Pharmacology of Drugs of Abuse and Addiction

Introduction and Overview

Drugs of abuse encompass a broad spectrum of psychoactive substances that are frequently misused, leading to significant morbidity, mortality, and socioeconomic burden. Understanding their pharmacologic properties is essential for clinicians involved in prevention, acute management, and long‑term care of individuals with substance use disorders. The pharmacologic framework of these agents informs evidence‑based therapeutic strategies, informs risk assessment, and guides the development of novel pharmacotherapies.

Clinical relevance is underscored by the rising prevalence of opioid overdose, the persistent challenge of alcohol dependence, and the expanding use of stimulants and cannabis. Medical and pharmacy students must acquire a robust pharmacologic foundation to participate effectively in multidisciplinary care teams, to counsel patients, and to contribute to public health initiatives.

Learning Objectives

• Describe the major pharmacodynamic classes of drugs commonly abused and the molecular targets mediating their effects.
• Explain the key pharmacokinetic determinants influencing drug exposure, distribution, and elimination in the context of abuse.
• Identify approved therapeutic uses of pharmacologic agents for addiction treatment and outline evidence‑based adjunctive interventions.
• Recognize common and serious adverse reactions, including those with high clinical impact, and understand strategies for monitoring and prevention.
• Apply knowledge of drug interactions, special population considerations, and regulatory frameworks to optimize patient safety.

Classification

Major Drug Classes and Categories

Drugs of abuse are traditionally grouped according to their primary pharmacologic actions and resultant behavioral effects. The principal categories include:

• Opioids – natural alkaloids (e.g., morphine), semi‑synthetic (e.g., codeine), and fully synthetic (e.g., fentanyl, methadone).
• Stimulants – sympathomimetic agents such as amphetamines, methylphenidate, and cocaine, which enhance catecholamine neurotransmission.
• Depressants – central nervous system depressants including benzodiazepines, barbiturates, and alcohol.
• Hallucinogens – serotonergic (e.g., LSD, psilocybin) and dissociative (e.g., ketamine, phencyclidine) agents that alter perception and cognition.
• Cannabis – cannabinoids such as Δ9‑tetrahydrocannabinol (THC) and cannabidiol (CBD), acting on cannabinoid receptors.
• Other – inhalants (e.g., nitrous oxide), inhaled anesthetics, and novel psychoactive substances (NPS) that mimic traditional classes.

Chemical Classification and Structural Features

Beyond pharmacologic action, chemical classification provides insight into synthetic pathways and metabolic liabilities. Opioids, for instance, share an indole structure in natural alkaloids, whereas synthetic opioids often contain a piperidine core. Stimulants range from phenethylamine derivatives (amphetamine) to benzylisoquinoline structures (cocaine). Depressants display diverse scaffolds, such as the imidazole ring in benzodiazepines and the barbiturate ring in phenobarbital. This structural taxonomy aids in predicting pharmacokinetic behavior and potential for cross‑reactivity among agents.

Mechanism of Action

Opioids

Opioid analgesics exert their primary effects by binding to μ‑opioid receptors (MOR) located throughout the central nervous system and peripheral tissues. Activation of MOR initiates G‑protein–coupled signaling, leading to inhibition of adenylate cyclase, decreased cyclic AMP, and opening of inwardly rectifying potassium channels. The resultant hyperpolarization of neuronal membranes reduces excitability, culminating in analgesia, euphoria, and respiratory depression.

Partial agonists (e.g., buprenorphine) occupy MOR but elicit submaximal responses, conferring a ceiling effect on respiratory depression while maintaining substantial analgesic and reinforcing properties. κ‑ and δ‑opioid receptors contribute to dysphoria, psychotomimetic effects, and modulation of mood, influencing the subjective experience of abuse.

Stimulants

Stimulants increase synaptic concentrations of dopamine, norepinephrine, and serotonin through inhibition of reuptake transporters (DAT, NET, SERT) and, in the case of cocaine, blockade of monoamine oxidase (MAO). Dopaminergic signaling in the nucleus accumbens enhances reward circuitry, reinforcing drug-taking behavior. Amphetamines also promote reverse transport of monoamines, further amplifying extracellular levels.

Depressants

Benzodiazepines potentiate gamma‑aminobutyric acid (GABA) neurotransmission by binding to an allosteric site on the GABA_A receptor, increasing chloride ion conductance and hyperpolarizing neuronal membranes. Barbiturates, in contrast, bind to a distinct site on GABA_A and can directly open chloride channels, producing a more profound CNS depression. Alcohol modulates multiple targets, including GABA_A receptors, NMDA glutamate receptors, and voltage‑gated calcium channels, contributing to its mixed excitatory and inhibitory effects.

Hallucinogens

Serotonergic hallucinogens such as LSD act as agonists or partial agonists at 5‑HT_2A receptors, leading to altered sensory processing and cognition. Dissociative agents like ketamine bind to NMDA receptors, producing a dissociative anesthetic state. The psychotomimetic effects are mediated by downstream modulation of glutamatergic and dopaminergic pathways.

Cannabis

THC is a partial agonist at CB₁ and CB₂ cannabinoid receptors, with CB₁ activation predominating in the CNS. Binding to CB₁ inhibits adenylate cyclase, reduces calcium influx, and increases potassium conductance, thereby modulating neurotransmitter release and producing psychoactive effects. CBD exhibits low affinity for cannabinoid receptors but modulates endocannabinoid tone via inhibition of fatty acid amide hydrolase (FAAH).

Pharmacokinetics

Absorption

Oral bioavailability varies substantially across classes. Opioids such as oxycodone have moderate first‑pass metabolism, whereas fentanyl demonstrates high lipophilicity, enabling rapid transdermal absorption. Stimulants (e.g., amphetamine) are well absorbed orally, but their bioavailability can be reduced by extensive first‑pass metabolism. Alcohol is absorbed rapidly through the stomach and small intestine, with peak plasma concentrations reached within 30–60 minutes. Cannabis THC is poorly absorbed orally (≈10 %) but achieves higher bioavailability via inhalation or transdermal routes.

Distribution

Volume of distribution (V_d) reflects the extent of tissue penetration. Opioids with high lipophilicity (e.g., fentanyl) possess V_d values exceeding 10 L/kg, facilitating central nervous system penetration and rapid onset of action. In contrast, hydrophilic opioids such as morphine have lower V_d (≈0.6 L/kg). Stimulants display moderate V_d (≈0.5–1.0 L/kg). Alcohol distributes uniformly in total body water, with limited protein binding (≈10 %). CBD shows a large V_d (≈30 L/kg) due to extensive tissue binding.

Metabolism

Metabolic pathways are pivotal in determining drug half‑life (t_1/2) and potential for interactions. Opioids are primarily metabolized by cytochrome P450 enzymes (CYP2D6, CYP3A4) and UDP‑glucuronosyltransferases (UGTs). Methadone is chiefly metabolized by CYP3A4 and CYP2B6. Stimulants undergo hepatic oxidation (CYP2D6 for amphetamine) and conjugation. Alcohol is oxidized by alcohol dehydrogenase to acetaldehyde and further metabolized by aldehyde dehydrogenase. Cannabis THC is metabolized by CYP3A4 and CYP2C9 to 11‑hydroxy‑THC, an active metabolite. CBD is metabolized primarily by CYP3A4 and CYP2C19, producing inactive metabolites.

Excretion

Renal clearance predominates for many opioids (e.g., morphine, codeine), whereas hepatic excretion via bile is significant for hydrophobic agents (e.g., fentanyl). Stimulants are mainly renally excreted as glucuronide conjugates. Alcohol is eliminated predominantly via oxidation, with a small proportion excreted unchanged in urine. THC metabolites are excreted in feces, and CBD metabolites are eliminated in urine.

Half‑Life and Dosing Considerations

Half‑life (t_1/2) ranges from minutes for alcohol (≈1.5 h) to days for fentanyl patches (≈8 days). Dosing regimens must account for individual variability in absorption, metabolism, and elimination. For example, methadone dosing requires adjustment for CYP3A4 inhibitors or inducers. Transdermal fentanyl patches are prescribed at maintenance doses of 12.5–50 µg/h, with patch changes every 72 h. Precise titration is essential to balance efficacy with respiratory depression risk.

Therapeutic Uses and Clinical Applications

Approved Indications

Several pharmacologic agents are approved for the treatment of substance use disorders. Methadone and buprenorphine are indicated for opioid dependence, providing substitution therapy that mitigates withdrawal and craving. Naltrexone (oral or intramuscular) is approved for alcohol and opioid dependence, acting as a μ‑opioid antagonist to block euphoria and reduce relapse. Disulfiram is employed in alcohol use disorder to induce unpleasant effects upon ethanol consumption. Acamprosate is indicated for alcohol dependence, modulating glutamatergic neurotransmission. For stimulant dependence, clonidine and lofexidine are used to attenuate withdrawal symptoms, while behavioral interventions remain primary.

Off‑Label and Emerging Therapies

Off‑label use of topiramate, gabapentin, or atypical antipsychotics is common in the management of stimulant or cannabis dependence, though evidence is variable. Novel approaches such as the use of extended‑release formulations of naltrexone, buprenorphine‑naloxone combinations, and emerging pharmacotherapies targeting the orexin system or the dopamine transporter are under investigation.

Adjunctive Clinical Applications

In the acute setting, benzodiazepines are routinely administered to manage opioid overdose, while naloxone is the antidote for opioid toxicity. For alcohol withdrawal, high‑dose benzodiazepines or phenobarbital mitigate seizures and delirium tremens. In stimulant intoxication, beta‑blockers may be used cautiously to manage tachycardia, although evidence remains limited. Cannabis‑related emergencies may involve antihistamines for hives or benzodiazepines for agitation.

Adverse Effects

Common Side Effects

• Opioids: constipation, nausea, pruritus, respiratory depression, sedation.
• Stimulants: hypertension, tachycardia, insomnia, anxiety, appetite suppression.
• Depressants: sedation, hypotension, respiratory depression (benzodiazepines), paradoxical agitation (barbiturates).
• Hallucinogens: nausea, dizziness, tachycardia, dysphoria.
• Cannabis: dizziness, impaired coordination, tachycardia, cognitive impairment.

Serious or Rare Adverse Reactions

Opioid‑induced respiratory depression remains the leading cause of death. Chronic opioid use can lead to endocrine disruption (hypogonadism), bone demineralization, and opioid‑induced hyperalgesia. Stimulant abuse may precipitate acute myocardial infarction, stroke, or neuropsychiatric crises. Alcohol dependence is associated with hepatotoxicity, pancreatitis, and increased risk of certain cancers. Cannabis use can lead to cannabinoid hyperemesis syndrome and, in vulnerable populations, psychosis.

Black Box Warnings

Opioid analgesics carry black box warnings for respiratory depression and overdose risk. Benzodiazepines are cautioned for dependence potential and risk of overdose when combined with opioids or alcohol. Naltrexone has a black box warning due to hepatotoxicity, particularly in patients with pre‑existing liver disease. Disulfiram warrants caution in patients with cardiac disease due to potential arrhythmias.

Drug Interactions

Major Drug‑Drug Interactions

Opioids and benzodiazepines share additive CNS depressive effects, increasing the risk of respiratory depression. CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) elevate plasma concentrations of methadone and fentanyl, potentially precipitating toxicity. Conversely, CYP3A4 inducers (e.g., rifampin, carbamazepine) reduce efficacy. Alcohol potentiates the sedative effects of benzodiazepines and barbiturates and increases the risk of withdrawal seizures.

Stimulants may interact with MAO inhibitors, leading to hypertensive crises. Cocaine can interact with anticoagulants, increasing the risk of bleeding. THC may potentiate the sedative effects of benzodiazepines and alcohol. Disulfiram interacts with alcohol, causing the disulfiram reaction, but also has additive effects with antipsychotics, potentially increasing extrapyramidal symptoms.

Contraindications

• Opioids are contraindicated in patients with significant respiratory compromise or severe COPD.
• Benzodiazepines should be avoided in patients with a history of substance misuse or severe hepatic impairment.
• Naltrexone is contraindicated in patients with acute hepatitis or hepatic failure.
• Disulfiram is contraindicated in patients with cardiac conduction abnormalities or uncontrolled hypertension.

Special Considerations

Pregnancy and Lactation

Opioid exposure during pregnancy may result in neonatal abstinence syndrome; however, controlled substitution therapy (methadone, buprenorphine) is preferred over abrupt cessation. Stimulants increase the risk of fetal growth restriction and preterm birth. Alcohol is teratogenic, with a risk of fetal alcohol spectrum disorders. Cannabis use during pregnancy is associated with low birth weight and neurodevelopmental deficits. Lactation with opioid therapy is generally considered safe, particularly with buprenorphine, but caution is advised with high‑dose methadone.

Pediatric and Geriatric Considerations

Pediatric patients metabolize many drugs more rapidly; dosing of opioids must account for higher hepatic clearance. In older adults, reduced renal function and altered pharmacokinetics necessitate dose reductions and monitoring for CNS depression. Age‑related changes in body composition also affect distribution of lipophilic agents.

Renal and Hepatic Impairment

Renal impairment necessitates dose adjustment for opioids primarily eliminated by the kidneys (e.g., morphine). Hepatic impairment reduces metabolism of CYP3A4 substrates (e.g., fentanyl, methadone), requiring careful titration. Stimulants may accumulate in hepatic dysfunction, increasing cardiovascular risk. Alcohol metabolism is significantly impaired in hepatic disease, heightening the risk of hepatotoxicity.

Summary and Key Points

• Drugs of abuse can be classified by pharmacodynamic action, chemical structure, and clinical effects.
• Opioid receptor activation, catecholamine reuptake inhibition, and GABA modulation are central mechanisms underlying abuse potential.
• Pharmacokinetic variability, particularly in metabolism and elimination, influences dosing, efficacy, and toxicity.
• Approved pharmacotherapies for addiction emphasize substitution or antagonism (methadone, buprenorphine, naltrexone, disulfiram, acamprosate).
• Adverse effects range from common symptoms (constipation, tachycardia) to life‑threatening complications (respiratory depression, cardiotoxicity).
• Drug interactions, especially involving CYP enzymes, can dramatically alter exposure and safety profiles.
• Special populations—including pregnant patients, the elderly, and those with organ dysfunction—require individualized pharmacologic strategies.
• Clinicians should remain vigilant for emerging therapies and continually update knowledge on evolving substance abuse patterns.

References

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