Ben Lewis

Severe deficit in brain reward function associated with fentanyl withdrawal in rats.

BACKGROUND During the last decade, there has been a strong increase in the use of the mu-opioid receptor agonist fentanyl. The aim of these studies was to investigate the effects of fentanyl withdrawal on brain reward function and somatic withdrawal signs. METHODS Fentanyl and saline were chronically administered via minipumps. An intracranial self-stimulation procedure was used to provide a measure of brain reward function. Somatic signs were recorded from a checklist of opioid abstinence signs. RESULTS The opioid receptor antagonist naloxone induced a dose-dependent elevation in brain reward thresholds and somatic withdrawal signs in fentanyl-treated rats. Discontinuation of fentanyl administration resulted in a time-dependent elevation of brain reward thresholds and somatic withdrawal signs. CONCLUSIONS These findings indicate that fentanyl withdrawal is associated with affective and somatic withdrawal signs. The severity of the deficit in brain reward function in this animal model suggests that affective fentanyl withdrawal symptoms may be a strong deterrent to abstinence.

CHARACTERIZING GENDER DIFFERENCES IN TREATMENT SEEKERS

BACKGROUND Available evidence suggests women may be more vulnerable to the effects of chronic alcohol consumption than men. The few investigations of gender differences in treatment-seeking populations have often involved study samples restricted by selection criteria (e.g., age, education). The current study examined gender differences in a heterogeneous sample of individuals seeking treatment for a substance use disorder. We examined alcohol drinking levels, age at drinking milestones (e.g., first drink, first intoxication), and progression from milestones to alcohol problems or treatment. Additionally, family history, spousal alcoholism, and nicotine use were analyzed. METHODS Participants included men (n = 274) and women (n = 257) in substance abuse treatment facilities. Participants completed inventories quantifying affect, intellectual ability, and drinking consequences. A family tree for substance use and personal histories for alcohol and nicotine use, including chronicity, frequency, and regularity, were collected. RESULTS Telescoping was not observed when progression from drinking milestones to alcoholism or alcohol problems was compared between men and women. In contrast, when considered as progression to treatment, marked telescoping effects were detected, with women entering treatment more rapidly by approximately 4 years. Familial differences included a greater proportion of women reporting alcoholic parents (73% women; 61% men) and alcoholic spouses (58% women; 38% men). Smoking behaviors were similar between genders; however, men reporting higher levels of alcohol consumption reported greater intensity of chronic smoking. Smoking and drinking behaviors were correlated among men, but not women. Rates of pretreatment drug problems were equivalent between genders. CONCLUSIONS When contrasted with the available literature, our data were only partially supportive of gender-contingent telescoping. While women did not experience alcohol problems or alcoholism earlier than men, they progressed to treatment more quickly. These results highlight the importance of carefully considering the sample and specific outcome variables when interpreting gender differences.

Sex differences in drug use among polysubstance users

BACKGROUND Available evidence indicates women with substance use disorders may experience more rapid progression through usage milestones (telescoping). The few investigations of sex differences in treatment-seeking populations often focus on single substances and typically do not account for significant polysubstance abuse. The current study examined sex differences in a heterogeneous sample of treatment seeking polysubstance users. We examined patterns of drug use, age at drug use milestones (e.g., initial use, regular use), and progression rates between milestones. Nicotine and alcohol use were also evaluated. METHODS Participants (n = 543; 288 women) completed personal histories of substance use, including chronicity, frequency, and regularity, as well as inventories assessing affect, and intellectual ability. RESULTS Rates of drug use and milestone ages varied by sex and specific drug. Analyses suggested pronounced telescoping effects for pain medication and marijuana, with women progressing more rapidly through usage milestones. CONCLUSIONS Our data were generally supportive of telescoping effects, although considerable variance in progression measures was noted. The contrast between the marked telescoping observed in pain medication use and the absence of telescoping in other opioids was of particular interest. The discrepancy in telescoping effects, despite shared pharmacologies, suggests the need for further work examining underlying psychosocial factors. These results highlight that the specific sample population, substance, and outcome measure should be carefully considered when interpreting sex differences in substance use.

Neurophysiological correlates of moderate alcohol consumption in older and younger social drinkers.

BACKGROUND Nearly 40% of adults aged 65 and older in the United States consume alcohol. Research in older adults has largely examined potential health effects of a moderate drinking lifestyle. Examination of acute effects in this population is generally lacking. To investigate alcohol-induced alteration of electrophysiological correlates of attention in this population, we employed a covert attentional task. We hypothesized that moderate alcohol administration as well as older age would reduce P3 amplitude and increase latency. We anticipated an interaction such that, relative to their age-matched controls, older adults receiving alcohol would be more affected than their younger counterparts. METHODS Participants included healthy older (aged 50 to 67; n = 20; 9 men) and younger (aged 25 to 35; n = 12; 5 men) moderate drinkers. Participants received either a moderate dose of alcohol (breath alcohol concentration ~50 mg/dl) or a placebo beverage. Following absorption, the task was administered and neurophysiological measures were obtained. P3 amplitude and latency were separately subjected to ANOVA across cue conditions using age and dose as independent variables. RESULTS As predicted, P3 amplitude in older adults was significantly lower than in younger adults across cue conditions. An age by alcohol interaction was detected, revealing that older adults receiving alcohol showed lower P3 amplitudes than any other group. An age effect for P3 latency was found, with older adults having longer latencies than their younger counterparts. A significant age by alcohol interaction for P3 latency was detected, revealing that older adults receiving alcohol displayed delayed P3 latencies relative to older adults receiving placebo. In contrast, younger adults receiving alcohol had reduced latency compared to those receiving placebo, although this effect did not reach significance. CONCLUSIONS Results suggest that older adults demonstrated alcohol-related shifts in P3 characteristics during an intentional attention task, whereas younger adults failed to demonstrate this pattern.

Sex differences in alcohol-related neurobehavioral consequences

In this chapter, we review existing research regarding sex differences in alcohols effects on neurobehavioral functions/processes. Drawn largely from laboratory studies, literature regarding acute alcohol administration and chronic alcohol misuse is explored focusing on commonly employed neuropsychologic domains (e.g., executive function, visuospatial skills, learning and memory, gait and balance), neurophysiologic measures (e.g., electroencephalography and event-related potentials), and structural and functional neuroimaging (e.g., magnetic resonance imaging (MRI), functional MRI, diffusion tensor imaging, positron emission tomography, and magnetic resonance spectroscopy). To provide a historical perspective on the development of these questions, we have included reference to early and more recent research. Additionally, specific biases, knowledge gaps, and continuing controversies are noted.

Acute Behavioral and Long-Term Health Effects of Moderate Alcohol Use in Older Adults

This review addresses current literature regarding health consequences associated with of a lifestyle or pattern of moderate drinking and the neurobehavioral effects of moderate drinking episodes in older adults. Discussed studies include both large-scale epidemiological investigations of the effect of moderate alcohol use on multiple health-related domains (e.g., cancer and cardiovascular disease risk) in older adults and laboratory investigations of moderate alcohol’s acute neurobehavioral effects. Numerous studies provide evidence that a pattern of moderate drinking is associated with both potential health benefits and risks for older adults, including evidence for reduced risk of cardiovascular disease and cognitive decline but elevated risk for some cancers, including of the oral cavity, esophagus, and breast. Furthermore, laboratory administration studies indicate that older adults may be more susceptible to neurobehavioral alteration as a result of acute moderate alcohol intake than their younger counterparts. It is clear from the extant literature that even relatively low BACs resulting from the practice of a moderate drinking lifestyle are not without risk. This risk should be balanced against potential benefits at the level of the individual drinker. Additional studies regarding moderate drinking in older adults are needed to address limitations of the literature, including consideration of potential sex effects, inclusion of less rarified samples in acute studies, and the use of longitudinal, prospective designs.

Cognitive flexibility during breath alcohol plateau is associated with previous drinking measures

Although the biphasic effects of acute alcohol during ascending and descending Breath Alcohol Concentrations (BrACs) are well described, the plateau period between peak and steadily descending BrACs is generally unrecognized and under-studied by researchers. Naturalistic examinations indicate such periods persist for substantial intervals, with a time frame of onset suggesting BrAC plateaus may co-occur with potentially risky behaviors (e.g., driving). The current pilot study examined neurocognitive performance during this period. Participants were healthy, community-residing moderate drinkers (n = 18). In the first phase of the study, the Digit Symbol Substitution and Trail Making Tasks were administered during BrAC plateau (M = 62 mg/dL). BrACs were negatively correlated with Digit Symbol performance but unrelated to other tasks. In contrast, performance on a derived Trail Making measure of set-shifting was positively associated with the maximum alcohol doses consumed in the preceding 6 months. Phase 2 analyses demonstrated that relationships between previous alcohol experience and cognitive performance were absent among individuals receiving placebo beverages. Taken together, these data suggest a relationship worthy of investigation between previous drinking experiences and cognitive flexibility during the plateau phase.

Effects of acute alcohol and driving complexity in older and younger adults

RationaleOur previous work demonstrated differential neurobehavioral effects of low-dose alcohol consumption on older and younger adults in a driving simulator. However, the ability to enhance or suppress a response in such context has yet to be examined.ObjectivesThe current study contrasted older and younger drivers’ responses to specific stimuli (i.e., relevant, irrelevant) in scenarios of differing complexity following low-dose acute alcohol administration.MethodsHealthy older (55–70) and younger (25–35) adults completed two driving scenarios (i.e., country and metropolis) both before and after consuming beverages targeted to reach peak BrACs of 0.00, 0.04, or 0.065%. Throughout the simulation, participants encountered relevant stimuli (e.g., pedestrians walking into the street) and irrelevant stimuli (e.g., pedestrians walking parallel). Peak deceleration, range of steering, and distance until brake application were assessed within a 450-ft window preceding each stimulus.ResultsFollowing low-dose alcohol consumption, older adults shifted from a strategy using both deceleration and steering to relying solely on deceleration in responding to relevant stimuli in the country. Older adults under both low and moderate alcohol conditions displayed an inability to withhold responses to irrelevant stimuli in the metropolis.ConclusionThese findings are consistent with our prior work showing differential effects of low-dose alcohol on older, relative to younger, adults. The interactive effects of age and alcohol, however, depend on stimulus type and environmental complexity. Continued investigation of neurobehavioral mechanisms in ecologically valid paradigms is necessary for understanding the implications of the combined impairing effects of alcohol and older age.

Differences in pituitary-adrenal reactivity in Black and White men with and without alcohol use disorder

BACKGROUND Treatment-seeking men with alcohol use disorder (AUD) classically exhibit a blunted hypothalamic-pituitary-adrenal (HPA) axis response to pharmacologic and behavioral provocations during the early phases of abstinence from alcohol. Independent of alcohol, a significant muting of HPA axis reactivity is also observed among racial minority (e.g. Black) individuals. The effect of AUD upon the altered HPA axis response of racial minority individuals has not been explored. The current work represents a secondary analysis of race and AUD status among a sample of men. METHODS Healthy male controls (17 White, 7 Black) and four-to six-week abstinent men with AUD (49 White, 13 Black) were administered a psychosocial stressor and two pharmacologic probes [ovine corticotropin releasing hormone (oCRH) and cosyntropin] to assess HPA axis reactivity. Plasma cortisol and adrenocorticotropin hormone (ACTH) were assessed at 10-20 min intervals prior to and following behavioral and pharmacological stimulation. Basal and net-integrated responses following provocations were analyzed to identify potential group differences. A measure of childhood adversity was also obtained to consider the implications of prior stressors upon HPA axis function. RESULTS A three-fold increase in oCRH-induced ACTH was seen in Black men relative to White men regardless of AUD status. Adversity exerted a dampening effect on this pituitary sensitivity within Black controls only. Adjusted for adversity, a significant blunting effect of AUD status on ACTH reactivity was identified within White participants following oCRH. No group differences were present following cosyntropin administration. In response to the psychosocial stressor, White, but not Black, men with AUD experienced the expected blunting of cortisol reactivity relative to White controls. Rather, Black men with AUD exhibited greater cortisol reactivity relative to White men with AUD. CONCLUSIONS Differences in HPA axis reactivity associated with race were present in men with and without AUD. Explanatory biological mechanisms of the relationship between alcohol use and/or stress, in both healthy and unhealthy populations, may require a reassessment in different racial populations.

Characterizing Anxiety Among Individuals Receiving Treatment for Alcohol and Substance Use Disorders

BACKGROUND: Despite high prevalence of generalized anxiety disorder (GAD) substance use disorder (SUD) comorbidity, little is known regarding demographic characteristics associated with GAD in SUD treatment seekers. OBJECTIVE: To characterize demographic differences between inpatient SUD treatment seekers reporting varying levels of GAD symptomatology. DESIGN: General linear models, chi-square test, t test, and correlational analyses were utilized to assess group differences. Groups included those with no history of significant anxiety (No GAD; n = 256), subclinical anxiety (Subclinical; n = 85), and those meeting GAD diagnostic criteria (GAD; n = 61). RESULTS: The No GAD group differed substantially from Subclinical and GAD individuals. With the exception of polysubstance use, no differences were found regarding Subclinical and GAD groups. CONCLUSION: Individuals with subclinical GAD symptoms and those meeting diagnostic criteria were nearly identical regarding precursors to problematic substance use, severity of use, and key mental health indicators. Findings suggest subclinical levels of GAD should not be overlooked when assessing and treating SUDs.