The Impact of Cannabis Use on Cognition in People with HIV: Evidence of Function-Dependent Effects and Mechanisms from Clinical and Preclinical Studies.

PURPOSE OF REVIEW: Cannabis may have beneficial anti-inflammatory effects in people with HIV (PWH); however, given this population's high burden of persisting neurocognitive impairment (NCI), clinicians are concerned they may be particularly vulnerable to the deleterious effects of cannabis on cognition. Here, we present a systematic scoping review of clinical and preclinical studies evaluating the effects of cannabinoid exposure on cognition in HIV. RECENT FINDINGS: Results revealed little evidence to support a harmful impact of cannabis use on cognition in HIV, with few eligible preclinical data existing. Furthermore, the beneficial/harmful effects of cannabis use observed on cognition were function-dependent and confounded by several factors (e.g., age, frequency of use). Results are discussed alongside potential mechanisms of cannabis effects on cognition in HIV (e.g., anti-inflammatory), and considerations are outlined for screening PWH that may benefit from cannabis interventions. We further highlight the value of accelerating research discoveries in this area by utilizing translatable cross-species tasks to facilitate comparisons across human and animal work.

The Role of Cannabis and The Endocannabinoid System in Sleep Regulation and Cognition: A Review of Human and Animal Studies.

OBJECTIVES: Both sleep and cognition are partially modulated by the endocannabinoid (ECB) system. Cannabis has been reported to have effects on sleep and cognition. This review aims to summarize the recent literature on the ECB system, the role of cannabis and the ECB system on sleep regulation and cognition. Further, this review will identify existing gaps in knowledge and suggest potential targets for future research. METHODS: We performed this review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Reports were identified by searching PubMed/MEDLINE, Embase, CINAHL, Web of Science, and PsycINFO for articles published through September 2021 for studies with data available on aspects of cognition, cannabis, or the ECB system, and sleep or circadian rhythms (CRs). RESULTS: We identified 6 human and 6 animal studies to be eligible for inclusion in this review. Several human studies found that cannabis use is not associated with changes in sleep quality or cognitive function. However, individual cannabinoids appeared to have independent effects on cognition and sleep; THC alone decreased cognitive performance and increased daytime sleepiness, whereas CBD alone had no effect on sleep or cognition. Animal studies demonstrated that manipulation of the ECB system altered activity and cognitive function, some of which appeared to be dependent on the light/dark cycle. CONCLUSION: The sleep-wake cycle and CRs are both likely modulated by the ECB system, potentially resulting in effects on cognition, however this area is critically understudied.

A Pilot Assessment of the Effects of HIV and Methamphetamine Dependence on Socially Dysregulated Behavior in the Human Behavioral Pattern Monitor.

Deficits in social cognition are seen in both people living with HIV (PWH) and people with a history of methamphetamine (METH) dependence. Dually affected individuals may experience additive negative effects on social cognition due to these conditions. We evaluated social cognition in 4 diagnostic groups (HIV-/METH-, HIV-/METH+, HIV+/METH-, HIV+/METH+). First, we used traditional social-emotional functioning assessments, the Difficulties in Emotion Regulation Scale and the Faux Pas Task, to determine any significant effects of METH dependence and HIV on social cognition. Next, we quantified social cognition using the Human Behavioral Pattern Monitor by evaluating social behavior represented by interaction with novel objects. METH dependence significantly affected social-emotional functions and HIV significantly affected on object interactions, however no significant additive effects were observed using these methods. The nuanced relationship between HIV and METH dependence suggests that other factors (i.e., adaptive life skills) likely mediate social cognition-related behaviors.

RESUMEN: Los déficits en la cognición social se observan tanto en las personas que viven con el VIH (PWH) como en las personas con antecedentes de dependencia de la metanfetamina (METH). Las personas con ambas condiciones pueden experimentar efectos negativos aditivos en la cognición social. Evaluamos la cognición social en 4 grupos de diagnóstico (VIH−/METH−, VIH−/METH+, VIH+/METH−, VIH+/METH+). En primer lugar, utilizamos evaluaciones tradicionales del funcionamiento socioemocional, la Escala de Dificultades en la Regulación Emocional y la Prueba de Faux Pas, para determinar efecto significativo debido a la dependencia de METH y el VIH en la cognición social. Entonces, cuantificamos la cognición social utilizando el Monitor de Patrones de comportamiento humano mediante la evaluación del comportamiento social representado por la interacción con objetos novedosos. La dependencia de METH afectó significativamente las funciones socioemocionales y el VIH afectó significativamente las interacciones con los objetos, sin embargo, no se observaron efectos aditivos significativos al usar estos métodos. La relación compleja entre el VIH y la dependencia de METH sugiere que otros factores (i.e., habilidades adaptativas) probablemente regulan los comportamientos relacionados con la cognición social.

The relationship between novelty-seeking traits and behavior: Establishing construct validity for the human Behavioral Pattern Monitor.

Novelty seeking is a tendency to approach new situations, putatively driven by the brain's catecholaminergic system. It is traditionally measured via self-report, but a laboratory-based paradigm, the human Behavioral Pattern Monitor (hBPM), quantifies behavior in a novel environment and has utility in cross-species studies of neuropsychiatric disorders. Our primary aim assessed whether self-reported novelty-seeking traits were associated with novelty-seeking behavior in the hBPM. An existing sample of 106 volunteers were categorized as high vs. low novelty seekers using the Temperament and Character Inventory (TCI). Subjects had been randomized to one dose of amphetamine (10 or 20 mg) or modafinil (200 or 400 mg), allowing us to explore whether a pharmacological catecholamine challenge further enhanced novelty-seeking behavior. High TCI novelty-seekers had more hBPM motor activity and novel object interactions. The exploratory analyses, although limited by low power, suggested that amphetamine and modafinil did not markedly moderate novelty-seeking traits. The hBPM demonstrates construct validity as a lab-based measure of novelty seeking and thus useful in translational studies of neuropsychiatric conditions and treatment options. Further research may illuminate whether a biological predisposition towards higher catecholaminergic activity, combined with the novelty-seeking trait, may increase propensity for risky and addictive behaviors.

Ntrk1 mutation co-segregating with bipolar disorder and inherited kidney disease in a multiplex family causes defects in neuronal growth and depression-like behavior in mice.

Previously, we reported a family in which bipolar disorder (BD) co-segregates with a Mendelian kidney disorder linked to 1q22. The causative renal gene was later identified as MUC1. Genome-wide linkage analysis of BD in the family yielded a peak at 1q22 that encompassed the NTRK1 and MUC1 genes. NTRK1 codes for TrkA (Tropomyosin-related kinase A) which is essential for development of the cholinergic nervous system. Whole genome sequencing of the proband identified a damaging missense mutation, E492K, in NTRK1. Induced pluripotent stem cells were generated from family members, and then differentiated to neural stem cells (NSCs). E492K NSCs had reduced neurite outgrowth. A conditional knock-in mouse line, harboring the point mutation in the brain, showed depression-like behavior in the tail suspension test following challenge by physostigmine, a cholinesterase inhibitor. These results are consistent with the cholinergic hypothesis of depression. They imply that the NTRK1 E492K mutation, impairs cholinergic neurotransmission, and may convey susceptibility to bipolar disorder.

Study of 45 candidate genes suggests CACNG2 may be associated with lithium response in bipolar disorder.

BACKGROUND: Bipolar disorder is a neuropsychiatric disorder that is characterized by fluctuations between manic and depressive phases. Lithium is the original and best mood stabilizing treatment for bipolar disorder. While its mechanism is not well understood, it is believed to have a strong genetic component, as several studies suggest that lithium responsiveness, in bipolar disorder, is heritable. In this study we aimed to identify genetic variants that are associated with lithium responsiveness in bipolar disorder. METHODS: Here we present two cohorts; a retrospective cohort in which patients were surveyed about their response to lithium, and a prospective cohort, in which patients were placed on a lithium monotherapy and monitored for their response to lithium. In both cohorts, patients were stratified into two categories in terms of lithium response; good responders and poor responders. 45 genes were selected based on previous associations with lithium pathways or bipolar disorder and 684 SNPs within these genes were selected to test for association with lithium response. RESULTS: While no single SNP was significant after correcting for multiple comparisons, there were several that were nominally significant (p < 0.05). Of these nominally significant SNPs, the most highly significant SNP in both the prospective and retrospective cohorts were found to be in CACNG2, or Stargazin. The second best association with lithium response was several SNPs in NRG1, a gene that has previously been associated with schizophrenia. CONCLUSIONS: Evidence for the association of lithium response with SNPs in CACNG2 is consistent with previous findings that have identified CACNG2 as associated with both bipolar disorder and lithium responsiveness.