Genetic characterization of the endocannabinoid system and psychiatric features in patients with migraine and medication overuse headache

Background: The endocannabinoid system (ECS) is one of the key endogenous systems regulating pain. Preclinical and clinical evidence suggests a dysregulation of the ECS in patients with migraine. The present study aimed to characterize the main ECS components in patients with chronic migraine and medication overuse headache (MOH) and episodic migraine (EM) at the gene expression level compared to healthy controls (HC) and to correlate the findings with psychopathological scales. Methods: In this cross-sectional study, consecutive patients with a diagnosis of EM and MOH were enrolled. Fatty acid amide hydrolase (FAAH) was assayed through quantitative enzyme-linked immunosorbent assay kits. The gene expression of ECS components (FAAH, N-arachidonoyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and N-acylethanolamine acid amidase (NAAA) enzymes, cannabinoid (CB) receptors, CB1 and CB2, transient receptor potential vanilloid type 1 (TRPV1) and peroxisome proliferator-activated receptor (PPAR)ɑ receptors was assayed in peripheral blood mononuclear cells through a real-time quantitative PCR. Clinical data including Migraine Disability Assessment (MIDAS) and Headache Impact Test-6 (HIT-6) were collected. Psychopathological status was assessed through the Hamilton Anxiety Rating Scale (HAM-A), the Hamilton Rating Scale for Depression (HAM-D) and the Toronto Alexithymia Scale (TAS-20). Results: The study included 31 patients (15 with EM, 16 with MOH) and 14 HC. The gene expression of FAAH, an enzyme involved in the degradation of the main endocannabinoid, was significantly lower in MOH patients (0.0002 ± 0.0002) than in EM patients (0.0008 ± 0.0006) (p = 0.005). There were no significant differences in gene expression among EM, MOH and HC groups for NAPE-PLD, NAAA, CB1, CB2, TRPV1 and PPARɑ. The levels of FAAH protein expression were significantly higher in MOH (2.9517 ± 2.2006 pg/μg) compared to EM patients (0.9225 ± 0.6878 pg/μg) (p = 0.025). In the clinical group (EM and MOH), we found a significant negative correlation between FAAH gene expression and FAAH enzyme protein (p = 0.014); FAAH gene expression negatively correlated with HIT-6 (p = 0.003) and MIDAS scores (p = 0.048), as well with all psychopathological scales, in more detail with TAS-20 (p = 0.029), HAM-A (p = 0.040) and HAM-D (p = 0.028). Conclusions: FAAH undergoes specific alterations in patients with MOH at gene expression levels, suggesting its potential as a blood biomarker for this condition. FAAH gene expression is possibly related to psychiatric comorbidities in migraine patients.