Potential Therapeutic Value of a Novel FAAH Inhibitor for the Treatment of Anxiety.

Posted on September 13, 2015 by David

“Anxiety disorders are among the most prevalent psychiatric diseases with high personal costs and a remarkable socio-economic burden. However, current treatment of anxiety is far from satisfactory.

Novel pharmacological targets have emerged in the recent years, and attention has focused on the endocannabinoid (eCB) system, given the increasing evidence that supports its central role in emotion, coping with stress and anxiety.

In the management of anxiety disorders, drug development strategies have left apart the direct activation of type-1 cannabinoid receptors to indirectly enhance eCB signalling through the inhibition of eCB deactivation, that is, the inhibition of the fatty acid amide hydrolase (FAAH) enzyme.

In the present study, we provide evidence for the anxiolytic-like properties of a novel, potent and selective reversible inhibitor of FAAH, ST4070, orally administered to rodents.

Altogether, ST4070 offers a promising anxiolytic-like profile in preclinical studies, although further studies are warranted to clearly demonstrate its efficacy in the clinic management of anxiety disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26360704

Cannabidiol as a Potential Treatment for Anxiety Disorders.

Posted on September 7, 2015 by David

“Cannabidiol (CBD), a Cannabis sativa constituent, is a pharmacologically broad-spectrum drug that in recent years has drawn increasing interest as a treatment for a range of neuropsychiatric disorders.

The purpose of the current review is to determine CBD’s potential as a treatment for anxiety-related disorders, by assessing evidence from preclinical, human experimental, clinical, and epidemiological studies.

We found that existing preclinical evidence strongly supports CBD as a treatment for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder when administered acutely; however, few studies have investigated chronic CBD dosing.

Likewise, evidence from human studies supports an anxiolytic role of CBD, but is currently limited to acute dosing, also with few studies in clinical populations.

Overall, current evidence indicates CBD has considerable potential as a treatment for multiple anxiety disorders, with need for further study of chronic and therapeutic effects in relevant clinical populations.”

http://www.ncbi.nlm.nih.gov/pubmed/26341731

The endocannabinoid, endovanilloid and nitrergic systems could interact in the rat dorsolateral periaqueductal gray matter to control anxiety-like behaviors.

Posted on July 22, 2015 by David

“Cannabinoid compounds usually produce biphasic effects in the modulation of emotional responses.

Low doses of the endocannabinoid anandamide (AEA) injected into the dorsolateral periaqueductal gray matter (dlPAG) induce anxiolytic-like effects via CB1 receptors activation.

However, at higher doses the drug loses this effect, in part by activating Transient Receptor Potential Vanilloid Type 1 (TRPV1).

Activation of these latter receptors could induce the formation of nitric oxide (NO). Thus, the present study tested the hypothesis that at high doses AEA loses it anxiolytic-like effect by facilitating, probably via TRPV1 receptor activation, the formation of NO.

…these results support the hypothesis that intra-dlPAG injections of high doses of AEA lose their anxiolytic effects by favoring TRPV1 receptors activity and consequent NO formation, which in turn could facilitate defensive responses.”

http://www.ncbi.nlm.nih.gov/pubmed/26187694

Neurobiological Interactions Between Stress and the Endocannabinoid System.

Posted on June 13, 2015 by David

“Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes.

A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response.

In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling play with respect to many of the effects of stress.

Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels.

Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a down-regulation or loss of cannabinoid type 1 (CB1) receptors.

With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception and synaptic plasticity.

More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and post-traumatic stress disorder.

Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress response.”

http://www.ncbi.nlm.nih.gov/pubmed/26068727

Anxiety, Stress, and Fear Response in Mice with Reduced Endocannabinoid Levels.

Posted on May 20, 2015 by David

Disruption of the endocannabinoid system through pharmacological or genetic invalidation of cannabinoid CB1 receptors has been linked to depression in humans and depression-like behaviors in mice.

We generated and used knockout mice lacking DAGL-α (Dagla-/-) to assess the behavioral consequences of reduced endocannabinoid levels in the brain…

Our findings demonstrate that the deletion of Dagla adversely affects the emotional state of animals and results in enhanced anxiety, stress, and fear responses.”

http://www.ncbi.nlm.nih.gov/pubmed/25981172

Smoke Your Troubles Away: Exploring the Effects of Death Cognitions on Cannabis Craving and Consumption.

Posted on May 8, 2015 by David

“When reminded of their death, participants craved cannabis, even though there was no change in their conscious negative mood… Results indicate that cannabis served as a buffer and prevented death-related thoughts from entering consciousness, thus acting as a defense mechanism against death anxiety.” http://www.ncbi.nlm.nih.gov/pubmed/25950588

http://www.thctotalhealthcare.com/category/anxiety-2/

The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs-A practical view.

Posted on March 21, 2015 by David

“The endocannabinoid system, comprising cannabinoid CB1 and CB2 receptors, their endogenous ligands anandamide and 2-arachidonoylglyerol, and their synthetic and metabolic enzymes, are involved in many biological processes in the body, ranging from appetite to bone turnover.

Compounds inhibiting the breakdown of anandamide and 2-arachidonoylglycerol increase brain levels of these lipids and thus modulate endocannabinoid signalling.

In the present review, the preclinical evidence that these enzymes are good targets for development of novel therapies for anxiety and depression are discussed from a practical, rather than mechanistic, point of view.

It is concluded that the preclinical data are promising, albeit tempered by problems of tolerance as well as effects upon learning and memory for irreversible monoacylglycerol lipase inhibitors, and limited by a focus upon male rodents alone.

Clinical data so far has been restricted to safety studies with inhibitors of anandamide hydrolysis and a hitherto unpublished study on such a compound in elderly patients with major depressive disorders, but under the dose regimes used, they are well tolerated and show no signs of “cannabis-like” behaviours.”

http://www.ncbi.nlm.nih.gov/pubmed/25791296

Cannabinoids & Stress: Impact of HU-210 on behavioral tests of anxiety in acutely stressed mice.

Posted on February 25, 2015 by David

“Anxiety disorders are one of the most prevalent classes of mental disorders affecting the general population, but current treatment strategies are restricted by their limited efficacy and side effect profiles.

Although the cannabinoid system is speculated to be a key player in the modulation of stress responses and emotionality, the vast majority of current research initiatives had not incorporated stress exposure into their experimental designs.

This study was the first to investigate the impact of exogenous cannabinoid administration in an acutely stressed mouse model, where CD1 mice were pre-treated with HU-210, a potent CB1R agonist, prior to acute stress exposure and subsequent behavioural testing.

Exogenouscannabinoid administration induced distinct behavioural phenotypes in stressed and unstressed mice…

These findings suggest that exogenous cannabinoids and acute stress act synergistically in an anxiogenic manner.

This study underlies the importance of including stress exposure into future anxiety-cannabinoid research due to the differential impact of cannabinoid administration on stressed and unstressed subjects.”

http://www.ncbi.nlm.nih.gov/pubmed/25707713

http://www.thctotalhealthcare.com/category/anxiety-2/

Effects of intra-infralimbic prefrontal cortex injections of cannabidiol in the modulation of emotional behaviors in rats: contribution of 5HT1A receptors and stressful experiences.

Posted on February 24, 2015 by David

“The infralimbic (IL) and prelimbic (PL) regions of the prefrontal cortex are involved in behavioral responses observed during defensive reactions.

Intra-PL or IL injections of cannabidiol (CBD), a major non-psychotomimetic cannabinoid present in the Cannabis sativa plant, result in opposite behavioral effects in the contextual fear conditioning (CFC) paradigm…

Together these results indicate that CBD effects in the IL depend on the nature of the animal model, being influenced by previous stressful experiences and mediated by facilitation of 5HT1A receptors-mediated neurotransmission.”

http://www.ncbi.nlm.nih.gov/pubmed/25701682

Cannabinoid CB1 receptors in the dorsal hippocampus and prelimbic medial prefrontal cortex modulate anxiety-like behavior in rats: additional evidence.

Posted on January 18, 2015 by David

“Endocannabinoids (ECBs) such as anandamide (AEA) act by activating cannabinoid type 1 (CB1) or 2 (CB2) receptors. The anxiolytic effect of drugs that facilitate ECB effects is associated with increase in AEA levels in several encephalic areas, including the prefrontal cortex (PFC).

Activation of CB1 receptors by CB1 agonists injected directly into these areas is usually anxiolytic.

However, depending on the encephalic region being investigated and on the stressful experiences, opposite effects were observed, as reported in the ventral HIP. In addition, contradictory results have been reported after CB1 activation in the dorsal HIP (dHIP).

Therefore, in the present paper we have attempted to verify if directly interfering with ECB metabolism/reuptake in the prelimbic (PL) portion of the medial PFC (MPFC) and dHIP would produce different effects in two conceptually distinct animal models: the elevated plus maze (EPM) and the Vogel conflict test (VCT).

We observed drugs which interfere with ECB reuptake/metabolism in both the PL and in the dentate gyrus of the dHIP induced anxiolytic-like effect, in both the EPM and in the VCT via CB1 receptors, suggesting CB1 signaling in these brain regions modulate defensive responses to both innate and learned threatening stimuli.

This data further strengthens previous results indicating modulation of hippocampal and MPFC activity via CB1 by ECBs, which could be therapeutically targeted to treat anxiety disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/25595265

http://www.thctotalhealthcare.com/category/anxiety-2/