Use, Abuse, and Addiction
Amphetamines and cocaine have high abuse potential and have been unequivocally shown to produce clinically defined Dependence (ICD-10), Substance Use Disorders (DSM-5), and addiction by most modern definitions. Compulsive use results in an exaggeration of the binge/intoxication stage of the addiction cycle (see What is Addiction), in which a user characteristically re-administers the drug regularly for days and then stops. A typical pattern of dependent cocaine use follows a cycle that appears to loop back on itself (Figure 4.10). Intense euphoria occurs first, which can be enhanced by increasing the speed at which the drug enters the brain (e.g., by the intravenous or smoked routes). Euphoria is followed immediately by dysphoria. The onset and intensity of the “high” and the subsequent dysphoria depend on the route of administration, with a more rapid and intense high and more rapid onset of dysphoria from smoked cocaine than from either the intranasal or oral routes. Repetitive movements (called stereotyped behavior or stereotypy), such as teeth grinding and pacing, may appear, as well as hyperactivity, rapid and frenzied speech (called “pressure speech”), and emotional instability. High doses can cause paranoia and hallucinations in some users, and heavy users may experience outright psychotic symptoms similar to the acute psychosis of paranoid schizophrenia. Within a binge, euphoria is followed by dysphoria and then more drug use. As this cycle continues, paranoia and psychosis ultimately develop in some people as the dose increases or the binge duration lengthens.
Figure 4.10 Different stages of the binge cycle associated with cocaine. Some individuals experience these stages in a single cocaine smoking episode with high doses; others experience them with low-dosage, chronic use patterns. Stage 1 (Euphoria) is marked by euphoria, affective lability, increased cognitive and motor performance, hyperalertness, hyperactivity, anorexia, and insomnia. Stage 2 (Dysphoria) is marked by sadness, melancholia, apathy, difficulty concentrating, anorexia, and insomnia. Stage 3 (Paranoia) is marked by suspiciousness, paranoia (both grandiosity and persecutory), hallucinations, and insomnia. Stage 4 (Psychosis) is marked by anhedonia, hallucinations, stereotyped behavior, paranoid delusions, insomnia, loss of impulse control, and disorientation. [From: Koob GF, Le Moal M. Neurobiology of Addiction. Academic Press, London, 2006. For further reading, see Siegel, 1982.]
With chronic psychostimulant use, the dose required to produce euphoria increases, and the subjective high decreases. Tolerance to the euphoric effects can also occur in subjects with one bout of cocaine administration. Human subjects show increases in the subjective sensations of intoxication during the rising phase of plasma cocaine levels (ascending limb) after smoking coca paste, but mood shifts dramatically to a negative state rapidly afterward. In fact, the mood state falls into a zone of dysphoria while plasma cocaine levels are still quite high (see Figure 1.9 in What is Addiction). Similar results have been seen in animal studies, in which a bout of 10 intravenously administered injections of cocaine lowered brain reward thresholds (reflecting increased brain reward function) immediately after the bout, but 80 injections only elevated brain reward thresholds (reflecting decreased brain reward function) immediately post-bout (see Figure 1.11 in What is Addiction?). Thus, as cocaine use and duration increase, the positive reinforcing effects are diminished while the resulting dysphoria increases. Oral administration of regularly spaced doses is less likely to produce tolerance to the subjective effects of psychostimulants, but intravenous or smoked administration can produce rapid acute tolerance. Tolerance does not develop into stereotyped behavior or psychosis induced by stimulants; rather, these effects show sensitization (i.e., an increase with repeated administration). Similar results have been found in animal studies, with tolerance developing to the anorexic and lethal effects of amphetamine but not to stereotyped behavior.
Figure 4.11 Phases of cocaine withdrawal following a binge. The duration and intensity of symptoms vary based on binge characteristics and diagnosis. Binges can range from under 4 hours to six or more days. [Modified from: Gawin FH, Kleber HD. Abstinence symptomatology and psychiatric diagnosis in cocaine abusers: clinical observations. Archives of General Psychiatry, 1986, (43), 107–113.]
A possible understanding of how amphetamines produce paranoid ideation and psychosis in humans can be derived from extending the analysis of overt motor effects of these drugs to their effects on cognitive function. Amphetamines are well known to produce paranoid psychotic episodes in individuals who abuse stimulants chronically or take large doses acutely. In one study of nine physically healthy volunteers who had previously administered large doses of amphetamine (and three who had previously experienced episodes of amphetamine-induced psychoses), repeated oral administration of 5–10 mg D-amphetamine produced paranoid delusions, often with blunted emotion in all subjects when a cumulative dose range of 55–75 mg was reached. Psychosis can also develop during withdrawal from an abuse cycle of amphetamine. This paranoid psychosis induced by stimulants, in its most severe form, is indistinguishable from nondrug-induced paranoid psychosis. Such paranoia can also produce actual physical toxicity, in which subjects believe that bugs (known as “crank bugs”) are crawling under their skin and need to be gouged out.
Withdrawal from chronic or high-dose cocaine use in humans is associated with relatively few overt physical signs but numerous motivationally relevant symptoms, such as dysphoria, depression, anxiety, anergia (lack of energy), insomnia, and drug craving. Three distinct withdrawal phases have been identified in outpatient studies of compulsive users (Figure 4.11). Phase 1 consists of a “crash” that lasts up to 4 days, with a rapid lowering of mood and energy and the acute onset of both agitation and depressive symptoms. Craving for the drug, anxiety, and paranoia peak during this phase and then are replaced by hyperphagia (increased energy) and insomnia. Phase 2 is characterized by prolonged dysphoria, anhedonia, lack of motivation, and increased craving that can last up to 10 weeks. Relapse is highly likely during this phase. Phase 3 is characterized by episodic craving that can last indefinitely. The withdrawal syndrome contributes to a cycle in which abstinence leads to withdrawal symptoms, and the associated dysphoria and craving, in turn, lead to relapse. Hospital inpatients, however, do not show these three withdrawal phases; instead, inpatients begin with high scores of mood-distress and craving that decrease gradually and steadily over several weeks, suggesting an important role for the environment in eliciting the cocaine withdrawal syndrome (Boxes 4.10 – 4.12).