The possible medicinal use of cannabinoids for chronic diseases emphasizes the need to understand the long-term effects of these compounds on the central nervous system. We provide a quantitative synthesis of empirical research pertaining to the non-acute (residual) effects of cannabis on the neurocognitive performance of adult human subjects. Out of 1,014 studies retrieved using a thorough search strategy, only 11 studies met essential a priori inclusion criteria, providing data for a total of 623 cannabis users and 409 non- or minimal users. Neuropsychological results were grouped into 8 ability domains, and effect sizes were calculated by domain for each study individually, and combined for the full set of studies. Using slightly liberalized criteria, an additional four studies were included in a second analysis, bringing the total number of subjects to 1,188 (i.e., 704 cannabis users and 484 non-users). With the exception of both the learning and forgetting domains, effect size confidence intervals for the remaining 6 domains included zero, suggesting a lack of effect. Few studies on the non-acute neurocognitive effects of cannabis meet current research standards; nevertheless, our results indicate that there might be decrements in the ability to learn and remember new information in chronic users, whereas other cognitive abilities are unaffected. However, from a neurocognitive standpoint, the small magnitude of these effect sizes suggests that if cannabis compounds are found to have therapeutic value, they may have an acceptable margin of safety under the more limited conditions of exposure that would likely obtain in a medical setting. (JINS, 2003, 9, 679–689.)

Objective: While HIV-associated neurocognitive disorders (HAND) remain prevalent despite combination antiretroviral therapy (CART), the clinical relevance of asymptomatic neurocognitive impairment (ANI), the most common HAND diagnosis, remains unclear. We investigated whether HIV-infected persons with ANI were more likely than those who were neurocognitively normal (NCN) to experience a decline in everyday functioning (symptomatic decline). Methods: A total of 347 human participants from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort were NCN (n = 226) or had ANI (n = 121) at baseline. Neurocognitive assessments occurred approximately every 6 months, with median (interquartile range) follow-up of 45.2 (28.7–63.7) months. Symptomatic decline was based on self-report (SR) or objective, performance-based (PB) problems in everyday functioning. Proportional hazards modeling was used to generate risk ratios for progression to symptomatic HAND after adjusting for baseline and time-dependent covariates, including CD4+ T-lymphocyte count (CD4), virologic suppression, CART, and mood. Results: The ANI group had a shorter time to symptomatic HAND than the NCN after adjusting for baseline predictors: adjusted risk ratios for symptomatic HAND were 2.0 (confidence interval [CI] 1.1–3.6; p = 0.02) for SR, 5.8 (CI 3.2–10.7; p < 0.0001) for PB, and 3.2 (CI 2.0–5.0; p < 0.0001) for either SR or PB. Current CD4 and depression were significant time-dependent covariates, but antiretroviral regimen, virologic suppression, and substance abuse or dependence were not. Conclusions: This longitudinal study demonstrates that ANI conveys a 2-fold to 6-fold increase in risk for earlier development of symptomatic HAND, supporting the prognostic value of the ANI diagnosis in clinical settings. Identifying those at highest risk for symptomatic decline may offer an opportunity to modify treatment to delay progression.

Background. Elevated plasma levels of interleukin (IL)-6, C-reactive protein (CRP), and D-dimer belong to the biological alterations of the “frailty syndrome,” defining increased vulnerability for diseases and mortality with aging. We hypothesized that, compatible with premature frailty, chronic stress and age are related in predicting inflammation and coagulation activity in Alzheimer caregivers. Methods. Plasma IL-6, CRP, and D-dimer levels were measured in 170 individuals (mean age 73 ± 9 years; 116 caregivers, 54 noncaregiving controls). Demographic factors, diseases, drugs, and lifestyle variables potentially affecting inflammation and coagulation were obtained by history and adjusted for as covariates in statistical analyses. Results. Caregivers had higher mean levels of IL-6 (1.38 ± 1.42 vs 1.00 ± 0.92 pg/mL, p =.032) and of D-dimer (723 ± 530 vs 471 ± 211 ng/mL, p <.001) than controls had. CRP levels were similar between groups (p =.44). The relationship between caregiver status and D-dimer was independent of covariates (p =.037) but affected by role overload. Age accounted for much of the relationship with IL-6. After controlling for covariates, the interaction between caregiver status and age was significant for D-dimer (β =.20, p =.029) and of borderline significance for IL-6 (β =.17, p =.090). Post hoc regression analyses indicated that, among caregivers, age was significantly correlated with both D-dimer (β =.50, p <.001) and IL-6 (β =.38, p =.001). Among controls, however, no significant relationship was observed between age and either D-dimer or IL-6. Conclusions. The interaction between caregiving status and age for D-dimer and IL-6 suggests the possibility that older caregivers could be at risk of a more rapid transition to the frailty syndrome and clinical manifestations of cardiovascular diseases.

Background: Elderly individuals who provide care to a spouse suffering from dementia bear an increased risk of coronary heart disease (CHD). Objective: To test the hypothesis that the Framingham CHD Risk Score would be higher in dementia caregivers relative to non-caregiving controls. Methods: We investigated 64 caregivers providing in-home care for their spouse with Alzheimer’s disease and 41 gender-matched non-caregiving controls. All subjects (mean age 70 ± 8 years, 75% women, 93% Caucasian) had a negative history of CHD and cerebrovascular disease. The original Framingham CHD Risk Score was computed adding up categorical scores for age, blood lipids, blood pressure, diabetes, and smoking with adjustment made for sex. Results: The average CHD risk score was higher in caregivers than in controls even when co-varying for socioeconomic status, health habits, medication, and psychological distress (8.0 ± 2.9 vs. 6.3 ± 3.0 points, p = 0.013). The difference showed a medium effect size (Cohen’s d = 0.57). A relatively higher blood pressure in caregivers than in controls made the greatest contribution to this difference. The probability (area under the receiver operator curve) that a randomly selected caregiver had a greater CHD risk score than a randomly selected non-caregiver was 65.5%. Conclusions: Based on the Framingham CHD Risk Score, the potential to develop overt CHD in the following 10 years was predicted to be greater in dementia caregivers than in non-caregiving controls. The magnitude of the difference in the CHD risk between caregivers and controls appears to be clinically relevant. Clinicians may want to monitor caregiving status as a routine part of standard evaluation of their elderly patients’ cardiovascular risk.

Approximately half of those infected with the human immunodeficiency virus (HIV) exhibit cognitive impairment, which has been related to cerebral white mat