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

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Recent Cannabis Use in HIV Is Associated With Reduced Inflammatory Markers in CSF and Blood

 Home“Objective: To determine whether cannabis may reduce HIV-related persistent inflammation, we evaluated the relationship of cannabis use in people with HIV (PWH) to inflammatory cytokines in CSF and blood plasma.

Conclusions: Recent cannabis use was associated with lower levels of inflammatory biomarkers, both in CSF and blood, but in different patterns. These results are consistent with compartmentalization of immune effects of cannabis. The principal active components of cannabis are highly lipid soluble and sequestered in brain tissue; thus, our findings are consistent with specific anti-neuroinflammatory effects that may benefit HIV neurologic dysfunction.”

https://pubmed.ncbi.nlm.nih.gov/32554630/

https://nn.neurology.org/content/7/5/e809

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

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

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Chronic Cannabidiol Alters Genome-Wide DNA Methylation in Adult Mouse Hippocampus: Epigenetic Implications for Psychiatric Disease

Environmental and Molecular Mutagenesis“Cannabidiol (CBD) is the primary non-psychoactive compound found in cannabis (Cannabis sativa) and an increasingly popular dietary supplement as a result of widespread availability of CBD-containing products.

CBD is FDA-approved for the treatment of epilepsy and exhibits anxiolytic, antipsychotic, prosocial, and other behavioral effects in animal and human studies, however, the underlying mechanisms governing these phenotypes are still being elucidated. The epigenome, particularly DNA methylation, is responsive to environmental input and can govern persistent patterns of gene regulation affecting phenotype across the life course.

In order to understand the epigenomic activity of chronic cannabidiol exposure in the adult brain, 12-week-old male C57BL/6 mice were exposed to either 20 mg/kg CBD or vehicle daily by oral administration for fourteen days. Hippocampal tissue was collected and reduced-representation bisulfite sequencing (RRBS) was performed. Analyses revealed 3,323 differentially methylated loci (DMLs) in CBD-exposed animals with a small skew toward global hypomethylation.

Genes for cell adhesion and migration, dendritic spine development, and excitatory postsynaptic potential were found to be enriched in a gene ontology term analysis of DML-containing genes, and disease ontology enrichment revealed an overrepresentation of DMLs in gene sets associated with autism spectrum disorder, schizophrenia, and other phenotypes.

These results suggest that the epigenome may be a key substrate for CBD’s behavioral effects and provides a wealth of gene regulatory information for further study.”

https://pubmed.ncbi.nlm.nih.gov/32579259/

https://onlinelibrary.wiley.com/doi/abs/10.1002/em.22396

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

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

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Cannabidiol Anticonvulsant Effect Is Mediated by the PI3Kγ Pathway

Neuropharmacology“The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt)/mechanistic target of rapamycin (mTOR) signaling pathway has been associated with several pathologies in the central nervous system (CNS), including epilepsy. There is evidence supporting the hypothesis that the PI3Kγ signaling pathway may mediate the powerful anticonvulsant properties associated with the cannabinoidergic system.

This work aims to investigate if the anticonvulsant and neuroprotective effects of cannabidiol (CBD) are mediated by PI3Kγ.

CDB increased latency and reduced the severity of pilocarpine-induced behavioral seizures, as well as prevented postictal changes, such as neurodegeneration, microgliosis and astrocytosis, in WT animals, but not in PI3Kγ-/-. CBD in vivo effects were abolished by pharmacological inhibition of cannabinoid receptor or mTOR. In vitro, PI3Kγ inhibition or deficiency also changed CBD protection observed in glutamate-induced cell death assay. Thus, we suggest that the modulation of PI3K/mTOR signaling pathway is involved in the anticonvulsant and neuroprotective effects of CBD.

These findings are important not only for the elucidation of the mechanisms of action of CBD, which are currently poorly understood, but also to allow the prediction of therapeutic and side effects, ensuring efficacy and safety in the treatment of patients with epilepsy.”

https://pubmed.ncbi.nlm.nih.gov/32574650/

“CBD is anticonvulsant in a model of pilocarpine-induced behavioral seizures. CB1 receptor mediates the effects of CBD. PI3Kγ pathway mediates the anticonvulsant neuroprotective effects of CBD.”

https://www.sciencedirect.com/science/article/abs/pii/S0028390820302240?via%3Dihub

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Current Application of Cannabidiol (CBD) in the Management and Treatment of Neurological Disorders

SpringerLink“Cannabidiol (CBD), which is nonintoxicating pharmacologically relevant constituents of Cannabis, demonstrates several beneficial effects. It has been found to have antioxidative, anti-inflammatory, and neuroprotective effects. As the medicinal use of CBD is gaining popularity for treatment of various disorders, the recent flare-up of largely unproven and unregulated cannabis-based preparations on medical therapeutics may have its greatest impact in the field of neurology. Currently, as lot of clinical trials are underway, CBD demonstrates remarkable potential to become a supplemental therapy in various neurological conditions. It has shown promise in the treatment of neurological disorders such as anxiety, chronic pain, trigeminal neuralgia, epilepsy, and essential tremors as well as psychiatric disorders. While recent FDA-approved prescription drugs have demonstrated safety, efficacy, and consistency enough for regulatory approval in spasticity in multiple sclerosis (MS) and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges still remain. In the current review, the authors have shed light on the application of CBD in the management and treatment of various neurological disorders.”

https://pubmed.ncbi.nlm.nih.gov/32556748/

https://link.springer.com/article/10.1007%2Fs10072-020-04514-2

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Plant Derived Versus Synthetic Cannabidiol: Wishes and Commitment of Epilepsy Patients

 cannabidiol | www.thctotalhealthcare.com“A special component of cannabis, cannabidiol (CBD), is currently in the focus of epilepsy treatment and research. In this context, we investigated patients’ expectations and preferences pertaining to plant-derived versus synthetic formulation of cannabidiol, as well as their willingness to get this treatment.

Methods: One hundred and four of 153 patients with different forms of epilepsy (54 % female, mean age 40 ± 16 yrs.) responded to the survey. The survey consisted of 8 questions addressing expectations of and concerns towards CBD treatment, preferences of plant-derived versus synthetic CBD, estimated monthly costs, and willingness to buy CBD at one’s own expense.

Results: The majority (73 %) of the responding epilepsy patients wished to receive plant-derived CBD; 5 % preferred synthetic CBD. Reasons for this choice were botanic origin, lack of chemistry, and the assumption of fewer and less dangerous side effects. Eighty-two percent of the patients estimated the monthly costs of CBD treatment to be below €500. Using the willingness-to-pay approach to assess the commitment of patients, 68 % could imagine buying the drug themselves. Fifty-three percent of these would be willing to pay up to €100, 40 % €100 to €200, and another 7 % €200 to €500 per month.

Conclusion: There is an overwhelming preference towards plant-derived cannabidiol in epilepsy patients, driven by the idea of organic substances being safer and better tolerated than synthetic. The willingness-to-pay approach reflects the high burden and pressure of uncontrolled epilepsy and the expectation of relief. Non-realistic ideas of pricing as well as what patients would be willing and able to pay confirm this perception.”

https://pubmed.ncbi.nlm.nih.gov/32554292/

“Epilepsy patients preferred plant-derived cannabidiol to synthetic cannabidiol.”

https://www.seizure-journal.com/article/S1059-1311(20)30175-8/pdf

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

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

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

A Cross-Sectional and Prospective Comparison of Medicinal Cannabis Users and Controls on Self-Reported Health

View details for Cannabis and Cannabinoid Research cover image“Despite widespread legalization, the impact of medicinal cannabis use on patient-level health and quality of life (QOL) has not been carefully evaluated.

The objective of this study was to characterize self-reported demographics, health characteristics, QOL, and health care utilization of Cannabis Users compared with Controls.

Results: Cannabis Users self-reported significantly better QOL [t(1054)=−4.19, p<0.001], greater health satisfaction [t(1045)=−4.14, p<0.001], improved sleep [children: t(224)=2.90, p<0.01; adults: [t(758)=3.03, p<0.01], lower average pain severity [t(1150)=2.34, p<0.05], lower anxiety [t(1151)=4.38, p<0.001], and lower depression [t(1210)=5.77, p<0.001] compared with Controls. Cannabis Users reported using fewer prescription medications (rate ratio [RR]=0.86; 95% confidence interval [CI]: 0.77–0.96) and were less likely to have a past-month emergency department visit (RR=0.61; 95% CI: 0.44–0.84) or hospital admission (RR=0.54; 95% CI: 0.34–0.87). Controls who initiated cannabis use after baseline showed significant health improvements at follow-up, and the magnitude of improvement mirrored the between-group differences observed at baseline.

Conclusions: Cannabis use was associated with improved health and QOL. Longitudinal testing suggests that group differences may be due to the medicinal use of cannabis. Although bias related to preexisting beliefs regarding the health benefits of cannabis in this sample should be considered, these findings indicate that clinical trials evaluating the efficacy of defined cannabinoid products for specific health conditions are warranted.

The key finding of this study is that medicinal cannabis use was associated with more positive ratings of health and QOL, assessed across multiple domains. Prospective analyses found that Controls showed improvement in health and QOL if they initiated medicinal cannabis use, and that Cannabis Users showed diminished health and QOL if they stopped cannabis use.”

https://www.liebertpub.com/doi/full/10.1089/can.2019.0096

“The Health Benefits of Medical Marijuana As Reported by Users. Using cannabis for medical reasons has been linked in a study to outcomes including better sleep, less anxiety, and taking fewer prescription medications.” https://www.newsweek.com/health-benefits-medical-marijuana-users-1511647

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous