The Contribution of Baseline Circulating Endocannabinoids to Individual Differences in Human Pain Sensitivity: A Quantitative Sensory Testing Study

The endocannabinoid (eCB) system—comprising cannabinoid receptors, eCBs (anandamide— AEA, 2-arachidonoylglycerol—2-AG) and related N -acylethanolamines (NAEs; N- palmitoylethanolamide—PEA, and N- oleoylethanolamide—OEA), and metabolizing enzymes (e.g., fatty acid amide hydrolase; FAAH)—modulates nociceptive circuits in rodents. In humans, the FAAH C385A polymorphism is associated with reduced pain sensitivity, suggesting eCB tone influences individual pain differences, but this has yet to be tested. Here, we determined whether the eCB system is associated with somatosensory and pain sensitivity measured with quantitative sensory testing (QST) in 91 healthy participants (39 males, 52 females). We tested three hypotheses: (1) FAAH C385A polymorphism, cannabis use, and sex affect serum eCB/NAE concentrations; (2) FAAH C385A carriers show altered pain sensitivity versus non-carriers; and (3) baseline serum eCB/NAE concentrations are associated with QST measures. eCB/NAE concentrations were not statistically different based on sex ( p > .05), based on FAAH genotype ( p > .05), and based on cannabis use ( p > .05). To address collinearity of AEA, OEA and PEA in linear regression analyses, we performed a factor analysis with principal components analysis, which identified a single component of FAAH substrates. Linear regressions found that FAAH genotype did not affect QST measures and that baseline 2-AG and FAAH substrate concentrations were not associated with QST measures, except pressure pain thresholds (PPT; p = 0.003), which were associated with AEA and OEA. Baseline eCB/NAE levels may not be a global predictor of QST somatosensory and pain tests in healthy adult humans; nonetheless, circulating FAAH substrate levels were associated with PPT.