Methamphetamine (meth) is a powerfully addictive drug that can cause aggression and violent behavior.

But how does it accomplish this? The answer, or at least part of it, now appears to have been found—meth works in the ventral inferior frontal gyrus region of the prefrontal cortex of the brain.

The study's senior investigator was Edythe London, Ph.D., a professor of psychiatry and behavioral sciences at the University of California at Los Angeles Semel Institute. Results were published online November 1 in the Archives of General Psychiatry.

The study included 76 subjects aged 18 to 55—half were meth-dependent volunteers and half were drug-free control volunteers. They were recruited using radio, Internet, and newspaper ads. All participated in the study on a residential basis for two to four weeks.

First the researchers evaluated subjects for aggression and found, as they had expected, that the meth-users group was more aggressive than the control group was. They also tested subjects for their ability to recognize emotional states and to describe them. The meth group turned out to be less adept at this exercise, and their deficits in recognizing and describing their emotional states correlated with their aggression scores. These results, too, were not surprising, the researchers noted.

But then came something that did surprise them. While subjects performed an emotion-arousing and emotion-regulating task, their brains were imaged with fMRI scans, and the scans showed that the amygdala in the meth group was just as good at regulating itself as the amygdala in the control group was. Therefore it looked as if amygdala function could not explain the aggression often displayed by meth users.

While the researchers were scanning the subjects' brains, however, they discovered something else—that the ventral aspect of the inferior frontal gyrus in the prefrontal cortex of the meth group was significantly less activated than the same brain area in the control group. Thus, a faulty ventral inferior frontal gyrus emerged as a possible explanation for aggressive behavior in the meth-using group.

The question then was how might a faulty ventral inferior frontal gyrus lead to aggression in meth users? Perhaps by dampening emotional insight, the researchers reasoned, since this area of the brain is known to be involved in emotional insight, and this group had difficulty recognizing and describing emotional states, and this difficulty in turn correlated with their aggression scores.

If this conclusion is correct, it has clinical implications, London told Psychiatric News. "Lack of emotional insight (alexithymia) and the ventral inferior frontal gyrus may be more useful therapeutic targets [for aggressive meth users] than emotional regulation and amygdala function are."

London noted as well that drugs other than meth can make people aggressive. "A large variety of drugs that affect brain function have been linked to aggression," she pointed out. "These include alcohol, hallucinogens, psychomotor stimulants such as amphetamines (including meth), and cocaine. While, the molecular mechanisms of action of these agents differ from one another, a unifying mechanism that can lead to aggression is an imbalance between subcortical systems that promotes rapid responses to environmental stimuli before cortical circuits important for evaluating the circumstances can come into play."

The study was funded by the National Institutes of Health, the UCLA General Clinical Research Center, the Katherine K. and Thomas P. Pike Chair in Addiction Studies, the Marjorie Green Family Trust, and a Guggenheim grant.

An abstract of "Neural Correlates of Affect Processing and Aggression in Methamphetamine Dependence" is posted at <http://archpsyc.ama-assn.org/cgi/content/abstract/archgenpsychiatry.2010.154v1>.