Drug addiction.

N Engl J Med 2003;349:975-86. Copyright © 2003 Massachusetts Medical Society. rug addiction is a chronic, relapsing disorder in which compulsive drug-seeking and drug-taking behavior persists despite serious negative consequences. Addictive substances induce pleasant states (euphoria in the initiation phase) or relieve distress. Continued use induces adaptive changes in the central nervous system that lead to tolerance, physical dependence, sensitization, craving, and relapse (Table 1). The addictive drugs discussed here are opioids, cannabinoids, ethanol, cocaine, amphetamines, and nicotine. The World Health Organization 1 and the American Psychiatric Association 2 use the term “substance dependence” rather than “drug addiction.” “Drug addiction,” however, emphasizes the behavioral connotation of the term and is less likely to be confused with physical dependence. 3 We use both terms interchangeably in this review. The American Psychiatric Association’s definition of substance dependence 2 requires a patient to meet at least three of the seven criteria listed in Table 1. Tolerance and physical dependence reflect physiological adaptation to the effects of a drug, whereas the remaining criteria define uncontrollable drug consumption. However, tolerance and physical dependence are neither necessary nor sufficient for a diagnosis of substance dependence. Substance abuse 2 or harmful use, 1 a less severe disorder, may result in dependence. Theories of addiction have mainly been developed from neurobiologic evidence and data from studies of learning behavior and memory mechanisms. They overlap in some aspects and are not mutually exclusive. None of them alone can explain all aspects of addiction. It is not our purpose to present a detailed assessment of these theories, especially because of the complexity of the problem. Generally, addictive drugs can act as positive reinforcers (producing euphoria) or as negative reinforcers (alleviating symptoms of withdrawal or dysphoria). Environmental stimuli (cues) associated with drug use itself can also induce a conditioned response (withdrawal or craving) in the absence of the drug. 4,5