Participants were requested to be abstinent from MA for at least 10 days prior to testing and were required to show a negative urine toxicology for any non-prescribed substance except cannabis, as well as a negative Breathalyzer test for alcohol on the day of neurocognitive testing.MA group comparisons of neuropsychological outcomes , demographics, depressive symptoms, alcohol and cannabis use, and other lifetime substance dependence were conducted using Student’s t tests, Wilcoxon Rank Sum tests, chi-square tests, and Fisher’s exact tests as appropriate. MA group differences in neurocognitive performance were evident across domains. Given this nonspecific pattern of MA group differences, and in order to limit multiple comparisons, we present the global T scores and global impairment classifications as outcome variables in linear and logistic regression analyses, respectively. Details of domain-specific results appear in Supplementary Table 2. We first tested whether MA group differences in global functioning were attenuated by differences in estimated premorbid ability and neuropsychiatric factors by entering MA status along with performance on the Wide Range Achievement Test Reading subtest , lifetime major depressive disorder , and lifetime average daily cannabis as covariates into each model. Age, education, race/ethnicity, and sex were not considered as model covariates because they were already included in the neurocognitive test T score demographic adjustments. Next, we added lifetime average daily alcohol use and days since last alcohol use to test whether historical alcohol use,grow table controlling for recency of alcohol use, incrementally predicted global functioning independent of MA status. Finally, an interaction term between MA status and lifetime average daily alcohol use was added to examine whether lifetime alcohol use modulated MA group differences in neurocognition.
To probe interaction effects, simple slope analyses were conducted by examining the association of global functioning with lifetime average daily alcohol use within each MA group, adjusting for covariates. To avoid multicollinearity with lifetime MDD, BDI-II was not included as a covariate in initial models. Instead, BDI-II was added as a post-hoc covariate to final models in order to rule out the potential confounding influence of active depressive symptoms. To enhance interpretability of the logistic regression results predicting likelihood of global neurocognitive impairment, we present odds ratios estimated with 95% confidence intervals . All analyses were performed using JMP Pro version 12.0.1 .The present study explored how lifetime patterns of alcohol consumption, specifically a metric averaging drinks per drinking day over the lifetime, related to neuropsychological performance among MA-dependent and MA-nonusing individuals. Based on the current literature detailing the independent, adverse neurobehavioral contributions of chronic MA and alcohol consumption, it was hypothesized that the MAþ group would exhibit worse neurocognitive performance and that greater alcohol use would exacerbate the deleterious neurocognitive effects of MA use. Consistent with prior studies, we demonstrate that MAþ individuals perform worse on average across all neurocognitive domains while exhibiting modestly higher rates of neurocognitive impairment and consuming more alcohol and cannabis than their MA– counterparts. Whereas heavier drinking increased the likelihood of global neurocognitive impairment in the absence of MA dependence, no additive effects of alcohol were observed among MAþ participants. Contrary to expectations, lifetime average daily alcohol use did not predict global T scores and in fact was associated with reduced risk of global neurocognitive impairment in the MAþ group. To our knowledge, this is the first study to explore potentially modulating effects of historical patterns of alcohol consumption, as opposed to recent heavy drinking, on MA-associated neurocognitive performance. Given the known neurotoxic and neurobehavioral consequences of heavy alcohol use , these results must be interpreted with caution. However, our finding that elevated historical levels of alcohol consumption attenuate MA-related global neurocognitive impairment is consistent with prior studies demonstrating that singly addicted stimulant abusers consistently experience greater levels of neurocognitive dysfunction than those who simultaneously abuse stimulants and alcohol .
These prior findings are particularly applicable to the current investigation as both studies classified participants based on lifetime patterns of chronic stimulant and alcohol use and administered comprehensive and validated neuropsychological batteries. Although studies of the neurocognitive effects of acute, combined stimulant and alcohol use may be less generalizable to our results, some studies have reported that administration of dextroamphetamine or amphetamine sulfate following ethanol-induced intoxication in humans may dampen ethanol-related neuropsychological decrements in psychomotor performance, executive function, and working memory . Nevertheless, further research is required to determine whether acute alcohol administration following MA-induced intoxication exhibits similar neurocognitive effects and to what extent such findings can be extrapolated to chronic substance abusers. Our unanticipated results with respect to MAþ participants necessitate that we critically examine potential statistical and behavioral confounds. The significant relationship between lifetime average daily alcohol use and the dichotomous global impairment variable, as opposed to the null effect of lifetime alcohol use on continuous global T scores, reflects fundamental differences between these two measures of global neurocognition. Global T scores are computed by averaging individual T scores across the entire battery and can represent performance across the entire neurocognitive spectrum . As a result, above average performance on some measures can mask impaired performance elsewhere. Conversely, the GDS-based impairment classification accounts for the frequency and severity of deficits across the test battery with less consideration given to performance in the normal range . Figure 1 demonstrates that although average global T scores in MAþ individuals remain stable as lifetime average daily alcohol use increases, resulting in a null association, there is greater variability in performance at low levels of alcohol use, resulting in a higher percentage of MAþ individuals being classified as impaired on the GDS at low levels of use. Similarly, the MAþ group had an average global T score that only fell .35 standard deviations below the mean , yet was twice as likely to have global impairment as compared to MA– individuals, suggesting that a global index of impairment may enhance detection of the subset of MA users that are disproportionally vulnerable to MA related brain insults. Conversely, MA group comparisons on domain-specific performance illustrate the utility of T scores in detecting subtle yet significant differences that do not necessarily translate to differences in rates of impairment.
The hypothesis that neurocognitive performance attributable to MA-induced neural injury may hinder the ability to detect the relatively subtle influence of alcohol is supported by evidence that MA abuse poses greater risk for neurocognitive deficits than alcohol abuse . Although our data demonstrate an adverse, multi-domain effect of MA dependence, this effect is modest and therefore unlikely to preclude us from detecting any additional influence of alcohol use patterns. From a poly substance use perspective, the strong positive correlation between self-reported lifetime MA and alcohol use indicates that the observed relationship between greater alcohol use and lower likelihood of global neurocognitive impairment is not an artifact of heavy drinkers having less exposure to MA. Although cannabis use correlated with alcohol use, and prior evidence suggests cannabis use may attenuate MA-related neurocognitive deficits , lifetime cannabis exposure did not suppress our significant findings nor did it account for variance in neurocognitive performance. Furthermore, the negligible effects of days since last alcohol use and depressive symptoms rule out MA group differences in recent alcohol consumption and psychiatric comorbidities as a source of variance in neurocognitive performance. In a meta-analysis examining the neurocognitive effects of duration of alcohol abstinence, Stavro and colleagues found that neurocognitive dysfunction decreased following sustained abstinence for at least a year. Importantly, this meta-analysis only included patients who met criteria for alcohol use disorder and excluded patients with non-alcohol substance use disorders. Given that the present study sample included MA dependent individuals with varying levels of alcohol consumption, neurocognitive recovery facilitated by increased duration of abstinence from alcohol may be more prominent for heavier drinking populations without comorbid substance use disorders. Moreover, our study criteria excluded DSMIV-based alcohol dependence within the past year as well as evidence of long-term lifetime alcoholism. Therefore, those meeting dependence criteria would have done so only in the past and on an episodic basis. With regard to MA group differences in time since last alcohol use, these are largely explained by many MAþ participants being in recovery and abstaining from all substances currently, vertical rack whereas MA– participants may include current social drinkers. Nevertheless, days since last alcohol use did not predict our outcomes. Drawing inferences about specific biological mechanisms underlying poly substance use in humans is particularly challenging given that substance use disorders, such as MA dependence, cannot be experimentally modeled as independent factors in randomized controlled trials, and observational studies are often under powered to examine potential confounds. Although the nature of our data prevents us from empirically investigating specific biological mechanisms that may explain the interactive effects of MA status and lifetime average daily alcohol use on neurocognitive functioning, we offer several plausible neurobiological interpretations. First, the cerebrovascular abnormalities evidenced in MA use are partially attributable to the vaso constrictive properties ofMA that result in platelet aggregation . Alcohol, in contrast, is recognized to have vasodilating properties that reduce platelet aggregation . Thus, alcohol-driven attenuation of MA-induced vasoconstriction may reduce the magnitude of neurovascular dysfunction and subsequent neurobehavioral deficits experienced by MA users.
It is important to note, however, that certain studies have demonstrated a biphasic vasoregulatory effect in which alcohol’s vasodilating properties may be limited to light-to-moderate drinkers, whereas heavier drinkers are at risk for a rebound effect in which an increase in platelet aggregation is observed following acute withdrawal from alcohol . An additional source of MA-associated neurotoxicity is the induction of brain hyperthermia through increased neural activation . Brain thermotoxicity is mediated through multi-level mechanisms in which adverse cellular , local , and systemic events can contribute to neurocognitive difficulties . Despite the sensations of warmth experienced during alcohol consumption, alcohol’s vasodilatory properties result in brain and body heat dissipation that may counteract the hyperthermic consequences of MA use. Animal experiments have demonstrated that rats exposed to alcohol before and after TBI recover from TBI-induced brain hyperthermia faster and exhibit fewer deficits in spatial learning than alcohol-naïve rats . Whether such thermoregulatory benefits of alcohol, and subsequent attenuation of neurocognitive impairments, hold in the context of MA-induced hyperthermia requires further investigation. Although the neurophysiological alterations associated with increased alcohol consumption may provide neuroprotective benefits in the context of MA addiction, our data demonstrate an adverse effect of lifetime average daily alcohol use on neurocognitive function in the absence of MA dependence. Unlike the MAþ group, who on average reported heavy lifetime alcohol consumption , MA− individuals on average reported low-risk alcohol intake , 2005. Neurocognitive performance in nondrinkers, low, and moderate drinkers has been widely studied yet has yielded mixed results. Whereas many researchers posit a “j-shaped” relationship, in which light-to-moderate consumption confers neurocognitive benefits over non drinking but heavy consumption is more neurotoxic than abstinence , other studies have either found no relationship or a negative association between low-to moderate consumption and neurobehavioral outcomes . Our findings are most consistent with the latter group of studies suggesting a deleterious dose-dependent effect of alcohol consumption, even at moderate levels, on cognition and brain structure . It is important to note that despite reaching statistical significance, our findings represent a small effect size in which one extra drink per day equates to about a one-half unit decrease in global T scores. As a result, the clinical significance of this relationship may be far more relevant for heavier drinkers with borderline neurocognitive performance than higher performing drinkers. Although the present study focuses on the conditional role of alcohol in MA-related neurocognitive performance, further studies that probe the neurocognitive effect of alcohol at varying levels of consumption and model non-linear relationships are warranted regardless of MA status. Understanding limitations of the current study may guide future research to clarify the observed differential effects of alcohol use on neurocognitive functioning among MAþ and MA− individuals. Unsurprisingly, the MAþ group displayed significantly greater lifetime average daily alcohol use than the MA− group. Although the distribution of residuals from regression models were carefully examined to ensure no assumptions of normality were violated, the group difference in lifetime average daily alcohol use may impact the reliability of our MA effect estimates at high levels of consumption in which the MA– group is underrepresented. Additionally, these estimates of lifetime alcohol consumption are fully dependent on participant self-report.