Cannabinoids and Cannabinoid Receptors: The Story So Far

 iScience journal (@iScience_CP) | Twitter“Like most modern molecular biology and natural product chemistry, understanding cannabinoid pharmacology centers around molecular interactions, in this case, between the cannabinoids and their putative targets, the G-protein coupled receptors (GPCRs) cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). Understanding the complex structure and interplay between the partners in this molecular dance is required to understand the mechanism of action of synthetic, endogenous, and phytochemical cannabinoids. This review, with 91 references, surveys our understanding of the structural biology of the cannabinoids and their target receptors including both a critical comparison of the extant crystal structures and the computationally derived homology models, as well as an in-depth discussion about the binding modes of the major cannabinoids. The aim is to assist in situating structural biochemists, synthetic chemists, and molecular biologists who are new to the field of cannabis research.”

https://pubmed.ncbi.nlm.nih.gov/32629422/

https://www.cell.com/iscience/pdf/S2589-0042(20)30488-0.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2589004220304880%3Fshowall%3Dtrue

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Cannabidiol and Sports Performance: A Narrative Review of Relevant Evidence and Recommendations for Future Research

Sports Medicine - Open Cover Image “Cannabidiol (CBD) is a non-intoxicating cannabinoid derived from Cannabis sativa. CBD initially drew scientific interest due to its anticonvulsant properties but increasing evidence of other therapeutic effects has attracted the attention of additional clinical and non-clinical populations, including athletes.

Unlike the intoxicating cannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC), CBD is no longer prohibited by the World Anti-Doping Agency and appears to be safe and well-tolerated in humans. It has also become readily available in many countries with the introduction of over-the-counter “nutraceutical” products.

The aim of this narrative review was to explore various physiological and psychological effects of CBD that may be relevant to the sport and/or exercise context and to identify key areas for future research. As direct studies of CBD and sports performance are is currently lacking, evidence for this narrative review was sourced from preclinical studies and a limited number of clinical trials in non-athlete populations.

Preclinical studies have observed robust anti-inflammatory, neuroprotective and analgesic effects of CBD in animal models. Preliminary preclinical evidence also suggests that CBD may protect against gastrointestinal damage associated with inflammation and promote healing of traumatic skeletal injuries. However, further research is required to confirm these observations.

Early stage clinical studies suggest that CBD may be anxiolytic in “stress-inducing” situations and in individuals with anxiety disorders. While some case reports indicate that CBD improves sleep, robust evidence is currently lacking. Cognitive function and thermoregulation appear to be unaffected by CBD while effects on food intake, metabolic function, cardiovascular function, and infection require further study.

CBD may exert a number of physiological, biochemical, and psychological effects with the potential to benefit athletes. However, well controlled, studies in athlete populations are required before definitive conclusions can be reached regarding the utility of CBD in supporting athletic performance.”

https://pubmed.ncbi.nlm.nih.gov/32632671/

“CBD has been reported to exert a number of physiological, biochemical, and psychological effects that have the potential to benefit athletes. For instance, there is preliminary supportive evidence for anti-inflammatory, neuroprotective, analgesic, and anxiolytic actions of CBD and the possibility it may protect against GI damage associated with inflammation and promote the healing of traumatic skeletal injuries.”

https://sportsmedicine-open.springeropen.com/articles/10.1186/s40798-020-00251-0

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The Seed of Industrial Hemp ( Cannabis sativa L.): Nutritional Quality and Potential Functionality for Human Health and Nutrition

nutrients-logo“Hempseeds, the edible fruits of the Cannabis sativa L. plant, were initially considered a by-product of the hemp technical fibre industry. Nowadays, following the restorationing of the cultivation of C. sativa L. plants containing an amount of delta-9-tetrahydrocannabinol (THC) <0.3% or 0.2% (industrial hemp) there is a growing interest for the hempseeds production due to their high nutritional value and functional features.

The goal of this review is to examine the scientific literature concerning the nutritional and functional properties of hempseeds. Furthermore, we revised the scientific literature regarding the potential use of hempseeds and their derivatives as a dietary supplement for the prevention and treatment of inflammatory and chronic-degenerative diseases on animal models and humans too.

In the first part of the work, we provide information regarding the genetic, biochemical, and legislative aspects of this plant that are, in our opinion essential to understand the difference between “industrial” and “drug-type” hemp. In the final part of the review, the employment of hempseeds by the food industry as livestock feed supplement and as ingredient to enrich or fortify daily foods has also revised.

Overall, this review intends to encourage further and comprehensive investigations about the adoption of hempseeds in the functional foods field.”

https://pubmed.ncbi.nlm.nih.gov/32610691/

https://www.mdpi.com/2072-6643/12/7/1935

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Administration of Δ9-Tetrahydrocannabinol (THC) Post-Staphylococcal Enterotoxin B Exposure Protects Mice From Acute Respiratory Distress Syndrome and Toxicity

Frontiers in Pharmacology welcomes new Field Chief Editor ...“Acute Respiratory Distress Syndrome (ARDS) is a life-threatening complication that can ensue following Staphylococcus aureus infection. The enterotoxin produced by these bacteria (SEB) acts as a superantigen thereby activating a large proportion of T cells leading to cytokine storm and severe lung injury.

Δ9Tetrahydrocannabinol (THC), a psychoactive ingredient found in Cannabis sativa, has been shown to act as a potent anti-inflammatory agent. In the current study, we investigated the effect of THC treatment on SEB-induced ARDS in mice.

While exposure to SEB resulted in acute mortality, treatment with THC led to 100% survival of mice. THC treatment significantly suppressed the inflammatory cytokines, IFN-γ and TNF-α. Additionally, THC elevated the induction of regulatory T cells (Tregs) and their associated cytokines, IL-10 and TGF-β. Moreover, THC caused induction of Myeloid-Derived Suppressor Cells (MDSCs).

THC acted through CB2 receptor as pharmacological inhibitor of CB2 receptors blocked the anti-inflammatory effects. THC-treated mice showed significant alterations in the expression of miRNA (miRs) in the lung-infiltrated mononuclear cells (MNCs). Specifically, THC caused downregulation of let7a-5p which targeted SOCS1 and downregulation of miR-34-5p which caused increased expression of FoxP3, NOS1, and CSF1R.

Together, these data suggested that THC-mediated alterations in miR expression in the lungs may play a critical role in the induction of immunosuppressive Tregs and MDSCs as well as suppression of cytokine storm leading to attenuation of SEB-mediated lung injury.”

https://pubmed.ncbi.nlm.nih.gov/32612530/

“In summary, the current study suggests that treatment of mice with THC post-SEB challenge protects mice from SEB-mediated toxicity by inhibiting inflammation and ARDS through the modulation of miRs. Because SEB is a super antigen that drives cytokine storm, our studies suggest that THC is a potent anti-inflammatory agent that has the potential to be used as a therapeutic modality to treat SEB-induced ARDS.

It is of interest to note that a significant proportion of Coronavirus disease 2019 (COVID-19) patients come down with sepsis and ARDS accompanied by cytokine storm. ”

https://www.frontiersin.org/articles/10.3389/fphar.2020.00893/full

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A Systematic Review of Minor Phytocannabinoids With Promising Neuroprotective Potential

British Journal of Pharmacology “Embase and Pubmed were systematically searched for articles addressing the neuroprotective properties of phytocannabinoids, aside from cannabidiol and Δ9 -tetrahydrocannabinol, including Δ9 -tetrahydrocannabinolic acid (Δ9 -THCA), Δ9 -tetrahydrocannabivarin (Δ9 -THCV), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabichromene (CBC), cannabichromenic acid (CBCA), cannabichromevarin (CBCV), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerivarin (CBGV), cannabigerovarinic acid (CBGVA), cannabichromevarinic acid (CBCVA) cannabidivarinic acid (CBDVA) and cannabinol (CBN).

CBG (range 5 mg.kg-1 to 20 mg.kg-1 ) and CBDV (range 0.2 mg.kg-1 to 400 mg.kg-1 ) displayed efficacy in models of Huntington’s disease and epilepsy.

CBC (10-75 mg.kg-1 ), Δ9 -THCA (20 mg.kg-1 ) and Δ9 -THCV (range 0.025-2.5 mg.kg-1 ) showed promise in models of seizure and hypomobility, Huntington’s and Parkinson’s disease.

Limited mechanistic data showed CBG, VCE.003, VCE.003.2 and Δ9 -THCA mediated some of their effects through PPARy, but no other receptors were probed. Further studies with these phytocannabinoids, and their combinations, are warranted across a range of neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/32608035/

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.15185

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Pharmacological Analysis of Cannabis Sativa: A Potent Herbal Plant

“Genus Cannabis belong to family Cannabaceae and is traditionally used as medicinal plant against many diseases notably asthma, malaria, treatment of skin diseases, diabetes and headache. The plant Cannabis sativa L. is flowering and an annual herbaceous plant located to eastern Asia but now of cosmopolitan distribution due to extensive cultivation.

Aim of the study: The aim of review is to provide a complete evaluation of the botanical, ethnological and chemical aspects of Cannabis sativa L., and its importance in pharmacological studies.

Results and discussions: This article briefly reviews the botany, traditional knowledge, pharmacological and therapeutic application of the plant C. sativa. This is an attempt to compile and document information about the chemical constituent, pharmacological and therapeutic effects of C. sativa as important herbal drug due to its safety and effectiveness. Studies have revealed its use as anti-bacterial, anti-fungal, anti-cancer, anti-inflammatory and improving testicular function in rats. Consumption of C. sativa is greater in all over the world among all other drugs of abuse in its various forms such as marijuana, hashish and cannabis oil. The study of herbal medicine spans the knowledge of biology, history, source, physical and chemical nature, and mechanism of action, traditional, medicinal and therapeutic use of drug. This article also provide knowledge about macroscopically and microscopically characters of Cannabis sativa with geographical sources. The wellknown cannabinoids are Tetrahydrocannabinol (THC), Cannabidiol (CBD) and Cannabichromene (CBC) and their pharmacological properties and importance have been extensively studied. Hence, efforts are required to establish and validate evidence regarding safety and practices of Ayurveda medicines.

Conclusion: Thes studies will help in expanding the current therapeutic potential of C. sativa and it also provide a strong support to its future clinical use as herbal medicines having safe in use with no side effects.”

https://pubmed.ncbi.nlm.nih.gov/32600228/

https://www.eurekaselect.com/183226/article

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Antioxidants Help Favorably Regulate the Kinetics of Lipid Peroxidation, Polyunsaturated Fatty Acids Degradation and Acidic Cannabinoids Decarboxylation in Hempseed Oil

 Scientific Reports“The seed of the hemp plant (Cannabis sativa L.) has been revered as a nutritional resource in Old World Cultures. This has been confirmed by contemporary science wherein hempseed oil (HSO) was found to exhibit a desirable ratio of omega-6 and omega-3 polyunsaturated fatty acids (PUFAs) considered optimal for human nutrition. HSO also contains gamma-linoleic acid (GLA) and non-psychoactive cannabinoids, which further contribute to its’ potential bioactive properties. Herein, we present the kinetics of the thermal stability of these nutraceutical compounds in HSO, in the presence of various antioxidants (e.g. butylated hydroxytoluene, alpha-tocopherol, and ascorbyl palmitate). We focussed on oxidative changes in fatty acid profile and acidic cannabinoid stability when HSO was heated at different temperatures (25 °C to 85 °C) for upto 24 h. The fatty acid composition was evaluated using both GC/MS and 1H-NMR, and the cannabinoids profile of HSO was obtained using both HPLC-UV and HPLC/MS methods. The predicted half-life (DT50) for omega-6 and omega-3 PUFAs in HSO at 25 °C was about 3 and 5 days, respectively; while that at 85 °C was about 7 and 5 hours respectively, with respective activation energies (Ea) being 54.78 ± 2.36 and 45.02 ± 2.87 kJ/mol. Analysis of the conjugated diene hydroperoxides (CDH) and p-Anisidine value (p-AV) revealed that the addition of antioxidants significantly (p < 0.05) limited lipid peroxidation of HSO in samples incubated at 25-85 °C for 24 h. Antioxidants reduced the degradation constant (k) of PUFAs in HSO by upto 79%. This corresponded to a significant (p < 0.05) increase in color stability and pigment retention (chlorophyll a, chlorophyll b and carotenoids) of heated HSO. Regarding the decarboxylation kinetics of cannabidiolic acid (CBDA) in HSO, at both 70 °C and 85 °C, CBDA decarboxylation led to predominantly cannabidiol (CBD) production. The half-life of CBDA decarboxylation (originally 4 days) could be increased to about 17 days using tocopherol as an antioxidant. We propose that determining acidic cannabinoids decarboxylation kinetics is a useful marker to measure the shelf-life of HSO. The results from the study will be useful for researchers looking into the thermal treatment of hempseed oil as a functional food product, and those interested in the decarboxylation kinetics of the acidic cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/32601363/

https://www.nature.com/articles/s41598-020-67267-0

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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

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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

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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

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