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Abstract: Oxidative stress can result in damage to the brain and other organs. To protect from oxidative damage, the human body possesses molecular defense systems, based on the activity of antioxidants, and enzymatic defense systems, including the enzymes catalase (CAT), superoxide dismutase (SOD), and thutathione peroxidase (GSH-Px). Although pre-clinical research has shown that stimulant use is associated with oxidative damage, oxidative stress and the antioxidant defense systems have not been evaluated in clinical samples of stimulant-dependent patients. This secondary analysis of data from the National Drug Abuse Treatment Clinical Trials 12-Step Facilitation for Stimulant Abusers (STAGE-12) study aimed to investigate the link between stimulant dependence and oxidative stress. Peripheral blood samples from 174 methamphetamine (n=48) and/or cocaine-dependent (n=126) participants as well as 30 normal control participants were analyzed for the enzyme activities of CAT, SOD, and GSH-Px, in the erythrocytes and the total antioxidant capacity and malondialdehye concentration in the plasma. Results showed an association of stimulant dependence with a depletion of total antioxidant capacity to 54.6 +/- 4.7%, which correlates with a reduced activity of the SOD to 71.3+/-0.03% compared with healthy control participants (100%). Conclusions: This is the first study to evaluate oxidative stress and antioxidant defense systems in a clinical sample of stimulant-dependent patients. Consistent with pre-clinical research findings demonstrating that stimulants decrease total antioxidant activity, the present study revealed that TAC was significantly lower in both cocaine-dependent and methamphetamine-dependent patients relative to normal controls. This could, in turn, render stimulant-dependent patients at greater risk for oxidative damage to the brain and other organs. Future research to replicate and extend these findings is warranted. Related protocols: CTN-0031, CTN-0031-A-1

Abstract:

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

Abstract:

Since stimulant use disorders (SUDs) remain prevalent across the lifespan, cognition is an important area of clinical care and research focus among aging adults with SUDs. This secondary analysis of data from the National Drug Abuse Treatment Clinical Trials Network (CTN) study “Stimulant Abuser Groups to Engage in 12-Step (STAGE-12),” protocol CTN-0031, suggests that decision-making, verbal learning/memory, executive function, and set shifting are important cognitive domains to screen clinically and treat in aging adults with SUDs. Some suggestions are made on how clinical treatment providers can use these results in a practical way. A neurocognitive assessment might be considered standard at initial and periodic follow-up visits. Providers might also consider adding adjunctive treatments in patient treatment plans to directly remediate impaired cognitive domains (e.g., decision-making, executive function). Finally, by capitalizing on unimpaired cognitive domains, treatment providers might modify their treatment approach to compensate for impaired domains — for example, instead of totally relying on verbal modalities, a provider might also consider using a visual one (e.g., pictures, white board, computer screen) to convey information and compensate for a patient’s impairment in verbal learning/memory. Future directions include potentially conducting pre/post neuroimaging of frontal cortical regions in aging adults with SUDs, correlating neuroimaging findings with neurocognitive measures in aging adults with SUDs, and developing cognitively remediating treatments (pharmacological and/or non-pharmacological) specific to affected cognitive domains (e.g., decision-making, verbal learning/memory, executive function, set shifting) in aging adults with SUDs.

Related protocols: CTN-0031-A-1

Abstract:

Greater impulsivity, assessed by the Barratt Impulsiveness Scale-11 (BIS-11) and Stroop interference scores, has been associated with treatment completion in cocaine-dependent patients. This study, an ancillary investigation of data from the National Drug Abuse Treatment Clinical Trials Network study CTN-0031, evaluated the relationships among impulsivity, stimulant-dependence diagnosis, and treatment completion. Six sites evaluating 12-step facilitation for stimulant abusers obtained the BIS-11 and Stroop Color Word test results from 182 methamphetamine- and/or cocaine-dependent participants. Methamphetamine-dependent, relative to cocaine-dependent, participants evidenced significantly greater BIS-11 non-planning and total scores. There was a trend for poorer response inhibition, measured by the Stroop, in cocaine-dependent, relative to methamphetamine-dependent, participants. Accounting for other factors related to treatment completion, BIS-11 motor score, and assessing the tendency to act without thinking predicted treatment completion for both cocaine-dependent and methamphetamine-dependent patients.

Conclusions: These results suggest that methamphetamine-dependent and cocaine-dependent patients may have different impulsivity profiles but that the BIS-11 may be useful in identifying both methamphetamine-dependent and cocaine-dependent patients who are at risk for treatment non-completion.

Related protocols: CTN-0031-A-1

Abstract:

Research suggests that impulsivity is a vulnerability factor for developing stimulant dependence, that women develop dependence more quickly than men, and that physical abuse can increase impulsivity and may have greater adverse health consequences in women. This study sought to tie these findings together by evaluating: (1) sex differences in disinhibition prior to lifetime initiation of stimulant abuse and (2) the relationship between physical abuse and disinhibition in stimulant-dependent patients. The Frontal Systems Behavior Scale (FrSBe) is a reliable and valid self-report assessment of three neurobehavioral domains associated with frontal systems functioning (Apathy, Disinhibition, and Executive Dysfunction, summer for a Total), that assesses pre-morbid functioning and has a specific cutoff for defining clinically significant abnormalities. As part of the CTN ancillary study CTN-0031-A-1, “An Evaluation of Neurocognitive Function, Oxidative Damage, and Their Association with Treatment Outcomes in Methamphetamine and Cocaine Abusers,” six sites evaluating 12-step facilitation for stimulant abusers obtained the FrSBe from 118 methamphetamine- and/or cocaine-dependent participants. Lifetime physical abuse was measured by the Addiction Severity Index (ASI). The proportion reporting clinical significant disinhibition was significantly higher in women (64.95) than in men (45%), with no significant difference on the other FrSBe scales. Physical abuse in women, but not men, was associated with worse functioning, with physically abused, relative to non-abused, women having a significantly greater proportion with clinically significant disinhibition (p<0.01) and total neurobehavioral abnormalities (p<0.01).

Conclusions: These findings suggest that women may have significantly greater disinhibition than men prior to lifetime initiation of stimulant abuse and that physical abuse in women is associated with greater disinhibition. A finding of poorer functioning in physically abused, relative to non-abused, women and no poorer functioning observed in abused, relative to non-abused, men is consistent with research finding that childhood abuse may have more adverse health consequences in women than men. This study contributes to research suggesting that impulsivity is a vulnerability trait for developing stimulant dependence.

Related protocols: CTN-0031-A-1

Abstract:

Frontal systems dysfunction is present in stimulant-dependent patients. However, it is unclear whether this dysfunction is a pre-morbid risk factor or stimulant-induced, is severe enough to be clinically relevant, and if it is relevant to treatment response. These questions were addressed using the Frontal Systems Behavior Scale (FrSBe), a reliable and valid self-report assessment of three neurobehavioral domains associated with frontal systems functioning (Apathy, Disinhibition, and Executive Dysfunction, summed for a Total), that assesses both pre- and post-morbid functioning, and has a specific cutoff for defining clinically significant abnormalities. In this ancillary investigation (protocol CTN-0031-A-1, “An Evaluation of Neurocognitive Function, Oxidative Damage, and Their Association with Treatment Outcomes in Methamphetamine and Cocaine Abusers”), six sites evaluating 12-step facilitation for stimulant abusers obtained the FrSBe from 180 methamphetamine- and/or cocaine-dependent participants. Dichotomous treatment response measures included self-reported stimulant use, stimulant urine drug screens, and treatment completion. A substantial percentage of participants retrospectively reported clinically significant neuro-behavioral abnormalities prior to lifetime stimulant abuse initiation (e.g., 67.5% on FrSBe-Total), with a significant increase in the proportion reporting such abnormalities for current functioning (86% on the FrSBe-Total; p<0.0001). Treatment response was significantly worse for participants with, relative to those without, clinically significant Disinhibition as measured by treatment non-completion (31.6% vs. 15.6%) and self-reported stimulant use during treatment (40.5% vs. 16.7%).

Conclusions: The present study revealed that stimulant-dependent patients evidence frontal systems dysfunction as measured by the FrSBe, that frontal systems dysfunction was present prior to the initiation of stimulant abuse based on retrospective ratings, that stimulant use was associated with significant worsening of frontal systems function, and that clinically significant Disinhibition was associated with poorer treatment response. The study results suggest that the FrSBe may have utility in evaluating the role of frontal systems dysfunction in stimulant-dependence, and that disinhibition may be a prime target for intervention in stimulant-dependent individuals. Future research to replicate, and expand on, the present findings seems warranted.

Related protocols: CTN-0031-A-1