Reducing endocannabinoid signaling in humans is usually sufficient to produce depressive symptoms [119,120]. As an example, the CB1 receptor antagonist/inverse agonist, rimonabant, has been used as a treatment for obesity in humans. However, its administration led to severe symptoms of anxiety and depression in a significant proportion of individuals [121,122], which resulted in the removal of rimonabant from the market [119]. Another line of evidence comes from genetic studies that showed that some genetic polymorphisms in CB1R and CB2R may be associated with major depression and bipolar disorder, as reviewed in [119]. Some of these genetic studies also showed that single nucleotide polymorphisms (SNPs) in the CB1R can increase the vulnerability to the development of a depressive episode following exposure to life stress [123], and confer an increased risk of antidepressant resistance [124]. It has also been found that SNPs in the CB1 receptor gene can result in blunted neuronal activation in response to rewarding stimuli [124]. A significant increase in the frequency of these CB1 receptor SNPs in patients with mood disorders was also observed [118].
