Cannabinoids in stress and anxiety

    August 31, 2022 4 min read

    Cannabinoids in stress and anxiety

    The general public is convinced that cannabinoids, and CBD in particular, are effective against ‘stress’ and ‘anxiety’. Studies in animal models and with healthy human volunteers do suggest an anxiolytic-like effect with CBD, and CBD has been shown to reduce anxiety in patients with diagnosed social anxiety disorder. Cannabinoid signaling almost certainly functions in reducing anxiety, but evidence for how well, and why, it appears to work is inconsistent and at times conflicting. 

    The reason for this is that the physiological stress response (like stress stimuli themselves) is multifactorial. In experiments, for example, the effects of genetic manipulations, of cannabinoid synthesis or reuptake inhibition, and of local brain treatments with cannabinoid ligands, all function in an interrelated manner. Cannabinoids affect anxiety is brain area-specific, moreover, which by itself can explain the inconsistency of findings with systemically injected ligands. Environmental conditions, too, have a large impact on effects in all experimental settings, which means that endocannabinoid signaling affects coping with external challenges in a manner at least as important as unconditionally decreasing anxiety. The nuanced relationship between cannabinoid signaling, anxiety, and coping styles is for the moment understudied, though it does hold promising therapeutic implications in time. Evidence from the comparatively few human studies of a putative anxiolytic role for CBD specifically is limited, furthermore, to acute dosing. 

    At the moment it is fair to say that CBD seems to be a promising drug for the treatment of diagnosed panic disorder. This opens the way to further trials to clarify the mechanism of action, and to establish safe and ideal therapeutic dosages. It is also safe to say that experimental intracisternal administration of cannabidiol in animals – that is, brain injections, not tinctures taken orally – have appeared to attenuate autonomic responses to stressors. 

    More broadly, that the endocannabinoid system, part of the mammalian cell-signaling network, is a reasonable target in general for anxiety, and trauma, and stress-related disorders is beyond doubt. On this the literature is clear. 


    Possible mechanisms of action

    It is in mechanisms of action, and the complex cascade of possible pathways, that deep study is just beginning. 

    At the most basic level, suppression of amygdalar endocannabinoid signaling activates the hypothalamic-pituitary-adrenal stress axis. It may be that a therapeutic tactic against this is to augment the on-demand recruitment of AEA and 2-AG, either by inhibiting the hydrolyzing enzymes, fatty acid amide hydrolyze (FAAH) and monoacylglycerol lipase (MAGL), or by targeted inhibition of cyclooxygenase-2 (COX-2). Another might be enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, which has produced anxiolytic effects under conditions of high environmental aversiveness in rats. Alternatively, blocking the activation of TRPV1 receptors, possibly in concert with the augmentation of AEA, could be an effective route to alleviating excessive anxiety and promoting stress-coping. It simply also may be that constituents of cannabis, like CBD, mediate anxiety and stress-related disorders by neural mechanisms that are independent of endocannabinoid signaling. 

    It is clear that the CB1 receptor specifically plays a modulatory role in the General Adaptation Syndrome. Genetic deletion of monoacylglycerol lipase impairs CB1 signaling and moderates anxiety-like behavior. Confusingly, CB1 and cholecystokinin (CCK2) receptors modulate, in an opposing way, electrically evoked [3H]GABA efflux from rat cerebral cortex cell cultures. That makes for possible relevance of cortical GABA transmission and anxiety. CB1 receptor signaling is certainly stress responsive, and maintaining robust action at this site provides resilience against the development of stress-related pathologies. Inhibition of endocannabinoid degradation seems to do this, in a temporarily and spatially restricted manner. Likewise, pharmacological blockade or genetic deletion of CB1 receptors, in turn, exerts anxiogenic-like effects, and even extinguishes aversive memories. Interestingly, pharmacological blockade of the transient receptor potential vanilloid type-1 (TRPV1) channel, which can be activated by anandamide as well, has diametrically opposite consequences. 

    It is clear that the CB2 receptor also has a role in stress-response, possibly in synergy with CB1. In a study of subchronic nicotine administration in stressed mice, both sites clearly functioned together, reversing the antidepressive effects of subchronic nicotine administration; nicotine, in an ineffective dose, co-administered with CB2 receptor ligands, also improved cognition (itself an integral part of stress-response). Other work has shown that anxious behavior induces elevated hippocampal CB2 receptor gene expression. 

    Previous stress experience complicates the experimental landscape. This has been shown with facilitation of endocannabinoid effects in the ventral hippocampus, which is related to anxiety behavior and has a high expression of CB1 receptors. Animals injected with AM404, an uptake inhibitor of anandamide, showed an anxiogenic-like effect if they were non-stressed, but decreased anxiety if they were stressed. Anxiolytic-like effects of AM404 were also observed in the Vogel conflict test, another model of anxiety involving previous exposure to stressful situations. 


    Toward justifiable therapeutic strategies

    Aligning the apparent anxiolytic effects of particular cannabinoids with their activity at the molecular level is the real task at hand. 

    Low doses of anandamide (arachidonoyl ethanolamide) and 2-arachidonoyl glycerol tend to induce anxiolytic-like effects, whereas high doses often cause the opposite. These probably subserve separate physiological roles, but some sort of pharmacological and functional redundancy also exists. Increasing either of them produces anti-anxiety effects under stressful conditions, but these effects do not occur if both are increased together. At stake is probably fatty acid amide hydrolase (FAAH) inhibition. If this is inhibited by a compound known as URB597, animals show reduced flight behavior and enhanced tolerance to external stressors. This demonstrates the general consequences of pharmacological enhancement of anandamide, but not 2-AG, signaling. 

    For CBD’s method of working, discoveries are just beginning. The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors in the dorsolateral periaqueductal gray. Response is reassuringly dose-dependent. It is also preventable by WAY100635, a 5HT1A receptor antagonist, but not by AM251, an antagonist of CB1 receptors. 



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    The foregoing is a report on trends and developments in the cannabinoid industry. No product described herein is intended to diagnose, treat, cure or prevent any disease or syndrome.