There is ample evidence in animals for a role of the ECS in depression with CB1 knockout mire developing anhedonia and impaired emotional reactions to stress. In other studies in rats, low doses of CB1 agonist were shown to have antidepressant effects. These effects were accompanied by increases in serotonergic nerve activity in the dorsal raphe nucleus. These findings in mice and rats are consistent with human trials of rimonabant, a CB1 antagonist that was studied as a weight loss drug. Repetitive transcranial magnetic stimulation (rTMS) appears to result in higher CB1 expression in the brain, with increased cell proliferation and increased brain-derived neurotrophic factor, an important nerve growth factor important for long-term memory. The beneficial effects of rTMS were blocked by CB1 receptor blockers. In humans, low serum levels of 2-AG have also been noted in the blood of women with depression, and lower levels were correlated with longer duration of the episode. Those same women treated with ECT saw increased endocannabinoid levels in addition to improved symptoms. A SNP in the CB1 receptor gene that resulted in lower expression of the gene placed carriers at great risk for depression and were less likely to respond to treatment, especially following trauma. The CB2 receptor polymorphism R63Q was associated with increased anxious and depressive phenotype risk in children exposed to trauma. Recent findings of the linkage between depression and chronic inflammatory conditions provides a potential clue to how this occurs. Disruption of the hypothalamic-pituitary -adrenal axis is an important feature of MDD. CB1 activation in the prefrontal cortex is necessary for termination of the stress response. Given the significant association between many polymorphisms and MDD, as well as the subjective antidepressant effects experienced by cannabis users, there can be no doubt that a significant proportion of MDD is due to endocannabinoid deficiency. Experimental models have long shown a biphasic effect of the ECS on anxiety symptoms. With lower amounts of CB1 activation, anxiety symptoms are decreased, while higher doses sometimes increased it. Functioning as a feedback inhibitor, ECS activation on glutamatergic neurons decreases anxiety symptoms by inhibiting anxiogenic glutamatergic nerve transmission. Activation of the ECS on GABAergic neurons causes anxiety by inhibiting anxiolytic GABAergic nerve transmission. TRPV1 receptors colocate with CB1 receptors in the periaqueductal gray matter. TRPV1 receptors have an opposing intracellular effect on calcium to CB1 receptor. At low doses of their common ligand, AEA, CB1 activation dominates and the result is anxiolysis. At higher concentrations, TRPV1 dominates and panic ensues. Panic disorder in human has also been linked to polymorphisms of CB1 gene, specifically rs1049353 and rs806368 polymorphisms. Connections between the amygdala and dorsal anterior cingulate gyrus are associated with anxiety, as is a connection between the amygdala and the hippocampus. Increased levels of 2-AG decreased both connections via decrease in glutamate release. ECS’s role in maintaining serotonin levels also prevents anxiety. High cannabinoid levels causing anxiety, CB1 receptor is also necessary to transition from reactive, phasic fear responses to sustained anxious states. A human polymorphism in CB2 gene that decreases its function was also associated with anxiety. Some anxiety conditions may be due to a simple endocannabinoid deficiency, but given the complexity of the regulation of anxiety by the ECS, many more anxiety conditions are the result of more mixed or localized endocannabinoid system dysfunction. The reward system begins with the ventral tegmental area (VTA), a collection of neurons in the midbrain and A10 dopaminergic neurons that project to the nucleus accumbens, part of the basal ganglia. Both regions contain CB1 receptors. CB1 receptor activation in the VTA increases both tonic and phasic firing. Tonic firing determines motivation to the reward, and phasic bursts establish long-term memories of the reward. Here, the ECS functions in a feedforward manner with more neuron activity leading to more 2-AG production. CB1 receptor activity may be balanced by the presence of CB2 receptor in VTA dopamine neurons. Activation of these receptors in the nucleus accumbens decreased dopamine release in response to cocaine in mouse studies. Polymorphisms that increase ECS have been linked to ETOH and nicotine addiction. This raises the possibility that states of endocannabinoid excess could lead to increased risk of dependence. Alterations in endocannabinoid function during acute psychosis have been noted, specifically increased CB1 activation and decreased CB2 activity as well. Increased levels of dopamine are associated with psychosis, and CB1 activation increases this in the mesolimbic areas of the brain while CB2 decreases it. Patients with higher ECS tone are at higher risk of psychosis, and a large meta-analysis has also shown that increasing doses of cannabis use are associated with greater risk of psychosis. There is also significant evidence of dysregulation of the ECS in schizophrenia. AEA levels were also found to be significantly elevated in the CSF of schizophrenic patients with their first episode of psychosis. Higher levels of AEA were actually protective against psychosis, though, indicating a potential compensatory mechanism in the body rather than a causal effect. It is possible that the excessive ECS tone seen in CSF of schizophrenics may exacerbate or cause some of the negative systems seen in the disease as well, including poor executive function, attention, and working memory.