A Randomized Double-Blind Controlled Trial of Creatine in Female Methamphetamine Users

Methamphetamine (MA) addiction is a public health concern that causes substantial harm to
individual users, and imposes an economic burden in the U.S. totaling up to $48.3 billion
annually. This study proposes to address a critical aspect of this problem: the lack of any
proven, FDA-approved pharmacological treatments for MA users. The proposal combines an
intervention designed to improve energy metabolism in the brain, and a neuroimaging technique
capable of measuring the neurochemicals that represent cerebral bioenergetic function. The
study will replicate and extend a key neuroimaging finding from the investigators recent MA
studies: that MA users have decreased phosphocreatine (PCr) levels in the brain, compared to
healthy volunteers. Phosphocreatine is the substrate reservoir for the creatine kinase
reaction, which reversibly converts PCr into adenosine triphosphate (ATP), the brain's major
energy supply, and creatine. Neuronal energy demands are met through a shift in reaction
equilibrium, which is designed to maintain the concentration of ATP constant. Research
results from the investigators recent study also showed that female MA users have lower brain
PCr levels compared to male users. These findings join the converging lines of evidence that
MA use is associated with mitochondrial dysfunction, i.e. deficient energy metabolism, in the
brain. Frequently, MA users also experience depression, as well as cognitive deficits.
Interestingly, both of these entities are also linked to mitochondrial dysfunction in the
brain.

The long-term goal of this research program is to define the alterations in brain chemistry
that underlie MA use disorders, and to utilize translational magnetic resonance spectroscopy
(MRS) neuroimaging to identify rational brain-based treatment targets. Once a
hypothesis-driven intervention is identified, MRS can then be further employed in treatment
studies, to verify that "target engagement" is achieved. The specific aims of this proposal
are an example of this stepwise scientific process: the nutritional supplement creatine will
be tested in a randomized, placebo-controlled study of women with MA use disorders, to
investigate creatine's effect on cerebral PCr levels, depressive symptoms, and MA usage.