Cannabis Constituents Reduce Seizure Behavior in Chemically-Induced and scn1a-mutant Zebrafish

Epilepsy and Behavior Journal | Epilepsy Foundation“Current antiepileptic drugs (AEDs) are undesirable for many reasons including the inability to reduce seizures in certain types of epilepsy, such as Dravet syndrome (DS) where in one-third of patients does not respond to current AEDs, and severe adverse effects that are frequently experienced by patients.

Epidiolex, a cannabidiol (CBD)-based drug, was recently approved for treatment of DS. While Epidiolex shows great promise in reducing seizures in patients with DS, it is used in conjunction with other AEDs and can cause liver toxicity. To investigate whether other cannabis-derived compounds could also reduce seizures, the antiepileptic effects of CBD, Δ9-tetrahydrocannabinol (THC), cannabidivarin (CBDV), cannabinol (CBN), and linalool (LN) were compared in both a chemically-induced (pentylenetetrazole, PTZ) and a DS (scn1Lab-/-) seizure models.

Cannabidiol (0.6 and 1 μM) and THC (1 and 4 μM) significantly reduced PTZ-induced total distance moved. At the highest THC concentration, the significant reduction in PTZ-induced behavior was likely the result of sedation as opposed to antiseizure activity.

In the DS model, CBD (0.6 μM), THC (1 μM), CBN (0.6 and 1 μM), and LN (4 μM) significantly reduced total distance traveled. Cannabinol was the most effective at reducing total distance relative to controls. In addition to CBD, other cannabis-derived compounds showed promise in reducing seizure-like activity in zebrafish.

Specifically, four of the five compounds were effective in the DS model, whereas in the PTZ model, only CBD and THC were, suggesting a divergence in the mode of action among the cannabis constituents.”

https://pubmed.ncbi.nlm.nih.gov/32585475/

“In the DS model, CBD, THC, CBN, and LN caused significant reduction in seizure behavior, while THC and CBD were effective in both models.”

https://linkinghub.elsevier.com/retrieve/pii/S1525505020303310

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

Cannabis Extract for the Treatment of Painful Tonic Spasms in a Patient With Neuromyelitis Optica Spectrum Disorder: A Case Report

Multiple Sclerosis and Related Disorders | Journal | ScienceDirect.com“Painful tonic spasm (PTS) is a common yet debilitating symptom in patients with neuromyelitis optica spectrum disorder (NMOSD), especially those with longitudinally extensive transverse myelitis. Although carbamazepine is an effective treatment, it poses the risk of severe adverse reactions, such as Steven-Johnson syndrome (SJS).

In this case report, we describe an NMOSD patient with severe PTS suffering from carbamazepine-induced SJS who responded well to cannabis extract. Since cannabinoids can ameliorate spasticity in an experimental autoimmune encephalomyelitis model through cannabinoid 1 (CB1) receptor activation, cannabis extract which includes delta-9-tetrahydrocannabinol (THC) is a potential treatment option for PTS in NMOSD patients.”

https://pubmed.ncbi.nlm.nih.gov/32559701/

“A cannabis extract has been approved for spasticity in multiple sclerosis (MS). Cannabis extract is a potential treatment for PTS in NMOSD patients.”

https://www.msard-journal.com/article/S2211-0348(20)30354-0/pdf

Cannabinoids as anti-ROS in Aged Pancreatic Islet Cells

Life Sciences“Cannabinoids are the chemical compounds with a high affinity for cannabinoid receptors affecting the central nervous system through the release of neurotransmitters. However, the current knowledge related to the role of such compounds in the regulation of cellular aging is limited. This study aimed to investigate the effect of cannabidiol and tetrahydrocannabinol on the function of aged pancreatic islets.

Main methods: The expression of p53, p38, p21, p16, and Glut2 genes and β-galactosidase activity were measured as hallmarks of cell aging applying real-time PCR, ELISA, and immunocytochemistry techniques. Pdx1 protein expression, insulin release, and oxidative stress markers were compared between young and aged rat pancreatic islet cells.

Key findings: Upon the treatment of aged pancreatic islets cells with cannabidiol and tetrahydrocannabinol, the expression of p53, p38, p21 and the activity of β-galactosidase were reduced. Cannabidiol and tetrahydrocannabinol increase insulin release, Pdx1, Glut2, and thiol molecules expression, while the oxidative stress parameters were decreased. The enhanced expression of Pdx1 and insulin release in aged pancreatic islet cells reflects the extension of cell healthy aging due to the significant reduction of ROS.

Significance: This study provides evidence for the involvement of cannabidiol and tetrahydrocannabinol in the oxidation process of cellular aging.”

https://pubmed.ncbi.nlm.nih.gov/32553926/

https://www.sciencedirect.com/science/article/abs/pii/S0024320520307190?via%3Dihub

Reactive oxygen species (ROS) are chemically reactive chemical species containing oxygen. ROS can damage lipid, DNARNA, and proteins, which, in theory, contributes to the physiology of aging.” https://en.wikipedia.org/wiki/Reactive_oxygen_species

Association Between Cannabis Use and Healthcare Utilization in Patients With Irritable Bowel Syndrome: A Retrospective Cohort Study

Cureus | LinkedIn“Irritable bowel syndrome (IBS) is a frequent cause of abdominal pain and altered bowel habits, which is associated with significant healthcare utilization.

The effects of the active compound of cannabis, Δ9-tetrahydrocannabinol (THC), on gut motility and tone have been studied in several experimental models. It is unknown whether these effects correlate with improved healthcare utilization among cannabis users.

The purpose of this study is to evaluate the impact of cannabis use on inpatient length of stay and resource utilization for patients with a primary discharge diagnosis of IBS.

Cannabis users were less likely to have the following: upper gastrointestinal endoscopy (17.9% vs. 26.1%; adjusted odds ratio [aOR]: 0.51 [0.36 to 0.73]; p<0.001) and lower gastrointestinal endoscopy (21.1% vs. 28.7%; aOR: 0.54 [0.39 to 0.75]; p<0.001). Additionally, cannabis users had shorter length of stay (2.8 days vs. 3.6 days; p=0.004) and less total charges (US$20,388 vs. US$23,624). There was no difference in the frequency of CT abdomen performed.

Cannabis use may decrease inpatient healthcare utilization in IBS patients. These effects could possibly be through the effect of cannabis on the endocannabinoid system.”

https://pubmed.ncbi.nlm.nih.gov/32528750/

“Our study provides evidence to suggest that cannabis use may decrease healthcare utilization and costs among hospitalized patients with IBS. These findings are likely attributable to the effects of cannabis’ active compound, THC, on gastrointestinal motility and colonic compliance. The role of cannabis in the treatment for IBS has potential for significant impact at the individual and population level given the burden of IBS on individual quality of life and healthcare expenditures.”

https://www.cureus.com/articles/30417-association-between-cannabis-use-and-healthcare-utilization-in-patients-with-irritable-bowel-syndrome-a-retrospective-cohort-study

Long-term Assessment of the Cognitive Effects of Nabiximols in Patients With Multiple Sclerosis: A Pilot Study

Clinical Neurology and Neurosurgery “Moderate to severe spasticity is commonly reported in Multiple Sclerosis (MS) and its management is still a challenge. Cannabinoids were recently suggested as add-on therapy for the treatment of spasticity and chronic pain in MS but there is no conclusive scientific evidence on their safety, especially on cognition and over long periods.

The aim of this prospective pilot study was to assess the long-term effects of a tetrahydrocannabinol-cannabidiol (THC/CBD) oromucosal spray (Sativex®) on cognition, mood and anxiety.

Results: Twenty per protocol patients were followed up and evaluated at baseline, 6 and 12 months. Domains involving processing speed and auditory verbal memory significantly improved within the first 6 months of therapy (SDMT: p < 0.001; CVLT: p = 0.0001). Mood and anxiety did not show any significant variation. Additionally, the NRS score significantly improved since the beginning (p < 0.0001).

Conclusions: These results are encouraging in supporting possible long-term benefits of Sativex on cognition and a wider role than symptom alleviator. Further studies on larger groups of patients would be necessary in order to test this intriguing possibility.”

https://pubmed.ncbi.nlm.nih.gov/32526487/

“Under Nabiximols some cognitive domains improved after 12 months, and the therapy was safely tolerated.”

https://www.sciencedirect.com/science/article/abs/pii/S0303846720303334?via%3Dihub

Δ9‐TETRAHYDROCANNABINOLIC ACID ALLEVIATES COLLAGEN‐INDUCED ARTHRITIS: ROLE OF PPARγ AND CB1 RECEPTORS

British Journal of Pharmacology “Δ9‐THCA‐A, the precursor of Δ9‐THC, is a non‐psychotropic phytocannabinoid that shows PPARγ agonistic activity. Herein, we investigated Δ9‐THCA ability to modulate classic cannabinoid receptors (CB1 and CB2) and evaluated its anti‐arthritis activity.

Experimental Approach

Cannabinoid receptors binding and intrinsic activity, as well as their downstream signaling were analyzed in vitro and in silico . The anti‐arthritis properties of Δ9‐THCA‐A were studied in human chondrocytes and in the murine model of collagen‐induced arthritis (CIA). Plasmatic disease biomarkers were identified by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) based on proteomic and ELISA assays.

Key Results

Functional and docking analyses showed that Δ9‐THCA‐A can act as an orthosteric CB1 agonist and also as a positive allosteric modulator in the presence of CP‐55,940. In addition, Δ9‐THCA‐A seemed to be an inverse agonist for CB2. In vivo experiments showed that Δ9‐THCA‐A reduced arthritis in CIA mice. Δ9‐THCA‐A prevented the infiltration of inflammatory cells; synovium hyperplasia and cartilage damage. Furthermore, Δ9‐THCA‐A inhibited the expression of inflammatory and catabolic genes on knee joints. The anti‐arthritic effect of Δ9‐THCA‐A was ablated by either SR141716 or T0070907. Analysis of plasmatic biomarkers as well as determination of cytokines and anti‐collagen antibodies confirmed that Δ9‐THCA‐A mediates its activity mainly through PPARγ and CB1 pathways.

Conclusion and Implications

Δ9‐THCA‐A modulates CB1 receptor through the orthosteric and allosteric binding sites. In addition, our studies document that Δ9‐THCA‐A exerts anti‐arthritis activity through CB1/PPARγ pathways, highlighting its potential for the treatment of chronic inflammatory diseases such as Rheumatoid Arthritis (RA).”

https://pubmed.ncbi.nlm.nih.gov/32510591/

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.15155

 British Pharmacological Society | Journals

Conversion of Cannabidiol (CBD) Into Psychotropic Cannabinoids Including Tetrahydrocannabinol (THC): A Controversy in the Scientific Literature

PubMed Overview “Cannabidiol (CBD) is a naturally occurring, non-psychotropic cannabinoid of the hemp plant Cannabis sativa L. and has been known to induce several physiological and pharmacological effects. While CBD is approved as a medicinal product subject to prescription, it is also widely sold over the counter (OTC) in the form of food supplements, cosmetics and electronic cigarette liquids. However, regulatory difficulties arise from its origin being a narcotic plant or its status as an unapproved novel food ingredient.

Regarding the consumer safety of these OTC products, the question whether or not CBD might be degraded into psychotropic cannabinoids, most prominently tetrahydrocannabinol (THC), under in vivo conditions initiated an ongoing scientific debate. This feature review aims to summarize the current knowledge of CBD degradation processes, specifically the results of in vitro and in vivo studies. Additionally, the literature on psychotropic effects of cannabinoids was carefully studied with a focus on the degradants and metabolites of CBD, but data were found to be sparse.

While the literature is contradictory, most studies suggest that CBD is not converted to psychotropic THC under in vivo conditions. Nevertheless, it is certain that CBD degrades to psychotropic products in acidic environments. Hence, the storage stability of commercial formulations requires more attention in the future.”

https://pubmed.ncbi.nlm.nih.gov/32503116/

 

Cannabinomics: Application of Metabolomics in Cannabis ( Cannabis sativa L.) Research and Development

frontiers in plant science – Retraction Watch “Cannabis (Cannabis sativa L.) is a complex, polymorphic plant species, which produces a vast array of bioactive metabolites, the two major chemical groups being cannabinoids and terpenoids. Nonetheless, the psychoactive cannabinoid tetrahydrocannabinol (Δ 9 -THC) and the non-psychoactive cannabidiol (CBD), are the two major cannabinoids that have monopolized the research interest.

Currently, more than 600 Cannabis varieties are commercially available, providing access to a multitude of potent extracts with complex compositions, whose genetics are largely inconclusive. Recently introduced legislation on Cannabis cultivation in many countries represents a great opportunity, but at the same time, a great challenge for Cannabis research and development (R&D) toward applications in the pharmaceutical, food, cosmetics, and agrochemical industries.

Based on its versatility and unique capabilities in the deconvolution of the metabolite composition of complex matrices, metabolomics represents an ideal bioanalytical tool that could greatly assist and accelerate Cannabis R&D. Among others, Cannabis metabolomics or cannabinomics can be applied in the taxonomy of Cannabis varieties in chemovars, the research on the discovery and assessment of new Cannabis-based sources of bioactivity in medicine, the development of new food products, and the optimization of its cultivation, aiming for improvements in yield and potency.

Although Cannabis research is still in its infancy, it is highly foreseen that the employment of advanced metabolomics will provide insights that could assist the sector to face the aforementioned challenges. Within this context, here, the current state-of-the-art and conceptual aspects of cannabinomics are presented.”

https://pubmed.ncbi.nlm.nih.gov/32457786/

https://www.frontiersin.org/articles/10.3389/fpls.2020.00554/full

www.frontiersin.org

Nabiximols Plus Robotic Assisted Gait Training in Improving Motor Performances in People With Multiple Sclerosis

szklerózis multiplex Archives | Magyar Orvosi Kannabisz Egyesület“Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, affecting ambulation even in people with only mild neurological signs. Patients with MS frequently experience spasticity, which contributes significantly to impair their motor functions, including ambulation, owing to muscle stiffness, spasms, and pain.

Objectives: To clarify the role of delta-9-tetrahydrocannabinol(THC):cannabidiol(CBD) oromucosal spray, coupled to robot-aided gait training (RAGT) using the Lokomat©Pro to improve functional ambulation in patients with MS.

Methods: We compared 20 patients with MS, who were treated with THC:CBD oromucosal spray in add-on to the ongoing oral antispastic therapy (OAT) (group A), with 20 individuals with MS (matched for clinical-demographic characteristics) who were treated only with OAT (group B). Both the groups underwent RAGT using the Lokomat-Pro (three 45-minute sessions per week). Our primary outcome measures were the Functional Independence Measure (FIM) and the 10 meters walking test (10MWT). As secondary outcome measures we evaluated the brain cortical excitability by using Transcranial Magnetic Stimulation. Both parameters were taken before and after the end of the RAGT.

Results: FIM improved in group A more than in group B (p<0.001). Moreover, 10MWT decreased in group A more than in group B (p<0.001). These clinical findings were paralleled by a more evident reshape of intracortical excitability in both upper and lower limbs, as suggested by motor evoked potential amplitude increase (p<0.001), intracortical inhibition strengthening (p<0.001), and intracortical facilitation decrease (p=0.01) in group A as compared to group B.

Conclusions: Our results suggest that the combined THC:CBD-RAGT approach could be useful in improving gait performance in patients with MS.”

https://pubmed.ncbi.nlm.nih.gov/32447249/

“The coupled therapy is preliminarily demonstrated as safe and efficacious.”

https://www.msard-journal.com/article/S2211-0348(20)30253-4/pdf