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Reduced ability to choose between conflicting stimuli corresponds to neural damage.

April 01, 2009
Lori Whitten, NIDA Notes Staff

Long-term methamphetamine abuse appears to induce lasting impairment to brain cells whose activity underpins a person's ability to attend to significant stimuli and screen out distractions.

In a recent NIDA-funded study, brain images of former methamphetamine abusers showed evidence of impairment in the anterior cingulate cortex (ACC), an area of the brain that is known to influence cognition and emotion and help regulate behavior and decisionmaking. These individuals also received lower scores, compared with individuals who never abused the drug, on a psychological test that measures the ability to stay on task. According to the NIDA-funded research team that documented the damage, one consequence might be to heighten former abusers' vulnerability to relapse.

"The cognitive process that is measured by the laboratory test we gave participants is most relevant to everyday life," says Dr. Ruth Salo of the University of California, Davis, whose team collaborated in the study with investigators from California Pacific Medical Center in San Francisco and Kaiser Chemical Dependence Recovery Program in Sacramento. "The former methamphetamine abusers' poorer performance on the test suggests that the neurochemical compromise we observed may give rise to problems in choosing between healthy and unhealthy behaviors."

See caption Neurochemical Marker of Damage Turns Up in Methamphetamine Abusers: These graphs show a set of three neurochemical signals from magnetic resonance spectroscopy of the anterior cingulate cortex brain region in two representative study participants, a nonabuser (left) and a past long-term methamphetamine abuser (right). In the abuser, the N-acetyl aspartate (NAA) peak is lower relative to the peaks of two control chemicals—choline (Cho) and creatine + phosphocreatine (Cr)—a result that suggests neural damage.

Drop in Neuronal Well-Being

Dr. Salo and colleagues used proton magnetic resonance spectroscopy (MRS) to visualize a chemical marker of neuronal health in 52 men and women aged 18 to 55. Although abstinent at the time of the study, 36 of the participants had regularly abused methamphetamine, reporting that it had been their primary drug for 12 years, on average. The other 16 participants had not abused illegal drugs or alcohol during the past 5 years and had never experienced methamphetamine dependence.

When researchers examined the MRS scans of the ACC in the former methamphetamine abusers, they observed a pattern that suggests neural injury (see figure above). The images revealed a diminished signal for N-acetyl aspartate (NAA), a byproduct of cellular energy production that is considered a sign of neuronal well-being. The investigators standardized their data by computing ratios of NAA and another brain chemical, creatine, which did not differ between groups in any brain region in the current study.

The ACC appeared to be a focal area for methamphetamine neurotoxicity. A comparison brain region—the primary visual cortex—showed no difference in neurochemical patterns between past methamphetamine abusers and participants who had not abused drugs.

The neurochemical result correlated with the trial participants' performance on the Stroop test, which measures a person's ability to screen out distractions, focus on the information that matters, and make choices in the face of conflicting inclinations. In the test, which was administered on the same day as the MRS session, the participants watched a computer screen on which sets of letters flashed. The participant's task was to announce, as quickly as possible, the color of letters used to display a word or a set of letters that does not represent a word. The task is easy when the meaning of the word and its color match (e.g., RED) or when the letters don't make up a word. In such instances, all participants answered quickly and erred only 1 to 2 percent of the time.

When the word and color do not match, however (e.g., RED), the need to suppress the habitual tendency to read the word and focus instead on the color of the letters slowed the response and led to more errors. The methamphetamine abusers found these adjustments more challenging than the nonabusers. They required 155 milliseconds longer, on average, to respond to nonmatched than to matched examples, while the nonabusers required only an additional 125 milliseconds. Both groups had an average error rate of 13 percent.

The associations between methamphetamine exposure, diminished NAA, and slower performance on the Stroop test held even when researchers made allowance for differences in other characteristics linked with brain health—for example, years of drug abuse, months of abstinence, and age. In earlier studies, the research team had demonstrated similar patterns of neural damage and attention problems in recently abstinent methamphetamine abusers, but without linking the two.

Prior research had also suggested that ACC function can affect recovery from methamphetamine abuse. In that study, led by Dr. Martin Paulus of the University of California, San Diego, high activity in a former user's ACC during a decisionmaking task predicted success in avoiding relapse during the next year ("Brain Activity Patterns Signal Risk of Relapse to Methamphetamine").

The attention problems observed by Dr. Salo's team in past methamphetamine abusers in the recent study are similar to those observed by other researchers in people who had abused cocaine. The similarity is not surprising: Both stimulants increase activity of dopamine neurons. Methamphetamine, however, may be particularly harmful because it has a longer duration of action (8 to 13 hours) than most other stimulants and is a powerful neurotoxin.

A Critical Link

"The findings of Dr. Salo's team, along with the results of other studies, suggest that long-term meth abuse causes damage to the ACC that impairs former abusers' ability to perform the Stroop task," says Dr. Steven Grant of NIDA's Division of Clinical Neuroscience and Behavioral Research. "The connection to a behavior with functional relevance is often missing in MRS studies, but this study makes that critical link."

According to Dr. Salo, awareness of abusers' specific cognitive deficits could also enable development of more effective relapse-prevention therapies. "The Stroop test taps into something people do in everyday life: make a choice in the face of conflicting impulses and inhibit a strong but detrimental tendency," Dr. Salo says.

"A person recovering from addiction may face a conflict on payday—for example, he or she must inhibit a strong impulse to buy drugs instead of paying rent and purchasing food. The neurobiological changes following long-term methamphetamine abuse appear to compromise this cognitive control. Our findings point to a specific addiction-related cognitive impairment and reinforce the importance of helping patients during therapy to develop key skills: making healthy choices and thinking about future consequences," Dr. Salo says.


Salo, R., et al. Attentional control and brain metabolite levels in methamphetamine abusers. Biological Psychiatry 61(11):1272-1280, 2007. [Abstract]