Decreased frontal lobe phosphocreatine levels in methamphetamine users

Abstract

Background: Mitochondria-related mechanisms have been suggested to mediate methamphetamine (METH) toxicity. However, changes in brain energetics associated with high-energy phosphate metabolism have not been investigated in METH users. Phosphorus-31 ((31)P) magnetic resonance spectroscopy (MRS) was used to evaluate changes in mitochondrial high energy phosphates, including phosphocreatine (PCr) and β-nucleoside triphosphate (β-NTP, primarily ATP in brain) levels. We hypothesized that METH users would have decreased high-energy PCr levels in the frontal gray matter.

Methods: Study participants consisted of 51 METH (age=32.8±6.7) and 23 healthy comparison (age=31.1±7.5) subjects. High-energy phosphate metabolite levels were compared between the groups and potential gender differences were explored.

Results: METH users had lower ratios of PCr to total pool of exchangeable phosphate (PCr/TPP) in the frontal lobe as compared to the healthy subjects (p=.001). The lower PCr levels in METH subjects were significantly associated with lifetime amount of METH use (p=.003). A sub-analysis for gender differences revealed that female METH users, who had lower daily amounts (1.1±1.0g) of METH use than males (1.4±1.7g), had significantly lower PCr/TPP ratios than male METH users, controlling for the amount of METH use (p=.02).

Conclusions: The present findings suggest that METH compromises frontal lobe high-energy phosphate metabolism in a dose-responsive manner. Our findings also suggest that the abnormality in frontal lobe high-energy phosphate metabolism might be more prominent in female than in male METH users. This is significant as decreased PCr levels have been associated with depressive symptoms, and poor responses to antidepressant treatment have been reported in those with decreased PCr levels.

Figure 1

Illustration of two dimensional MRSI grid placement: (A) Sagittal and (B) Axial views. Dotted red line in the figure shows frontal lobe region of interest. (C) A representative ³¹P spectrum is displayed in frequency domain with 10 Hz exponential filtering. Abbreviations: PCr, phosphocreatine; PME, phosphomonoester; PDE, phosphodiester; α-, β-, γ-NTP (nucleoside triphosphate).

Figure 2

Comparison of frontal lobe phosphorus metabolites levels in methamphetamine (METH, n=51) dependent subjects compared to healthy controls (HC, n=23). Phosphocreatine levels were significantly reduced in METH users compared to HC (p<0.001). There were no significant differences in β-NTP levels between the HC and METH groups. Error bars represent 95% confidence intervals. * Indicates statistically significant difference. Abbreviations: TPP, total pool of exchangeable phosphate.

Figure 3

Comparison of gender difference in PCr levels. (A) In METH-dependent subjects, female METH users (n=23) had significantly lower PCr levels compared to male METH users (n=28). (B) Healthy subjects did not show significant gender difference. Error bars represent 95% confidence intervals. * Indicates statistically significant difference. Abbreviations: TPP, total pool of exchangeable phosphate.

Figure 4

Significant relationship (p=0.003) between PCr/TPP levels and total amount of lifetime METH use (gram) in METH-dependent subjects (regression analysis using robust estimator of variance (White, 1980). Gray line and area denote predicted 95% confidence interval. Abbreviations: TPP, total pool of exchangeable phosphate.