4 CHAPTER 4 76 Abstract Disruption of the endocannabinoid system may play a role in both migraine and depression, two conditions that are often comorbid. However, the evidence for this is limited. Here we measured the levels of endocannabinoids (eCBs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the endocannabinoid analogue docosahexaenoylethanolamine (DHEA) in the cerebrospinal fluid (CSF) of n = 194 individuals with episodic migraine between attacks (n = 97 migraine with aura and n = 97 migraine without aura) and n = 94 healthy volunteers, using micro-liquid chromatography – tandem mass spectrometry (micro-LC-MS/MS). Groups were age- and sexmatched. Timing and processing of sampling was protocolized. Multivariate linear regression analyses for log10-transformed eCB concentrations were performed to compare groups. Covariates that were included were sex, age, BMI, alcohol and cigarette consumption and lifetime depression. No differences were detected between individuals with migraine with or without aura and healthy controls in the CSF for AEA (P = 0.46, P = 0.07), 2-AG (P = 0.40, P = 1.00) and DHEA (P = 0.65, P = 0.79), respectively. The covariates sex, smoking, age, and BMI had an effect on various eCBs. For 2-AG, levels were positively correlated with lifetime depression (β = 0.060; 95% CI: 0.020 to 0.10, P = 0.003). CSF endocannabinoid 2-AG is associated with depression, but CSF endocannabinoids seem not to be useful biomarkers to differentiate interictal migraine individuals from controls. This study emphasizes the complexity of the endocannabinoid system in relation to migraine and depression. KEYWORDS: Migraine, depression, cerebrospinal fluid, endocannabinoids, biomarker
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