N-acetylcysteine normalizes glutamate levels in cocaine-dependent patients: a randomized crossover magnetic resonance spectroscopy study

Abstract

Treatment with N-acetylcysteine (NAC) normalizes glutamate (Glu) homeostasis and prevents relapse in drug-dependent animals. However, the effect of NAC on brain Glu levels in substance-dependent humans has not yet been investigated. Proton magnetic resonance spectroscopy ((1)H MRS) was used to investigate Glu changes in the dorsal anterior cingulate cortex (dACC) after a single dose of NAC in cocaine-dependent patients and normal controls. In an open-label, randomized, crossover study, 8 cocaine-dependent patients and 14 healthy controls underwent two scan sessions: one group receiving no compound and the other following a single administration of 2400 mg NAC. The Barratt Impulsiveness Scale was administered to examine the relation between dACC Glu levels and impulsivity. In the medication-free condition, Glu levels in the dACC were significantly higher in cocaine-dependent patients compared with healthy controls. After administration of NAC, Glu levels were reduced in the cocaine-dependent group, whereas NAC had no effect in healthy controls. Higher baseline Glu levels were associated with higher impulsivity, and both were predictive of greater NAC-induced Glu reduction. The current findings indicate that NAC can normalize elevated Glu levels in cocaine-dependent patients. These findings may have important implications for treatment, because abnormal Glu levels are related to relapse, and treatment with NAC prevented relapse in animal studies. Furthermore, clinical studies have indicated beneficial effects of NAC in cocaine-dependent patients, and the current study suggests that these beneficial effects might in part be mediated by the ability of NAC to normalize glutamatergic abnormalities.

Figures

Figure 1

Voxel placement in left dorsal anterior cingulate cortex for localized single-voxel 1H MRS and a representative spectrum in a healthy control subject. Chemical shift is indicated in parts per million (p.p.m.). Cr, creatine; Glu, glutamate; NAA, N-acetylaspartate.

Figure 2

Effect of a single dose of NAC (2400 mg) on Glu/Cr in the left dACC in both CD and HC groups (mean±SE). Medication-free Glu/Cr was significantly higher in the CD group when compared with the HC group. Administration of NAC reduced Glu/Cr in the CD group, whereas it had no effect on the HC group.

Figure 3

NAC-induced Glu/Cr decreases in the dACC were significantly predicted by (a) medication-free Glu/Cr in the dACC (R2=0.50, p<0.001) and (b) trait impulsivity measured by the BIS-11 total score (R2=0.22, p=0.03), across groups.