Antiemetic Effects of Cannabinoid Agonists in Nonhuman Primates

Journal of Pharmacology and Experimental Therapeutics“Attenuating emesis elicited by both disease and medical treatments of disease remains a critical public health challenge.

Although cannabinergic medications have been used in certain treatment-resistant populations, FDA-approved cannabinoid antiemetics are associated with undesirable side effects, including cognitive disruption, that limit their prescription. Previous studies have shown that a metabolically stable analog of the endocannabinoid anandamide, methanandamide (mAEA), may produce lesser cognitive disruption than that associated with the primary psychoactive constituent in cannabis, Δ9-tetrahydrocannabinol (Δ9-THC), raising the possibility that endocannabinoids may offer a therapeutic advantage over currently used medications.

The present studies were conducted to evaluate this possibility by comparing the antiemetic effects of Δ9-THC (0.032-0.1 mg/kg) and mAEA (3.2-10.0 mg/kg), against nicotine- and lithium chloride (LiCl)-induced emesis and prodromal hypersalivation in squirrel monkeys.

These studies systematically demonstrate for the first time the antiemetic effects of cannabinoid agonists in nonhuman primates. Importantly, although Δ9-THC produced superior antiemetic effects, the milder cognitive effects of mAEA demonstrated in previous studies suggests that it may provide a favorable treatment option under clinical circumstances in which antiemetic efficacy must be balanced against side-effect liability.

SIGNIFICANCE STATEMENT: Emesis has significant evolutionary value as a defense mechanism against ingested toxins; however, it is also one of the most common adverse symptoms associated with both disease and medical treatments of disease. The development of improved anti-emetic pharmacotherapies has been impeded by a paucity of animal models.

The present studies systematically demonstrate for the first time the antiemetic effects of the phytocannabinoid Δ9-tetrahydrocannabinol and endocannabinoid-analog methanandamide in nonhuman primates.”

https://pubmed.ncbi.nlm.nih.gov/32561684/

http://jpet.aspetjournals.org/content/early/2020/06/19/jpet.120.265710

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Cannabinoid CP55940 Selectively Induces Apoptosis in Jurkat Cells and in Ex Vivo T-cell Acute Lymphoblastic Leukemia Through H 2 O 2 Signaling Mechanism

 Leukemia Research‘T-cell acute lymphoblastic leukemia (T-ALL) is a highly heterogeneous malignant hematological disorder arising from T-cell progenitors.

This study was aimed to evaluate the cytotoxic effect of CP55940 on human peripheral blood lymphocytes (PBL) and on T-ALL cells (Jurkat).

In conclusion, CP55940 selectively induces apoptosis in Jurkat cells through a H2O2-mediated signaling pathway.

Our findings support the use of cannabinoids as a potential treatment for T-ALL cells.”

https://pubmed.ncbi.nlm.nih.gov/32540572/

https://www.sciencedirect.com/science/article/abs/pii/S0145212620300941?via%3Dihub

“CP 55,940 is a synthetic cannabinoid which mimics the effects of naturally occurring THC (one of the psychoactive compounds found in cannabis)”  https://en.wikipedia.org/wiki/CP_55,940

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Localisation of Cannabinoid and Cannabinoid-Related Receptors in the Equine Dorsal Root Ganglia

Publication cover image“Growing evidence recognises cannabinoid receptors as potential therapeutic targets for pain. Consequently, there is increasing interest in developing cannabinoid receptor agonists for treating pain.

As a general rule, to better understand the actions of a drug, it would be of extreme importance to know the cellular distribution of its specific receptors. The localisation of cannabinoid receptors in the dorsal root ganglia of the horse has not yet been investigated.

Conclusions: This study highlighted the expression of cannabinoid receptors in the sensory neurons and glial cells of the dorsal root ganglia. These findings could be of particular relevance for future functional studies assessing the effects of cannabinoids in horses to manage pain.”

https://pubmed.ncbi.nlm.nih.gov/32524649/

https://beva.onlinelibrary.wiley.com/doi/abs/10.1111/evj.13305

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Cannabinoid as Beneficial Replacement Therapy for Psychotropics to Treat Neuropsychiatric Symptoms in Severe Alzheimer’s Dementia: A Clinical Case Report

CrossFit | 190629“Alzheimer’s Dementia (AD) is a devastating neurodegenerative disease that affects approximately 17% of people aged 75-84. Neuropsychiatric symptoms (NPS) such as delusions, agitation, anxiety, and hallucinations are present in up to 95% of patients in all stages of dementia. To date, any approved and effective pharmacological interventions for the treatment of NPS are still not available.

We describe a clinical case of a female patient diagnosed with AD with continuous cognitive decline and dementia-related behavioral symptoms. Between 2008 and 2019, the patient was examined half-yearly at the memory clinic of the Medical University of Innsbruck. At each visit, cognitive state and pharmacological treatment were evaluated. In addition, NPs were assessed by using the neuropsychiatric inventory (NPI). In 2018, the patient progressed to severe AD stage and presented with progressive NPs (anxiety, suspected delusions, agitation, aggressive behavior, and suspected pain due to long immobility).

Consequently, off-label treatment with low-dose dronabinol was initiated, which facilitated a reduction of psychopharmacological treatment from six to three psychotropics. At the same time, the patient’s emotional state improved, while disruptive behavior, aggression, and sedation decreased significantly. This case report underpins the need for randomized, controlled trials to explore the effect of cannabinoid receptor agonists on behavioral and psychological symptoms in patients with severe AD.”

https://pubmed.ncbi.nlm.nih.gov/32477187/

“Cannabinoids have a distinct pharmacologic profile that may offer an alternative pharmacologic approach to antipsychotics and sedatives for treating NPs in patients with AD. In addition, the beneficial effect on appetite and pain may significantly improve quality of life of AD-patients and their caregivers.”

https://www.frontiersin.org/articles/10.3389/fpsyt.2020.00413/full

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Pharmacological Data of Cannabidiol- And Cannabigerol-Type Phytocannabinoids Acting on Cannabinoid CB 1, CB 2 and CB 1/CB 2 Heteromer Receptors

Pharmacological Research“Background: Recent approved medicines whose active principles are Δ9Tetrahidrocannabinol (Δ9-THC) and/or cannabidiol (CBD) open novel perspectives for other phytocannabinoids also present in Cannabis sativa L. varieties. Furthermore, solid data on the potential benefits of acidic and varinic phytocannabinoids in a variety of diseases are already available. Mode of action of cannabigerol (CBG), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabidivarin (CBDV) and cannabigerivarin (CBGV) is, to the very least, partial.

Hypothesis/purpose: Cannabinoid CB1 or CB2 receptors, which belong to the G-protein-coupled receptor (GPCR) family, are important mediators of the action of those cannabinoids. Pure CBG, CBDA, CBGA, CBDV and CBGV from Cannabis sativa L. are differentially acting on CB1 or CB2 cannabinoid receptors.

Study design: Determination of the affinity of phytocannabinoids for cannabinoid receptors and functional assessment of effects promoted by these compounds when interacting with cannabinoid receptors.

Methods: A heterologous system expressing the human versions of CB1 and/or CB2 receptors was used. Binding to membranes was measured using radioligands and binding to living cells using a homogenous time resolved fluorescence resonance energy transfer (HTRF) assay. Four different functional outputs were assayed: determination of cAMP levels and of extracellular-signal-related-kinase phosphorylation, label-free dynamic mass redistribution (DMR) and ß-arrestin recruitment.

Results: Affinity of cannabinoids depend on the ligand of reference and may be different in membranes and in living cells. All tested phytocannabinoids have agonist-like behavior but behaved as inverse-agonists in the presence of selective receptor agonists. CBGV displayed enhanced potency in many of the functional outputs. However the most interesting result was a biased signaling that correlated with differential affinity, i.e. the overall results suggest that the binding mode of each ligand leads to specific receptor conformations underlying biased signaling outputs.

Conclusion: Results here reported and the recent elucidation of the three-dimensional structure of CB1 and CB2 receptors help understanding the mechanism of action that might be protective and the molecular drug-receptor interactions underlying biased signaling.”

https://pubmed.ncbi.nlm.nih.gov/32470563/

https://www.sciencedirect.com/science/article/abs/pii/S1043661820312482?via%3Dihub

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Cannabinoid Receptor Type 2: A Possible Target in SARS-CoV-2 (CoV-19) Infection?

ijms-logo“In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency.”

https://pubmed.ncbi.nlm.nih.gov/32471272/

https://www.mdpi.com/1422-0067/21/11/3809

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Biological potential of varinic-, minor-, and acidic phytocannabinoids.

Pharmacological Research“While natural Δ9-tetrahidrocannabinol (Δ9THC), cannabidiol (CBD), and their therapeutic potential have been extensively researched, some cannabinoids have not been widely investigated.

The present article compiles data from the literature that highlights research on and the therapeutic possibilities of lesser known phytocannabinoids, which we have divided into varinic, acidic, and “minor” (i.e., cannabinoids that are not present in high quantities in common varieties of Cannabis sativa L).

A growing interest in these compounds, which are enriched in some cannabis varieties, has already resulted in enough preclinical information to show that they are promising therapeutic agents for a variety of diseases.

Each phytocannabinoid has a “preferential” mechanism of action, and often target the cannabinoid receptors CB1 and/or CB2. The recent resolution of the structure of cannabinoid receptors demonstrates the atypical nature of cannabinoid binding, and that different binding modes depend on the agonist or partial agonist/inverse agonist, which allows for differential signaling, even acting on the same cannabinoid receptor. In addition, other players and multiple signaling pathways may be targeted/engaged by phytocannabinoids, thereby expanding the mechanistic possibilities for therapeutic use.”

https://www.ncbi.nlm.nih.gov/pubmed/32416215

https://www.sciencedirect.com/science/article/abs/pii/S1043661820311099?via%3Dihub

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Targeting Cannabinoid Receptor 2 on Peripheral Leukocytes to Attenuate Inflammatory Mechanisms Implicated in HIV-Associated Neurocognitive Disorder.

 SpringerLink“HIV infection affects an estimated 38 million people. Approximately 50% of HIV patients exhibit neurocognitive dysfunction termed HIV-Associated Neurocognitive Disorder (HAND). HAND is a consequence of chronic low-level neuroinflammation due to HIV entry into the brain. Initially, monocytes become activated in circulation and traffic to the brain. Monocytes, when activated, become susceptible to infection by HIV and can then carry the virus across the blood brain barrier. Once in the brain, activated monocytes secrete chemokines, which recruit virus-specific CD8+ T cells into the brain to further promote neuroinflammation. HAND is closely linked to systemic inflammation driven, in part, by HIV but is also due to persistent translocation of microorganisms across the GI tract. Persistent anti-viral responses in the GI tract compromise microbial barrier integrity. Indeed, HIV patients can exhibit remarkably high levels of activated (CD16+) monocytes in circulation.

Recent studies, including our own, show that HIV patients using medical marijuana exhibit lower levels of circulating CD16+ monocytes than non-cannabis using HIV patients. Cannabis is a known immune modulator, including anti-inflammatory properties, mediated, in part, by ∆9-tetrahydrocannabinol (THC), as well as less characterized minor cannabinoids, such as cannabidiol (CBD), terpenes and presumably other cannabis constituents. The immune modulating activity of THC is largely mediated through cannabinoid receptors (CB) 1 and 2, with CB1 also responsible for the psychotropic properties of cannabis.

Here we discuss the anti-inflammatory properties of cannabinoids in the context of HIV and propose CB2 as a putative therapeutic target for the treatment of neuroinflammation. Graphical Abstract HIV-associated neurocognitive disorder is a systemic inflammatory disease leading to activation of plasmacytoid dendritic cells, monocytes and T cells. Monocyte and CD8 T cell migration across the BBB and interaction with astrocytes promotes neurotoxic inflammatory mediators release. CB2 ligands are proposed as therapeutics capable of suppressing systemic and localized inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/32409991

https://link.springer.com/article/10.1007%2Fs11481-020-09918-7

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Beneficial effects of the phytocannabinoid Δ9-THCV in L-DOPA-induced dyskinesia in Parkinson’s disease.

Neurobiology of Disease“The antioxidant and CB2 receptor agonist properties of Δ9-tetrahydrocannabivarin (Δ9-THCV) afforded neuroprotection in experimental Parkinson’s disease (PD), whereas its CB1 receptor antagonist profile at doses lower than 5 mg/kg caused anti-hypokinetic effects.

In the present study, we investigated the anti-dyskinetic potential of Δ9-THCV (administered i.p. at 2 mg/kg for two weeks), which had not been investigated before.

In summary, our data support the anti-dyskinetic potential of Δ9-THCV, both to delay the occurrence and to attenuate the magnitude of dyskinetic signs. Although further studies are clearly required to determine the clinical significance of these data in humans, the results nevertheless situate Δ9-THCV in a promising position for developing a cannabinoid-based therapy for patients with PD.”

https://www.ncbi.nlm.nih.gov/pubmed/32387338

“Δ9-THCV exhibited anti-dyskinetic properties in L-DOPA-treated Pitx3ak mutant mice. It delayed the onset of dyskinetic signs and reduced their neurochemical changes. It also reduced their intensity when given once dyskinesia was already present. This potential adds to other properties of Δ9-THCV as antiparkinsonian therapy.

In summary, our data support the anti-dyskinetic potential of Δ9-THCV to ameliorate adverse effects caused by L-DOPA, in particular delaying the occurrence and attenuating the magnitude of dyskinetic signs. This adds to its promising symptom-alleviating and neuroprotective properties described previously. Although further studies are clearly required to determine the clinical significance of these data in humans, the results nevertheless situate Δ9-THCV in a promising position for developing a cannabinoid-based therapy for PD patients.”

https://www.sciencedirect.com/science/article/pii/S0969996120301674?via%3Dihub

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Anti-inflammatory effects of lenabasum, a cannabinoid receptor type 2 agonist, on macrophages from cystic fibrosis.

Home Page: Journal of Cystic Fibrosis“Lenabasum is an oral synthetic cannabinoid receptor type 2 agonist previously shown to reduce the production of key airway pro-inflammatory cytokines known to play a role in cystic fibrosis (CF). In a double-blinded, randomized, placebo-control phase 2 study, lenabasum lowered the rate of pulmonary exacerbation among patients with CF. The present study was undertaken to investigate anti-inflammatory mechanisms of lenabasum exhibits in CF macrophages.

RESULTS:

Lenabasum had no effect on differentiation, polarization and function of macrophages from healthy individuals. However, in CF macrophages lenabasum downregulated macrophage polarization into the pro-inflammatory M1 phenotype and secretion of the pro-inflammatory cytokines IL-8 and TNF-α in a dose-dependent manner. An improvement in phagocytic activity was also observed following lenabasum treatment. Although lenabasum did not restore the impaired polarization of anti-inflammatory M2 macrophage, it reduced the levels of IL-13 and enhanced the endocytic function of CF MDMs. The effects of lenabasum on MDMs with CFTR inhibited by C-172 were not as obvious.

CONCLUSION:

In CF macrophages lenabasum modulates macrophage polarization and function in vitro in a way that would reduce inflammation in vivo. Further studies are warranted to determine the link between activating the CBR2 receptor and CFTR.”

https://www.ncbi.nlm.nih.gov/pubmed/32387042

https://www.cysticfibrosisjournal.com/article/S1569-1993(20)30094-1/pdf

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