Background and History
Amphetamine is the parent compound of a family of synthetic psychostimulants. It is available in two chemical forms, 1-amphetamine (trade name Benzedrine) and d-ampheta- mine (also called dextroamphetamine; trade name Dexedrine). Other members of this family are methamphet- amine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), and 3,4-methyl- enedioxy-N-ethylamphetamine (MDE). These compounds are structurally related to the neurotransmitter DA.
Two naturally occurring plant compounds that are similar in structure to amphetamine. One of these is cathinone, which is the primary active ingredient in khat (alternately spelled qat) (Catha edulis), an evergreen shrub native to East Africa and the Arabian peninsula. A second amphetamine-like compound is ephedrine, which comes from the herb Ephedra vulgaris. Chinese physicians have used Ephedra (known to them as ma huang) for more than 5000 years as an herbal remedy. Like other amphetamine-like substances, ephedrine reduces appetite, and it also provides a subjective feeling of height-ened energy. For these reasons, a number of companies began to market ephedra-containing dietary supplements as weight loss products sold in health food stores. These supplements became so popular that in 1999, the General Accounting Office estimated that Americans were consuming about 2 billion doses of ephedra-containing products each year!
Unfortunately, ephedrine sharply elevates blood pressure and exerts other sympathomimetic effects as well. These effects can increase the risk of heart attack or stroke, particularly with large drug doses or in vulnerable individuals. Due to the many reports of adverse reactions (including several deaths) associated with the use of ephedra, the Food and Drug Administration (FDA) became increasingly concerned about this substance. Then in February of 2003, national headlines were made when a young Baltimore Orioles pitcher named Steve Bechler collapsed and died during spring training in Florida. Struggling to control his weight, Bechler had been taking high doses of a popular ephedra- containing supplement, and the Broward County coroner ruled that ephedra was a likely contributory factor in the pitcher’s death. As a consequence of this and other reported adverse reactions, the FDA officially banned the sale of ephedra-containing dietary supplements in April 2004.
Interestingly, ephedra played a key role in the development of amphetamine. In the 1920s, purified ephedrine was found to be a valuable antiasthmatic agent due to its powerful bronchodilator (widening of the airways) action.* However, the medical profession soon became concerned that demand for ephedrine might exceed its supply and therefore began to search for an appropriate synthetic substitute. That substitute turned out to be amphetamine, which had first been synthesized in 1887 by Edeleano. The Smith, Kline & French pharmaceutical company introduced an amphetamine-containing inhaler in 1932. The inhaler, which contained 250 mg of Benzedrine in a cotton plug, proved to be effective in temporarily relieving nasal or bronchial congestion. Unfortunately, however, some individuals began to overuse these inhalers,
particularly since many varieties could be purchased without a prescription. Other people learned to open the container, remove the amphetamine-containing plug, and either chew the cotton, swallow it, or extract it to recover the drug for the purpose of injection. Amphetamine in tablet form was first marketed in 1935 as a treatment for a sleep disorder called narcolepsy (see the discussion on therapeutic uses of the drug). By the 1940s, amphetamine had become so widely embraced by the medical profession that one author documented 39 supposed clinical uses for the drug. In addition, many American military personnel were given amphetamine to forestall sleep and maintain a heightened level of alertness during prolonged periods on duty.
After World War II, the United States experienced a surge in the street use of amphetamine. During the 1950s and 1960s, students were casually using amphetamines in the same way that caffeine is presently taken to remain awake during pre-exam all-nighters. The peak of amphetamine use in the United States occurred during the early 1970s, when the legal production of amphetamine exceeded 10 billion (!) tablets, and at least one survey estimated that approximately 25% of young men had used stimulant drugs (mainly amphetamine or related compounds) on one or more occasions. Since that time, cocaine has generally supplanted amphetamine as the major abused psychostimulant. One exception to this trend, however, has been a recent upsurge in methamphetamine use in certain parts of the country.
In the following discussion, amphetamine and methamphetamine are presented together because of their similar neurochemical and behavioral effects. MDMA, MDA, and MDE are covered in a separate section at the end of the post because they differ in important ways from the other amphetamines.
Basic Pharmacology of Amphetamine
Amphetamine is typically taken either orally or by IV or sub-cutaneous injection (the latter is sometimes called “skin popping”). Street names for amphetamine include “uppers,” “bennies,” “dexies,” “black beauties,” and “diet pills.” Because absorption from the gastrointestinal tract is relatively slow, it may take up to 30 minutes for behavioral effects to be experienced after a typical oral dose of 5 to 15 mg. In contrast, IV injection provides a much more rapid and intense “high” than oral consumption and has much greater abuse potential.
Methamphetamine is more potent than amphetamine in its effects on the central nervous system and is therefore favored by substance abusers when it is available. Typical street names for methamphetamine are “meth,” “speed,” “crank,” “zip,” and “go.” The drug can be taken orally, snorted, injected intravenously, or smoked. Smoking methamphetamine can be accomplished either using a glass pipe or by heating the compound on a piece of aluminum foil (a practice sometimes called “chasing the dragon”). Methamphetamine hydrochloride in a crystalline form particularly suitable for smoking (called “ice” or “crystal” on the street) began showing up Hawaii in the 1980s. This material has since spread to many parts of the country, particularly in the West, South, and Midwest. Because “ice” is inexpensive to make and highly addictive, it poses a serious risk for society’s attempts to control and reduce the incidence of stimulant abuse.
Some amphetamine or methamphetamine users (called “speed freaks”) go on binges, or “runs,” of repeated IV injections to experience recurrent highs. During a run, the drug is typically injected approximately every 2 hours for a period as long as 3 to 6 days or more. Little sleep or eating occurs during a run. The user finally becomes exhausted, ends the run, and goes to sleep for many hours. Barbiturates or other depressant drugs are sometimes used either to “take the edge off” during a run or to assist in sleeping following the run. Yet another approach is to moderate the extreme stimulatory effect of IV amphetamine or methamphetamine by combining it with heroin to yield a so-called “speedball.”
Amphetamine and methamphetamine are metabolized by the liver, though at a slow rate. Metabolites, as well as some unmetabolized drug molecules, are mainly excreted in the urine. The elimination half-life of amphetamine ranges from 7 to more than 30 hours depending on the pH of the urine. Because of this long half-life, users obtain a much longer- lasting “high” from a single dose of amphetamine or methamphetamine than they can get from a dose of cocaine.
Mechanisms of Amphetamine Action
Amphetamine and methamphetamine are indirect agonists of the catecholaminergic systems. Unlike cocaine, which only blocks catecholamine reuptake, amphetamine and methamphetamine also release catecholamines from nerve terminals. At very high doses, these compounds can even inhibit catecholamine metabolism by monoamine oxidase.
Studies on the mechanism of catecholamine release by amphetamine have particularly focused on DA. The results of this research suggest that two related drug actions are involved. One action is to cause DA molecules to be released from inside the vesicles into the cytoplasm of the nerve terminal. These DA molecules are subsequently transported outside of the terminal by a reversal of the DAT. The result is a massive increase in synaptic DA concentrations and an associated stimulation of dopaminergic transmission.
In animals, amphetamine- or methamphetamine-stimulated DA release has been demonstrated using techniques such as in vivo microdialysis. Brain imaging studies have likewise provided evidence for DA release in humans following IV amphetamine injection in the laboratory (Drevets et al., 2001). It is important to recognize that the NE-releasing effects of amphetamines occur not only in the brain but also in the sympathetic nervous system. Consequently, these compounds exert potent sympathomimetic actions similar to those seen with cocaine.
Behavioral and Neural Effects of Amphetamine
Amphetamine is a psychostimulant that has therapeutic uses
Like cocaine, amphetamine causes heightened alertness, increased confidence, feelings of exhilaration, reduced fatigue, and a generalized sense of well-being in human users. A number of other effects have also been observed, including improved performance on simple, repetitive psychomotor tasks; a delay in sleep onset; and a reduction in sleep time, particularly with respect to REM (rapid eye movement) sleep. Indeed, amphetamine permits sustained physical effort without rest or sleep, which accounts for its distribution to military personnel during World War II as well as its occasional use by truck drivers and other workers desirous of foregoing sleep for extended periods of time. The drug can also enhance athletic performance and is therefore one of the many banned substances in athletic competitions. In rodents and other animals, amphetamine elicits behavioral activation (locomotor stimulation and stereotypy) similar to that seen with cocaine. It is also highly reinforcing, as shown by numerous studies involving drug self-administration or place conditioning.
Although amphetamine is a controlled substance, it does have a few medical uses. As mentioned earlier, one such use is in the treatment of narcolepsy. Narcolepsy typically involves recurring and irresistible attacks of sleepiness during the daytime hours, although other symptoms may also be present. Amphetamine and particularly methylphenidate are even more widely used in treating children with ADHD.
High closes or chronic use of amphetamine or methamphetamine can cause psychotic reactions as well as brain damage
Psychotic reactions More than 30 years ago, several research groups first described in some high-dose amphetamine users a psychotic reaction consisting of visual and/or auditory hallucinations, behavioral disorganization, and the development of a paranoid state with delusions of persecution. Users may experience the same hallucination of a parasitic skin infestation described earlier for cocaine. These reactions to amphetamine usually do not occur upon first exposure to the drug, but only after a chronic abuse pattern has developed. Furthermore, in at least one study the paranoia and hallucinations did not typically begin until the second or third day of a “speed run.”
With the increasing use of methamphetamine, the incidence of psychotic reactions to this substance is growing. Anecdotal reports suggest that high-dose methamphetamine use can also lead to violent behavior. Finally, some methamphetamine users who had an earlier psychotic reaction may undergo spontaneous recurrences known as “flashbacks” even while abstinent from the drug. These flashbacks can be triggered by stressful events and may reflect heightened stress sensitivity in former psychostimulant users.
Neurotoxicity There is a special danger to methamphetamine users due to the neurotoxic properties of this substance. Investigators have known for many years that administration of multiple doses of methamphetamine to animals causes long-lasting reductions in the levels of DA, tyrosine hydroxylase (the key enzyme in DA synthesis), and the DAT in the striatum (McCann and Rucaurte, 2004). These changes are indicative of damage to DA axons and terminals, which has been confirmed by histological experiments showing the presence of degenerating fibers. Methamphetamine also produces damage to serotonergic fibers in several parts of the brain, including the neocortex, hippocampus, and striatum.
Until recently, no one knew whether human methamphetamine users suffer the same consequences as methamphetamine-treated experimental animals. Now, however, there are at least two different imaging studies reporting reduced DAT density in the striatum of methamphetamine users, even in individuals who had been abstinent from the drug for many months or longer (McCann et al., 1998; Volkow et al., 2001a). Decreases in neurotransmitter transporters sometimes reflect loss of the corresponding (in this case, DA) nerve fibers, since the transporters are located on the membrane of these fibers. Note, for example, the large reduction in DAT in the striatum of a Parkinson’s disease patient, where the dopaminergic innervation of the striatum is known to be severely compromised. At this point, we can’t be certain that the reduced DA transporter density in methamphetamine users is a sign of DA neurotoxicity, although such an interpretation is consistent with the animal studies. Moreover, since there appears to be a progressive loss of dopaminergic neurons and fibers during normal human aging, even a modest amount of damage to this system early in life could predispose the individual to developing Parkinson’s disease later on.
MDMA—The Entactogenic Amphetamine
Three members of the amphetamine family, MDMA, MDA, and MDE, differ from the others in terms of their chemical structures, neurochemical actions, and behavioral effects. We will focus on MDMA due to its significant recreational use in the United States and elsewhere.
MDMA was developed and patented by the Merck pharmaceutical company in 1914. The drug was essentially forgotten for the next 50 to 60 years. However, in the 1970s a small group of psychotherapists began to use MDMA as a therapeutic adjunct. They argued that MDMA caused clients to become more communicative, to open up their emotions, and to experience greater closeness or empathy with other individuals (Greer and Tolbert, 1986). These reports led David Nichols, a chemist who has studied the structure and actions of MDMA and related drugs, to coin the term entac- togen to distinguish these compounds from both the psychostimulants and hallucinogens (Nichols, 1986). Entactogen was derived by combining the Latin tactus, meaning “touch,” with the Greek roots en-, for “within,” and -gen, meaning “to produce or originate.” Thus entactogens are supposed to elicit a “touching within,” or, in more direct terms, an enhanced ability to introspect and to confront disturbing or painful emotions.
MDMA also began to be used recreationally under such street names as “ecstasy,” “XTC,” and “Adam.” In response to several reports of toxic reactions (including some fatalities) to MDMA and the resulting adverse publicity, the Drug Enforcement Administration (DEA) gave MDMA a Schedule I classification (no accepted medical use and a high abuse potential) in 1985. However, making MDMA illegal failed to stem its increasing use by large numbers of adolescents and young adults.
Much MDMA use occurs at dances called “raves.” Dancers typically consume one or two tablets, each containing about 100 to 200 mg of MDMA. The drug reportedly produces mild euphoria, enhanced sensory perception, increased energy, feelings of well-being and self-confidence, a desire to be with and interact with other people, and sometimes sexual arousal. MDMA does not generally have hallucinogenic effects, although hallucinations can occur with high doses of MDA. MDMA can also cause a variety of physiological responses, including increased heart rate and blood pressure, elevated body temperature, sweating and salivation, tremor, trismus (tightening of the jaw muscles), and bruxism (teeth grinding). When MDMA is consumed at a dance, the rise in body temperature and loss of fluids produced by the drug are exacerbated by environmental conditions and by the physical exertion of the dancer. This can lead to fatal consequences if one is not careful. Thus dancers are advised to take frequent breaks to cool off and to consume sufficient water (though not too much) to replace lost body fluids.
We saw earlier that amphetamine and methamphetamine stimulate the release and block the reuptake of catecholamines. We also noted that methamphetamine has neurotoxic effects on the DA system. MDMA differs from amphetamine and methamphetamine in that its primary mode of action is to enhance the release of 5-HT and inhibit 5-HT reuptake. It also stimulates DA release, but not as powerfully as in the case of 5-HT. Activation of serotonergic transmission by MDMA is thought to mediate many of the drug’s behavioral effects and to be responsible for the differences between MDMA and amphetamine or methamphetamine.
Unfortunately, there is a dark side to MDMA that most users either ignore or refuse to believe. Numerous animal studies involving both rodents and nonhuman primates have documented that MDMA exposure, particularly repeated exposure, damages serotonergic pathways in the brain (Boot et al., 2000). Although the 5-HT-containing cell bodies in the raphe nuclei appear to be unaffected, the evidence indicates decreased 5-HT levels and a pruning of serotonergic axons and terminals in various forebrain areas such as the cortex and hippocampus. By “pruning,” we mean that some of the branches of these fibers have been lost, presumably yielding a reduced number of serotonergic synapses in the affected brain areas. Thus, MDMA initially stimulates serotonergic activity, but this acute stimulation is followed by diminished serotonergic function. The damaged serotonergic fibers slowly regrow, but such regrowth is not entirely normal. Some brain areas regain their usual serotonergic innervation, some show a long-lasting deficit in the density of serotonergic fibers, and a few areas actually develop an excessive serotonergic input (Fischer et al., 1995; Hatzidimitriou et al., 1999). The behavioral consequences of this abnormal reinnervation pattern are not yet known.
Do humans suffer from the same losses after using MDMA? Some critics have pointed out that serotonergic neurotoxicity in animals occurs at significantly higher MDMA doses than those generally consumed by humans. However, this argument does not take into account species differences in drug metabolism and sensitivity. For example, rats require much higher doses of many psychoactive drugs (on the basis of milligrams per kilogram of body weight) to show the same pharmacological effects as humans. Apart from the dosing issue, there is mounting evidence for MDMA-related serotonergic neurotoxicity in heavy users. Most of this evidence is indirect, because thus far there has been little opportunity to examine the brains of MDMA users postmortem.
Nevertheless, various studies comparing chronic MDMA users to control subjects have shown reduced 5-HIAA (the principal 5-HT metabolite) levels in the cerebrospinal fluid, a decreased density of the 5-HT transporter (a marker for serotonergic fibers and terminals) using brain imaging methods, and diminished hormonal responses to pharmacological challenge of the serotonergic system (Boot et al., 2000; Parrott, 2001). Certain reservations can be raised over these studies— MDMA users typically take other illicit drugs as well, so it is possible that the observed effects are not actually due to MDMA; effects obtained in the human studies are usually of smaller magnitude than those observed in animal models; and most studies have investigated very heavy users with a lifetime consumption of hundred of doses, leaving open the question of whether lighter use produces the same effects. Nevertheless, the results taken together strongly suggest that (at least heavy) MDMA use does lead to serotonergic abnormalities that may be indicative of actual damage to the nerve fibers.
Several research groups in both the United States and Europe have additionally reported an association between heavy MDMA use and cognitive deficits on neuropsychological tests (Parrott, 2001). Decreased performance on memory tasks is a particularly common finding. It is not yet clear whether the cognitive effects of chronic MDMA exposure are caused by serotonergic damage. However, it is worth noting that two of the brain areas heavily affected in animals, namely the hippocampus and cortex, play key roles in memory and other cognitive functions. There is currently insufficient evidence to ascertain whether a few doses of MDMA are harmful to the individual. On the other hand, there is certainly sufficient reason to avoid regular use of this or related substances (that is, MDA or MDE), given both the neurochemical and neuropsychological findings presented here.
Amphetamine and methamphetamine are synthetic psychomotor stimulants that are closely related structurally to two similarly acting plant compounds, cathinone and ephedrine. Amphetamine was first introduced in the United States in 1932 in the form of a nasal inhaler. People soon realized that they could achieve powerful stimulatory and euphoric effects by consuming the drug orally or by injecting it. The incidence of amphetamine use and abuse grew until a peak was attained in the 1970s. Since that time, the drug has been largely supplanted by cocaine, except for a recent upsurge in methamphetamine use in certain parts of the country. Until recently, ephedra was contained in numerous dietary supplements used for energy enhancement and weight loss, but this substance has been banned by the FDA due to adverse reactions.
Amphetamine is typically taken orally or by IV or subcutaneous injection. Crystalline methamphetamine, which is more potent than amphetamine, can also be taken by snorting or smoking. Some amphetamine or methamphetamine users take the drug repeatedly in binges called speed runs. Both drugs are metabolized slowly by the liver, thus causing a longer duration of action than cocaine.
Amphetamine and methamphetamine are indirect catecholamine agonists. They stimulate release of DA and NE from nerve terminals and block the reuptake of these neurotransmitters. At high doses, there is also an inhibition of the catecholamine-degrading enzyme monoamine oxidase. Central DA release has been demonstrated in both animals and humans. Amphetamine and methamphetamine also have sympathomimetic effects due to their effects on NE in the sympathetic nervous system.
Acute administration of amphetamine to humans leads to a well-known constellation of behavioral reactions, including increased arousal, reduced fatigue, and feelings of exhilaration. Sleep is delayed, and performance of simple, repetitive tasks is improved. Therapeutically, amphetamine is used in the treatment of narcolepsy. Both amphetamine and another stimulant, methylphenidate, are also widely prescribed for children suffering from attention-deficit/hyper- activity disorder (ADHD). At relatively low doses, these stimulants produce calming and attention-enhancing effects that differ from the typical responses found in adults taking higher drug doses. In experimental animals, amphetamine acts much like cocaine. It elicits dose-dependent stimulation of locomotion and stereotyped behaviors, and it is highly reinforcing in self-administration and place conditioning paradigms.
Heavy use of amphetamine or methamphetamine can lead to the development of a psychotic state that closely resembles paranoid schizophrenia. Psychotic reactions may recur as flashbacks even after the user has been abstinent from the drug for a prolonged period. There is also substantial evidence from animal studies that methamphetamine can have neurotoxic effects on the dopaminergic and serotonergic systems. Recent results from brain imaging studies suggest that DA neurotoxicity may also occur in humans, which raises the possibility of increased vulnerability to Parkinson’s disease as the affected individuals grow older.
MDMA and the related drugs MDA and MDE differ in several ways from amphetamine and methamphetamine. MDMA has been called an entactogen due to its reported ability to increase emotional openness and empathy in a psychotherapeutic context. This compound is used recreationally at dances called raves, where it causes feelings of euphoria, heightened sensory awareness, increased energy, enhanced well-being and self-confidence, and greater sociability. Physiologically, MDMA leads to elevated body temperature and fluid loss, which can be potentially dangerous at a dance or other situation involving physical exertion. Neurochemically, MDMA acutely stimulates 5-HT release, inhibits 5-HT reuptake, and also has some DA-releasing effects. In experimental animals, repeated MDMA treatment leads to a depletion in 5-HT and a pruning of serotonergic fibers in the cortex and hippocampus. Monkey studies have shown long-lasting serotonergic deficits following MDMA exposure.
Studies of human MDMA users have been controversial due to issues around dose levels, subject selection, and control for use of illicit drugs other than MDMA. Nevertheless, the findings to date strongly support the existence of serotonergic deficits and cognitive (particularly memory) problems in heavy MDMA users. Consequently, it is prudent to avoid regular use of MDMA or related substances.