In Vivo Imaging of Translocator Protein in Long-term Cannabis Users

Question Is the expression of 18-kDa translocator protein altered in long-term cannabis users? Findings In this case-control study of 24 long-term cannabis users and 27 non-cannabis-using controls, cannabis users showed higher neuroimmune activation or translocator protein levels compared with controls, with a more prominent implication for those with cannabis use disorder. Greater brain translocator protein levels were associated with chronic stress and anxiety as well as higher circulating C-reactive protein levels. Meaning The finding of higher translocator protein levels in cannabis users is an important step forward in understanding the role of cannabis in vivo in the brain; more complementary preclinical systems are needed to explain the role of cannabinoids and translocator protein in neuroimmune signaling. Importance Cannabis is the most commonly used illicit drug in the world. Cannabinoids have been shown to modulate immune responses; however, the association of cannabis with neuroimmune function has never been investigated in vivo in the human brain. Objective To investigate neuroimmune activation or 18-kDa translocator protein (TSPO) levels in long-term cannabis users, and to evaluate the association of brain TSPO levels with behavioral measures and inflammatory blood biomarkers. Design, Setting, and Participants This cross-sectional study based in Toronto, Ontario, recruited individuals from January 1, 2015, to October 30, 2018. Participants included long-term cannabis users (n = 24) and non-cannabis-using controls (n = 27). Cannabis users were included if they had a positive urine drug screen for only cannabis and if they used cannabis at least 4 times per week for the past 12 months and/or met the criteria for cannabis use disorder. All participants underwent a positron emission tomography scan with [F-18]FEPPA, or fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide. Main Outcomes and Measures Total distribution volume was quantified across regions of interest. Stress and anxiety as well as peripheral measures of inflammatory cytokines and C-reactive protein levels were also measured. Results In total, 24 long-term cannabis users (mean [SD] age, 23.1 [3.8] years; 15 men [63%]) and 27 non-cannabis-using controls (mean [SD] age, 23.6 [4.2] years; 18 women [67%]) were included and completed all study procedures. Compared with the controls, cannabis users had higher [F-18]FEPPA total distribution volume (main group effect: F-1,F-48 = 6.5 [P = .01]; ROI effect: F-1,F-200 = 28.4 [P < .001]; Cohen d = 0.6; 23.3% higher), with a more prominent implication for the cannabis use disorder subgroup (n = 15; main group effect: F-1,F-39 = 8.5 [P = .006]; ROI effect: F-1,F-164 = 19.3 [P < .001]; Cohen d = 0.8; 31.5% higher). Greater TSPO levels in the brain were associated with stress and anxiety and with higher circulating C-reactive protein levels in cannabis users. Conclusions and Relevance The results of this study suggest that TSPO levels in cannabis users, particularly in those with cannabis use disorder, are higher than those in non-cannabis-using controls. The findings emphasize the need for more complementary preclinical systems for a better understanding of the role of cannabinoids and TSPO in neuroimmune signaling. This study conducts in vivo data imaging of the brain of long-term cannabis users and nonusers to examine the association between translocator protein levels, stress and anxiety, and cannabis use behaviors among young adults.