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AIDS: acquired immune deficiency syndrome

CDC: U.S. Centers for Disease Control and Prevention

CNS: central nervous system

DA: dopamine

DAT: dopamine transporter

DEA: Drug Enforcement Agency

DMT: N, N-dimethyltryptamine

DOM: dimethoxymethylamphetamine

EEG: electroencephalogram

FDA: U.S. Food and Drug Administration

GABA: γ-aminobutyric acid

GI: gastrointestinal

GPCR: G protein–coupled receptor

5HT: serotonin

LSD: lysergic acid diethylamide

MDA: methylenedioxyamphetamine

MDMA: methylenedioxymethamphetamine

MOR: μ opioid receptor

NE: norepinephrine

NMDA: N-methyl-D-aspartate

PCP: phenycyclidine

Δ-9-THC: Δ-9-tetrahydrocannabinol


The terminology of drug dependence, abuse, and addiction has long elicited confusion that stems from the fact that repeated use of certain prescribed medications can produce neuroplastic changes resulting in two distinctly abnormal states. The first state is dependence, or “physical” dependence, produced when there is progressive pharmacological adaptation to the drug resulting in tolerance. Tolerance is a normal reaction that is often mistaken for a sign of “addiction.” In the tolerant state, repeating the same dose of a drug produces a smaller effect. If the drug is abruptly stopped, a withdrawal syndrome ensues in which the adaptive responses are now unopposed by the drug. The appearance of withdrawal symptoms is the cardinal sign of “physical” dependence. Addiction, the second abnormal state produced by repeated drug use, occurs in only a minority of those who initiate drug use; addiction leads progressively to compulsive, out-of-control drug use.

Addiction can be considered as a form of maladaptive memory. Addiction begins with the administration of substances (e.g., cocaine) or behaviors (e.g., the thrill of gambling) that directly and intensely activate brain reward circuits. Activation of these circuits motivates normal behavior, and most humans simply enjoy the experience without being compelled to repeat it. For some (∼16% of those who try cocaine), the experience produces strong conditioned associations to environmental cues that signal the availability of the drug or the behavior. The individual becomes drawn into compulsive repetition of the experience, focusing on the immediate pleasure despite negative long-term consequences and neglect of important social responsibilities. The distinction between dependence and addiction is important because patients with pain sometimes are deprived of adequate opioid medication by their physician simply because they have shown evidence of tolerance or they exhibit withdrawal symptoms if the analgesic medication is stopped or reduced abruptly. The most recent revision of the classification system (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; see American Psychiatric Association, 2013) makes a clear distinction between normal tolerance and a drug use disorder involving compulsive drug seeking.


Most of those who initiate use of a drug with addiction potential do not develop a drug use disorder. Many variables operate simultaneously to influence the likelihood that a beginning drug user will lose control and develop an addiction. These variables can be organized into ...

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