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.

Inclusion Criteria:

• Female gender, ages 18-55 inclusive
• Current primary diagnosis of MA dependence or abuse, with MA preferred drug of abuse
• Current diagnosis of Major Depressive Disorder
• Current HAMD score > 15
• Clinical Global Impressions Severity depression score > 4
• If currently taking a psychotropic medication for depressed mood, regimen must be stable for > 4 weeks before randomization

Exclusion Criteria:

• Persons unable to provide adequate consent
• Persons who are at clinically significant suicidal or homicidal risk
• Primary substance-related diagnosis other than MA dependence or abuse
• Comorbid substance dependence diagnosis, other than nicotine (substance abuse diagnoses are not excluded)
• Positive pregnancy test
• Positive test for the antibody to the Human Immunodeficiency Virus (HIV)
• History of renal disease

week 8

Participant report