Tag Archives: CBD

Tetrahydrocannabinol and cannabidiol oromucosal spray in resistant multiple sclerosis spasticity: consistency of response across subgroups from the SAVANT randomized clinical trial.

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 Publication Cover“To determine whether differences in disability status, spasticity severity, and spasticity duration at treatment start in patients with resistant multiple sclerosis (MS) spasticity might influence response to add-on tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (nabiximols) versus further re-adjustment of optimized first-line antispasticity medication.

Methods: Using the database from the Sativex® as Add-on therapy Vs. further optimized first-line ANTispastics (SAVANT) study, this post hoc analysis evaluated spasticity severity (0-10 Numerical Rating Scale [NRS] scores) and pain severity (0-10 NRS scores) evolution from randomization (baseline) to week 12 (end of double-blind treatment) in defined subgroups: Expanded Disability Status Scale [EDSS] score subgroups (< 6 and ≥6); spasticity severity 0-10 NRS score subgroups (4 to ≤6 and >6), and spasticity duration subgroups (< 5 and ≥5 years).

Results: THC:CBD oromucosal spray (nabiximols) halved mean severity scores for spasticity and pain in all subgroups. Active treatment significantly improved mean spasticity severity scores versus placebo from week 4 onwards in both EDSS subgroups, in the severe spasticity subgroup, and in both spasticity duration subgroups. Active treatment significantly improved mean pain severity scores versus placebo in the ≥6 EDSS subgroup, in the severe spasticity subgroup and in both spasticity duration subgroups.

Conclusion: Add-on THC:CBD oromucosal spray (nabiximols) consistently relieves resistant spasticity across subgroups defined by baseline EDSS score, spasticity severity NRS score and spasticity duration. Patients with moderate resistant MS spasticity benefit numerically from treatment; patients with severe resistant spasticity achieve significant therapeutic gains. Spasticity-associated pain often improves similarly in the same subgroups.”

https://www.ncbi.nlm.nih.gov/pubmed/32065006

https://www.tandfonline.com/doi/abs/10.1080/00207454.2020.1730832?journalCode=ines20

Phytocannabinoids promote viability and functional adipogenesis of bone marrow-derived mesenchymal stem cells through different molecular targets.

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Biochemical Pharmacology“The cellular microenvironment plays a critical role in the maintenance of bone marrow-derived mesenchymal stem cells (BM-MSCs) and their subsequent cell lineage differentiation. Recent studies suggested that individuals with adipocyte-related metabolic disorders have altered function and adipogenic potential of adipose stem cell subpopulations, primarily BM-MSCs, increasing the risk of heart attack, stroke or diabetes.

In this study, we explored the potential therapeutic effect of some of the most abundant non-euphoric compounds derived from the Cannabis sativa plant (or phytocannabinoids) including tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabigerol (CBG), cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), by analysing their pharmacological activity on the viability of endogenous BM-MSCs as well as their ability to alter BM-MSC proliferation and differentiation into mature adipocytes.

We provide evidence that CBD, CBDA, CBGA and THCV (5 µM) increase the number of viable BM-MSCs; whereas only CBG (5 µM) and CBD (5 µM) alone or in their combination promote their maturation into adipocytes via distinct molecular mechanisms. These effects were revealed both in vitro and in vivo. In addition, phytocannabinoids prevented the insulin signalling impairment induced by palmitate in adipocytes differentiated from BM-MSCs.

Our study highlights phytocannabinoids as a potential novel pharmacological tool to regain control of functional adipose tissue in unregulated energy homeostasis often occurring in metabolic disorders including type 2 diabetes mellitus (T2DM), aging and lipodystrophy.”

https://www.ncbi.nlm.nih.gov/pubmed/32061773

“The promiscuous pharmacology of phytocannabinoids makes them viable candidates for new medicines for the treatment of metabolic syndromes through the simultaneous resolution of collective complications due to impaired development, maintenance, activity and function of the adipose tissue. Furthermore, phytocannabinoids are generally well tolerated in comparison to potent synthetic PPAR agonists, and combination treatments may further improve their efficacy at lower doses.”

https://www.sciencedirect.com/science/article/pii/S0006295220300873?via%3Dihub

Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D and 3D glioblastoma cell cultures.

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 Scientific Reports“Radiotherapy combined with chemotherapy is the major treatment modality for human glioblastoma multiforme (GBM). GBMs eventually relapse after treatment and the average survival of GBM patients is less than two years.

There is some evidence that cannabidiol (CBD) can induce cell death and increases the radiosensitivity of GBM by enhancing apoptosis. Beside initiation of death, CBD has been demonstrated as an inducer of autophagy.

In the present study, we address the question whether CBD simultaneously induces a protective effect in GBM by upregulating autophagy. Addition of chloroquine that suppressed autophagic flux to 2D GBM cultures increased CBD-induced cell death, presenting proof for the protective autophagy.

Blockage of autophagy upregulated radiation-induced cytotoxicity but only modestly affected the levels of cell death in CBD- or CBD/γ-irradiated 3D GBM cultures. Furthermore, CBD enhanced the pro-apoptotic activities of JNK1/2 and MAPK p38 signaling cascades while partially downregulated the pro-survival PI3K-AKT cascade, thereby changing a balance between cell death and survival.

Suppression of JNK activation partially reduced CBD-induced cell death in 3D GBM cultures. In contrast, co-treatment of CBD-targeted cells with inhibitors of PI3K-AKT-NF-κB, IKK-NF-κB or JAK2-STAT3 pathways killed surviving GBM cells in both 2D and 3D cultures, potentially improving the therapeutic ratio of GBM.”

https://www.ncbi.nlm.nih.gov/pubmed/32060308

“Killing efficiency of cannabinoids (CBD, THC and their combination CBD+THC) against GBM in vitro and in animal experiments has been elucidated in numerous studies during the last 15 years. Additional investigations also confirmed a cytotoxic role of cannabinoids for several other types of cancer. A number of studies demonstrated the efficiency of combined treatments of cannabinoids together with γ-irradiation in both cell culture and in animal experiments.”

https://www.nature.com/articles/s41598-020-59468-4

The proposed mechanisms of action of CBD in epilepsy.

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Image result for epileptic disorders journal“Highly purified cannabidiol (CBD) (approved as Epidiolex® in the United States and as EPIDYOLEX from the EU agency) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials. While the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, CBD possesses affinity for multiple targets, across a range of target classes, resulting in functional modulation of neuronal excitability, relevant to the pathophysiology of many disease types, including epilepsy. Here we present the pharmacological data supporting the role of three such targets, namely Transient receptor potential vanilloid-1 (TRPV1), the orphan G protein-coupled receptor-55 (GPR55) and the equilibrative nucleoside transporter 1 (ENT-1).”

 https://www.ncbi.nlm.nih.gov/pubmed/32053110
https://www.jle.com/fr/revues/epd/e-docs/the_proposed_mechanisms_of_action_of_cbd_in_epilepsy_316095/article.phtml

Cannabidiol treatment in an adolescent with multiple substance abuse, social anxiety and depression.

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 “In this report, we present a case of a 16,9-year-old patient with multiple substance use disorder (cannabis, MDMA, cocaine, ecstacy), severe depression, social phobia and narcissistic personality disorder.We administered Cannabidiol (CBD) capsules in different dosages (starting dosage 100 mg up to 600 mg over 8 weeks) after unsuccessful treatment with antidepressants.

CBD was a safe and well tolerated medication for this patient. Upon treatment with CBD and cessation of the antidepressant medication, the patient improved regarding depressive as well as anxiety symptoms including simple phobias and symptoms of paranoia and dissociation.

Furthermore, the patient quit abusing illegal drugs including THC without showing withdrawal symptoms. This is the first report of CBD medication in a patient with multiple substance use disorder with a positive outcome.Until today it is not clear if CBD holds promise as a therapeutic option in substance use disorder as RCTs are lacking, but in this single case the substance seems to work in various domains.”

https://www.ncbi.nlm.nih.gov/pubmed/32052321

https://link.springer.com/article/10.1007%2Fs40211-020-00334-0

Cannabinoid receptor expression in non-small cell lung cancer. Effectiveness of tetrahydrocannabinol and cannabidiol inhibiting cell proliferation and epithelial-mesenchymal transition in vitro.

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Image result for plos one “Patients with non-small cell lung cancer (NSCLC) develop resistance to antitumor agents by mechanisms that involve the epithelial-to-mesenchymal transition (EMT). This necessitates the development of new complementary drugs, e.g., cannabinoid receptors (CB1 and CB2) agonists including tetrahydrocannabinol (THC) and cannabidiol (CBD).

The combined use of THC and CBD confers greater benefits, as CBD enhances the effects of THC and reduces its psychotropic activity. We assessed the relationship between the expression levels of CB1 and CB2 to the clinical features of a cohort of patients with NSCLC, and the effect of THC and CBD (individually and in combination) on proliferation, EMT and migration in vitro in A549, H460 and H1792 lung cancer cell lines.

METHODS:

Expression levels of CB1, CB2, EGFR, CDH1, CDH2 and VIM were evaluated by quantitative reverse transcription-polymerase chain reaction. THC and CBD (10-100 μM), individually or in combination (1:1 ratio), were used for in vitro assays. Cell proliferation was determined by BrdU incorporation assay. Morphological changes in the cells were visualized by phase-contrast and fluorescence microscopy. Migration was studied by scratch recolonization induced by 20 ng/ml epidermal growth factor (EGF).

RESULTS:

The tumor samples were classified according to the level of expression of CB1, CB2, or both. Patients with high expression levels of CB1, CB2, and CB1/CB2 showed increased survival reaching significance for CB1 and CB1/CB2 (p = 0.035 and 0.025, respectively).

Both cannabinoid agonists inhibited the proliferation and expression of EGFR in lung cancer cells, and CBD potentiated the effect of THC. THC and CBD alone or in combination restored the epithelial phenotype, as evidenced by increased expression of CDH1 and reduced expression of CDH2 and VIM, as well as by fluorescence analysis of cellular cytoskeleton.

Finally, both cannabinoids reduced the in vitro migration of the three lung cancer cells lines used.

CONCLUSIONS:

The expression levels of CB1 and CB2 have a potential use as markers of survival in patients with NSCLC. THC and CBD inhibited the proliferation and expression of EGFR in the lung cancer cells studied. Finally, the THC/CBD combination restored the epithelial phenotype in vitro.”

https://www.ncbi.nlm.nih.gov/pubmed/32049991

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228909

Targeting GPCRs Against Cardiotoxicity Induced by Anticancer Treatments.

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Image result for frontiers in cardiovascular medicine“Novel anticancer medicines, including targeted therapies and immune checkpoint inhibitors, have greatly improved the management of cancers. However, both conventional and new anticancer treatments induce cardiac adverse effects, which remain a critical issue in clinic.

Cardiotoxicity induced by anti-cancer treatments compromise vasospastic and thromboembolic ischemia, dysrhythmia, hypertension, myocarditis, and cardiac dysfunction that can result in heart failure. Importantly, none of the strategies to prevent cardiotoxicity from anticancer therapies is completely safe and satisfactory.

Certain clinically used cardioprotective drugs can even contribute to cancer induction. Since G protein coupled receptors (GPCRs) are target of forty percent of clinically used drugs, here we discuss the newly identified cardioprotective agents that bind GPCRs of adrenalin, adenosine, melatonin, ghrelin, galanin, apelin, prokineticin and cannabidiol.

We hope to provoke further drug development studies considering these GPCRs as potential targets to be translated to treatment of human heart failure induced by anticancer drugs.”

https://www.ncbi.nlm.nih.gov/pubmed/32039239

https://www.frontiersin.org/articles/10.3389/fcvm.2019.00194/full

“Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis.”  https://www.ncbi.nlm.nih.gov/pubmed/25569804

Adjunctive Cannabidiol in Patients with Dravet Syndrome: A Systematic Review and Meta-Analysis of Efficacy and Safety.

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 “Dravet syndrome (DS) is one of the most severe forms of drug-resistant epilepsy and available interventions fail to control seizures in most patients.

Cannabidiol (CBD) is the first in a new class of antiepileptic drugs with a distinctive chemical structure and mechanism of action.

The aim of this systematic review was to evaluate the efficacy and safety of CBD as adjunctive treatment for seizures in patients with DS using meta-analytical techniques.

CONCLUSIONS:

Adjunctive CBD resulted in a greater reduction in convulsive seizure frequency than placebo and a higher rate of AEs in patients with DS presenting with seizures uncontrolled by concomitant antiepileptic therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/32040850

https://link.springer.com/article/10.1007%2Fs40263-020-00708-6

Abrupt withdrawal of cannabidiol (CBD): A randomized trial.

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Cover image volume 103, Issue “The rationale of this study was to assess occurrence of withdrawal symptoms induced by abrupt cessation of cannabidiol (CBD) after prolonged administration in healthy volunteers.

CONCLUSION:

In healthy volunteers, no evidence of withdrawal syndrome was found with abrupt discontinuation of short-term treatment with CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/32036242

“There was no evidence of a physical withdrawal syndrome after abrupt cessation of CBD.”

https://www.epilepsybehavior.com/article/S1525-5050(19)31116-3/fulltext

“Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa” https://www.ncbi.nlm.nih.gov/pubmed/19690824

Neuroprotective effect of chronic administration of cannabidiol during the abstinence period on methamphetamine-induced impairment of recognition memory in the rats.

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“Neuropsychiatric disorders, such as addiction, are associated with cognitive impairment, including learning and memory deficits.

Previous research has demonstrated that the chronic use of methamphetamine (METH) induces long-term cognitive impairment and cannabidiol (CBD), as a neuroprotectant, can reverse spatial memory deficits induced by drug abuse.

The study aimed to evaluate the effect of CBD on METH-induced memory impairment in rats chronically exposed to METH (CEM).

For the induction of CEM, animals received METH (2 mg/kg, twice/day) for 10 days. Thereafter, the effect of intracerebroventricular (ICV) administration of CBD (32 and 160 nmol) during the (10 days) abstinence period on spatial memory was evaluated using the Y-Maze test, while recognition memory was examined using the novel object recognition (NOR) test.

The results revealed a significant increase in the motor activity of METH-treated animals compared with the control group and, after the 10-day abstinence period, motor activity returned to baseline. Notably, the chronic administration of METH had impairing effects on spontaneous alternation performance and recognition memory, which was clearly observed in the NOR test.

Additionally, although the ICV administration of CBD (160 nmol) could reverse long-term memory, a lower dose (32 nmol) did not result in any significant increase in exploring the novel object during short-term memory testing.

These novel findings suggest that the chronic administration of METH induces memory impairment and presents interesting implications for the potential use of CBD in treating impairment deficits after chronic exposure to psychostimulant drugs such as METH.”

https://www.ncbi.nlm.nih.gov/pubmed/32032100

https://journals.lww.com/behaviouralpharm/Abstract/publishahead/Neuroprotective_effect_of_chronic_administration.99194.aspx