Global neuropsychological impairment and dependence on basic and instrumental activities of daily living are more common among PWH who also use MA than among those who do not, with an additive effect of HIV and MA on neuronal injury and glial activation . Despite these negative effects, perceived benefits, such as sexual enhancement and relief of negative psychosocial symptoms, continue to drive MA use among PWH . MA functions by stimulating monoamine release , and facilitates hyperactivity, euphoria, feelings of increased mental and physical capacity, and riskier sexual behavior . Among the general population, prolonged MA use can have detrimental effects on alertness, mood, cognition, and activity levels . MA use also has been associated with poor sleep quality, increased sleep latency, and daytime sleepiness . Cessation of MA is often accompanied by withdrawal symptoms such as anxiety, depression, and craving that can further contribute to poor sleep quality. The adverse effects of MA also contribute to functional decline , such as unemployment , which also may exacerbate sleep disturbance. Among MA-using PWH, poorer adherence and missing ART doses after MA use have been reported, in part due to disrupted sleep-wake cycles . Taken together, acute and chronic MA use can have multiple direct and indirect effects on sleep quality.This study evaluates effects of lifetime MA use on self-reported sleep quality among participants with or without HIV infection.
The hypothesis was that lifetime MA use disorder would be associated with poorer sleep quality, particularly among PWH,drying rack cannabis and that this would relate to poor outcomes, including poorer cognition, reduced independence in activities of daily living, unemployment, and poorer life quality. Participants included 225 HIV-seropositive and 88 HIV-seronegative adults enrolled in NIH-funded research studies at the UC San Diego’s HIV Neurobehavioral Research Center . All participants completed a standard, selfreport evaluation of sleep quality as well as comprehensive neurobehavioral and neuromedical assessments. Exclusion criteria were: 1) sleep apnea or restless leg syndrome; 2) disruptions to sleep due to temporary circumstances ; 3) history of comorbid neurological illness or injury that would affect cognitive functioning ; 4) history of psychotic disorder; 5) alcohol dependence within a year; and 6) low premorbid verbal IQ as estimated by a Wide Range Achievement Test-4 score less than 80. The study protocol was approved by the UC San Diego Institutional Review Board and each participant provided written, informed consent. All participants completed the Pittsburgh Sleep Quality Index , a self-report questionnaire that assesses perceptions of average sleep quality and disturbances over the past 30 days . The PSQI is a widely used and well-validated measure of subjective sleep quality in adults . The PSQI has 19-items that assesses seven components of sleep, including quality, latency, duration, efficiency, disturbances, use of medications to aid sleeping, and daytime sleepiness. Component scores range from 0 to 3 . Items were summed to generate a continuous global sleep score ranging from 0 to 21. Global scores > 5 indicate problematic sleep . For purposes of the present study, the continuous global PSQI score and dichotomous sleep quality classification were used as outcome variables. All participants underwent a standardized medical history interview, neuromedical examination, and blood and urine collection.
HIV serological status was confirmed via ELISA and Western blot test, and HIV RNA levels were measured in plasma by rtPCR . Current CD4+ T-cell count was measured in blood by clinical flow cytometry. Additional HIV disease and treatment variables included nadir CD4+ T-cell count, AIDS diagnosis, estimated duration of HIV disease, and current ART regimen. MA use characteristics were self-reported. Comorbid medical conditions and current medication use were determined by self-report and medical chart review.All participants completed a comprehensive and validated neurocognitive assessment across seven neurocognitive domains commonly affected by HIV and MA use ; these include verbal fluency, executive functioning, speed of information processing, learning and memory , working memory/attention, and motor. Using established normative standards, test scores were adjusted for known influences on neurocognitive performance . Deficit scores were calculated for each domain and averaged across the test battery to derive a global deficit score ranging from 0 to 5 . Dependence in instrumental activities of daily living was determined using a revised version of the Lawton and Brody ADL questionnaire , in which participants rated current degree of independence as compared to prior best level of independence across 13 IADL domains. Participants were classified as IADL “dependent” if they endorsed requiring increased assistance in at least 2 IADL domains. Employment status and symptoms of cognitive difficulties in daily life were determined via the Patient’s Assessment of Own Functioning Inventory . The Karnofsky Performance Status Scale is a clinician administered assessment of disease-related functional impairment with a range from 0 to 100 with standard intervals of 10 . Self-reported physical and mental health quality of life were assessed using the Medical Outcomes Study Short-Form Survey . Physical and mental health composite scores were calculated via validated summary score formulas derived from an obliquely rotated factor solution .Group differences on demographics, neuropsychiatric and neuromedical characteristics, HIV disease and treatment parameters, MA use history, and global sleep outcomes were tested using analysis of variance , Kruskal-Wallis tests, Chi-square statistics, or Fisher’s Exact test .
Two-tailed t-tests were used to compare groups on HIV disease and methamphetamine use characteristics. Follow-up pairwise comparisons were conducted using Tukey’s Honest Significant Difference or Wilcoxon tests for continuousoutcomes,commercial greenhouse supplies or Bonferroni-corrections for categorical outcomes. Cohen’s d measured effect size for pairwise comparisons of means. Based on the pattern of univariable group differences in global sleep health and the small sample size of the HIV−/MA+ group, multiple linear regression examined global sleep scores as a function of MA status and clinical covariates specifically within PWH. Covariates included clinical variables from Table I with univariable associations with the primary independent variable [MA status ] as well as associations with the primary dependent variable with p values < 0.10. Variables sex and sexual orientation were included based on theoretical evidence . Additionally, HIV disease and treatment covariates were included to determine if HIV specific factors attenuated the effects of MA status on global sleep in PWH. Stepwise regression models used backward selection based on Akaike Information Criterion to select the optimal model. To determine potential co-occuring neurobehavioral functional impairments associated with poor sleep quality within the dual-risk HIV+/MA+ group, additional nominal logistic regression models based on AIC were run to examine the association between problematic sleep membership and neurobehavioral outcomes . Covariates were selected based on univariable associations with global PSQI and did not include HIV or methamphetamine characteristics. Rates of MA use are elevated among PWH and are associated with poorer sleep quality in the general population . The present study is the first to explore the relationships between past MA use disorder, HIV disease, and sleep quality. Our results demonstrate that PWH who have a history of prior MA use disorder had significantly poorer sleep quality and were more likely to be classified as problematic sleepers than those without a lifetime disorder. This relationship between lifetime MA use disorder among PWH is robust to MA group differences in bio-psychosocial factors and is linked to sleep quality above and beyond the effects of HIV disease severity and other established risk factors for poor sleep. Further, poorer sleep quality among PWH with comorbid lifetime MA use disorder was associated with a number of neurobehavioral functional outcomes, including decreased physical and mental life quality, IADL dependence, unemployment and clinician-rated functional disability. As expected, lifetime MA use disorder was negatively associated with sleep quality; however, this finding was isolated to PWH and independent of recent MA use. In addition, MA use characteristics did not differ by HIV serostatus, suggesting sleep among PWH may be specifically related to the effects of non-recent MA use. Prior studies have demonstrated detrimental effects of MA on neurobehavioral health specific to PWH, including neurocognitive impairment and associated everyday life consequences such as unemployment and difficulties performing activities of daily living . It is possible that disrupted sleep may mediate the link between MA and functional outcomes, although longitudinal studies are needed to determine causality.
Depressive symptoms in the HIV+/MA+ group are also consistent with prior research . While depressive symptoms were also associated with global PSQI scores, as expected, this did not attenuate the relationship between MA and global PSQI scores in PWH, suggesting additional mechanisms underlying MA-related sleep disturbance independent of mood.One explanation for our findings is the combined, long-term CNS effects of excessive MA use and HIV on brain structures and/or pathways responsible for sleep regulation. While MA’s major mechanism of action is through increased activity of the mesolimbic dopamine system , emerging evidence supports that GABA-ergic dysfunction results from abuse of amphetamines . Projection systems of GABA include the reticular nucleus of the thalamus to the rostral brainstem reticular formation, a structure critical for sleep regulation. Further, GABA also promotes sleep via hypothalamic projections that inhibit serotonergic, noradrenergic, histaminergic, and cholinergic arousal systems . Future studies linking GABA to MA use and sleep quality are necessary to establish this theoretical mechanism of action. Also, while the lack of evidence of sleep disturbance in the very small HIV−/MA+ group would not support long-term effects of MA use on CNS mechanisms important for sleep, a much larger subject sample would be needed to draw any confident conclusions about HIV−/MA+ individuals. Prior literature on the prevalence of sleep disturbance in PWH is variable and comparisons between demographically matched, HIV serostaus groups on sleep quality is lacking. In a meta-analysis of self-reported sleep disturbance in PWH, the overall prevalence was 58% . No comparisons have been made with HIV-uninfected individuals from the same population to determine whether this prevalence is higher than in this type of comparison group. The current findings suggest HIV status alone may not elicit poor perception of sleep, however, fragmented sleep has been identified in chronic health conditions even without the patient’s perception of poor sleep . Consistent with prior literature , detectable HIV RNA was associated with poorer perceived sleep quality in our multiple regression analyses, but the specific mechanism for this association could not be established. Other literature has suggested that HIV infection is linked to objective sleep measurements, including reduced slow wave sleep and reduced rapid eye movement latency . However, studies have failed to detect similar associations between HIV disease severity and objective sleep measurements , highlighting the uncertainty to which HIV infection, by itself, may contribute to reductions in sleep quality. The study has several limitations. First, the data are cross-sectional and cannot determine causality. Lifetime MA use disorder is suspected to precede self-reported poor sleep within the last 30 days, however, such self-reported sleep disturbances may be longstanding and could even have served as a precursor to problematic substance use . Thus, future longitudinal evaluations or with increased sample size, the use of structural equation modeling, would be helpful in better determining the timing, duration, and directionality of associations between MA use disorders and sleep. This goes alongside our report of neurobehavioral outcomes associated with problematic sleep within PWH with a history of MA use disorder. While theoretically, sleep should have some influence on function, it is also possible that there is some unique third variable quality within the HIV+/MA+ group that leads to both poor sleep and poor neurobehavioral outcomes. Again, a longitudinal research design or a larger sample size may help in teasing out the directionality of our findings. Second, the small sample size of the HIV−/MA+ group hinders our ability to detect statistically significant associations between MA use and other findings with the HIV− participants. For example, the difference between HIV+/MA+ and HIV−/MA+ groups on global PSQI was not statistically significant , yet the effect size suggests a nontrivial difference . While our sample did not demonstrate an interaction between HIV and MA possibily due to this limitation, this relationship may exist. Further, while lifetime MA use disorder independently contributed to sleep quality in PWH, we did not observe a recent MA use effect on sleep. We should note that this too may be due to low power, with very few participants reporting use in the last 30 days.