GABAergic and endocannabinoid dysfunction in anxiety – future therapeutic targets?

Posted on January 14, 2013 by David

“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.”

http://www.ncbi.nlm.nih.gov/pubmed/19075727

Endocannabinoid system dysfunction in mood and related disorders.

Posted on January 14, 2013 by David

“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.”

http://www.ncbi.nlm.nih.gov/pubmed/21916860

Expression pattern of the cannabinoid receptor genes in the frontal cortex of mood disorder patients and mice selectively bred for high and low fear.

Posted on January 14, 2013 by David

“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.”

http://www.ncbi.nlm.nih.gov/pubmed/22534181

Endocannabinoid system and mood disorders: Priming a target for new therapies.

Posted on January 14, 2013 by David

“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.”

http://www.ncbi.nlm.nih.gov/pubmed/23261685

The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system.

Posted on January 14, 2013 by David

“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.”

http://www.ncbi.nlm.nih.gov/pubmed/23298518

Interleukin-1β causes anxiety by interacting with the endocannabinoid system.

Posted on January 14, 2013 by David

“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.”

http://www.ncbi.nlm.nih.gov/pubmed/23035099

Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects.

Posted on January 14, 2013 by David

“Over the last few years considerable attention has focused on cannabidiol (CBD), a major non-psychotropic constituent of Cannabis. In Part I of this review we present a condensed survey of the chemistry of CBD; in Part II, to be published later, we shall discuss the anti-convulsive, anti-anxiety, anti-psychotic, anti-nausea and anti-rheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors and its mechanism of action is yet unknown. In Part II we shall also present evidence that it is conceivable that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its anti-oxidative effect.”

http://www.ncbi.nlm.nih.gov/pubmed/12505688

http://www.scribd.com/doc/52920296/Cannabidiol-an-Overview-of-Some-Chemical-and-Pharmacological-Aspects-Part-I-Chemical-Aspects

Cannabidiol enhances consolidation of explicit fear extinction in humans.

Posted on January 14, 2013 by David

“Whilst Cannabidiol (CBD), a non-psychotomimetic cannabinoid, has been shown to enhance extinction learning in rats, its effects on fear memory in humans have not previously been studied. These findings provide the first evidence that CBD can enhance consolidation of extinction learning in humans and suggest that CBD may have potential as an adjunct to extinction-based therapies for anxiety disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/23307069

Pot Stirring – ELLE

Posted on January 14, 2013 by David

“Some are using marijuana as their drug of choice to curb anxiety.”

“A thimbleful is all it takes. After a day’s work, I pinch off a small amount of marijuana and put it in a steel-tooth grinder. The flowers, covered in tiny white diamonds of THC, release a piney scent when crushed. I turn on the TV, and instead of taking a glass of wine with my evening news, I take out my vaporizer and set it on the coffee table.

Outside the walls of my bungalow in Oakland, California, I can hear the rush-hour traffic, but I’ve already changed into my Big Lebowski–style robe and slippers. I tap the ground flakes into a canister that I attach to another piece, this one with a bag on the end, and set both on the vaporizer. I flip the switch, and the bag slowly inflates with plumes of white smoke. Once it’s fully clouded, I attach a mouthpiece to the canister, put this to my lips, and press. On the inhale, the cannabinoids taste like sunned grass. My prescription for anxiety disorder didn’t always begin and end with an herb. But I’ve run through enough pharmaceutical drugs to know that pot dulls my panic better than any pill.”

Alzheimer’s Disease

Posted on January 10, 2013 by David

“Alzheimer’s disease (AD), also called Alzheimer disease, senile dementia of the Alzheimer type, primary degenerative dementia of the Alzheimer’s type, or simply Alzheimer’s, is the most common form of dementia. This incurable, degenerative, and terminal disease was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. Most often, it is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer’s can occur much earlier. In 2006, there were 26.6 million sufferers worldwide. Alzheimer’s is predicted to affect 1 in 85 people globally by 2050.

Although the course of Alzheimer’s disease is unique for every individual, there are many common symptoms. The earliest observable symptoms are often mistakenly thought to be ‘age-related’ concerns, or manifestations of stress. In the early stages, the most common symptom is inability to acquire new memories, observed as difficulty in recalling recently observed events. When AD is suspected, the diagnosis is usually confirmed with behavioral assessments and cognitive tests, often followed by a brain scan if available.

As the disease advances, symptoms include confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as their senses decline. Gradually, bodily functions are lost, ultimately leading to death. Individual prognosis is difficult to assess, as the duration of the disease varies. AD develops for an indeterminate period of time before becoming fully apparent, and it can progress undiagnosed for years. The mean life expectancy following diagnosis is approximately seven years. Fewer than three percent of individuals live more than fourteen years after diagnosis.

The cause and progression of Alzheimer’s disease are not well understood. Research indicates that the disease is associated with plaques and tangles in the brain. Currently used treatments offer a small symptomatic benefit; no treatments to delay or halt the progression of the disease are, as of yet, available. As of 2008, more than 500 clinical trials have been conducted for identification of a possible treatment for AD, but it is unknown if any of the tested intervention strategies will show promising results. A number of non-invasive, life-style habits have been suggested for the prevention of Alzheimer’s disease, but there is a lack of adequate evidence for a link between these recommendations and reduced degeneration. Mental stimulation, exercise, and a balanced diet are suggested, as both a possible prevention and a sensible way of managing the disease.”

Video: http://www.medicalmarijuanainc.com/index.php/alzheimer-s-disease