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

Abstract

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 (H 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. H 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 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.

Neurocognitive, Autonomic, and Mood Effects of Adderall: A Pilot Study of Healthy College Students

“…These findings indicate that healthy college students experience substantive increases in emotional and autonomic activation in the period following Adderall consumption. These effects are consistent with the large increases in activated positive emotion, subjective drug effects, physiological activity and frontal brain glutamate in healthy young adults after consumption of other psychostimulant drugs, such as 20 mg oral d-amphetamine sulfate [ 36 , 38 ], 20 mg oral Desoyxn ® [ 38 ], and 0.6 mg/kg oral methylphenidate [ 37 ].…”

“…These domains are readily evaluated by self-report measures such as the Drug Effects Questionnaire, which evaluates subjective ratings of drug liking and drug high [ 34 ]; the Positive Activation scale, which evaluates the presence and intensity of activated emotion such as elation and euphoria [ 35 ]; and the Perceived Drug Effect Self-Report scale, a measure of that evaluates personal perceptions of whether one’s cognitive ability has improved after drug consumption [ 29 ]. Psychostimulant-induced changes in activated positive emotion, subjective drug responses, and autonomic activation are typically large in size [ 36 , 37 , 38 ], with a smaller evidentiary base regarding psychostimulant drug effects on self-perceptions of cognitive functioning [ 29 ]. Very few studies evaluate Adderall effects on neurocognitive function in the context of drug-induced changes in activated emotion, subjective drug experience, autonomic activation, and changes in meta-cognition.…”

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

“…Much research has investigated dopamine‐glutamate relationships in humans using pharmacological challenges. Amphetamine administration has been shown to increase cortical glutamate levels, as measured using 1 H‐MRS, but dopamine antagonists do not have consistent effects on glutamate levels as measured using 1 H‐MRS. Several, but not all, PET studies have found that ketamine administration is associated with striatal dopamine release.…”

Increased Absolute Glutamate Concentrations and Glutamate-to-Creatine Ratios in Patients With Methamphetamine Use Disorders

“…White et al ( 12 ) examined the concentration of glutamine metabolites in 26 healthy individuals following oral administration of single, clinically relevant doses of amphetamine (20 mg), MA (20 mg), or placebo. Using MRS, the authors revealed that d-amphetamine administration increased levels of glutamate, glutamine, and creatine in the dorsal anterior cingulate cortex (dACC) 3 days after the peak drug reaction (140–150 min post-ingestion).…”