“With a lifetime prevalence of up to 25% anxiety disorders are among the most frequently occurring psychiatric disorders. The etiology of anxiety is considered to be multifactorial with an interaction of neurobiological, psychological and environmental factors. With regard to neurobiological factors, several neurochemical systems and neuroanatomical circuits have been discussed to be involved. In particular, anxiety might be a result of insufficient inhibitory control, pointing towards a major role of the gamma-amino-butyric acid (GABA) system in these disorders. Preclinical and clinical studies discuss a decreased GABAergic inhibition in anxiety and patients with anxiety disorders. In view of these findings it is intriguing that benzodiazepines, which currently represent the most potent and powerful anxiolytic agents, act through an enhancement of GABAergic inhibition targeting the GABAA receptor. Thus, it has been suggested that the GABAergic system might represent a promising future target for new pharmacologic strategies for the treatment of anxiety. Closely linked to the GABAergic system is the endocannabinoid system, which might also play an important role in this group of disorders. The endocannabinoid system has particularly been involved in extinction learning, suggesting a key role of this system in the process of fear extinction. In this paper, both the GABAergic and the endocannabinoid system will be reviewed with regard to their role in anxiety and anxiety disorders in humans with particular attention to findings from genetic and neuroimaging studies. Moreover, both systems will be discussed as potential therapeutic targets.”
Tag Archives: endocannabinoid system
Endocannabinoid system dysfunction in mood and related disorders.
“The endocannabinoid (EC) system is widely distributed throughout the brain and modulates many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. This article examines the therapeutic potential of cannabinoids in psychiatric disorders.
We propose (hypothesize) that the EC system, which is homoeostatic in cortical excitation and inhibition, is dysfunctional in mood and related disorders. Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) variously combine antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions, suggesting a therapeutic potential in mood and related disorders. Currently, cannabinoids find a role in pain control. Post mortem and other studies report EC system abnormalities in depression, schizophrenia and suicide. Abnormalities in the cannabinoid-1 receptor (CNR1) gene that codes for cannabinoid-1 (CB1) receptors are reported in psychiatric disorders. However, efficacy trials of cannabinoids in psychiatric disorders are limited but offer some encouragement.
CONCLUSION:
Research is needed to elucidate the role of the EC system in psychiatric disorders and for clinical trials with THC, CBD and synthetic cannabinoids to assess their therapeutic potential.”
Expression pattern of the cannabinoid receptor genes in the frontal cortex of mood disorder patients and mice selectively bred for high and low fear.
“Although the endocannabinoid system (ECS) has been implicated in brain development and various psychiatric disorders, precise mechanisms of the ECS on mood and anxiety disorders remain unclear. Here, we have investigated developmental and disease-related expression pattern of the cannabinoid receptor 1 (CB1) and the cannabinoid receptor 2 (CB2) genes in the dorsolateral prefrontal cortex (PFC) of humans. Using mice selectively bred for high and low fear, we further investigated potential association between fear memory and the cannabinoid receptor expression in the brain…
These results suggest that the CB1 in the PFC may play a significant role in regulating mood and anxiety symptoms. Our study demonstrates the advantage of utilizing data from postmortem brain tissue and a mouse model of fear to enhance our understanding of the role of the cannabinoid receptors in mood and anxiety disorders.”
Endocannabinoid system and mood disorders: Priming a target for new therapies.
“The endocannabinoid system (ECS), comprising two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana’s psychoactive principle ∆(9)-tetrahydrocannabinol [∆(9)-THC]), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and the proteins for endocannabinoid biosynthesis and degradation, has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during physiopathological conditions. In the brain activation of this system modulates the release of excitatory and inhibitory neurotransmitters and of cytokines from glial cells. As such, the ECS is strongly involved in neuropsychiatric disorders, particularly in affective disturbances such as anxiety and depression. It has been proposed that synthetic molecules that inhibit endocannabinoid degradation can exploit the selectivity of endocannabinoid action, thus activating cannabinoid receptors only in those tissues where there is perturbed endocannabinoid turnover due to the disorder, and avoiding the potential side effects of direct CB1 and CB2 activation. However, the realization that endocannabinoids, and AEA in particular, also act at other molecular targets, and that these mediators can be deactivated by redundant pathways, has recently led to question the efficacy of such approach, thus opening the way to new multi-target therapeutic strategies, and to the use of non-psychotropic cannabinoids, such as cannabidiol (CBD), which act via several parallel mechanisms, including indirect interactions with the ECS. The state of the art of the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in mood disorders is discussed in this review article.”
The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system.
“Cannabidiol (CBD), the main non-psychotomimetic component of the plant Cannabis sativa, exerts therapeutically promising effects on human mental health such as inhibition of psychosis, anxiety and depression. However, the mechanistic bases of CBD action are unclear. Here we investigate the potential involvement of hippocampal neurogenesis in the anxiolytic effect of CBD in mice subjected to 14 d chronic unpredictable stress (CUS). Repeated administration of CBD (30 mg/kg i.p., 2 h after each daily stressor) increased hippocampal progenitor proliferation and neurogenesis in wild-type mice. Ganciclovir administration to GFAP-thymidine kinase (GFAP-TK) transgenic mice, which express thymidine kinase in adult neural progenitor cells, abrogated CBD-induced hippocampal neurogenesis. CBD administration prevented the anxiogenic effect of CUS in wild type but not in GFAP-TK mice as evidenced in the novelty suppressed feeding test and the elevated plus maze. This anxiolytic effect of CBD involved the participation of the CB1 cannabinoid receptor, as CBD administration increased hippocampal anandamide levels and administration of the CB1-selective antagonist AM251 prevented CBD actions. Studies conducted with hippocampal progenitor cells in culture showed that CBD promotes progenitor proliferation and cell cycle progression and mimics the proliferative effect of CB1 and CB2 cannabinoid receptor activation. Moreover, antagonists of these two receptors or endocannabinoid depletion by fatty acid amide hydrolase overexpression prevented CBD-induced cell proliferation.
These findings support that the anxiolytic effect of chronic CBD administration in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signalling.”
Interleukin-1β causes anxiety by interacting with the endocannabinoid system.
“Interleukin-1β (IL-1β) is involved in mood alterations associated with inflammatory illnesses and with stress. The present investigation identifies a previously unrecognized interaction between a major proinflammatory cytokine and the endocannabinoid system in the pathophysiology of anxiety.”
The endocannabinoid system and Alzheimer’s disease.
“The importance of the role of the endocannabinoid system (ECS) in neurodegenerative diseases has grown during the past few years. Mostly because of the high density and wide distribution of cannabinoid receptors of the CB(1) type in the central nervous system (CNS), much research focused on the function(s) that these receptors might play in pathophysiological conditions.
Our current understanding, however, points to much diverse roles for this system. In particular, other elements of the ECS, such as the fatty acid amide hydrolase (FAAH) or the CB(2) cannabinoid receptor are now considered as promising pharmacological targets for some diseases and new cannabinoids have been incorporated as therapeutic tools.
Although still preliminary, recent reports suggest that the modulation of the ECS may constitute a novel approach for the treatment of Alzheimer’s disease (AD). Data obtained in vitro, as well as in animal models for this disease and in human samples seem to corroborate the notion that the activation of the ECS, through the use of agonists or by enhancing the endogenous cannabinoid tone, may induce beneficial effects on the evolution of this disease.”
Targeting the endocannabinoid system in Alzheimer’s disease.
“The endocannabinoid system is rapidly emerging as a potential drug target for a variety of immune-mediated central nervous system diseases. There is a growing body of evidence suggesting that endocannabinoid interventions may have particular relevance to Alzheimer’s disease. Here we present a review of endocannabinoid physiology, the evidence that underscores its utility as a potential target for intervention in Alzheimer’s disease, and suggest future pathways of research.
Inflammation and oxidative stress are generally accepted as a critical risk factor for the development of AD, and interventions such as cannabinoids that attenuate these risks without arresting microglial activity and have innate neuroprotective benefits are attractive as potential preventative treatments for AD.
There is a potential for the development of CB1 interventions, whether agonists or antagonists, with applications for a variety of cognitive disorders including neurodegenerative disorders and schizophrenia. The recent discovery of a CB1 receptor Positron Emission Tomography tracer for clinical use may provide the opportunity to evaluate the impact of the regional distribution of CB1 receptors in brain on domain-specific cognitive performance (memory, executive function, praxis) in healthy individuals. Additionally, if AD is a disease of overproduction of eCBs, this may be visualized in case-control CB1receptor binding studies.
The emerging data suggest that the eCB system is a potential target for immune and/or cognitive intervention in AD. A wealth of available chemical compounds capable of intervening in the eCB system at a variety of levels and the success with which these compounds have been used in animal models suggest the potential for human drug development. What is missing is a clear direction for that development based on a concise conceptualization of eCB system function in both health and in neurodegenerative and inflammatory conditions such as AD. Focused experiments are now required to move the field forward.”
The role of the endocannabinoid system in Alzheimer’s disease: facts and hypotheses.
“Unlike other neuroinflammatory disorders, like Parkinson’s disease, Huntington’s disease and multiple sclerosis, little is still known of the role of the endocannabinoid system in Alzheimer’s disease (AD). This is partly due to the poor availability of animal models that are really relevant to the human disease, and to the complexity of AD as compared to other neurological states. Nevertheless, the available data indicate that endocannabinoids are likely to play in this disorder a role similar to that suggested in other neurodegenerative diseases, that is, to represent an endogenous adaptive response aimed at counteracting both the neurochemical and inflammatory consequences of beta-amyloid-induced tau protein hyperactivity, possibly the most important underlying cause of AD.
Furthermore, plant and synthetic cannabinoids, and particularly the non-psychotropic cannabidiol, might also exert other, non-cannabinoid receptor-mediated protective effects, including, but not limited to, anti-oxidant actions. There is evidence, from in vivo studies on beta-amyloid-induced neurotoxicity, also for a possible causative role of endocannabinoids in the impairment in memory retention, which is typical of AD.
This might open the way to the use of cannabinoid receptor antagonists as therapeutic drugs for the treatment of cognitive deficits in the more advanced phases of this disorder. The scant, but nevertheless important literature on the regulation and role of the endocannabinoid system in AD, and on the potential treatment of this disorder with cannabinoids and endocannabinoid-based drugs, are discussed in this mini-review.”
Cannabidiol as an Emergent Therapeutic Strategy for Lessening the Impact of Inflammation on Oxidative Stress
“Growing evidence suggests that the endocannabinoid system, which includes the CB1 and CB2 G protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system, but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development.
This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types I and II diabetes, atherosclerosis, Alzheimer’s disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain.
Cannabidiol (CBD) is the major nonpsychotropic cannabinoid compound derived from the plant Cannabis sativa, commonly known as marijuana…
Conclusions
Inflammation and oxidative stress are intimately involved in the genesis of many human diseases. Unraveling that relationship therapeutically has proven challenging, in part because inflammation and oxidative stress “feed off” each other. However, CBD would seem to be a promising starting point for further drug development given its anti-oxidant (although relatively modest) and anti-inflammatory actions on immune cells, such as macrophages and microglia. CBD also has the advantage of not having psychotropic side effects. Studies on models of human diseases support the idea that CBD attenuates inflammation far beyond its antioxidant properties, for example, by targeting inflammation-related intracellular signaling events. The details on how CBD targets inflammatory signaling remain to be defined.
The therapeutic utility of CBD is a relatively new area of investigation that portends new discoveries on the interplay between inflammation and oxidative stress, a relationship that underlies tissue and organ damage in many human diseases.”