Studies Show How Speed Exacts Toll on Brain

A team at Brookhaven National Laboratory has published two reports in which they detail the actions of methamphetamine in the brain, showing how it leads to damage of dopaminergic neurons.

A similar study by researchers at the University of California at San Diego reports specific cognitive dysfunction tied to that damage. However, the second Brookhaven report offers some hope that the damage may not be entirely permanent.

Nora Volkow, M.D., Linda Chang, M.D., and their colleagues at Brookhaven report in the December 2001 American Journal of Psychiatry (AJP) that methamphetamine acts on some of the same brain mechanisms as cocaine and alcohol.

The team used positron emission tomography (PET) scans to measure the level of dopamine D2 receptors and to assess the rate of glucose metabolism in the brains of 15 methamphetamine abusers. They compared those results with the same scans and measurements from 20 people who were not drug abusers.

Those using methamphetamine were found to have lower levels of dopamine receptors and lowered rates of glucose metabolism in the orbitofrontal cortex, a region of the brain linked to compulsive behaviors.

The researchers postulate that disruption of the metabolism of the orbitofrontal cortex may contribute to compulsive drug intake in individuals with addiction.

The association between decreased dopamine receptors and lowered metabolism of glucose in the orbitofrontal cortex has previously been reported in individuals addicted to cocaine and alcohol. This is the first association, according to Volkow, of the effects with methamphetamine use. The work was funded by the National Institute on Drug Abuse.

Cognitive Deficits

In a report in the January issue of Neuropsychopharmacology (NPP), Marc A. Shuckit, M.D., and his colleagues at UCSD and the San Diego Veterans Administration Medical Center, used functional magnetic resonance imaging (fMRI) to determine the relationship between decision-making dysfunction and neural activity in different brain regions of individuals addicted to methamphetamine.

The team hypothesized that decision-making difficulties in those addicted to methamphetamine and other stimulants might be due to differences in task-related activation of neurons in the prefrontal cortex.

They studied 10 addicted subjects and 10 control subjects, matched for age and level of education. Each performed a two-choice prediction task and a two-choice response task during an fMRI scan. The researchers assessed subjects’ bias toward one of the two choices, delay in completing the task, and used mutual information measures to evaluate the underlying strategies the subjects used to complete the tasks.

The team reported that subjects addicted to methamphetamine were more influenced in completing the current task by the outcome of the immediately preceding two-choice task. They also saw less activation of the specific areas of both the orbitofrontal cortex and prefrontal cortex on the fMRI scans.

These results, the authors concluded, support the basic hypothesis that stimulant-dependent subjects develop fundamental cognitive deficits during decision-making tasks that are consistent with both orbitofrontal and prefrontal damage caused by the drug of abuse.

This study was funded through the Department of Veterans Affairs.

Possible Recovery

The neuronal damage from methamphetamine use may not be permanent, however. The Brookhaven team led by Volkow reported in the December 1, 2001, issue of the Journal of Neuroscience (JN) that methamphetamine-damaged brain cells may recover after prolonged abstinence from the drug. However, the team cautioned, the extent of recovery may not be enough to regain lost cognitive function associated with the damage.

The team again used PET scans, this time to measure levels of dopamine transporters, of which the dopamine D2 receptor is one part. The team studied addicted individuals enrolled in a rehabilitation program monitored by a California state drug court.

Dopamine transporter levels were studied in five methamphetamine abusers who were able to stay free of drug use throughout the study. The first scan was taken within six months of the last use of methamphetamine, with a second evaluation occurring at least nine months later.

Levels of dopamine transporters measured during the second PET scan increased significantly, between 16 percent and 19 percent, compared with the baseline scan. The longer the period between the first and second scans, the greater the percentage of recovery. In addition, those who had used methamphetamine for a shorter period or in smaller quantities also recovered more dopamine transporters than did long-term, heavy users of the drug.

“This indicates,” Volkow said in a NIDA press release announcing the results, “that the length and severity of use may ultimately limit the amount and speed of recovery of dopamine transporters.”

In addition to scanning dopamine levels, the subjects in the second Brookhaven study were given a battery of tests to evaluate skills known to be associated with dopamine transporters, including evaluations for gross motor function, fine motor coordination, and memory function. Slight improvement in some motor and memory skills was noted, but the improvements were not statistically significant.

“One explanation,” Volkow said, “could be that neuropsychological function requires other brain systems that may have been affected by methamphetamine use for which recovery may be slower or not present.”

The second Brookhaven study was funded by both NIDA and the National Institutes of Health.

An abstract of the AJP article is posted on the Web at http://ajp.psychiatryonline.org/cgi/content/abstract/158/12/2015; an abstract of the NPP article can be accessed at www.elsevier.com/gej-ng/10/33/33/show/ by searching on “Shuckit”; and an abstract of the JN article is posted at www.jneurosci.org/. ▪

AM J PSYCHIATRY 2001 158 2015

J NEUROSCI 2001 21 9414