Category Archives: Anxiety

Distinct roles of neuronal and microglial CB2 cannabinoid receptors in the mouse hippocampus.

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“The effects of cannabinoids are primarily mediated by type-1 cannabinoid receptors in the brain and type-2 cannabinoid receptors (CB2Rs) in the peripheral immune system. However, recent evidence demonstrates that CB2Rs are also expressed in the brain and implicated in neuropsychiatric effects. Diverse types of cells in various regions in the brain express CB2Rs but the cellular loci of CB2Rs that induce specific behavioral effects have not been determined. To manipulate CB2R expression in specific types of cells in the dorsal hippocampus of adult mice, we used Cre-dependent overexpression and CRISPR-Cas9 genome editing techniques in combination with adeno-associated viruses and transgenic mice. Elevation and disruption of CB2R expression in microglia in the CA1 area increased and decreased, respectively, contextual fear memory. In CA1 pyramidal neurons, disruption of CB2R expression enhanced spatial working memory, whereas their overexpression reduced anxiety levels assessed as an increase in the exploration time in the central area of open field. Interneuronal CB2Rs were not involved in the modulation of cognitive or emotional behaviors tested in this study. The targeted manipulation of CB2R expression in pyramidal neurons and microglia suggests that CB2Rs in different types of cells in the mature hippocampus play distinct roles in the regulation of memory and anxiety.”

https://www.ncbi.nlm.nih.gov/pubmed/28888955

http://www.sciencedirect.com/science/article/pii/S0306452217306292

Therapeutical strategies for anxiety and anxiety-like disorders using plant-derived natural compounds and plant extracts.

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“Anxiety and anxiety-like disorders describe many mental disorders, yet fear is a common overwhelming symptom often leading to depression. Currently two basic strategies are discussed to treat anxiety: pharmacotherapy or psychotherapy. In the pharmacotherapeutical clinical approach, several conventional synthetic anxiolytic drugs are being used with several adverse effects. Therefore, studies to find suitable safe medicines from natural sources are being sought by researchers. The results of a plethora experimental studies demonstrated that dietary phytochemicals like alkaloids, terpenes, flavonoids, phenolic acids, lignans, cinnamates, and saponins or various plant extracts with the mixture of different phytochemicals possess anxiolytic effects in a wide range of animal models of anxiety. The involved mechanisms of anxiolytics action include interaction with γ-aminobutyric acid A receptors at benzodiazepine (BZD) and non-BZD sites with various affinity to different subunits, serotonergic 5-hydrodytryptamine receptors, noradrenergic and dopaminergic systems, glutamate receptors, and cannabinoid receptors. This review focuses on the use of both plant-derived natural compounds and plant extracts with anxiolytic effects, describing their biological effects and clinical application.”

https://www.ncbi.nlm.nih.gov/pubmed/28863384

 

Cannabidiol Does Not Dampen Responses to Emotional Stimuli in Healthy Adults.

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“Introduction: Cannabidiol (CBD) is a nonpsychoactive constituent of whole plant cannabis that has been reported to reduce anxiety-like behaviors in both pre-clinical and human laboratory studies. Yet, no controlled clinical studies have demonstrated its ability to reduce negative mood or dampen responses to negative emotional stimuli in humans. The objective of this study was to investigate the effects of CBD on responses to negative emotional stimuli, as a model for its potential anxiety-reducing effects.

Discussion: CBD did not dampen responses to negative emotional stimuli and did not affect feelings of social rejection. The high dose of CBD (900 mg) marginally reduced attentional bias toward happy and sad facial expressions, and produced a slight increase in late-session heart rate. CBD did not produce detectable subjective effects or alterations in mood or anxiety.

Conclusion: These findings indicate that CBD has minimal behavioral and subjective effects in healthy volunteers, even when they are presented with emotional stimuli. Further research into the behavioral and neural mechanisms of CBD and other phytocannabinoids is needed to ascertain the clinical function of this drug.”

https://www.ncbi.nlm.nih.gov/pubmed/28861510

 http://online.liebertpub.com/doi/10.1089/can.2017.0014

Even High Doses of Oral Cannabidol Do Not Cause THC-Like Effects in Humans

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Mary Ann Liebert, Inc. publishers

“Cannabidiol (CBD) is a cannabinoid of the cannabis plant devoid of intoxicating effects. It may be of therapeutic value in a large number of diseases, including epilepsy, anxiety disorders, depression, schizophrenic psychosis, inflammatory diseases, dystonia, nausea, and vomiting without causing relevant or severe side effects.

No biosynthetic enzyme or pathway exists in the human body to convert CBD to THC.

This short communication examines the question whether the experimental data presented in a study by Merrick et al. are of clinical relevance. These authors found that cannabidiol (CBD), a major cannabinoid of the cannabis plant devoid of psychotropic effects and of great interest for therapeutic use in several medical conditions, may be converted in gastric fluid into the psychoactive cannabinoids delta-8-THC and delta-9-THC to a relevant degree. They concluded that “the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a positive physiological response.” They issued a warning concerning oral use of CBD and recommend the development of other delivery methods.

However, the available clinical data do not support this conclusion and recommendation, since even high doses of oral CBD do not cause psychological, psychomotor, cognitive, or physical effects that are characteristic for THC or cannabis rich in THC. On the contrary, in the past decades and by several groups, high doses of oral CBD were consistently shown to cause opposite effects to those of THC in clinical studies. In addition, administration of CBD did not result in detectable THC blood concentrations.

Thus, there is no reason to avoid oral use of CBD, which has been demonstrated to be a safe means of administration of CBD, even at very high doses.”

https://www.ncbi.nlm.nih.gov/pubmed/28861499

http://online.liebertpub.com/doi/full/10.1089/can.2016.0036

“A Conversion of Oral Cannabidiol to Delta9-Tetrahydrocannabinol Seems Not to Occur in Humans.”  https://www.ncbi.nlm.nih.gov/pubmed/28861507

The novel cannabinoid receptor GPR55 mediates anxiolytic-like effects in the medial orbital cortex of mice with acute stress.

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Biomed Central

“The G protein-coupled receptor 55 (GPR55) is a novel cannabinoid receptor, whose exact role in anxiety remains unknown. The present study was conducted to explore the possible mechanisms by which GPR55 regulates anxiety and to evaluate the effectiveness of O-1602 in the treatment of anxiety-like symptoms. Mice were exposed to two types of acute stressors: restraint and forced swimming. Anxiety behavior was evaluated using the elevated plus maze and the open field test. We found that O-1602 alleviated anxiety-like behavior in acutely stressed mice. We used lentiviral shRNA to selective ly knockdown GPR55 in the medial orbital cortex and found that knockdown of GPR55 abolished the anxiolytic effect of O-1602. We also used Y-27632, a specific inhibitor of ROCK, and U73122, an inhibitor of PLC, and found that both inhibitors attenuated the effectiveness of O-1602. Western blot analysis revealed that O-1602 downregulated the expression of GluA1 and GluN2A in mice. Taken together, these results suggest that GPR55 plays an important role in anxiety and O-1602 may have therapeutic potential in treating anxiety-like symptoms.”

 https://www.ncbi.nlm.nih.gov/pubmed/28800762
https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-017-0318-7

Blunted stress reactivity in chronic cannabis users

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Psychopharmacology

“One of the most commonly cited reasons for chronic cannabis use is to cope with stress.

Consistent with this, cannabis users have shown reduced emotional arousal and dampened stress reactivity in response to negative imagery.

Chronic cannabis use is associated with blunted stress reactivity.” https://link.springer.com/article/10.1007/s00213-017-4648-z?no-access=true

“WSU study: Regular marijuana users more calm under stress” http://komonews.com/news/local/wsu-study-regular-marijuana-users-more-calm-under-stress
 

Endocannabinoid Transport Proteins: Discovery of Tools to Study Sterol Carrier Protein-2.

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Elsevier

“The endocannabinoid (eCB) neurotransmitter system regulates diverse neurological functions including stress and anxiety, pain, mood, and reward. Understanding the mechanisms underlying eCB regulation is critical for developing targeted pharmacotherapies to treat these and other neurologic disorders.

Cellular studies suggest that the arachidonate eCBs, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), are substrates for intracellular binding and transport proteins, and several candidate proteins have been identified. Initial evidence from our laboratory indicates that the lipid transport protein, sterol carrier protein 2 (SCP-2), binds to the eCBs and can regulate their cellular concentrations.

Here, we present methods for evaluating SCP-2 binding of eCBs and their application to the discovery of the first inhibitor lead molecules. Using a fluorescent probe displacement assay, we found SCP-2 binds the eCBs, AEA (Ki=0.68±0.05μM) and 2-AG (Ki=0.37±0.02μM), with moderate affinity. A series of structurally diverse arachidonate analogues also bind SCP-2 with Ki values between 0.82 and 2.95μM, suggesting a high degree of tolerance for arachidonic acid head group modifications in this region of the protein. We also report initial structure-activity relationships surrounding previously reported inhibitors of Aedis aegypti SCP-2, and the results of an in silico high-throughput screen that identified structurally novel SCP-2 inhibitor leads.

The methods and results reported here provide the basis for a robust probe discovery effort to fully elucidate the role of facilitated transport mediated by SCP-2 in eCB regulation and function.”

https://www.ncbi.nlm.nih.gov/pubmed/28750817

http://www.sciencedirect.com/science/article/pii/S007668791730174X?via%3Dihub

 

An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol.

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“Cannabidiol (CBD) has been traditionally used in Cannabis-based preparation, however historically, it has received far less interest as a single drug than the other components of Cannabis. Currently, CBD generates considerable interest due to its beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, and anti-inflammatory properties. Therefore, the CBD scaffold becomes of increasing interest for medicinal chemists. This review provides an overview of the chemical structure of natural and synthetic CBD derivatives including the molecular targets associated with these compounds. A clear identification of their biological targets has been shown to be still very challenging.”  https://www.ncbi.nlm.nih.gov/pubmed/28701957

http://journal.frontiersin.org/article/10.3389/fphar.2017.00422/full

Cannabinoids prevent the differential long-term effects of exposure to severe stress on hippocampal- and amygdala-dependent memory and plasticity.

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“Exposure to excessive or uncontrolled stress is a major factor associated with various diseases including post-traumatic stress disorder (PTSD). The consequences of exposure to trauma are affected not only by aspects of the event itself, but also by the frequency and severity of trauma reminders. It was suggested that in PTSD, hippocampal-dependent memory is compromised while amygdala-dependent memory is strengthened.

Several lines of evidence support the role of the endocannabinoid (eCB) system as a modulator of the stress response.

In this study we aimed to examine cannabinoids modulation of the long-term effects (i.e., 1 month) of exposure to a traumatic event on memory and plasticity in the hippocampus and amygdala.

Cannabinoids prevent the differential long-term effects of exposure to severe stress on hippocampal- and amygdala-dependent memory and plasticity.

Taken together, these findings suggest the involvement of the endocannabinoid system, and specifically CB1 receptors, in the opposite effects of severe stress on memory and plasticity in the hippocampus and amygdala.”  https://www.ncbi.nlm.nih.gov/pubmed/28667676

http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002/hipo.22755

The cannabinoid ligand LH-21 reduces anxiety and improves glucose handling in diet-induced obese pre-diabetic mice.

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“LH-21 is a triazol derivative that has been described as a low-permeant neutral CB1 antagonist, though its pharmacology is still unclear. It has been associated with anti-obesity actions in obese rats. However, its role in preventing type 2 diabetes (T2D) onset have not been studied yet. Given CB1 receptors remain as potential pharmacological targets to fight against obesity and T2D, we wanted to explore the metabolic impact of this compound in an animal model of obesity and pre-diabetes as well as the lack of relevant actions in related central processes such as anxiety. These results suggest that LH-21 can be a new candidate to fight against diabetes onset. Indeed, this compound shows potential in counteracting obesity-related anxiety.” https://www.ncbi.nlm.nih.gov/pubmed/28638091   https://www.nature.com/articles/s41598-017-03292-w

“Anti-obesity efficacy of LH-21, a cannabinoid CB(1) receptor antagonist with poor brain penetration, in diet-induced obese rats.”  https://www.ncbi.nlm.nih.gov/pubmed/21951309

“Antiobesity effects of the novel in vivo neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole–LH 21.”  https://www.ncbi.nlm.nih.gov/pubmed/16750544