Endocannabinoid cerebrospinal fluid levels in migraine and its relation to symptoms of depression

BackgroundDisruption of the endocannabinoid system has been implicated in both migraine and depression, which are frequently comorbid in patients. Nevertheless, supporting evidence for this hypothesis is limited. Hence, we investigated whether the endocannabinoid system is disrupted in interictal migraine patients and whether confounding factors were of influence.MethodsTo this end, we measured the levels of endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), and the endocannabinoid analogue docosahexaenoylethanolamine (DHEA) in the cerebrospinal fluid (CSF), obtained from 194 individuals with episodic migraine between attacks (97 migraine with aura and 97 migraine without aura individuals) and from 94 healthy volunteers, using micro-liquid chromatography - tandem mass spectrometry (micro-LC-MS/MS). Groups were age- and sex-matched. Timing and processing of sampling was protocolized. Multivariate linear regression analyses for log₁₀-transformed endocannabinoid concentrations were performed to compare groups. Covariates that were included were sex, age, BMI, substance use and depressive symptoms.ResultsNo differences were detected between individuals with migraine with or without aura and healthy controls in the CSF for AEA (p = 0.46, p = 0.08), 2-AG (p = 0.46, p = 0.90) and DHEA (p = 0.58, p = 0.79), respectively. For 2-AG, levels were, however, positively correlated with depressive symptoms (β = 0.053; 95% CI: 0.014 to 0.093, p = 0.008).ConclusionCSF endocannabinoids (AEA, 2-AG, and DHEA) may not serve as effective biomarkers for distinguishing interictal episodic migraine patients from controls. Instead, CSF levels of 2-AG are linked to depressive symptoms, shedding further light on the relevance of endocannabinoids in patients with migraine and depression. This study highlights the intricate nature of the endocannabinoid system concerning episodic migraine and confounding factors.