Cannabinoids in depression

by Duncan Fisher

September 06, 2022 - 3 min read

Pre-clinical studies have demonstrated that both agonists and antagonists of endocannabinoid receptors act similarly to antidepressants. The endocannabinoid system is part of the body’s neural cell-signaling network. Animal experiments and clinical studies have also demonstrated that impairment of the ECS pathway is present in depression models and in human patients. Responses to the cannabinoid agents are relatively fast, and most probably involve noradrenergic, serotoninergic, and glutamatergic release, and modulate the hypothalamic-pituitary-adrenal axis. Enhancement of endocannabinoid signaling could therefore be a novel therapeutic avenue for the treatment of depression. To this aim there have been proposed cannabinoid receptor agonists or synthetic molecules that inhibit endocannabinoid degradation. The latter ones do not induce the psychotropic side effects by direct CB1 receptor activation, but elicit antidepressant-like effects by enhancing the monoaminergic neurotransmission, that promotes hippocampal neurogenesis and normalizes the hyperactivity of the HPA, as the standard antidepressants do.

That CB1 is involved in the possible mechanisms of action is clear. CB1-cannabinoid receptors are known to be involved in the modulation of non-synaptic serotonin release from the rat hippocampus. CB1 cannabinoid receptor ligands also augment the antidepressant-like activity of the biometals magnesium and zinc. An autopsy study has describing elevated levels of CB1 receptor activity in the prefrontal cortex in both depression and alcoholism. Pharmacological activation of cannabinoid receptor 1, finally, or blockade of αCaMKII has successfully restored long-term synaptic depression in the lateral habenula in one animal model of depression. Yet decreased CB1 receptor expression is also likely associated with the development of post stroke depression. Antidepressants given chronically have elevated CB1 receptor density in the cortical structures and hippocampal areas, while a decrease of CB1 receptor density has been observed in the striatum after IMI and ESC treatment. CB1 receptor expression decreases in the dorsal striatum after chronic administration of IMI and ESC, and rises in the hippocampus after chronic ESC and TIA treatment. 

An increase in CB2 receptor expression has also been observed in the cortical structures and hippocampus after chronic administration of ESC and TIA, while a decrease in this expression has been noted in the striatum and cerebellum after chronic IMI treatment. Interaction between CB2 gene expression and stressors increases the risk of depression-like behaviors that may be linked with neuro-immune crosstalk.

Like CB1 agonists, fatty acid amide hdyrolase (FAAH) inhibitors share mechanisms with other antidepressants: the ability to enhance central serotonergic and noradrenergic transmission and promote neurogenesis in the hippocampus. FAAH inhibitors, compared with direct CB1 agonists, exhibit distinct pharmacological properties that quell adverse cannabinoid effects and widen the therapeutic window. One dual inhibitor of the FAAH and TRPV1 channels shows a dose-dependent effect on depression-like behaviour in rats, and dysfunction in fatty acid amide hydrolase is also associated with depressive-like behavior in Wistar Kyoto rats. This has intriguing clinical possibilities. Most depressive-like behaviors triggered by adolescent Δ9-tetrahydrocannabinol exposure can be rescued by manipulating endocannabinoid signaling in adulthood with the anandamide-inactivating enzyme FAAH inhibitor, URB597. However, the molecular mechanisms underlying URB597's antidepressant-like properties remain to be established.

The dietary supplement N-Palmitoylethanolamide (PEA), a fatty acid amide belonging to the endocannabinoid system, targets the peroxisome proliferator-activated receptor-alpha (PPAR-α), and also the endocannabinoid system, binding the G-protein-coupled receptor 55, a non-CB1/CB2 cannabinoid receptor, and as well the CB1/CB2 receptors, though with a weak affinity. Preclinical studies have shown antidepressant activity of PEA in animal paradigms of depression and of depression associated with neuropathic pain and traumatic brain injury. In the context of translational medicine, PEA is increased in stress conditions, and a randomized, double-blind study in depressed patients has indicated a rapid antidepressant action of PEA when associated with citalopram.

Toward a therapeutic strategy

Activation of cannabinoid receptors has elicited antidepressant-like effects in a mouse model of social isolation stress. Behavioral abnormality after this was then mitigated by the synthetic cannabinoid WIN55, 212-2.

Cannabidiol (CBD) as well exhibits an anti-anxiety and antidepressant effects in animal models. Experiments with CBD demonstrate non-activation of neuroreceptors CB1 and CB2. CBD may attenuate motivational dysfunction through activation of the 5-HT1A receptor and elevations in endocannabinoid tone. Given the multitude of molecular targets for CBD, there is substantial potential for additional beneficial effects through actions at other receptors.


DiolPure products contain PureForm CBD™ transformed from aromatic terpenes for pharmaceutical-grade purity. PureForm CBD™ is bioidentical to CBD extracted from hemp and cannabis, but free of any residual cannabinoids like THC or impurities or chemicals that can associate with traditional plant-derived production processes. 

The foregoing is a report on trends and developments in cannabinoid industry research. No product description herein is intended as a recommendation for diagnosis, treatment, cure or prevention of any disease or syndrome. 

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