Methamphetamine (MA) use is a significant public health concern for which there are no FDA-approved treatments. This proposal is a competing renewal of DA027135, a clinical trial of CDP-choline for MA users. That study found that female MA users have decreased brain phosphocreatine (PCr) levels, compared with both male MA users and female healthy controls. Following up on this key translational finding, preliminary data collected at our site suggests that when administered to female MA users, creatine monohydrate supplementation is associated with increased brain PCr, N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA). Clinically, creatine was associated with decreased depression and anxiety symptoms. It may also reduce MA use, measured by urine drug screens. This proposal follows expert recommendations to target cognitive enhancement, and neuronal repair, in developing pharmacotherapies for stimulant addiction. Decreased brain PCr concentrations, measured by 31P magnetic resonance spectroscopy (31P-MRS), are associated with poorer depression outcomes. Female MA users have increased rates of depression, and more severe depressive symptoms than males. Because negative mood is associated MA craving, depression may contribute to the risk of relapse. Creatine supplementation increases brain PCr and levels in human studies and animal models, thereby helping maintain neuronal bioenergetics, and mitochondrial energy production. MA use is associated with decreased brain NAA, and MA also alters the glutamine-glutamate-GABA system. Sustained abstinence from MA is associated with increased NAA, indicating some degree of normalization of neuronal function. Notably, increasing GABA-ergic activity has been shown to reduce MA self- administration, and to block both the development and reinstatement of MA-triggered conditioned place preference. Upregulation of GABA also improves MA-induced cognitive deficits. In our preliminary study, our neurochemical findings included: (1) A significan relationship between the glutamine/glutamate ratio and lifetime amount of MA use; and (2) Increased NAA and GABA concentrations following 8 weeks of creatine supplementation in female MA users. The glutamine/glutamate ratio is important for neuronal/glial viability, as mitochondrial function is tightly coupled with glutamine-glutamate-GABA metabolism. Thus, the proposed study implements 1H-MRS to measure NAA, GABA and the glutamine/glutamate ratio, as complements to our key 31P-MRS finding of decreased PCr in female MA users. In summary, in women with MA use disorders, creatine is a hypothesis-generated intervention aimed at restoring neurochemistry, reducing depression and anxiety symptoms, and improving cognitive function. Thus, we propose a placebo-controlled clinical trial of creatine, paired with a translational multinuclear spectroscopic neuroimaging study, for females with MA use disorders.