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Neuropsychopharmacology. 2018 Jun;43(7):1498-1509. doi: 10.1038/s41386-018-0027-7. Epub 2018 Mar 6.

Psychostimulant drug effects on glutamate, Glx, and creatine in the anterior cingulate cortex and subjective response in healthy humans.

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Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA.
Department of Behavioral and Social Sciences, School of Public Health, and Institute for Brain Science, Brown University, Providence, RI, USA.
Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA.
Department of Neuroscience, Brown University, Providence, RI, USA.
Neuroscience Graduate Program, Brown University, Providence, RI, USA.
Department of Radiology, CAIR Program, Alberta Children's Hospital Research Institute, and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
Department of Clinical and Health Psychology, and Center for Cognitive Aging and Memory, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
Department of Neurology, Center for Neuropsychological Studies, University of Florida College of Medicine, Gainesville, FL, USA.
Brain Rehabilitation Research Center, Malcom Randall Veterans Affairs Medical Center, Gainesville, FL, USA.
Neuroscience Undergraduate Program, Brown University, Providence, RI, USA.


Prescription psychostimulants produce rapid changes in mood, energy, and attention. These drugs are widely used and abused. However, their effects in human neocortex on glutamate and glutamine (pooled as Glx), and key neurometabolites such as N-acetylaspartate (tNAA), creatine (tCr), choline (Cho), and myo-inositol (Ins) are poorly understood. Changes in these compounds could inform the mechanism of action of psychostimulant drugs and their abuse potential in humans. We investigated the acute impact of two FDA-approved psychostimulant drugs on neurometabolites using magnetic resonance spectroscopy (1H MRS). Single clinically relevant doses of d-amphetamine (AMP, 20 mg oral), methamphetamine (MA, 20 mg oral; Desoxyn®), or placebo were administered to healthy participants (n = 26) on three separate test days in a placebo-controlled, double-blinded, within-subjects crossover design. Each participant experienced all three conditions and thus served as his/her own control. 1H MRS was conducted in the dorsal anterior cingulate cortex (dACC), an integrative neocortical hub, during the peak period of drug responses (140-150 m post ingestion). D-amphetamine increased the level of Glu (p = .0001), Glx (p = .003), and tCr (p = .0067) in the dACC. Methamphetamine increased Glu in females, producing a significant crossover interaction pattern with gender (p = .02). Drug effects on Glu, tCr, and Glx were positively correlated with subjective drug responses, predicting both the duration of AMP liking (Glu: r = +.49, p = .02; tCr: r = +.41, p = .047) and the magnitude of peak drug high to MA (Glu: r = +.52, p = .016; Glx: r = +.42, p = .049). Neither drug affected the levels of tNAA, Cho, or Ins after correction for multiple comparisons. We conclude that d-amphetamine increased the concentration of glutamate, Glx, and tCr in the dACC in male and female volunteers 21/2 hours after drug consumption. There was evidence that methamphetamine differentially affects dACC Glu levels in women and men. These findings provide the first experimental evidence that specific psychostimulants increase the level of glutamatergic compounds in the human brain, and that glutamatergic changes predict the extent and magnitude of subjective responses to psychostimulants.

[Available on 2019-06-01]
[Indexed for MEDLINE]

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