Tag Archives: cannabinoid

Pre- and post-conditioning treatment with an ultra-low dose of Δ9-tetrahydrocannabinol (THC) protects against pentylenetetrazole (PTZ)-induced cognitive damage.

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Behavioural Brain Research

“Preconditioning, a phenomenon where a minor noxious stimulus protects from a subsequent more severe insult, and post-conditioning, where the protective intervention is applied following the insult, offer new insight into the neuronal mechanism(s) of neuroprotection and may provide new strategies for the prevention and treatment of brain damage. We have previously reported that a single administration of an extremely low dose of Δ(9)-tetrahydrocannabinol (THC; the psychoactive ingredient of marijuana) to mice induced minor long-lasting cognitive deficits.

In the present study we examined the possibility that such a low dose of THC will protect the mice from more severe cognitive deficits induced by the epileptogenic drug pentylenetetrazole (PTZ). THC (0.002 mg/kg, a dose that is 3-4 orders of magnitude lower than the doses that induce the conventional effects of THC) was administered 1-7 days before, or 1-3 days after the injection of PTZ (60 mg/kg). The consequences of this treatment were studied 3-7 weeks later by various behavioral tests that evaluated different aspects of memory and learning.

We found that a single administration of THC either before or after PTZ abolished the PTZ-induced long-lasting cognitive deficits.

Biochemical studies indicated a concomitant reduction in phosphorylated-ERK (extracellular signal-regulated kinase) in the cerebella of mice 7 weeks following the injection of THC.

Our results suggest that a pre- or post-conditioning treatment with extremely low doses of THC, several days before or after brain injury, may provide safe and effective long-term neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/21315768

https://www.sciencedirect.com/science/article/pii/S0166432811001094?via%3Dihub

The Endocannabinoid System Is Present in Rod Outer Segments from Retina and Is Modulated by Light.

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“The aim of the present research was to evaluate if the endocannabinoid system (enzymes and receptors) could be modulated by light in rod outer segment (ROS) from bovine retina. First, we analyzed endocannabinoid 2-arachidonoylglycerol (2-AG) metabolism in purified ROS obtained from dark-adapted (DROS) or light-adapted (LROS) retinas. To this end, diacylglycerol lipase (DAGL), monoacylglycerol lipase (MAGL), and lysophosphatidate phosphohydrolase (LPAP) enzymatic activities were analyzed using radioactive substrates. The protein content of these enzymes and of the receptors to which cannabinoids bind was determined by immunoblotting under light stimulus. Our results indicate that whereas DAGL and MAGL activities were stimulated in retinas exposed to light, no changes were observed in LPAP activity. Interestingly, the protein content of the main enzymes involved in 2-AG metabolism, phospholipase C β1 (PLCβ1), and DAGLα (synthesis), and MAGL (hydrolysis), was also modified by light. PLCβ1 content was increased, while that of lipases was decreased. On the other hand, light produced an increase in the cannabinoid receptors CB1 and CB2 and a decrease in GPR55 protein levels. Taken together, our results indicate that the endocannabinoid system (enzymes and receptors) depends on the illumination state of the retina, suggesting that proteins related to phototransduction phenomena could be involved in the effects observed.”

https://www.ncbi.nlm.nih.gov/pubmed/31016476

https://link.springer.com/article/10.1007%2Fs12035-019-1603-5

Structural Insights into CB1 Receptor Biased Signaling.

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“The endocannabinoid system has emerged as a promising target for the treatment of numerous diseases, including cancer, neurodegenerative disorders, and metabolic syndromes. Thus far, two cannabinoid receptors, CB1 and CB2, have been discovered, which are found predominantly in the central nervous system (CB1) or the immune system (CB2), among other organs and tissues. CB1 receptor ligands have been shown to induce a complex pattern of intracellular effects. The binding of a ligand induces distinct conformational changes in the receptor, which will eventually translate into distinct intracellular signaling pathways through coupling to specific intracellular effector proteins. These proteins can mediate receptor desensitization, trafficking, or signaling. Ligand specificity and selectivity, complex cellular components, and the concomitant expression of other proteins (which either regulate the CB1 receptor or are regulated by the CB1 receptor) will affect the therapeutic outcome of its targeting. With an increased interest in G protein-coupled receptors (GPCR) research, in-depth studies using mutations, biological assays, and spectroscopic techniques (such as NMR, EPR, MS, FRET, and X-ray crystallography), as well as computational modelling, have begun to reveal a set of concerted structural features in Class A GPCRs which relate to signaling pathways and the mechanisms of ligand-induced activation, deactivation, or activity modulation. This review will focus on the structural features of the CB1 receptor, mutations known to bias its signaling, and reported studies of CB1 receptor ligands to control its specific signaling.”

https://www.ncbi.nlm.nih.gov/pubmed/31013934

https://www.mdpi.com/1422-0067/20/8/1837

Cannabinoid Regulation of Fear and Anxiety: an Update.

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“Anxiety- and trauma-related disorders are prevalent and debilitating mental illnesses associated with a significant socioeconomic burden. Current treatment approaches often have inadequate therapeutic responses, leading to symptom relapse. Here we review recent preclinical and clinical findings on the potential of cannabinoids as novel therapeutics for regulating fear and anxiety.

RECENT FINDINGS:

Evidence from preclinical studies has shown that the non-psychotropic phytocannabinoid cannabidiol and the endocannabinoid anandamide have acute anxiolytic effects and also regulate learned fear by dampening its expression, enhancing its extinction and disrupting its reconsolidation. The findings from the relevant clinical literature are still very preliminary but are nonetheless encouraging. Based on this preclinical evidence, larger-scale placebo-controlled clinical studies are warranted to investigate the effects of cannabidiol in particular as an adjunct to psychological therapy or medication to determine its potential utility for treating anxiety-related disorders in the future.”

https://www.ncbi.nlm.nih.gov/pubmed/31030284

https://link.springer.com/article/10.1007%2Fs11920-019-1026-z

Cannabidiol-loaded microspheres incorporated into osteoconductive scaffold enhance mesenchymal stem cell recruitment and regeneration of critical-sized bone defects.

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Materials Science and Engineering: C

“Recruitment of mesenchymal stem cells (MSCs) to an injury site and their differentiation into the desired cell lineage are implicated in deficient bone regeneration. To date, there is no ideal structure that provides these conditions for bone regeneration. In the current study, we aim to develop a novel scaffold that induces MSC migration towards the defect site, followed by their differentiation into an osteogenic lineage. We have fabricated a gelatin/nano-hydroxyapatite (G/nHAp) scaffold that delivered cannabidiol (CBD)-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres to critical size radial bone defects in a rat model. The fabricated scaffolds were characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM), and then analyzed for porosity and degradation rate. The release profile of CBD from the PLGA microsphere and CBD-PLGA-G/nHAp scaffold was analyzed by fluorescence spectroscopy. We performed an in vitro assessment of the effects of CBD on cellular behaviors of viability and osteogenic differentiation. Radiological evaluation, histomorphometry, and immunohistochemistry (IHC) analysis of all defects in the scaffold and control groups were conducted following transplantation into the radial bone defects. An in vitro migration assay showed that CBD considerably increased MSCs migration. qRT-PCR results showed upregulated expression of osteogenic markers in the presence of CBD. Histological and immunohistochemical findings confirmed new bone formation and reconstruction of the defect at 4 and 12 week post-surgery (WPS) in the CBD-PLGA-G/nHAp group. Immunofluorescent analysis revealed enhanced migration of MSCs into the defect areas in the CBD-PLGA-G/nHAp group in vivo. Based on the results of the current study, we concluded that CBD improved bone healing and showed a critical role for MSC migration in the bone regeneration process.”

https://www.ncbi.nlm.nih.gov/pubmed/31029357

https://www.sciencedirect.com/science/article/pii/S0928493118303606?via%3Dihub

Dissociable effects of cannabis with and without cannabidiol on the human brain’s resting-state functional connectivity.

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“Two major constituents of cannabis are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the main psychoactive component; CBD may buffer the user against the harmful effects of THC.

AIMS:

We examined the effects of two strains of cannabis and placebo on the human brain’s resting-state networks using fMRI.

CONCLUSIONS:

THC disrupts the DMN, and the PCC is a key brain region involved in the subjective experience of THC intoxication. CBD restores disruption of the salience network by THC, which may explain its potential to treat disorders of salience such as psychosis and addiction.”

https://www.ncbi.nlm.nih.gov/pubmed/31013455

https://journals.sagepub.com/doi/abs/10.1177/0269881119841568?journalCode=jopa

“CBD in cannabis could reduce psychosis risk from high strength skunk, study shows. Buffer effect could point to a protective mechanism that may help ‘treat disorders like psychosis and addiction’. Cannabidiol (CBD), a chemical derived from the cannabis plant, can counteract the effects of high strength “skunk” strains and may help to reduce the risk of serious mental health conditions like psychosis, according to a new study.” https://www.independent.co.uk/news/health/cannabis-skunk-cbd-thc-psychosis-addiction-ucl-a8882991.html

Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results.

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Epilepsy Research

“Since 2014, patients with severe treatment-resistant epilepsies (TREs) have been receiving add-on cannabidiol (CBD) in an ongoing, expanded access program (EAP), which closely reflects clinical practice.

We conducted an interim analysis of long-term efficacy and tolerability in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) who received CBD treatment through December 2016.

CONCLUSIONS:

Results from this interim analysis support add-on CBD as an effective long-term treatment option in LGS or DS.”

https://www.ncbi.nlm.nih.gov/pubmed/31022635

https://www.sciencedirect.com/science/article/pii/S0920121118305837?via%3Dihub

A Novel Standardized Cannabis sativa L. Extract and Its Constituent Cannabidiol Inhibit Human Polymorphonuclear Leukocyte Functions.

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“Cannabis and cannabinoids offer significant therapeutic benefits for a wide scope of pathological conditions. Among them, the clinical issues rooted in inflammation stand out, nonetheless, the underlying mechanisms are not yet plainly understood. Circumstantial evidence points to polymorphonuclear leukocytes (PMN) as targets for the anti-inflammatory effects of cannabis. Therefore, we conducted this study to assess the effects of CM5, a novel Cannabis sativa L. extract standardized in 5% cannabidiol (CBD), on human PMN functions, including cell migration, oxidative metabolism and production of tumour necrosis factor (TNF)-α. We then sought to investigate whether such effects could be ascribed to its content in CBD. Cell migration was assessed by the Boyden chamber assay, oxidative metabolism by means of spectrofluorimetric measurement of reactive oxygen species (ROS) production, and TNF-α was measured by real time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Results show that both CM5 and CBD inhibit PMN migration, ROS and TNF-α production, indicating that CBD may be the main item responsible for the effects of CM5. CM5 is however more potent than CBD on cell migration and TNF-α production, and less effective on ROS production, suggesting that beyond CBD, other components of the cannabis plant may contribute to the biological effects of the extract. As a whole, such results support the use of cannabis standardized extract and CBD to stem inflammation; however, they also warrant in-depth investigation of the underlying cellular and molecular mechanisms to better exploit their therapeutic potential.”

https://www.ncbi.nlm.nih.gov/pubmed/31013912

https://www.mdpi.com/1422-0067/20/8/1833

Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials.

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“Cannabidiol (CBD) is one of the cannabinoids with non-psychotropic action, extracted from Cannabis sativa. CBD is a terpenophenol and it has received a great scientific interest thanks to its medical applications. This compound showed efficacy as anti-seizure, antipsychotic, neuroprotective, antidepressant and anxiolytic. The neuroprotective activity appears linked to its excellent anti-inflammatory and antioxidant properties. The purpose of this paper is to evaluate the use of CBD, in addition to common anti-epileptic drugs, in the severe treatment-resistant epilepsy through an overview of recent literature and clinical trials aimed to study the effects of the CBD treatment in different forms of epilepsy. The results of scientific studies obtained so far the use of CBD in clinical applications could represent hope for patients who are resistant to all conventional anti-epileptic drugs.”

https://www.ncbi.nlm.nih.gov/pubmed/31013866

https://www.mdpi.com/1420-3049/24/8/1459

The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

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“The endocannabinoid system (ECS) has been placed in the anti-cancer spotlight in the last decade. The immense data load published on its dual role in both tumorigenesis and inhibition of tumor growth and metastatic spread has transformed the cannabinoid receptors CB1 (CB1R) and CB2 (CB2R), and other members of the endocannabinoid-like system, into attractive new targets for the treatment of various cancer subtypes.

Although the clinical use of cannabinoids has been extensively documented in the palliative setting, clinical trials on their application as anti-cancer drugs are still ongoing. As drug repurposing is significantly faster and more economical than de novo introduction of a new drug into the clinic, there is hope that the existing pharmacokinetic and safety data on the ECS ligands will contribute to their successful translation into oncological healthcare.

CB1R and CB2R are members of a large family of membrane proteins called G protein-coupled receptors (GPCR). GPCRs can form homodimers, heterodimers and higher order oligomers with other GPCRs or non-GPCRs. Currently, several CB1R and CB2R-containing heteromers have been reported and, in cancer cells, CB2R form heteromers with the G protein-coupled chemokine receptor CXCR4, the G protein-coupled receptor 55 (GPR55) and the tyrosine kinase receptor (TKR) human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2).

These protein complexes possess unique pharmacological and signaling properties, and their modulation might affect the antitumoral activity of the ECS. This review will explore the potential of the endocannabinoid network in the anti-cancer setting as well as the clinical and ethical pitfalls behind it, and will develop on the value of cannabinoid receptor heteromers as potential new targets for anti-cancer therapies and as prognostic biomarkers.”

https://www.ncbi.nlm.nih.gov/pubmed/31024307

https://www.frontiersin.org/articles/10.3389/fphar.2019.00339/full