Tag Archives: cannabis

Targeting the Endocannabinoid CB1 Receptor to Treat Body Weight Disorders: A Preclinical and Clinical Review of the Therapeutic Potential of Past and Present CB1 Drugs

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biomolecules-logo“Obesity rates are increasing worldwide and there is a need for novel therapeutic treatment options.

The endocannabinoid system has been linked to homeostatic processes, including metabolism, food intake, and the regulation of body weight.

Rimonabant, an inverse agonist for the cannabinoid CB1 receptor, was effective at producing weight loss in obese subjects. However, due to adverse psychiatric side effects, rimonabant was removed from the market.

More recently, we reported an inverse relationship between cannabis use and BMI, which has now been duplicated by several groups.

As those results may appear contradictory, we review here preclinical and clinical studies that have studied the impact on body weight of various cannabinoid CB1 drugs. Notably, we will review the impact of CB1 inverse agonists, agonists, partial agonists, and neutral antagonists.

Those findings clearly point out the cannabinoid CB1 as a potential effective target for the treatment of obesity. Recent preclinical studies suggest that ligands targeting the CB1 may retain the therapeutic potential of rimonabant without the negative side effect profile. Such approaches should be tested in clinical trials for validation.”

https://pubmed.ncbi.nlm.nih.gov/32512776/

https://www.mdpi.com/2218-273X/10/6/855

Medicinal Cannabis Effective for Chronic Insomnia in Clinical Trial

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April 2020 cover“A randomized double-blind clinical trial evaluating the efficacy of a medicinal cannabis formulation (ZTL-101; Zelira Therapeutics Ltd, Perth, Australia) for treating chronic insomnia showed that the therapy is effective and safe.

Participants treated with medicinal cannabis went to sleep faster, slept significantly longer, and went back to sleep sooner after waking. Those participants reported significant improvements in quality of life, including feeling rested after sleep, feeling less stressed and less fatigued, and overall improved functioning.

For the trial, 23 participants were treated with the therapy for 14 nights, and after a 1-week washout period, received a placebo for 14 nights. Each participant took a single dose (.5 ml of 11.5 mg total cannabinoids) or a double dose (1 ml of 23 mg total cannabinoids) of the therapy, delivered sublingually, according to their symptoms.

“The fact that ZTL-101 treatment achieved statistically significant, dose-responsive improvements across a broad range of key insomnia indices is impressive, particularly given the relatively short 2-week dosing window,” said Peter Eastwood, director, Centre for Sleep Science, University of Western Australia.”

https://practicalneurology.com/news/medicinal-cannabis-effective-for-chronic-insomnia-in-clinical-trial

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

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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

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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/

 

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

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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

Evaluation of Repeated or Acute Treatment With Cannabidiol (CBD), Cannabidiolic Acid (CBDA) or CBDA Methyl Ester (HU-580) on Nausea and/or Vomiting in Rats and Shrews

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 SpringerLink“Rationale: When acutely administered intraperitoneally, the non-psychoactive cannabinoid cannabidiol (CBD), its acidic precursor cannabidiolic acid (CBDA) and a stable methyl ester of CBDA (HU-580) reduce lithium chloride (LiCl)-induced conditioned gaping in male rats (a selective preclinical model of acute nausea) via activation of the serotonin 1A (5-HT1A) receptor.

Objectives: To utilise these compounds to manage nausea in the clinic, we must determine if their effectiveness is maintained when injected subcutaneously (s.c) and when repeatedly administered. First, we compared the effectiveness of each of these compounds to reduce conditioned gaping following repeated (7-day) and acute (1-day) pretreatments and whether these anti-nausea effects were mediated by the 5-HT1A receptor. Next, we assessed whether the effectiveness of these compounds can be maintained when administered prior to each of 4 conditioning trials (once per week). We also evaluated the ability of repeated CBD (7 days) to reduce LiCl-induced vomiting in Suncus murinus. Finally, we examined whether acute CBD was equally effective in male and female rats.

Results: Both acute and repeated (7 day) s.c. administrations of CBD (5 mg/kg), CBDA (1 μg/kg) and HU-580 (1 μg/kg) similarly reduced LiCl-induced conditioned gaping, and these effects were blocked by 5HT1A receptor antagonism. When administered over 4 weekly conditioning trials, the anti-nausea effectiveness of each of these compounds was also maintained. Repeated CBD (5 mg/kg, s.c.) maintained its anti-emetic efficacy in S. murinus. Acute CBD (5 and 20 mg/kg, s.c.) administration reduced LiCl-induced conditioned gaping similarly in male and female rats.

Conclusion: When administered repeatedly (7 days), CBD, CBDA and HU-580 did not lose efficacy in reducing nausea and continued to act via agonism of the 5-HT1A receptor. When administered across 4 weekly conditioning trials, they maintained their effectiveness in reducing LiCl-induced nausea. Repeated CBD also reduced vomiting in shrews. Finally, CBD’s anti-nausea effects were similar in male and female rats. This suggests that these cannabinoids may be useful anti-nausea and anti-emetic treatments for chronic conditions, without the development of tolerance.”

https://pubmed.ncbi.nlm.nih.gov/32488349/

https://link.springer.com/article/10.1007%2Fs00213-020-05559-z

Cannabidiol Disrupts Conditioned Fear Expression and Cannabidiolic Acid Reduces Trauma-Induced Anxiety-Related Behaviour in Mice

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Behavioural Pharmacology (journal) - Wikipedia“The major phytocannabinoid cannabidiol (CBD) has anxiolytic properties and lacks tetrahydrocannabinol-like psychoactivity. Cannabidiolic acid (CBDA) is the acidic precursor to CBD, and this compound appears more potent than CBD in animal models of emesis, pain and epilepsy. In this short report, we aimed to examine whether CBDA is more potent than CBD in disrupting expression of conditioned fear and generalised anxiety-related behaviour induced by Pavlovian fear conditioning. Mice underwent fear conditioning and 24 h later were administered CBD and CBDA before testing for fear expression and generalized anxiety-like behaviour. We found that CBD and CBDA had dissociable effects; while CBD but not CBDA disrupted cued fear memory expression, CBDA but not CBD normalized trauma-induced generalized anxiety-related behaviour. Neither phytocannabinoid affected contextual fear expression. Our findings form the basis for future experiments examining whether phytocannabinoids, alone and in combination, are effective in these mouse models of fear and anxiety.”

https://pubmed.ncbi.nlm.nih.gov/32483052/

https://journals.lww.com/behaviouralpharm/Abstract/9000/Cannabidiol_disrupts_conditioned_fear_expression.99176.aspx

A Pilot Randomised Placebo-Controlled Trial of Cannabidiol to Reduce Severe Behavioural Problems in Children and Adolescents With Intellectual Disability

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 British Journal of Clinical Pharmacology“Introduction: Severe Behavioural Problems (SBP) are a major contributor to morbidity in children with Intellectual Disability (ID). Medications used to treat SBP in ID are associated with a high risk of side effects. Cannabidiol has potential therapeutic effects in SBP. This pilot study aimed to investigate the feasibility of conducting a randomized placebo-controlled trial of cannabidiol to reduce SBP in children with ID.

Methods: Double-blind, placebo-controlled, two-armed, parallel-design, randomised controlled trial of cannabidiol in children aged 8 – 16 years with ID and SBP. Participants were randomized 1:1 to receive either 98% cannabidiol in oil (Tilray, Canada) or placebo orally for 8 weeks. The dose was up-titrated over 9 days to 20mg/kg/day in two divided doses, with a maximum dose of 500mg twice/day. The feasibility and acceptability of all study components were assessed.

Results: Eight children were randomised, and all completed the full study protocol. There were no Serious Adverse Events or drop-outs. Protocol adherence for key study components was excellent: study visits 100%, medication adherence 100%, blood tests 92%, and questionnaire completion 88%. Parents reported a high degree of acceptability with the study design. All parents reported they would recommend the study to other families with children with similar problems. There was an efficacy signal in favour of active drug.

Conclusions: The findings suggest that the study protocol is feasible and acceptable to patients with ID and SBP and their families.”

https://pubmed.ncbi.nlm.nih.gov/32478863/

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bcp.14399

High Expression of Cannabinoid Receptor 2 on Cytokine-Induced Killer Cells and Multiple Myeloma Cells

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ijms-logo“Multiple myeloma (MM) is characterized by aberrant bone marrow plasma cell (PC) proliferation and is one of the most common hematological malignancies. The potential effect of cannabinoids on the immune system and hematological malignancies has been poorly characterized.

Cannabidiol (CBD) may be used to treat various diseases. CBD is known to exert immunomodulatory effects through the activation of cannabinoid receptor 2 (CB2), which is expressed in high levels in the hematopoietic system.

Cytokine-induced killer (CIK) cells are a heterogeneous population of polyclonal T lymphocytes obtained via ex vivo sequential incubation of peripheral blood mononuclear cells (PBMCs) with interferon-γ (IFN-γ), anti CD3 monoclonal antibody, and IL-2. They are characterized by the expression of CD3+ and CD56+, which are surface markers common to T lymphocytes and natural killer (NK) cells. CIK cells are mainly used in hematological patients who suffer relapse after allogeneic transplantation.

Here, we investigated their antitumor effect in combination with pure cannabidiol in KMS-12 MM cells by lactate dehydrogenase LDH cytotoxicity assay, CCK-8 assay, and flow cytometry analysis. The surface and intracellular CB2 expressions on CIK cells and on KMS-12 and U-266 MM cell lines were also detected by flow cytometry.

Our findings confirm that the CB2 receptor is highly expressed on CIK cells as well as on MM cells. CBD was able to decrease the viability of tumor cells and can have a protective role for CIK cells. It also inhibits the cytotoxic activity of CIKs against MM at high concentrations, so in view of a clinical perspective, it has to be considered that the lower concentration of 1 µM can be used in combination with CIK cells. Further studies will be required to address the mechanism of CBD modulation of CIK cells in more detail.”

https://pubmed.ncbi.nlm.nih.gov/32471216/

https://www.mdpi.com/1422-0067/21/11/3800

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

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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