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One of the main effects of the endocannabinoid system in the brain is stress adaptation with presynaptic endocannabinoid receptor 1 ( CB1  receptors) playing a major role. In the present study, we investigated whether the effect of the  CB1  receptor coding   CNR1   gene on migraine and its symptoms is conditional on life stress. In a cross‐sectional European population ( n  = 2426), recruited from Manchester and Budapest, we used the  ID ‐Migraine questionnaire for migraine screening, the Life Threatening Experiences questionnaire to measure recent negative life events ( RLE ), and covered the   CNR1   gene with 11  SNPs . The main genetic effects and the   CNR1   ×  RLE  interaction with age and sex as covariates were tested. None of the  SNPs  showed main genetic effects on possible migraine or its symptoms, but 5  SNPs  showed nominally significant interaction with  RLE  on headache with nausea using logistic regression models. The effect of rs806366 remained significant after correction for multiple testing and replicated in the subpopulations. This effect was independent from depression‐ and anxiety‐related phenotypes. In addition, a Bayesian systems‐based analysis demonstrated that in the development of headache with nausea all  SNPs  were more relevant with higher  a posteriori  probability in those who experienced recent life stress. In summary, the   CNR1   gene in interaction with life stress increased the risk of headache with nausea suggesting a specific pathological mechanism to develop migraine, and indicating that a subgroup of migraine patients, who suffer from life stress triggered migraine with frequent nausea, may benefit from therapies that increase the endocannabinoid tone.

Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress