Effect of Cannabis Use on Synaptic Density in Older Adults

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PROJECT SUMMARY AND ABSTRACT Background: This new R21 application is to examine the effects of cannabis use on in vivo hippocampal synaptic density and cognition among older adults (in response to NOSI (NOT-DA-20-014): “Cannabis, Prescription Opioid, or Prescription Benzodiazepine Drug Use Among Older Adults”). Cannabis is one of the most commonly and widely used illicit drugs; cannabis use is increasing among men and women older than 55 years, and older adults (age>50yrs) represent the fastest growing cannabis-using age group; the legalization of “medical” and recreational cannabis use continues to spread globally; the potency of cannabis has been steadily increasing, and the rates of cannabis use and cannabis use disorder (CUD) are increasing. Therefore, it is important to understand the consequences of chronic cannabis exposure on brain structure and function in older adults. Contrary to studies in adolescents and young adults, in animal studies, administration of cannabinoids to older adult rodents has been shown to result in increased hippocampal synaptic density and improved cognitive function. It is now possible to examine synaptic density in vivo using [11C]UCB-J, a positron emission tomography (PET) tracer with high specificity for synaptic vesicle protein SV2A. We recently showed that in young adults with cannabis use disorder (CUD), in vivo hippocampal synaptic vesicle density, as measured by [11C] UCB-J binding (BPND), was ~10% lower than healthy controls. Additionally, young adult CUD participants performed worse on a hippocampal verbal memory task, and verbal memory performance correlated with hippocampal [11C]UCB-J binding. However, whether cannabis-using older adults have altered in vivo hippocampal synaptic density has not been examined to-date. The purpose of this study is to compare in vivo hippocampal synaptic vesicle density in cannabis-using older adults, and to relate changes in in vivo hippocampal synaptic density to hippocampal function (verbal and spatial memory). Hypotheses: Cannabis-using older adults (age>50yrs) will demonstrate increased hippocampal [11C]UCB- J binding (BPND) compared to age-, gender-, BMI-, IQ-matched healthy controls. Furthermore, this increase in [11C]UCB-J binding will be associated with improved hippocampal function (verbal and spatial memory). Methods: We will compare in vivo hippocampal synaptic density in cannabis-using older adults (age >50yrs, first initiation of cannabis use after age 40yrs) using [11C]UCB-J PET and the High Resolution Research Tomograph and age-, gender-, BMI-, IQ-matched healthy controls (HCs) with due consideration for sex as a biological variable. The relationship between hippocampal [11C]UCB-J binding, verbal memory, and measures of cannabis exposure (age of initiation of use and lifetime exposure) will be explored. Impact: This is the first study, to our knowledge, to examine the effects of cannabis use on in vivo hippocampal synaptic density in older adults.