption, thereby influencing the subjective “rush” and addictive potential.
Intravenous (IV) and Smoking/Inhalation: These routes provide the most rapid delivery to the brain, producing effects within seconds. Examples include IV heroin or cocaine, and smoked crack cocaine or methamphetamine. The rapid rise in brain concentration (steep dC/dt) is strongly correlated with high reinforcement.
Intranasal (Snorting): Absorption occurs across the nasal mucosa, with effects typically beginning within 5-10 minutes, as seen with powdered cocaine or heroin.
Oral: This route has slower and more variable absorption due to first-pass metabolism. Onset of action can range from 20 minutes to over an hour, as with orally ingested opioids, benzodiazepines, or MDMA.
Transdermal/Mucosal: Some substances, like nicotine via patches or gums, are absorbed through skin or buccal mucosa for slower, sustained delivery.

Distribution

Most drugs of abuse are lipophilic, facilitating rapid crossing of the blood-brain barrier. Volume of distribution (V_d) varies widely. For instance, lipophilic drugs like THC and phencyclidine have very large V_d values, accumulating in fatty tissues and leading to prolonged elimination. Ethanol, in contrast, distributes into total body water.

Metabolism

Hepatic metabolism is the primary route of biotransformation. Genetic polymorphisms in metabolic enzymes can significantly alter individual risk and response.
Phase I Reactions: Often catalyzed by the cytochrome P450 (CYP) system. For example, cocaine is hydrolyzed by plasma and hepatic esterases. Opioids like codeine are prodrugs activated by CYP2D6 to morphine. MDMA is metabolized by CYP2D6, and inhibition of this enzyme can lead to toxic concentrations.
Phase II Reactions: Conjugation reactions (glucuronidation, sulfation) are common for opioids (e.g., morphine-6-glucuronide is an active metabolite) and cannabinoids.
Ethanol Metabolism: Follows zero-order kinetics at typical doses, primarily via alcohol dehydrogenase (ADH) to acetaldehyde, which is then metabolized by aldehyde dehydrogenase (ALDH). Disulfiram inhibits ALDH, causing an aversive acetaldehyde accumulation.

Excretion

Renal excretion of parent drug or metabolites is common. The degree of ionization and lipophilicity influences reabsorption. Some drugs or metabolites undergo enterohepatic recirculation, prolonging their effect. Pulmonary excretion is relevant for volatile substances like inhaled anesthetics or alcohol (measured in breath).

Half-life and Dosing Considerations

The elimination half-life (t_1/2) dictates dosing frequency and the onset of withdrawal symptoms. Short-acting drugs (e.g., cocaine, t_1/2 ≈ 1 hour; heroin, t_1/2 ≈ 30 minutes) produce intense, short-lived highs and frequent re-dosing, leading to rapid cycles of reinforcement and withdrawal. Long-acting drugs (e.g., methadone, t_1/2 ≈ 24-36 hours; diazepam, t_1/2 ≈ 20-50 hours) produce a more stable effect and are often used in medication-assisted treatment to prevent withdrawal and craving.

Therapeutic Uses/Clinical Applications

Several drugs with high abuse potential have important, well-defined roles in clinical medicine. Their use requires careful risk-benefit assessment and monitoring.

Approved Indications

Opioids: Remain the cornerstone for management of moderate-to-severe acute pain (post-operative, traumatic) and cancer-related pain. Specific agents like methadone and buprenorphine are approved for the treatment of opioid use disorder (OUD).
Benzodiazepines: Indicated for the short-term management of anxiety disorders, insomnia, alcohol withdrawal, muscle spasticity, and as pre-anesthetic medications. Their use beyond 2-4 weeks is generally discouraged due to tolerance and dependence.
Stimulants: Amphetamine (e.g., mixed amphetamine salts) and methylphenidate are first-line pharmacotherapies for Attention-Deficit/Hyperactivity Disorder (ADHD). Modafinil is used for narcolepsy and shift work sleep disorder.
Cannabinoids: Dronabinol (synthetic THC) and nabilone are approved for chemotherapy-induced nausea and vomiting and for appetite stimulation in AIDS-associated anorexia. Cannabidiol (CBD) is approved for certain childhood epilepsy syndromes.
Ketamine: Used as a dissociative anesthetic, particularly in pediatric and veterinary medicine. An intranasal formulation of esketamine (the S-enantiomer) is approved for treatment-resistant depression.
Barbiturates: Now largely replaced by safer agents, but still used in specific contexts like epilepsy (phenobarbital), euthanasia, and severe intracranial hypertension.

Off-Label Uses

Off-label use is common but must be approached with caution. Examples include the use of low-dose naltrexone for chronic pain or autoimmune conditions, ketamine infusion for acute suicidality, and certain benzodiazepines for agitation. The use of psychedelics like psilocybin or MDMA in psychotherapy for post-traumatic stress disorder or depression is an area of active clinical research but remains investigational in most jurisdictions.

Adverse Effects

Adverse effects range from acute, dose-related toxicity to chronic organ damage and psychiatric sequelae. The risk profile is often exacerbated by polysubstance use, variable purity of illicit drugs, and route of administration.

Common Side Effects

Side effects are often extensions of the drugs’ pharmacological actions.
CNS Depressants: Sedation, drowsiness, ataxia, slurred speech, impaired judgment, and memory deficits.
Opioids: Constipation, nausea, vomiting, pruritus, miosis, respiratory depression, and sedation.
Stimulants: Insomnia, anorexia, weight loss, tachycardia, hypertension, anxiety, irritability, and hyperthermia.
Hallucinogens: Perceptual distortions, anxiety, paranoia, dizziness, and impaired coordination.
Cannabinoids: Dry mouth, conjunctival injection, tachycardia, impaired short-term memory, and reduced psychomotor performance.

Serious/Rare Adverse Reactions

Cardiovascular: Stimulants can cause acute coronary syndromes, arrhythmias, cardiomyopathy, and aortic dissection. Cocaine use is a known risk factor for myocardial infarction in young adults.
Neurological: Seizures can be induced by stimulants, withdrawal from depressants, or high doses of opioids (like tramadol or meperidine). Hemorrhagic and ischemic strokes are associated with stimulant and cannabinoid use. Wernicke-Korsakoff syndrome is a consequence of thiamine deficiency in chronic alcoholism.
Psychiatric: Chronic stimulant use can induce a paranoid psychosis indistinguishable from schizophrenia. Hallucinogens may precipitate persistent psychosis or hallucinogen persisting perception disorder (HPPD). Depression and anxiety are common in withdrawal from most substances.
Pulmonary: Smoking any substance can lead to chronic bronchitis. “Crack lung” is a syndrome of acute pulmonary injury following crack cocaine inhalation. Opioids can cause non-cardiogenic pulmonary edema.
Infectious Diseases: IV drug use is a major risk factor for blood-borne infections including HIV, hepatitis B, and hepatitis C, as well as bacterial endocarditis and skin/soft tissue infections.
Other Organ Toxicity: Ethanol causes hepatic steatosis, hepatitis, cirrhosis, and pancreatitis. Inhalants can cause leukoencephalopathy and renal tubular acidosis. Anabolic steroids can cause hepatotoxicity and peliosis hepatis.

Black Box Warnings

Several medications used in addiction treatment or with abuse potential carry FDA Black Box Warnings, the strongest safety alert.
Buprenorphine: Warns of the risk of life-threatening respiratory depression and coma, particularly when misused by self-injection or combined with other CNS depressants like benzodiazepines.
Naltrexone: Carries a warning for hepatotoxicity at high doses and the risk of precipitated opioid withdrawal if administered to a patient with physical dependence.
Disulfiram: Warns of the risk of hepatotoxicity.
Methadone: Has multiple warnings regarding life-threatening respiratory depression, QT interval prolongation and torsades de pointes, and the risks of accidental ingestion by children.

Drug Interactions

Drug interactions are a major source of morbidity and mortality in substance-using populations, often due to pharmacodynamic synergy or altered metabolism.

Major Drug-Drug Interactions

Additive CNS Depression: The combination of different CNS depressants (e.g., opioids + benzodiazepines + ethanol) produces synergistic respiratory depression, sedation, and coma. This interaction is responsible for a significant proportion of fatal overdoses.
Enzyme Inhibition and Induction:
Inhibition: Ethanol acutely inhibits CYP2E1, but chronic use induces it. Fluoxetine (a CYP2D6 inhibitor) can increase toxicity from MDMA or codeine (by preventing its conversion to the less active morphine). Cimetidine can inhibit the metabolism of many drugs.
Induction: Chronic ethanol use, barbiturates, and carbamazepine induce CYP enzymes, increasing the metabolism and reducing the efficacy of other drugs, including anticoagulants, antiepileptics, and antiretrovirals.
Cardiovascular Effects: Combining stimulants (e.g., cocaine and amphetamine) or combining stimulants with medications that also prolong the QT interval (e.g., methadone, certain antipsychotics) can lead to severe hypertension, arrhythmias, or cardiac arrest.
Serotonergic Syndrome: A potentially fatal condition caused by excessive serotonin activity. Risk is increased when serotonergic drugs of abuse (MDMA, LSD, certain opioids like tramadol) are combined with other serotonergic agents like selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), or St. John’s Wort.

Contraindications

Absolute contraindications are specific to each agent but generally include:
Opioids: In acute respiratory depression, acute asthma, or paralytic ileus.
Benzodiazepines: In patients with acute narrow-angle glaucoma, significant respiratory insufficiency, or sleep apnea.
Stimulants: In patients with symptomatic cardiovascular disease, advanced arteriosclerosis, hyperthyroidism, or a history of drug abuse (relative contraindication for therapeutic use).
Disulfiram: In patients with severe myocardial disease, psychosis, or hypersensitivity.
Acamprosate: In patients with severe renal impairment.
Naltrexone: In patients currently dependent on opioids, with acute hepatitis, or liver failure.

Special Considerations

Use in Pregnancy and Lactation

Substance use during pregnancy poses significant risks to both the mother and fetus. Management requires a multidisciplinary approach.
Opioids: Chronic opioid use is associated with neonatal abstinence syndrome (NAS), a drug withdrawal syndrome in the newborn characterized by irritability, hypertonia, tremors, and feeding difficulties. Medication-assisted treatment with methadone or buprenorphine is the standard of care for pregnant women with OUD, as it stabilizes the mother and improves prenatal care adherence, leading to better overall outcomes than continued illicit use or forced detoxification.
Alcohol: Ethanol is a known teratogen. Fetal alcohol spectrum disorders (FASD) represent a range of lifelong physical, behavioral, and cognitive impairments. There is no known safe amount of alcohol during pregnancy.
Stimulants: Cocaine and methamphetamine use are associated with placental abruption, preterm birth, low birth weight, and potential neurodevelopmental effects.
Cannabis: Data are mixed but suggest an association with low birth weight and potential effects on neurodevelopment. Use is not recommended.
Nicotine: Smoking is associated with intrauterine growth restriction, preterm birth, and sudden infant death syndrome (SIDS).
Lactation: Most drugs are excreted in breast milk. The benefits of breastfeeding must be weighed against potential infant exposure. Methadone and buprenorphine are generally considered compatible with breastfeeding at maternal therapeutic doses. Alcohol, cocaine, and phencyclidine are contraindicated.

Pediatric and Geriatric Considerations

Pediatrics: Adolescents are at heightened neurodevelopmental risk from substance use. The maturing prefrontal cortex is particularly vulnerable, potentially increasing the risk of developing persistent substance use disorders and cognitive deficits. Pharmacokinetics may differ; for example, adolescents may metabolize some drugs more rapidly than adults.
Geriatrics: Age-related changes in pharmacokinetics and pharmacodynamics increase vulnerability. Reduced hepatic metabolism and renal clearance can lead to higher and more prolonged drug levels. Increased brain sensitivity to CNS depressants and reduced baroreceptor response increase the risk of falls, confusion, and respiratory depression. Polypharmacy is a major concern, increasing the risk of dangerous interactions.

Renal and Hepatic Impairment

Renal Impairment: Drugs or active metabolites excreted renally (e.g., morphine-6-glucuronide) can accumulate, necessitating dose reduction. Methadone and buprenorphine are preferred in renal failure as they are primarily metabolized hepatically.
Hepatic Impairment: Liver disease impairs the metabolism of most drugs of abuse and medications for addiction. For opioids, fentanyl, buprenorphine, and methadone may be preferred over morphine or oxycodone in severe impairment due to less reliance on hepatic glucuronidation. Dose reduction and careful monitoring are essential. Acamprosate is contraindicated in severe renal impairment but can be used with caution in hepatic impairment, whereas disulfiram is contraindicated in severe hepatic disease.

Summary/Key Points

• Drugs of abuse are classified by their primary CNS effects: depressants, opioids, stimulants, hallucinogens, and cannabinoids. Each class has a distinct mechanism of action but commonly converges on the mesolimbic dopamine system to produce reinforcement.
• Addiction is a chronic brain disorder characterized by compulsive use despite harm, driven by neuroadaptations in reward, stress, and executive control circuits. Key processes include reinforcement, tolerance, physical dependence, and sensitization.
• Pharmacokinetics, particularly the speed of onset of drug effect, is a critical determinant of abuse liability. Intravenous and smoked routes produce the most rapid delivery and highest reinforcement potential.
• Many drugs of abuse have legitimate medical uses (e.g., opioids for pain, stimulants for ADHD), requiring careful risk assessment, patient monitoring, and adherence to prescribing guidelines to minimize misuse.
• Adverse effects are extensive and can affect every organ system. Acute risks include respiratory depression from depressants and cardiovascular events from stimulants. Chronic risks include infection, organ failure, and psychiatric illness.
• Polysubstance use is common and dangerous, often leading to synergistic toxicity, particularly from combined CNS depressants which cause fatal respiratory depression.
• Pharmacotherapy for substance use disorders is evidence-based and includes agonist maintenance (methadone, buprenorphine for OUD), antagonist therapy (naltrexone for OUD or alcohol use disorder), and partial agonists. These treatments normalize brain function, reduce craving and withdrawal, and improve social outcomes.
• Special populations, including pregnant women, adolescents, and the elderly, require tailored approaches due to unique pharmacokinetic, pharmacodynamic, and risk-benefit considerations.

Clinical Pearls

• In managing suspected opioid overdose, naloxone administration is lifesaving. Due to its short half-life relative to many opioids, repeated dosing or a continuous infusion may be necessary to prevent re-narcotization.
• Benzodiazepine withdrawal can be life-threatening and typically requires a slow, tapered dose reduction rather than abrupt discontinuation.
• When prescribing controlled substances with abuse potential, utilizing prescription drug monitoring program (PDMP) data, employing urine drug screening, and establishing clear treatment agreements are standard components of risk mitigation.
• The treatment of substance use disorders is most effective when pharmacotherapy is combined with behavioral interventions such as cognitive-behavioral therapy, contingency management, and mutual-help groups.
• Clinicians should maintain a non-stigmatizing, patient-centered approach, recognizing substance use disorder as a chronic medical condition, to effectively engage patients in care.

References

1. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
4. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
5. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
6. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.