An evaluation of the anti-hyperalgesic effects of cannabidiolic acid-methyl ester (CBDA-ME) in a preclinical model of peripheral neuropathic pain.

Publication cover image“Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable.

KEY RESULTS:

In males, CBDA-ME elicited a significant concentration-dependent chronic anti-hyperalgesic effect, also influencing both nociceptive and non-nociceptive mechanoreceptors, which were not observed in females at any of the concentrations tested.

CONCLUSION AND IMPLICATIONS:

Initiating treatment of a peripheral nerve injury with CBDA-ME at an early stage post-surgery provides anti-nociception in males, warranting further investigation into potential sexual dimorphisms underlying this response.”

https://www.ncbi.nlm.nih.gov/pubmed/31981216

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14997

The Role of Cannabidiol (CBD) in Chronic Pain Management: An Assessment of Current Evidence.

 “Given the growing challenges in chronic pain management coupled with the ongoing consequences of the opioid epidemic, pain management practitioners are looking into more effective, innovative, and safer alternatives to treat pain.

Cannabis-based medicine had been described for hundreds of years but only recently have we seen the more scientific, evidence-based approach to its use, and ongoing investigations continue to explore its potential medical benefits.

While historically more attention has been paid to the psychoactive component of the cannabis plant Δ9-tetrahydrocannabinol (THC), there have been fewer scientific studies on the medical use of the cannabidiol (CBD) – a non-psychoactive component of the cannabis plant.

RECENT FINDINGS:

By examining recent literature, we investigated the use of CBD and its potential role in pain management. Since there are currently no approved pharmaceutical products that contain CBD alone for the management of pain, this review focused on nabiximols (which is a combined product of THC/CBD in a 1:1 ratio) as the only pharmaceutical product available that contains CBD and is being used for the management of pain.

It is difficult to definitely attribute the therapeutic properties to CBD alone since it is always administered with THC.

Based on the available literature, it is difficult to make a recommendation for the use of CBD in chronic pain management. It is also important to note that there are many CBD products currently available as supplements, but these products are non-pharmaceuticals and lack the appropriate clinical studies to support their efficacy claims.”

https://www.ncbi.nlm.nih.gov/pubmed/31980957 

https://link.springer.com/article/10.1007%2Fs11916-020-0835-4

Abnormal Cannabidiol Affects Production of Pro-Inflammatory Mediators and Astrocyte Wound Closure in Primary Astrocytic-Microglial Cocultures.

molecules-logo “Abnormal cannabidiol (abn-CBD) exerts neuroprotective effects in vivo and in vitro. In the present study, we investigated the impact of abn-CBD on the glial production of proinflammatory mediators and scar formation within in vitro models. Primary astrocytic-microglial cocultures and astrocytic cultures from neonatal C57BL/6 mice and CB2 receptor knockout mice were stimulated with lipopolysaccharide (LPS), and the concentrations of tumor necrosis factor α (TNFα), interleukin-6 (IL-6) and nitrite were determined. Furthermore, we performed a live cell microscopy-based scratch-wound assay. After LPS stimulation, TNFα, IL-6 and nitrite production was more strongly increased in cocultures than in isolated astrocytes. Abn-CBD treatment attenuated the LPS-induced production of TNFα and nitrite in cocultures, while IL-6 production remained unaltered. In isolated astrocytes, only LPS-induced TNFα production was reduced by abn-CBD. Similar effects were observed after abn-CBD application in cocultures of CB2 knockout mice. Interestingly, LPS-induced TNFα and nitrite levels were far lower in CB2 knockout cultures compared to wildtypes, while IL-6 levels did not differ. In the scratch-wound assay, treatment with abn-CBD decelerated wound closure when microglial cells were present. Our data shows a differential role of abn-CBD for modulation of glial inflammation and astrocytic scar formation. These findings provide new explanations for mechanisms behind the neuroprotective potential of abn-CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/31979350

https://www.mdpi.com/1420-3049/25/3/496

Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation.

molecules-logo“Cannabinoid receptor 1 (CB1) activation has been reported to reduce transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced inflammatory responses and is anti-nociceptive and anti-inflammatory in corneal injury.

We examined whether allosteric ligands, can modulate CB1 signaling to reduce pain and inflammation in corneal hyperalgesia.

Corneal hyperalgesia was generated by chemical cauterization of cornea in wildtype and CB2 knockout (CB2-/-) mice. The novel racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229 were examined alone or in combination with the orthosteric CB1 agonist Δ8-tetrahydrocannabinol (Δ8-THC). Pain responses were assessed following capsaicin (1 µM) stimulation of injured corneas at 6 h post-cauterization. Corneal neutrophil infiltration was also analyzed. GAT228, but not GAT229 or GAT211, reduced pain scores in response to capsaicin stimulation.

Combination treatments of 0.5% GAT229 or 1% GAT211 with subthreshold Δ8-THC (0.4%) significantly reduced pain scores following capsaicin stimulation. The anti-nociceptive effects of both GAT229 and GAT228 were blocked with CB1 antagonist AM251, but remained unaffected in CB2-/- mice. Two percent GAT228, or the combination of 0.2% Δ8-THC with 0.5% GAT229 also significantly reduced corneal inflammation.

CB1 allosteric ligands could offer a novel approach for treating corneal pain and inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31968549

https://www.mdpi.com/1420-3049/25/2/417

Microglial Phenotypes and Their Relationship to the Cannabinoid System: Therapeutic Implications for Parkinson’s Disease.

 Image result for molecules journal“Parkinson’s disease is a neurodegenerative disorder, the motor symptoms of which are associated classically with Lewy body formation and nigrostriatal degeneration.

Neuroinflammation has been implicated in the progression of this disease, by which microglia become chronically activated in response to α-synuclein pathology and dying neurons, thereby acquiring dishomeostatic phenotypes that are cytotoxic and can cause further neuronal death.

Microglia have a functional endocannabinoid signaling system, expressing the cannabinoid receptors in addition to being capable of synthesizing and degrading endocannabinoids. Alterations in the cannabinoid system-particularly an upregulation in the immunomodulatory CB2 receptor-have been demonstrated to be related to the microglial activation state and hence the microglial phenotype.

This paper will review studies that examine the relationship between the cannabinoid system and microglial activation, and how this association could be manipulated for therapeutic benefit in Parkinson’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31973235

“Microglia activation states and cannabinoid system: Therapeutic implications.  There is accumulating evidence indicating that cannabinoids (CBs) might serve as a promising tool to modify the outcome of inflammation, especially by influencing microglial activity. Microglia has a functional endocannabinoid (eCB) signaling system, composed of cannabinoid receptors and the complete machinery for the synthesis and degradation of eCBs. These actions make CBs a promising therapeutic tool to avoid the detrimental effects of inflammation and possibly paving the way to target microglia in order to generate a reparative milieu in neurodegenerative diseases.” https://www.ncbi.nlm.nih.gov/pubmed/27373505

“These findings imply that a hypofunction or a dysregulation of the endocannabinoid system may be responsible for some of the symptoms of these diseases. Scientific evidence shows that cannabis can provide symptomatic relief in several neurodegenerative diseases.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070159/

“Cannabinoids can have neuroprotective effects, and this can be exploited for therapeutic strategies against neurodegenerative diseases”   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243800/

The effect of orally administered dronabinol on optic nerve head blood flow in healthy subjects- a randomized clinical trial.

Publication cover image“It has been hypothesized that besides its intraocular pressure (IOP) lowering potential, tetrahydrocannabinol (THC) may also improve ocular hemodynamics.

The aim of the present study was to investigate whether single oral administration of dronabinol, a synthetic THC, alters optic nerve head blood flow (ONHBF) and its regulation in healthy subjects.

The study was carried out in a randomized, placebo-controlled, double-masked, two-way crossover design in twenty-four healthy subjects. For each study participant, two study days were scheduled, on which they either received capsules containing 5mg dronabinol or placebo. ONHBF was measured with laser Doppler flowmetry at rest and while the study participants performed isometric exercise for six minutes to increase mean arterial blood pressure (MAP). This was repeated one hour after drug intake. Ocular perfusion pressure (OPP) was calculated as 2/3MAP-IOP.

Dronabinol was well tolerated and no cannabinoid-related psychoactive effects were reported.

Neither administration of dronabinol nor placebo had an effect on IOP, MAP or OPP. In contrast, dronabinol significantly increased ONHBF at rest by 9.5±8.1% whereas placebo did not show a change in ONHBF (0.3±7.4% vs. baseline, p<0.001 between study days). Dronabinol did not alter the autoregulatory response of ONHBF to isometric exercise.

In conclusion, the present data indicate that low dose dronabinol increases ONHBF in healthy subjects without affecting IOP, OPP or inducing psychoactive side effects. In addition, dronabinol does not alter the autoregulatory response of ONHBF to an experimental increase in OPP. Further studies are needed to investigate whether this effect can also be observed in glaucoma patients.”

https://www.ncbi.nlm.nih.gov/pubmed/31977076

https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.1797

The anticonvulsant effects of cannabidiol in experimental models of epileptic seizures: from behavior and mechanisms to clinical insights.

Neuroscience & Biobehavioral Reviews“Epilepsy is a neurological disorder characterized by the presence of seizures and neuropsychiatric comorbidities. Despite the number of antiepileptic drugs, one-third of patients did not have their seizures under control, leading to pharmacoresistance epilepsy.

Cannabis sativa has been used since ancient times in Medicine for the treatment of many diseases, including convulsive seizures.

In this context, Cannabidiol (CBD), a non-psychoactive phytocannabinoid present in Cannabis, has been a promising compound for treating epilepsies due to its anticonvulsant properties in animal models and humans, especially in pharmacoresistant patients. In this review, we summarize evidence of the CBD anticonvulsant activities present in a great diversity of animal models. Special attention was given to behavioral CBD effects and its translation to human epilepsies.

CBD anticonvulsant effects are associated with a great variety of mechanisms of action such as endocannabinoid and calcium signaling. CBD has shown effectiveness in the clinical scenario for epilepsies, but its effects on epilepsy-related comorbidities are scarce even in basic research. More detailed and complex behavioral evaluation about CBD effects on seizures and epilepsy-related comorbidities are required.”

https://www.ncbi.nlm.nih.gov/pubmed/31954723

“CBD presents anticonvulsant behavioral effects in animal models of epilepsy. CBD induces neuroprotection in animal models of epileptic seizures. Multiple mechanisms of action are associated to CBD anticonvulsant effects. Animal models support CBD therapeutic use for epilepsies treatment.”

https://www.sciencedirect.com/science/article/pii/S014976341931067X?via%3Dihub

Cannabinoids CB2 Receptors, One New Promising Drug Target for Chronic and Degenerative Pain Conditions in Equine Veterinary Patients.

Journal of Equine Veterinary Science“Osteoarticular equine disease is a common cause of malady; in general, its therapy is supported on steroids and nonsteroidal anti-inflammatories. Nevertheless, many side effects may develop when these drugs are administered. Nowadays, the use of new alternatives for this pathology attention is demanded; in that sense, cannabinoid CB2 agonists may represent a novel alternative.

Cannabinoid belongs to a group of molecules known by their psychoactive properties; they are synthetized by the Cannabis sativa plant, better known as marijuana.

The aim of this study was to contribute to understand the pharmacology of cannabinoid CB2 receptors and its potential utilization on equine veterinary patients with a chronic degenerative painful condition. In animals, two main receptors for cannabinoids are recognized, the cannabinoid receptor type 1 and the cannabinoid receptor type 2. Once they are activated, both receptors exert a wide range of physiological responses, as nociception modulation.

Recently, it has been proposed the use of synthetic cannabinoid type 2 receptor agonists; those receptors looks to confer antinociceptive properties but without the undesired psychoactive side effects; for that reason, veterinary patients, whit chronical degenerative diseases as osteoarthritis may alleviate one of the most common symptom, the pain, which in some cases for several reasons, as patient individualities, or side effects produced for more conventional treatments cannot be attended in the best way.”

https://www.ncbi.nlm.nih.gov/pubmed/31952645

https://www.sciencedirect.com/science/article/abs/pii/S073708061930629X?via%3Dihub

The role of cannabinoids in the treatment of cancer.

“The aim of this review article is to summarize current knowledge about the role of cannabinoids and cannabinoid receptors in tumor disease modulation and to evaluate comprehensively the use of cannabinoids in cancer patients.

METHOD:

According to the PRISMA protocol, we have included data from a total of 105 articles.

RESULTS:

Cannabinoids affect cancer progression by three mechanisms. The most important mechanism is the stimulation of autophagy and affecting the signaling pathways leading to apoptosis. The most important mechanism of this process is the accumulation of ceramide. Cannabinoids also stimulate apoptosis by mechanisms independent of autophagy. Other mechanisms by which cannabinoids affect tumor growth are inhibition of tumor angiogenesis, invasiveness, metastasis, and the modulation of the anti-tumor immune response.

CONCLUSION:

In addition to the symptomatic therapy of cancer patients, the antitumor effects of cannabinoids (whether in monotherapy or in combination with other cancer therapies) have promising potential in the treatment of cancer patients. More clinical trials are needed to demonstrate the antitumor effect of cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/31950844

http://www.elis.sk/index.php?page=shop.product_details&flypage=flypage.tpl&product_id=6509&category_id=158&option=com_virtuemart&vmcchk=1&Itemid=1

Cannabinoid Receptor 2 Modulates Maturation of Dendritic Cells and Their Capacity to Induce Hapten-Induced Contact Hypersensitivity.

ijms-logo“Contact hypersensitivity (CHS) is an established animal model for allergic contact dermatitis. Dendritic cells (DCs) play an important role in the sensitization phase of CHS by initiating T cell responses to topically applied haptens. The cannabinoid receptors 1 (CB1) and 2 (CB2) modulate DC functions and inflammatory skin responses, but their influence on the capacity of haptenized DCs to induce CHS is still unknown. We found lower CHS responses to 2,4-dinitro-1-fluorobenzene (DNFB) in wild type (WT) mice after adoptive transfer of haptenized Cnr2-/- and Cnr1-/-/Cnr2-/- bone marrow (BM) DCs as compared to transfer of WT DCs. In contrast, induction of CHS was not affected in WT recipients after transfer of Cnr1-/- DCs. In vitro stimulated Cnr2-/- DCs showed lower CCR7 and CXCR4 expression when compared to WT cells, while in vitro migration towards the chemokine ligands was not affected by CB2. Upregulation of MHC class II and co-stimulatory molecules was also reduced in Cnr2-/- DCs. This study demonstrates that CB2 modulates the maturation phenotype of DCs but not their chemotactic capacities in vitro. These findings and the fact that CHS responses mediated by Cnr2-/- DCs are reduced suggest that CB2 is a promising target for the treatment of inflammatory skin conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/31940843

https://www.mdpi.com/1422-0067/21/2/475