Enhancing Endocannabinoid Control of Stress with Cannabidiol

Abstract

The stress response is a well-defined physiological function activated frequently by life events. However, sometimes the stress response can be inappropriate, excessive, or prolonged; in which case, it can hinder rather than help in coping with the stressor, impair normal functioning, and increase the risk of somatic and mental health disorders. There is a need for a more effective and safe pharmacological treatment that can dampen maladaptive stress responses. The endocannabinoid system is one of the main regulators of the stress response. A basal endocannabinoid tone inhibits the stress response, modulation of this tone permits/curtails an active stress response, and chronic deficiency in the endocannabinoid tone is associated with the pathological complications of chronic stress. Cannabidiol is a safe exogenous cannabinoid enhancer of the endocannabinoid system that could be a useful treatment for stress. There have been seven double-blind placebo controlled clinical trials of CBD for stress on a combined total of 232 participants and one partially controlled study on 120 participants. All showed that CBD was effective in significantly reducing the stress response and was non-inferior to pharmaceutical comparators, when included. The clinical trial results are supported by the established mechanisms of action of CBD (including increased N-arachidonylethanolamine levels) and extensive real-world and preclinical evidence of the effectiveness of CBD for treating stress.

Keywords: AEA; CBD; N-arachidonylethanolamine; cannabidiol; endocannabinoid; hypothalamus–pituitary–adrenal axis; stress.

Figure 1

CB_1/2 signaling in the nervous system. The two main endocannabinoids, AEA and 2-AG, are synthesized in response to neuronal depolarization and/or Ca⁺² influx, via cleavage of membrane phospholipids, such as phosphatidylethanolamine (PE), in the postsynaptic membrane. For AEA, Ca⁺²-dependent N-acyltransferase (NAT) first produces N-arachidonoyl PE (NAPE), which is then hydrolyzed by phospholipase D (NAPE-PLD). For 2-AG, Ca⁺² influx and/or cortisol stimulates phospholipase C (PLC), which hydrolyzes phosphatidylinositol (PI) into diacylglycerol (DAG), which is hydrolyzed by diacylglycerol lipase (DGL). AEA and 2-AG feedback in a retrograde manner to CB_1/2 receptors on presynaptic terminals. CB_1/2 are coupled to G_i/o-proteins that function to inhibit adenylyl cyclase and voltage-gated calcium channels and activate potassium channels, thus, suppressing afferent neurotransmitter release. In the brain, CB_1/2 signaling has a basal tone that depends on AEA production in response to neuronal activity. This tone can be rapidly reduced, by increased hydrolyzation of AEA to arachidonic acid (AA) and ethanolamine (EA) by FAAH that is in the post-synaptic endoplasmic reticulum. The main action of CBD is to competitively inhibit binding of AEA to its aqueous transporter, fatty acid binding protein (FABP), thereby inhibiting the degradation of AEA by FAAH and increasing CB_1/2 receptor signaling tone. Moreover, 2-AG is not degraded by FAAH but by monoacylglycerol lipase (MAGL), which is located near CB_1/2 on the pre-synaptic membrane [15,39].

Figure 2

Endocannabinoid regulation of the stress response. Without a stressor (No Stress) basal AEA tone maintains CB₁ signaling constraint of the stress response and a cool, calm, collected, and happy state. Acute presentation of a stressor (Acute Stress) elevates FAAH hydrolysis of AEA, reducing CB₁ signaling and permitting activation of the stress response [13,15,32,39]. Secretion of cortisol by the stress response provides Negative Feedback by increasing 2-AG production, which increases CB₁ signaling and terminates the stress response [15]. Repeated presentation of the same stressor progressively increases 2-AG levels, possibly by reduced MAGL expression and degradation of 2-AG, which causes progressively higher CB₁ signaling and Habituation to the stress response [4,15]. Chronic Stress causes a downregulation of CB₁ that impairs feedback inhibition and facilitates persistence of the stress response and high cortisol levels, which precipitates or exacerbates illness (complications) [5,15,40].

Figure 3

Cannabidiol (CBD) mechanism of action. The main action of CBD is to increase CB₁ and CB₂ signaling by preventing N-arachidonylethanolamine (AEA) degradation. This constrains the stress response and its manifestations both via its inhibition of the stress response and (independently) inhibition of some manifestations such as the anxiety, neuroinflammation, and GIT dysfunction. For example, CB₁ signaling inhibits stress-associated anxiety by both constraining the stress response and by CB₁ activity on forebrain glutamatergic neurons [41,42,43]. CBD also acts independently of CB₁/CB₂ signaling by increasing serotonergic 5HT_1A signaling, increasing PPARγ signaling and desensitizing TPRV1, which inhibit stress-associated anxiety, neuroinflammation and GIT dysfunction, respectively.