Methamphetamine

Acute Effects

Although research efforts continue to focus on the effects of MA, there are limited data on MA's effects on humans (CSAT, 1997). Much of the available information has been surmised from the literature on cocaine. However, the physiological effects of MA are generally similar to those of cocaine: increased heart rate, elevated blood pressure, elevated body temperature, increased respiratory rate, and pupillary dilation. Other acute effects include rapid heart rate, irregular heart rate, and irreversible, stroke-producing damage to small blood vessels in the brain.

MA's psychological effects, like those of cocaine, include a heightened sense of well-being or euphoria, increased alertness, increased vigor, decreased food intake, and decreased sleep time. Acute administration has been shown to increase socialization in humans. High doses may produce repetitive and automatic acts in both humans and animals, and in humans, may cause irritability, aggressive behavior, excitement, auditory hallucinations, and paranoia (delusions and psychosis).

Dangerously elevated body temperature and convulsions occur with MA overdoses, and if not treated immediately, can result in death. With continued use, tolerance develops to the behavioral effects, and repeated exposure may produce sensitization. MA users tend to engage in violent behavior. Mood changes are common, with the user rapidly changing from friendly to hostile.

The course of addiction to MA is believed to be similar to that of cocaine. Even the underlying neurological effects of MA are similar to the effects produced by cocaine: increased levels of free dopamine in the brain's limbic reward system. The MA "withdrawal syndrome" is like that of cocaine, but due to the longer effects of MA, withdrawal may be more intense and protracted.

Several hours after last use, the MA user experiences a drastic drop in mood and energy levels. Sleep--which may be promoted by the use of secondary substances such as alcohol, barbiturates, and benzodiazepines--finally begins and may last for several days. Upon awakening, the user may experience severe depression, perhaps lasting for several weeks. While in this depressed state, the user has an increased risk of suicide. But once the user feels that she "has recovered" from a bingeing episode, cravings set in, and the cycle often begins again.

There are three essential differences between cocaine and MA. First, MA is thought to enhance CNS neurotransmission by increasing the presynaptic release of dopamine within the limbic reward system. Second, recent research has demonstrated MA's neurotoxicological effects in animals and has begun to support the hypothesis that MA is neurotoxic in humans. Unlike cocaine, MA does cross neuronal cell membranes and will enter into the microscopic sacs (called vesicles) where neurons store dopamine.

MA is believed to damage the storage sacs and the neurons' axonal endings such that dopamine leaks uncontrollably into the synapse (see Figure 2-9). MA can also cause neurotoxicity indirectly by mobilizing dopamine out of the safe storage vesicles within the neuron and into the neuron's cytoplasm (i.e., the cell's internal material) where it is converted to toxic and reactive chemicals. Third, cocaine is rapidly metabolized by plasma and tissue enzymes, whereas MA is metabolized at a much slower rate, which results in a longer duration of action (Cook, 1991; ONCDP, 1998b). Although the half-life (effective duration of action) of cocaine is 1 to 2 hours, a single dose of MA may produce an effect for 8 to 12 hours. The fact that MA is metabolized at a slower rate also allows more time for MA to exert its neurotoxicological effects.

The sustained high plasma levels suggest considerable dangers in repeated smoking of MA because remarkably higher plasma concentrations could be expected to occur if the dose is repeated, even at fairly long intervals (Cook, 1991).

Chronic Effects

Chronic abuse of MA may result in inflammation of the heart lining and, among users who inject the drug, damaged blood vessels and skin abscesses. Chronic users may also have episodes of violent behavior, paranoia, anxiety, confusion, and insomnia. Heavy users show progressive social and occupational deterioration. Psychotic symptoms may sometimes persist for months or years after use has ceased.

Some of the most frightening research findings about MA suggest that its prolonged use not only modifies behaviors, but literally changes the brain in fundamental and long-lasting ways. Animal studies have shown that chronic use of MA can significantly reduce brain dopamine levels for up to 6 months after last use, with less significant reductions persisting for up to 4 years. MA impairs the functioning of both the dopamine system and the serotonin system (serotonin is another important CNS neurotransmitter).

MA-induced neuronal toxicity is specific to certain brain regions (primarily the limbic reward system), and this toxicity is reflected both biochemically and anatomically. The adverse effects produced by MA are often long-lasting, and there is some speculation that some types of damage may be permanent. Finally, these impairments in brain functioning may underlie the cognitive and emotional deficits seen in many MA users. Understanding the chronic effects of MA use is essential for treatment providers who serve this population.

Animal studies have shown that high dose regimens of MA significantly deplete neurotransmitter levels, particularly those of dopamine (e.g., Seiden et al., 1976). Subsequent studies replicated these findings (e.g., Ricaurte et al., 1980) and demonstrated that these depletions were evident up to 4 years after cessation of MA administration (Woolverton et al., 1989). A more recent study demonstrated that chronic amphetamine exposure in monkeys could produce long-term effects on the brain's ability to produce dopamine (Melega et al., 1997a).

Significant depletion of dopamine persisted 6 months later; even after 1 year, the brain dopamine levels were only at 80 percent of their preexposure levels. In a radiotracer study of humans, Iyo and colleagues (Iyo et al., 1993) revealed reductions in dopamine receptor binding availability in brain areas such as the frontal cortex and striatum in MA users. Although there is little current evidence on MA's chronic effects in humans, animal research has proven that prolonged or heavy use of MA dramatically reduces the brain's ability to produce dopamine.

Numerous animal studies have demonstrated that MA can damage both dopamine and serotonin systems (e.g., Peat et al., 1983; Robinson and Becker, 1986; Seiden et al., 1976; Trulson and Trulson, 1982a, 1982b; Wagner et al., 1979). MA toxicity occurs after repeated high-dose administration, and it is selective for certain neuronal systems, particularly those in the limbic reward system (e.g., striatum, substantia nigra, nucleus accumbens).

Within these brain circuits, MA has been shown to reduce the number of nerve fibers, impair normal physiological functioning, and destroy both axons and axon terminals (i.e., at synaptic junctions). These studies have also shown that MA toxicity is highly dependent on dose, route of administration, and frequency with which the drug is given.

Prolonged or heavy use of MA decreases the brain's ability to manufacture dopamine. This impairment may persist for up to 1 year after the user has stopped taking MA. Researchers now believe that those changes in dopamine and the damage done to dopamine and serotonin neurons are responsible for the chronic effects of MA use that are much more pronounced than the acute effects.

If MA does indeed cause damage to dopamine and serotonin systems in humans, then there are ramifications to consider. One of the outcomes of chronic MA use is psychosis. Psychotic individuals are often treated with drugs to reverse or return their brain functions to normal, and most antipsychotic medications work by changing the activities of the dopamine and serotonin neurons.
 
The unanswered question is: Will antipsychotic medications be able to effectively treat MA-induced psychoses in individuals whose dopamine and serotonin systems have been impaired by chronic MA abuse? To date, there have been few, if any, studies investigating antipsychotic medications for the treatment of chronic MA abuse and dependence.

In summary, although there is much evidence of MA's neurotoxicity in animals, the issue of whether MA causes permanent damage to dopamine and serotonin neurons in humans remains very much an unanswered question. Because of the inherent dangers associated with this type of research, the information will have to come from postmortem studies, advanced neuroimaging studies, and the development of new strategies for detecting neurotoxicity--possibly through the use of operant behavioral pharmacology. Finally, the degree of neurotoxicity must be placed in perspective, and the functional consequences require further scrutiny to determine the impact of chronic MA abuse on human brain function.

Summary

Recent research has shown how stimulants such as cocaine and MA exert their effects on the user's nervous system and change the user's feelings, emotions, and behavior. There is now a greater understanding of neurological reinforcement systems, how substance use can lead to dependence, and the roles that craving and memory play in sustaining addiction.

Although there is currently a dearth of research regarding the neurologic, medical, psychiatric, and neurocognitive effects of stimulants in humans (CSAT, 1994b, 1997), animal studies have demonstrated cocaine's and MA's ability to disrupt normal brain function and cause long-lasting and perhaps permanent neurological impairments.
 
With continuing research and the development of new imaging technologies, the full extent of these stimulants' effects on humans will eventually be revealed. This new information should continue to assist in the development of new and improved approaches for treating stimulant use disorders.

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SAMHSA/CSAT Treatment Improvement Protocols
TIP 33: Treatment for Stimulant Use Disorders
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.chapter.57310