Even though PRS were correlated with conduct disorder, associations between the PRS and trajectory membership persisted even after controlling for conduct disorder. Thus, general deviance does not appear to fully account for these associations. Our study had several limitations, including a modest target sample size . Further replication studies in larger, independent samples are warranted. Also, the current analyses were restricted to individuals of European ancestry, so we cannot confidently extrapolate our conclusions to other populations. Thirdly, COGA is ascertained for genetic liability to addiction, which may have influenced findings. Our ‘high’ group is somewhat larger than those noted in two prior general-population longitudinal studies, but similar to one study that over sampled for tobacco smoking and lower than a study with over-representation of individuals from high crime neighborhoods. Thus, similar classes have been noted, although there is much variability in their class size. Fourthly, while self-report of perceived peer use is commonly studied and does not significantly differ from actual peer use, it is possible that it is less objective than reports by peer nominees. Furthermore, as we did not have reports of concurrent peer cannabis use at older ages , we cannot speculate whether trajectory membership was associated with subsequent affiliations with cannabis-using peers. Fifthly, we binned frequency of use data into 20-unit intervals and this may have obscured the identification of smaller classes. For instance, our method combined those using one to two times in the past year with those who may have used cannabis 15–20 times. However, sensitivity analyses with 10-unit intervals provided similar results. It is also possible that reported frequency at the upper end of use was imprecise . It is hoped that with larger discovery efforts of both cannabis use and of cannabis use disorders the predictive quality of PRS, not merely in terms of what they predict, but also when and how they do so, will be elucidated more clearly. However, this study highlights that even as discovery GWAS sample sizes grow and PRS begin to attain a greater level of precision, it will be of paramount importance to consider not only how genetic liability shapes health and behavior, but also the environmental context within which such behavior unfolds .According to the Center for Disease Control data , falls are the leading cause of fatal and nonfatal injuries among adults aged ≥ 65 years . For older adults, falls and associated injuries threaten their health, independence, and quality of life. More than a third of people aged 65 and older living independently fall each year , representing a major public health problem.
Aging HIV+ individuals have an increased prevalence of many fall-related risk factors, and a study has previously shown that the fall rate among middle-aged HIV+ individuals on effective antiretroviral therapy mirrors that of uninfected adults aged 65 or older . In addition to their high risk of falls, HIV+ individuals may be at a greater risk of sustaining an injurious fall or fracture due to underlying low bone density, low body weight, peripheral neuropathy, neurocognitive impairment, and frailty . Cannabis is used recreationally as well as for different medical indications among HIV+ individuals and studies have shown an improvement of neuropathic pain in HIV+ individuals using cannabis cultivation technology. According to a National Academies of Sciences, Engineering, and Medicine 2017 report, there is conclusive or substantial evidence for the use of cannabis for the treatment of chronic pain . Cannabis use is also legal for recreational purposes in many states in the USA, which has likely increased its use in the general population. The active components in cannabis are known as cannabinoids, and the main cannabinoids are tetrahydrocannabinol and cannabidiol . Cannabinoid receptors are expressed in the brain and are involved in its health and disease; CB1 receptors are found in the brain region that mediate the control of balance and CB2 receptors are found in immune cells in the brain, playing a role in neuroinflammation . THC and CBD interact with these receptors, thereby influencing balance and neuroinflammation. THC is the primary psychoactive component in cannabis, and it is associated with variable degrees of drowsiness , dizziness, and sedation , which alone or together could contribute to imbalance and consequently to falls during acute intoxication. By way of contrast, CBD is the major non-psychoactive component of cannabis and has been shown to be anti-inflammatory in models . Despite the potential health benefits of cannabis use for HIV infection, the relationship between long-term cannabis use and balance disturbances remains unknown. In this study, we compared the prevalence of balance disturbances among HIV+ and HIV− cannabis users, controlling for relevant covariates. We hypothesized that long-term cannabis use in HIV+ individuals might be associated with more severe balance disturbances than in HIV− individuals due to potential neurotoxic interactions between HIV infection and cannabis.The study comprised 3664 ambulatory HIV+ and HIV− individuals enrolled in multiple NIH-funded research studies at the University of California, San Diego HIV Neurobehavioral Research Program . Participants were enrolled between September 2003 and June 2017, and the most recent evaluation was used for each participant. At the time of enrollment, all participants provided written, informed consent. Secondary data analysis was performed. Inclusion criteria for this analysis included completion of a structured clinical interview which provided details regarding the occurrence of cannabis use and balance disturbances and completion of a neurological examination.
The clinical interview and the physical examination were performed on all participants. Exclusion criteria included blindness, being a wheelchair user and experiencing falls as a consequence of sustaining a violent blow, loss of consciousness or sudden onset of paralysis as in stroke or epilepsy. We excluded individuals with other neurologic conditions such as motor neuron disease, Parkinson disease, and multiple sclerosis. Individuals with stroke were excluded only if they had persistent neurological deficits after their stroke. Recognizing that peripheral neuropathy and vestibular disease are common in HIV+ individuals, we did not exclude these conditions. Additionally, urine samples were collected at screening and participants with a positive toxicology report were excluded.Cannabis and other substance use data were collected using the interviewer-administered timeline follow-back assessment , a gold-standard measure for retrospectively assessing detailed alcohol and drug use characteristics. The TLFB uses a calendar method to evaluate daily patterns and frequency of substance use over a specified period. It has high retest reliability, convergent and discriminant validity with other measures, agreement with collateral informants’ reports of participants’ substance use, and agreement with urine toxicology assays .Other cannabis variables assessed self-reported frequency, density, cumulative dose, and total years of cannabis use. For the present analysis, we used the total quantity of cannabis use as the predictor variable. The main study aim was to assess interactions between HIV infection and long-term cannabis use on balance disturbance; therefore, total quantity of cannabis use as predictor provides an estimate of potential cumulative toxicity. We used the Composite International Diagnostic Interview version 2.1. to reliably assess substance use disorder.A structured clinical interview was administered to participants by trained interviewers to collect any history of balance disturbance. Inter-examiner reliability was ensured through systematic training. Participants were asked about balance problems in the past few days up to the previous 10 years. Balance disturbances were self-reported and classified according to their severity into the following categories: normal; occasionally unsteady, and no falls; frequently unsteady, some near falls, and rare falls; and must use a cane, walker, or other prop.
We recoded balance disturbances into no or minimal balance disturbances and moderate-severe balance disturbances.This method has been previously used in a study of the influence of distal sensory polyneuropathy on balance disturbances in HIV+ individuals . The presence or absence of ataxia was assessed during the gait examination .We collected data on HIV disease characteristics including current and nadir CD4 count, plasma viral load < 50 copies/mL , duration of HIV infection, historical AIDS status, and current use of ART. We asked about the use of medications commonly associated with balance problems: antihypertensives, sedatives, and opioids. We also collected data on age, gender, race/ethnicity, and education. History of long term alcohol abuse and diabetes were also reported. Height and weight were measured in order to calculate the body mass index . Chronic distal sensory polyneuropathy was diagnosed based on the presence of any of the following abnormal findings in a distal , symmetrical distribution during physical examination: reduced sharp sensation, vibration sense, or reflexes.Comparisons between HIV+ vs. HIV− groups and moderate-severe vs. no or minimal imbalance in participant characteristics were performed using Student t tests for continuous variables and Fisher’s exact test for binary and categorical variables. Using similar methods, HIV disease characteristics were compared in HIV+ individuals with moderate severe vs. no or minimal imbalances. Prior to statistical analyses, current and nadir CD4 counts were square root transformed to better fit a normal distribution. Multivariate logistic regression was applied to determine the interaction effect of total quantity of indoor grow cannabis use with HIV status on balance disturbance. Age, gender, cDSPN symptoms, gait ataxia, opioid medications, and sedatives were included as covariates in the adjusted model after variable selection. The effect sizes are presented as Cohen’s d or odds ratios; Cohen’s d was calculated by dividing the difference of means by the root-mean-standard-error and the odds ratios were used to quantify effect sizes for nominal variables. Statistical analyses were completed with JMP Pro 14. Alpha was set at 0.05.Controlling for age, gender, cDSPN symptoms, gait ataxia, opioid medication, and sedatives, we evaluated the relationship between self-reported balance disturbances and cannabis use by HIV status. We observed a statistically significant interaction between HIV status and total quantity of cannabis use as regards balance disturbances such as while total quantity of cannabis use was associated with more severe balance disturbances in HIV−individuals, it was unrelated to balance disturbances in HIV+ individuals . In a sensitivity analysis, we found similar results after excluding participants with more severe balance disturbances.
Contrary to our hypothesis, this study provides evidence that more extensive, long-term cannabis use among HIV+ individuals is not associated with a higher likelihood of balance disturbances. While we did not find any research study in the literature to compare with our findings, one prior report found that the occurrence of balance disturbances was associated with a 13-fold higher odds of recurrent falls among HIV+ individuals . It is not clear why the more frequent use of cannabis was not associated with a higher likelihood of balance disturbances in the HIV+ group, but a plausible explanation is that any deleterious effects of cannabis are counteracted by its effect of reducing inflammation . Yet, the difference between HIV+ and HIV− individuals in cannabis-associated balance disturbances as both acute effect and chronic effect suggest that neuroinflammatory differences alone may not explain these results. In the brain, CB2 receptor expression is associated with inflammation and it is primarily localized to microglia . This selective localization together with the modulatory effect of the CB2 receptor on microglia function is particularly relevant since microglial cells have a significant role in neuroinflammation in HIV infection. In fact, HIV-infected monocytes not only infect brain resident cells upon migration into the CNS but also produce proinflammatory cytokines, which in turn, further activate microglia. These activated microglia, along with perivascular macrophages, are the main contributors to neuroinflammation in HIV infection, resulting in neuronal dysfunction and death . In contrast, more prolonged chronic cannabis use was related to more severe imbalance among the HIV− individuals. One potential mechanism for this is adverse effects on the cerebellum and basal ganglia, both of which express high levels of CB1 receptors. Prior research found that chronic cannabis use in HIV− individuals was associated with increased postural sway in individuals who were not acutely intoxicated. Our results are similar to those of Bidwell et al. who found that balance function was impaired after immediate cannabis use and different from those of Pearson-Dennett et al. who found that the effect of long-term cannabis use was associated with long-lasting changes in open-chain elements of walking gait, but the magnitude of change was not clinically detectable. Those studies assessed balance impairment after immediate cannabis use in small samples. In contrast, our study focused on prolonged use of cannabis and had more power due to the large population size.