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

Abstract

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 PARTICIPANTSThis 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 [ 18 F]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. RESULTSIn 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 [ 18 F]FEPPA total distribution volume (main group effect: F 1,48 = 6.5 [P = .01]; ROI effect: F 1,200 = 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 1,39 = 8.5 [P = .006]; ROI effect: F 1,164 = 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 RELEVANCEThe 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.

Microglia imaging in methamphetamine use disorder: a positron emission tomography study with the 18 kDa translocator protein radioligand [F‐18]FEPPA

“…Furthermore, we found no significant difference using an ANCOVA between brain TSPO binding in the small MA smoking (n = 8) and nonsmoking groups (n = 3) and no significant correlation between [F‐18]FEPPA binding and number of cigarettes typically used. A recent study found elevated [F‐18]FEPPA binding in chronic cannabis users 40 ; in our small sampled study, we do not find difference between MA users who used cannabis vs those who did not.…”

“…However, results of a PET study showed no association with cocaine use on brain TSPO binding (using a secondgeneration tracer) in the human. 33 Brody et al 37,38 40 ; in our small sampled study, we do not find difference between MA users who used cannabis vs those who did not.…”

Fatty acid amide hydrolase is lower in young cannabis users

“…A second possibility is that the lower FAAH in CU is a compensatory mechanism to account for a downregulation of anandamide in CU. Alternatively, given that THC has been shown to suppress immune responses in cell models, 44 Boileau et al proposed that CU might exhibit lower FAAH alongside a decrease in microglia activity/density; however, findings from our group do not support this postulation 45 …”

Personality traits in psychosis and psychosis risk linked to TSPO expression: a neuroimmune marker

“…Time-activity curves were extracted for the cerebellum, dorsolateral prefrontal cortex (DLPFC), and medial prefrontal cortex (MPFC) using a validated in-house imaging pipeline (Rusjan et al, 2006). These ROIs were chosen based on previous literature reporting relevant alterations in TSPO and on their established importance to schizophrenia-spectrum disorders (Da Silva, Hafizi, Rusjan et al, 2019;Da Silva, Hafizi, Watts et al, 2019;Hafizi et al, 2018). All regions of interest were delineated using a proton density MRI in each participant.…”