A major toxic effect of amphetamine in humans is the development of a schizophrenia-like psychosis after repeated long-term use. The first report of an amphetamine psychosis occurred in 1938, but the condition was considered rare. Administration of amphetamine to normal volunteers with no histories of psychosis (Griffith et al., 1968) resulted in a clear-cut paranoid psychosis in five of the six subjects who received ¿-amphetamine for one to five days (120-220 mg/day), which cleared when the drug was discontinued. Unless the user continues to take the drug, the psychosis usually clears within a week, although the possibility exists for prolonged symptomology. This amphetamine psychosis has been thought to represent a reasonably accurate model of schizophrenia, including symptoms of persecution, hyperactivity and excitation, visual and auditory hallucinations, and changes in body image. In addition, it has been suggested that there is sensitization to the development of a stimulant psychosis—once an individual has experienced this toxic effect, it is readily reinitiated, sometimes at lower doses and even following long drug-free periods.

Amphetamine abusers taking repeated doses of the drug can develop repetitive behavior patterns which persist for hours at a time. These can take the form of cleaning, the repeated dismantling of small appliances, or the endless picking at wounds on the extremities. Such repetitive stereotyped patterns of behavior are also seen in nonhumans administered repeated doses of amphetamines and other stimulant drugs, and they appear to be related to dopaminergic facilitation. Cessation of amphetamine use after high-dose chronic intake is generally accompanied by lethargy, depression, and abnormal sleep patterns. This pattern of behavior, opposite to the direct effects of amphetamine, does not appear to be a classical abstinence syndrome. The symptoms may be related to the long-term lack of sleep and food intake that accompany chronic stimulant use as well as to the cate-cholamine depletion that occurs as a result of chronic use.

Animals given unlimited access to amphetamine will self-administer it reliably, alternating days of high intake with days of low intake. They become restless, tremulous, and ataxic, eating and sleeping little. If allowed to continue self-administering the drug, most will take it until they die. Animals maintained on high doses of amphetamines develop tolerance to many of the physically and behaviorally debilitating effects, but they also develop irreversible damage in some parts of the brain, including long-lasting depletion of dopamine. It has been suggested that the prolonged anhedonia seen after long-term human amphetamine use may be related to this, although the evidence for this is not very strong.

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