The methamphetamine molecule is structurally similar to amphetamine and to the neurotransmitter dopamine, a brain chemical that plays an important role in the reinforcement of rewarding behaviors, but it is quite different from cocaine.45 Although these stimulants have similar behavioral and physiological effects, there are some major differences in the basic mechanisms of how they work.
In contrast to cocaine, which is quickly removed from and almost completely metabolized in the body, methamphetamine has a much longer duration of action, and a larger percentage of the drug remains unchanged in the body. Methamphetamine therefore remains in the brain longer, which ultimately leads to prolonged stimulant effects.46
Although both methamphetamine and cocaine increase levels of dopamine, administration of methamphetamine in animal studies leads to much higher levels of dopamine, because nerve cells respond differently to the two drugs. Cocaine prolongs dopamine actions in the brain by blocking the re-absorption (re-uptake) of the neurotransmitter by signaling nerve cells. At low doses, methamphetamine also blocks the re-uptake of dopamine, but it also increases the release of dopamine, leading to much higher concentrations in the synapse (the gap between neurons), which can be toxic to nerve terminals.38,39
Neuroimaging studies have demonstrated alterations in the activity of the dopamine system that are associated with reduced motor speed and impaired verbal learning.6,7,8 Studies in chronic methamphetamine users have also revealed severe structural and functional changes in areas of the brain associated with emotion and memory, which may account for many of the emotional and cognitive problems observed in these individuals.9,10,11
Research in primate models has found that methamphetamine alters brain structures involved in decision-making and impairs the ability to suppress habitual behaviors that have become useless or counterproductive. The two effects were correlated, suggesting that the structural change underlies the decline in mental flexibility.12 These changes in brain structure and function could explain why methamphetamine addiction is so hard to treat and has a significant chance of relapse early in treatment.
Methamphetamine misuse greatly reduces the binding of dopamine to dopamine transporters (highlighted in red and green) in the striatum, a brain area important in memory and movement. With prolonged abstinence, dopamine transporters in this area can be restored.
Methamphetamine misuse also has been shown to have negative effects on non-neural brain cells called microglia. These cells support brain health by defending the brain against infectious agents and removing damaged neurons. Too much activity of the microglial cells, however, can assault healthy neurons. A study using brain imaging found more than double the levels of microglial cells in people who previously misused methamphetamine compared to people with no history of methamphetamine misuse, which could explain some of the neurotoxic effects of methamphetamine.13
Some of the neurobiological effects of chronic methamphetamine misuse appear to be, at least, partially reversible. In the study just mentioned, abstinence from methamphetamine resulted in less excess microglial activation over time, and users who had remained methamphetamine-free for 2 years exhibited microglial activation levels similar to the study’s control subjects.
Function in other brain regions did not recover even after 14 months of abstinence, indicating that some methamphetamine-induced changes are very long lasting.
