Neurochemical alterations in methamphetamine-dependent patients treated with cytidine-5'-diphosphate choline: a longitudinal proton magnetic resonance spectroscopy study

Abstract

Cytidine-5'-diphosphate choline (CDP-choline), as an important intermediate for major membrane phospholipids, may exert neuroprotective effects in various neurodegenerative disorders. This longitudinal proton magnetic resonance spectroscopy ((1)H-MRS) study aimed to examine whether a 4-week CDP-choline treatment could alter neurometabolite levels in patients with methamphetamine (MA) dependence and to investigate whether changes in neurometabolite levels would be associated with MA use. We hypothesized that the prefrontal levels of N-acetyl-aspartate (NAA), a neuronal marker, and choline-containing compound (Cho), which are related to membrane turnover, would increase with CDP-choline treatment in MA-dependent patients. We further hypothesized that this increase would correlate with the total number of negative urine results. Thirty-one treatment seekers with MA dependence were randomly assigned to receive CDP-choline (n=16) or placebo (n=15) for 4 weeks. Prefrontal NAA and Cho levels were examined using (1)H-MRS before medication, and at 2 and 4 weeks after treatment. Generalized estimating equation regression analyses showed that the rate of change in prefrontal NAA (p=0.005) and Cho (p=0.03) levels were greater with CDP-choline treatment than with placebo. In the CDP-choline-treated patients, changes in prefrontal NAA levels were positively associated with the total number of negative urine results (p=0.03). Changes in the prefrontal Cho levels, however, were not associated with the total number of negative urine results. These preliminary findings suggest that CDP-choline treatment may exert potential neuroprotective effects directly or indirectly because of reductions in drug use by the MA-dependent patients. Further studies with a larger sample size of MA-dependent patients are warranted to confirm a long-term efficacy of CDP-choline in neuroprotection and abstinence.

Figure 1

Voxel placement (a) and representative spectra of a methamphetamine-dependent patient (b). (a) Typical location of voxel (white box) located on the midfrontal gray matter shown in axial T2-weighted magnetic resonance image. (b) Representative proton magnetic resonance spectra of one methamphetamine-dependent patients. LCModel estimated baselines are in smooth gray line. LCModel fit to metabolite signals are in red heavy line. The raw data is in thin gray trace. At the top of each plot, the residual signal after fitting is displayed. NAA, N-acetyl-aspartate/N-acetyl-aspartyl glutamate; Cr, creatine/phosphocreatine; Cho, phosphocholine/glycerophosphocholine; mI, myo-inositol.

Figure 2

Changes in cerebral NAA and Cho levels over the 4-week treatment period in CDP-choline (n=16) and placebo (n=15)-treated MA-dependent patients. Cerebral NAA and Cho levels were corrected values. The p-values in each figure were calculated by F-test for the interaction between group and time in the GEE model. Error bars represent the standard errors. CDP-choline, cytidine-5′-diphosphate choline; MA, methamphetamine; NAA, N-acetyl-aspartate/N-acetyl-aspartyl glutamate; Cho, phosphocholine/glycerophosphocholine; CSF, cerebrospinal fluid; GEE, generalized estimating equation.

Figure 3

Relationships between percentage changes in prefrontal NAA levels over the 4-week treatment period and the total number of negative urine results in CDP-choline-treated MA-dependent patients. Scatter plots were depicted based on 12 CDP-choline-treated patients whose second follow-up MRS scan at 4 weeks was available. CDP-choline, cytidine-5′-diphosphate choline; MA, methamphetamine; NAA, N-acetyl-aspartate/N-acetyl-aspartyl glutamate.