Prevalence and socioeconomic factors in the prescription of concurrent amphetamine and alprazolam.

OBJECTIVE: Goals were to determine the prevalence of concurrent prescription of amphetamine and alprazolam, and examine variation by socioeconomic factors. METHODS: Washington State's Prescription Monitoring Program was reviewed for calendar years 2013 through 2017. Individuals receiving more than 180 days of amphetamine, alprazolam or both were tabulated for each zip code. Prescription rates were compared between zip codes with variation in rural/urban setting and fraction of low and high income households using a multiple regression. RESULTS: One in 3920 individuals in the general population of Washington State were taking a combination of alprazolam and amphetamine. The statewide prevalence of this combination increased 40.2% between 2013 and 2017. The prevalence of the combination in each zip code is significantly positively correlated with the fraction of high income households, p < 0.001, and urban area, p < 0.05. In contrast, the prevalence of amphetamine increased with both the fraction of high income, p < 0.001, and low income households, p < 0.01, with an incremental increase over twice as large with fraction of high income (b = 232 (25)) than low income households (b = 102 (38)). In contrast, alprazolam decreased in prevalence with the fraction of high income households, p < 0.05. CONCLUSIONS: The prevalence of concurrent prescription of alprazolam and amphetamine correlates with local socioeconomic factors, including greater household income, instead of the prevalence of FDA indications, including anxiety disorders or ADHD. More clinical studies are required to establish efficacy and guidelines for safe use to mitigate the increased risk of accidents in patients taking concurrent amphetamine and alprazolam.

Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice.

Rapamycin extends lifespan and attenuates age-related pathologies in mice when administered through diet at 14 parts per million (PPM). Recently, we reported that daily intraperitoneal injection of rapamycin at 8 mg/kg attenuates mitochondrial disease symptoms and progression in the Ndufs4 knockout mouse model of Leigh Syndrome. Although rapamycin is a widely used pharmaceutical agent dosage has not been rigorously examined and no dose-response profile has been established. Given these observations we sought to determine if increased doses of oral rapamycin would result in more robust impact on mTOR driven parameters. To test this hypothesis, we compared the effects of dietary rapamycin at doses ranging from 14 to 378 PPM on developmental weight in control and Ndufs4 knockout mice and on health and survival in the Ndufs4 knockout model. High dose rapamycin was well tolerated, dramatically reduced weight gain during development, and overcame gender differences. The highest oral dose, approximately 27-times the dose shown to extend murine lifespan, increased survival in Ndufs4 knockout mice similarly to daily rapamycin injection without observable adverse effects. These findings have broad implications for the effective use of rapamycin in murine studies and for the translational potential of rapamycin in the treatment of mitochondrial disease. This data, further supported by a comparison of available literature, suggests that 14 PPM dietary rapamycin is a sub-optimal dose for targeting mTOR systemically in mice. Our findings suggest that the role of mTOR in mammalian biology may be broadly underestimated when determined through treatment with rapamycin at commonly used doses.