4 CHAPTER 4 88 affected the stability of the compounds studied, even though they were stored at the recommended -80°C.38 However, only minor changes of oxylipins were observed after prolonged storage at -80°C of blood samples and the metabolome and lipidome of CSF were found to be stable for longer periods.38, 39 Our study has several strengths. First, we studied and compared CSF from a uniquely large group of people with migraine and controls, who were carefully matched for major confounding factors such as sex, age, and timing of sampling. Moreover, unlike other CSF studies, control samples were collected from people who were truly healthy and had not undergone a lumbar punction because of neurological symptoms and almost all had no first-degree relatives with migraine.40 Second, when investigating a putative role of eCBs in disease, it is crucial to use standardized protocols and to correct the statistical model for possible confounders such as BMI, sex, age, weekly alcohol consumption, daily cigarettes use,41-46 and most importantly, lifetime depression,25, 27, 47-49 which is an established comorbid condition in migraine. Although people with major depression were excluded in our study, we found a positive correlation between 2-AG and lifetime depression as screened with validated tools (HADS-D and CESD) for depressive symptomatology. Previous research on the role of AEA and 2-AG in depression has been conducted primarily in individuals with major depressive disorder (MDD).27, 47, 48 The hypothalamic–pituitary–adrenal (HPA) -axis, neurogenesis and neuroinflammation have all been implicated in the etiology of MDD,50 and all are dependent on proper functioning of the endocannabinoid system,25 suggesting a crucial role for the endocannabinoid system in MDD. Given the increased risk of depression in migraine, it is important to realize that depressive symptoms may have a significant effect on eCB levels, even when MDD has been ruled out.The association between migraine and eCBs may therefore depend on depressive symptomatology rather than on migraine itself. Future studies should therefore take depressive symptomology into account when studying the role of the endocannabinoid system in migraine. In conclusion, CSF endocannabinoid 2-AG levels are 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.
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