Methamphetamine (METH) is a stimulant drug that is toxic primarily to dopaminergic and serotonergic neurons and may lead to inflammatory changes in the brain. Additionally, the glutamatergic system is altered following METH exposure. Therefore, concentrations of brain glutamate + glutamine (GLX) were assessed during abstinence from chronic METH abuse. Twenty-five subjects with a history of METH dependence (age 31.8 +/- 7.4 years, 14 women and 11 men) and 28 control subjects without a history of drug abuse (age 32.6 +/- 8.8 years, 14 women) were enrolled. Twelve of the METH subjects were followed and rescanned 5 months later. METH users had used the drug 5.9 +/- 1.7 times per week, for 109 +/- 69 months, and had been abstinent for 2.1 +/- 3.0 months. GLX was measured in the basal ganglia and frontal gray and white matter, using proton magnetic resonance spectroscopy. While overall GLX concentrations at baseline were similar between METH and control subjects, METH users with less than or equal to 1 month of abstinence showed reduced frontal gray matter GLX (p = 0.01). Time of abstinence correlated positively with GLX in frontal gray (p < 0.0001) and white matter (p = 0.03). After 5 months, changes in frontal gray matter GLX showed a trend to correlate inversely with the duration of abstinence (p = 0.07). Subjects with craving symptoms had lower frontal gray matter GLX than those without craving (-8%, p = 0.05). These findings suggest dynamic abnormalities in brain GLX in recently abstinent METH users, with a depletion of the glutamatergic system in METH users within the first 2 months of abstinence and some normalization during prolonged abstinence. Since craving may contribute to relapse, medications that normalize GLX may minimize craving in METH users.