The role of the eCBS in humans is beginning to garner considerable interest. Congruent with the preclinical observation that CB1 deficient rodents exhibit melancholic features21, and remarkably consistent with our findings, a study of depressed patients found that those with the rs1049353 AA genotype were more likely to respond well to antidepressant treatment22. Relatedly, GG individuals appeared resistant to treatment, particularly if they were female and had melancholic depression. Another study identified 2.46 increased odds of patients with MDD carrying the A allele65. Additionally, a study of FAAH (fatty acid amide hydrolase, encoding the enzyme involved in hydrolysis of anandamide, and also a component of the eCBS) and reward-related human brain function noted that 385A (reduced enzymatic activity) carriers show decreased threat-related amygdala reactivity and increased reward-related reactivity in the ventral striatum66 indicating its putative role in stress adaptation. One prior study has also explored the interaction between stress and CNR1 in the etiology of mood-related conditions - Juhasz et al23 found that a CNR1 haplotype, including rs1049353, was associated with neuroticism, agreeableness, and depressive symptoms. Exposure to recent negative
