Preliminary evaluation of a model of stimulant use, oxidative damage and executive dysfunction.

Illicit substance use increases oxidative stress and oxidative stress has been found to be associated with deficits in memory, attention and problem-solving. This ancillary investigation of National Drug Abuse Treatment Clinical Trials Network protocol CTN-0031 (Stimulant Abuser Groups to Engage in 12-Step (STAGE-12)) aimed to test a model of the association among oxidative DNA damage, a severe form of oxidative stress, and stimulant use, executive function, and stimulant-use outcomes. Six sites evaluating 12-step facilitation for stimulant abusers obtained peripheral blood samples from methamphetamine-dependent (n=45) and cocaine-dependent (n=120) participants. The blood samples were submitted to a comet assay to assess oxidative DNA damage. Executive Dysfunction was assessed with the Frontal Systems Behavior Scale (FrSBe), which is a reliable and valid self-report assessment of executive dysfunction, disinhibition and apathy. Stimulant-use measures included self-reported stimulant use and stimulant urine drug screens (UDS). While more recent cocaine use (<30 days abstinence) was associated with greater oxidative DNA damage, the results did not support the hypothesized relationship between oxidative DNA damage, executive dysfunction and stimulant use outcomes for cocaine-dependent patients. Support for the model was found for methamphetamine-dependent patients, with oxidative DNA damage significantly greater in methamphetamine-dependent patients with executive dysfunction and with executive dysfunction being a significant mediator of oxidative DNA damage and stimulant use during active treatment. As predicted, neither disinhibition nor apathy were significant mediators of oxidative damage and future stimulant use.

Conclusions: Consistent with preclinical research suggesting that oxidative stress plays a role in the cytotoxic effects of stimulants, this study found an inverse relationship between length of abstinence from cocaine and methamphetamine and oxidative damage level. The present results also suggest that methamphetamine is neurotoxic as assessed by executive dysfunction but cocaine is not, which is consistent with research finding that methamphetamine, but not cocaine, is toxic to dopamine and serotonin neurons. These findings provide preliminary support for a model in which oxidative damage resulting from methamphetamine use results in executive dysfunction, which in turn increases vulnerability to future stimulant use.

Related protocols: CTN-0031-A-1