Amphetamine

AMPHETAMINE

Amphetamine was first synthesized in 1887, but its central nervous system (CNS) stimulant effects were not noted at that time. After rediscovery, in the early 1930s, its use as a respiratory stimulant was established and its properties as a central nervous system stimulant were described. Reports of abuse soon followed. As had occurred with cocaine products when they were first introduced in the 1880s, amphetamine was promoted as being an effective cure for a wide range of ills without any risk of addiction. The medical profession enthusiastically explored the potentials of amphetamine, recommending it as a cure for everything from alcohol hangover and depression to the vomiting of pregnancy and weight reduction. These claims that it was a miracle drug contributed to public interest in the amphetamines, and they rapidly became the stimulant of choice—since they were inexpensive, readily available, and had a long duration of action.

Derivatives of amphetamine, such as Methamphetamine, were soon developed and both oral and intravenous preparations became available for therapeutic uses. Despite early reports of an occasional adverse reaction, enormous quantities were consumed in the 1940s and 1950s, and their liability for abuse was not recognized. During World War II, the amphetamines, including methamphetamine, were widely used as stimulants by the military in the United States, Great Britain, Germany, and Japan, to counteract fatigue, to increase alertness during battle and night watches, to increase endurance, and to elevate mood. It has been estimated that approximately 200 million Benzedrine (amphetamine) tablets were dispensed to the U.S. armed forces during World War II. In fact, much of the research on performance effects of the amphetamines was carried out on enlisted personnel during this period, as the various countries sought ways of maintaining an alert and productive armed force. Although amphetamine was found to increase alertness, little data were collected supporting its ability to enhance performance.

Since 1945, use of the amphetamines and Co-Caine appears to have alternated in popularity, with several stimulant epidemics occurring in the United States. There was a major epidemic of amphetamine and methamphetamine abuse (both oral and intravenous) in Japan right after the war. The epidemic was reported to have involved, at its peak, some half-million users and was related to the release with minimal regulatory controls of huge quantities of surplus amphetamines that had been made for use by the Japanese military. Despite this experience, there were special regulations governing their manufacture, sale, or prescription in the United States until 1964 (Kalant, 1973).

The first major amphetamine epidemic in the United States peaked in the mid-1960s, with approximately 13.5 percent of the university population estimated, in 1969, to have used amphetamines at least once. By 1978, use of the amphetamines had declined substantially, contrasting with the increase of cocaine use by that time. The major amphetamine of concern in the United States in the 1990s is methamphetamine, with pockets of "ice" (smoked methamphetamine) abuse.

Amphetamines are now controlled under Schedule II of the Controlled Substances Act. Substances classified within this schedule are found to have a high potential for abuse as well as currently accepted medical use within the United States. Amphetamine, methamphetamine, cocaine, Methylphenidate, and phenmetrazine are all stimulants included in this schedule.

MEDICAL UTILITY

Amphetamines are frequently prescribed for the treatment of narcolepsy, obesity, and for childhood Attention Deficit Disorder. They are clearly efficacious in the treatment of narcolepsy, one of the first conditions to be successfully treated with these drugs. Although patients with this disorder can require large doses of amphetamine for prolonged periods of time, attacks of sleep can generally be prevented. Interestingly, tolerance does not seem to develop to the therapeutic effects of these drugs, and most patients can be maintained on the same dose for years.

Although the amphetamines have been used extensively in the treatment of obesity, considerable evidence exists for a rapid development of tolerance to the anorectic (appetite loss) effects of this drug, with continued use having little therapeutic effect. These drugs are extremely effective appetite suppressants, but after several weeks of use the dose must be increased to achieve the same appetite-suppressant effect. People remaining on the amphetamines for prolonged periods of time to decrease food intake can reach substantial doses, resulting in toxic side effects (e.g., insomnia, irritability, increased heart rate and blood pressure, and tremulousness). Therefore, these drugs should only be taken for relatively short periods of time (4-6 weeks). In addition, long-term follow-up studies of patients who were prescribed amphetamines for weight loss have not found any advantage in using this medication to maintain weight loss. Data indicate that weight lost under amphetamine maintenance is rapidly gained when amphetamine use is discontinued. In addition to the lack of long-term efficacy, the dependence-producing effects of amphetamines make them a poor choice of maintenance medication for this problem.

The use of amphetamines in the treatment of attention deficit disorders in children, remains extremely controversial. It has been found that the amphetamines have a dramatic effect in reducing restlessness and distractibility as well as lengthening attention span, but there are side effects. These include reports of growth impairment in children, insomnia, and increases in heart rate. Those promoting their use point to their potential benefits and they advocate care in limiting treatment dose and duration. Opponents of their use, while agreeing that they provide some short-term benefits, conclude that these do not outweigh their disadvantages. Amphetamine therapy has also been attempted, but with little success, in the treatment of Parkinson's disease, and both amphetamine and cocaine have been suggested for the treatment of depression, although the evidence to support their efficacy does not meet current standards demanded by the U.S. Food and Drug Administration.

PHARMACOLOGY

The amphetamines act by increasing concentrations of the neurotransmitters Dopamine and Norepinephrine at the neuronal synapse, thereby augmenting release and blocking uptake. It is the augmentation of release that differentiates amphetamines from cocaine, which also blocks uptake of these transmitters. Humans given a single moderate dose of amphetamine generally show an increase in activity and talkativeness, and they report euphoria, a general sense of well-being, and a decrease in both food intake and fatigue. At higher doses repetitive motor activity (i.e., stereotyped behavior) is often seen, and further increases in dose can lead to convulsions, coma, and death. This class of drugs increases heart rate, respiration, diastolic and systolic blood pressure, and high doses can cause cardiac arrhythmias. In addition, the amphetamines have a suppressant effect on both rapid eye movement sleep (REM)—the stage of sleep associated with dreaming—and total sleep. The half-life of amphetamine is about ten hours, quite long when compared to a stimulant like cocaine, which has a half-life of approximately one hour, or even methamphetamine which has a half-life of about five hours.

The amphetamine molecule has two isomers: the d -(+) and l -(-) isomers. There is marked stereo-selectivity in their biological actions, with the d -isomer (dextroamphetamine) considerably more potent. For example, it is more potent as a locomotor stimulant, in inducing stereotyped behavior patterns, and in eliciting central nervous system excitatory effects. The isomers appear to be equipotent as cardiovascular stimulants. The basic amphetamine molecule has been modified in a number of ways to accentuate various of its actions. For example, in an effort to obtain appetite suppressants with reduced cardiovascular and central nervous system effects, structural modifications yielded such medications as diethylproprion and fenfluramine, while other structural modifications have enhanced the central nervous system stimulant effects and reduced the cardiovascular and anorectic actions, yielding medications such as methylphenidate and phenmetrazine. These substances share, to a greater or lesser degree, the properties of amphetamine.

TOXICITY

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 d -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 catecholamine 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.

BEHAVIORAL EFFECTS

Nonhumans.

As with all Psychomotor Stimulant drugs, at low doses animals are active and alert, showing increases in responding maintained by other reinforcers, but often decreasing food intake. Higher doses produce species-specific repetitive behavior patterns (stereotyped behavior), and further increases in dose are followed, as in humans, by convulsions, hyperthermia, and death. Tolerance (loss of response to a certain dose) develops to many of amphetamine's central effects, and cross-tolerance among the stimulants has been demonstrated in rats. Thus, for example, animals tolerant to the anorectic effects of amphetamine also show tolerance to cocaine's anorectic effects. Although there is tolerance development to many of amphetamine's effects, sensitization develops to amphetamine's effects on locomotor activity. Thus, with repeated administration, doses of amphetamine that initially did not result in hyperactivity or stereotypy can, with repeated use, begin to induce those behaviors when injected daily for several weeks. In addition, there is cross-sensitization to this effect, such that administration of one stimulant can induce sensitization to another one. In contrast to cocaine, however (in which an increased sensitivity to its convulsant effects develops with repeated use), amphetamines have an anticonvulsive effect.

Learned behaviors, typically generated by operant schedules of reinforcement, are generally affected by the amphetamines in a rate-dependent fashion. Thus, behaviors that occur at relatively low rates in the absence of the drug tend to be increased at low-to-moderate doses of amphetamine, while behaviors occurring at relatively high frequencies tend to be suppressed by those doses of amphetamine. In addition, with high doses most behaviors tend to be suppressed. As is seen with other stimulants, such as cocaine, environmental variables and behavioral context can play a role in modulating these effects. For example, behavior under strong stimulus control shows tolerance to repeated amphetamine administration much more rapidly than does behavior under weak stimulus control. In addition, if the amphetamine-induced behavioral disruption has the effect of interfering with reinforcement delivery, tolerance to that effect develops rapidly. Tolerance does not develop to the amphetamine-induced disruptions when reinforcement density is increased or remains the same.

Amphetamines can serve as reinforcers in nonhumans and, as described above, can produce severely toxic consequences when available in an unlimited fashion. However, when available for a few hours a day, animals will take them in a regular fashion, showing little or no tolerance to their reinforcing effects.

Humans.

A substantial number of studies have been carried out evaluating the effects of amphetamines on learning, cognition, and other aspects of performance. The data indicate that under most conditions the amphetamines are not general performance enhancers. When there is improvement in performance associated with amphetamine administration, it can usually be attributed to a reduction in the deterioration of performance due to fatigue or boredom. Attention lapses that impair performance after sleep deprivation appear to be reduced by amphetamine administration; however, as sleep deprivation is prolonged, this effect is reduced. A careful review of the literature in this area (Laties & Weiss, 1981) concluded that improvement is more obvious with complex, as compared with simple, tasks.

In addition, in trained athletes, whose behavior shows little variability, only very small improvements can be seen. Laties and Weiss have argued persuasively, however, that the small changes in performance induced by amphetamines can result in the 1 to 2 percent improvement that may make the difference in a close athletic competition. Although the facilitation in performance after amphetamine does not appear to be substantial, it is sufficient to "spell the difference between a gold medal" and any other. Unfortunately, such data have led athletes to take stimulants prior to athletic events, particularly those in which strenuous activity is required over prolonged periods (e.g., bicycle racing), leading to hyperthermia, collapse, and even death in some cases.

The mood-elevating effects of the amphetamines are generally believed to be related to their abuse. Their use is accompanied by reports of increased self-confidence, elation, frequently euphoria, friendliness, and positive mood. When amphetamine is administered repeatedly, tolerance develops rapidly to many of its subjective effects (such that the same dose no longer exerts much of an effect). This means that the user must take increasingly larger amounts of amphetamine to achieve the same effect. As with nonhuman research subjects, there is however, little or no evidence for the development of tolerance to amphetamine's reinforcing effects.

Experienced stimulant users, given a variety of stimulant drugs, often cannot differentiate among cocaine, amphetamine, methamphetamine, and methlyphenidate—all of which appear to have similar profiles of action. Since these drugs have different durations of action, however, it becomes easier to make this differentiation over time.

ABUSE

In the United States in the 1950s, nonmedical amphetamine use was prevalent among college students, athletes, truck drivers, and housewives. The drug was widely publicized by the media when very little evidence of amphetamine toxicity was available. Pills were the first form to be widely abused. Use of the drug expanded as production of amphetamine and methamphetamine increased significantly, and abusers began to inject it. An extensive black market in amphetamines developed, and it has been estimated that 50 to 90 percent of the quantity commercially produced was diverted into illicit channels. In the 1970s, manufacture of amphetamines was substantially curtailed, amphetamines were placed in Schedule II of the Controlled Substances Act, and abuse of these substances was substantially reduced. Perhaps only by coincidence, as amphetamine use declined, cocaine use increased.

The amphetamines, as with other stimulants, are generally abused in multiple-dose cycles (i.e., binges), in which people take the drug repeatedly for some period of time, followed by a period in which they take no drug. Amphetamines are often taken every three or four hours for periods as long as three or four days, and dosage can escalate dramatically as tolerance develops. Like cocaine binges, these amphetamine-taking occasions are followed by a "crash" period in which the user sleeps, eats, and does not use the drug. Abrupt cessation from amphetamine use is usually accompanied by depression. Mood generally returns to normal within a week, although craving for the drug can last for months.

There is little evidence for the development of physical dependence to the amphetamines. Although some experts view the "crash" (with lethargy, depression, exhaustion, and increased appetite) that can follow a few days of moderate-to-high dose use as meeting the criteria for a withdrawal syndrome, others believe that the symptoms can also be related to the effects of chronic stimulant use. When using stimulants people do not eat or sleep very much and, as well, catecholamine depletion may well be contributing to these behavioral changes.

TREATMENT

As of the mid-1990s, little information is available about the treatment of amphetamine abusers, and no reports of successful pharmacological interventions exist in the treatment literature. As with cocaine abuse, the most promising nonpharmacological approaches include behavioral therapy, Relapse Prevention, rehabilitation (e.g., vocational, educational, and social-skills training), and supportive psychotherapy. Unlike cocaine, however, minimal clinical trials with potential treatment medications for amphetamine abuse have been carried out. The few that have been attempted report no success in reducing a return to amphetamine use.

(See also: Amphetamine Epidemics ; Pharmacokinetics ; Treatment )

BIBLIOGRAPHY

Angrist, B., & Sudilovsky, A. (1978). Central nervous system stimulants: Historical aspects and clinical effects. In L. L. Iversen, S. D. Iverson, & S. H. Snyder (Eds.), Handbook of psychopharmacology. New York: Plenum.

Griffith, J. D., et al. (1970). E. Costa and S. Garattini (Eds.), Amphetamines and related compounds. New York: Raven Press.

Grilly, D. M. (1989). Drugs and human behavior. Needham, MA: Allyn & Bacon.

Kalant, O. J. (1973). The amphetamines: Toxicity and addiction. Springfield, IL: Charles C. Thomas.

Laties, V.G., & Weiss, B. (1981). Federation proceedings, 40, 2689-2692.

Marian W. Fischman