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Neuroprotection of Cannabidiol, Its Synthetic Derivatives and Combination Preparations against Microglia-Mediated Neuroinflammation in Neurological Disorders

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“The lack of effective treatment for neurological disorders has encouraged the search for novel therapeutic strategies. Remarkably, neuroinflammation provoked by the activated microglia is emerging as an important therapeutic target for neurological dysfunction in the central nervous system. In the pathological context, the hyperactivation of microglia leads to neuroinflammation through the release of neurotoxic molecules, such as reactive oxygen species, proteinases, proinflammatory cytokines and chemokines.

Cannabidiol (CBD) is a major pharmacologically active phytocannabinoids derived from Cannabis sativa L. CBD has promising therapeutic effects based on mounting clinical and preclinical studies of neurological disorders, such as epilepsy, multiple sclerosis, ischemic brain injuries, neuropathic pain, schizophrenia and Alzheimer’s disease.

A number of preclinical studies suggested that CBD exhibited potent inhibitory effects of neurotoxic molecules and inflammatory modulators, highlighting its remarkable therapeutic potential for the treatment of numerous neurological disorders. However, the molecular mechanisms of action underpinning CBD’s effects on neuroinflammation appear to be complex and are poorly understood.

This review summarises the anti-neuroinflammatory activities of CBD against various neurological disorders with a particular focus on their main molecular mechanisms of action, which were related to the downregulation of NADPH oxidase-mediated ROS, TLR4-NFκB and IFN-β-JAK-STAT pathways. We also illustrate the pharmacological action of CBD’s derivatives focusing on their anti-neuroinflammatory and neuroprotective effects for neurological disorders. We included the studies that demonstrated synergistic enhanced anti-neuroinflammatory activity using CBD and other biomolecules.

The studies that are summarised in the review shed light on the development of CBD, including its derivatives and combination preparations as novel therapeutic options for the prevention and/or treatment of neurological disorders where neuroinflammation plays an important role in the pathological components.”

https://pubmed.ncbi.nlm.nih.gov/35956911/

“Cannabinoids are a group of terpenophenolic compounds derived from the Cannabis sativa L. plant. The preclinical studies summarised in this review supported the therapeutic use of CBD in treating neurological disorders from its action in addressing microglia-mediated neuroinflammation. The findings of this review shed light on the development of CBD and relevant compounds as novel and more advantageous therapeutics to prevent or treat neurological disorders by targeting microglia-mediated neuroinflammation.”

https://www.mdpi.com/1420-3049/27/15/4961/htm


Phytochemical differences of hemp ( Cannabis sativa L.) leaves from different germplasms and their regulatory effects on lipopolysaccharide-induced inflammation in Matin-Darby canine kidney cell lines

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“The increasing demand of hemp (Cannabis sativa L.) has attracted more interest in exploring its phytochemical profile and bioactivities, such as anti-inflammatory effect. In this study, the phytochemicals of different hemp leaves were investigated, with the content order: total saponins content (TSC) > total alkaloids content (TAC) > total phenolics content (TPC) > total flavonoids content (TFC) > cannabinoids.

Hemp leaves from Shanxi accumulated higher flavonoids and cannabinoids (i.e., THC, CBD, and CBN), while phenolics were more abundant in those from Hunan. A lipopolysaccharide (LPS)-induced inflammatory Matin-Darby canine kidney (MDCK) cell model was established to evaluate the anti-inflammatory effects of hemp leaf extracts.

Hemp leaf extracts, especially the D129 and c7, significantly increased cell viability of LPS-induced inflammatory MDCK cells, and D132 significantly decreased the secretion of pro-inflammatory cytokines (TNF-α and IL-6) and the lactate dehydrogenase (LDH) activity. Except for c12, other hemp leaf extracts obviously decreased the cell morphological damage of LPS-induced inflammatory MDCK cells.

The correlation analysis revealed that cannabinol (CBN) and TPC showed the strongest correlation with anti-inflammatory activities, and hierarchical clustering analysis also showed that hemp germplasms from Shanxi might be good alternatives to the common cultivar Ym7 due to their better anti-inflammatory activities.

These results indicated that hemp leaves were effective in LPS-induced inflammatory MDCK cells, and flavonoids and cannabinoids were potential geographical markers for distinguishing them, which can provide new insights into the anti-inflammatory effect of hemp leaves and facilitate the application of hemp leaves as functional ingredients against inflammatory-related disorders.”

https://pubmed.ncbi.nlm.nih.gov/35938104/

“The current findings demonstrated that the contents of various phytochemicals in hemp leaves were generally descending from TSC > TAC > TPC > TFC > cannabinoids. In addition, hemp leaves (0.05 mg/mL), especially hemp leaves cultivated in Shanxi (D129, D130, D132, D134, D142, and D361), reduced the release of pro-inflammatory cytokines (TNF-α), reduced LDH levels, and inhibited the cell morphological changes and the membrane damage of LPS-induced inflammatory MDCK cells. Furthermore, correlation analysis indicated phenolics and CBN might be the leading contributors to protecting the MDCK cells from LPS-induced inflammation. Meanwhile, hierarchical clustering indicated hemp leaves from Shanxi performed a better anti-inflammatory activity than the common cultivar Ym7. Thus, it is suggested that these germplasms from Shanxi can be good alternatives to Ym7. Overall, the present study provides scientific evidence for the anti-inflammatory potential of hemp leaves, which can be used in nutraceuticals and functional foods.”

https://www.frontiersin.org/articles/10.3389/fnut.2022.902625/full


Synthetic cannabinoid poisonings and access to the legal cannabis market: findings from US national poison centre data 2016-2019

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“Aim: To investigate trends in synthetic cannabinoid exposures reported to United States (US) poison control centres, and their association with status of state cannabis legalisation.

Methods: A retrospective study of National Poison Data System (NPDS) data from 2016 to 2019 identified and associated synthetic poisoning reports with annual state cannabis law and market status. State status was categorised as restrictive (cannabis illegal or limited medical legalisation), medical (allowing THC-containing medical cannabis use) and permissive (allowing non-medical use of THC-containing cannabis by adults). We categorised a subset of states with permissive policies by their implementation of legal adult possession/use and opening retail markets, on a quarterly basis. Mixed-effects Poisson regression models assessed synthetic exposures associated with legal status, first among all states using annual counts, and then among states that implemented permissive law alone using quarterly counts.

Results: A total of 7600 exposures were reported during the study period. Overall, reported synthetic exposures declined over time. Most reported exposures (64.8%) required medical attention, and 61 deaths were documented. State implementation of medical cannabis law was associated with 13% fewer reported annual exposures. Adoption of permissive state cannabis policy was independently and significantly associated with 37% lower reported annual synthetic exposures, relative to restrictive policies (IRR: 0.63, 95% CI: 0.50-0.79). Among states with permissive law during the period, implementation of legal adult possession/use was associated with 22% fewer reported quarterly exposures. Opening of retail markets was associated with 36% fewer reported exposures, relative to states with medical cannabis only.

Conclusions: Adoption of permissive cannabis law was associated with significant reductions in reported synthetic cannabinoid exposures. More permissive cannabis law may have the unintended benefit of reducing both motivation and harms associated with use of synthetic cannabis products.”

https://pubmed.ncbi.nlm.nih.gov/35942512/

“The gradual reduction of prohibitions against plant-based cannabis offers an opportunity to study use of cannabis and powerful synthetic analogues that may have been used as natural cannabis substitutes. Our study identified an association between more liberal policies (legalisation) for natural cannabis and declines in reported synthetic cannabinoid poisonings. This finding suggests a potential effect of policy change on substance use behaviours that may have long-term public health implications.”

https://www.tandfonline.com/doi/full/10.1080/15563650.2022.2099887

Cannabis Use and Sinonasal Symptoms in US Adults

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Medflixs - JAMA Otolaryngology Formation

“Importance: Cannabis is the most commonly used illicit substance in the US and worldwide. Understanding the association between cannabis use and sinonasal symptoms may help clinicians and patients better understand the symptomatology associated with cannabis use.

Objective: To assess the association between frequency of cannabis use and presence of sinonasal symptoms in a nationally representative sample of US adults.

Design, setting, and participants: This population-based, retrospective cross-sectional study included adults aged 20 to 69 years who had completed data on sinonasal symptoms and substance use for the 2013 to 2014 National Health and Nutrition Examination Survey. The data were analyzed in February 2022.

Exposures: Cannabis use frequency.

Main outcomes and measures: Presence of sinonasal symptoms, demographic information, and medical history were obtained from National Health and Nutrition Examination Survey questionnaires. Presence of any sinonasal symptoms was defined as responding yes to any of a series of questions assessing rhinologic symptoms. Regular cannabis users were defined as using cannabis 15 or more times within the last 30 days. Nonregular users were defined as using cannabis fewer than 15 times within the last 30 days. Multivariable models were used to examine the association between frequency of cannabis use and presence of sinonasal symptoms while adjusting for demographic characteristics and medical comorbidities.

Results: The study included 2269 adults with a mean (SD) age of 36.5 (12.4) years (1207 women [53.2%]; 330 Asian [14.5%], 739 Black [32.6%], 461 Hispanic [20.3%], and 656 White [28.9%] individuals). The prevalence of sinonasal symptoms among regular cannabis users (45.0%; 95% Cl, 38.9%-51.1%) was lower than the prevalence among never users (64.5%; 95% Cl, 58.3%-68.8%). Compared with adults who had never used cannabis, regular cannabis users were less likely to have sinonasal symptoms (odds ratio, 0.22, 95% CI, 0.10-0.50). Current tobacco smokers were more likely to have sinonasal symptoms (odds ratio, 1.96; 95% CI, 1.17-3.28). The most common sinonasal symptoms reported were nasal congestion (62.8%; 95% Cl, 60.2%-65.4%) and change in smell (17.8%; 95% Cl, 15.2%-20.9%).

Conclusions and relevance: This cross-sectional study found that the prevalence of sinonasal symptoms was lower among regular cannabis users. Further research is needed to elucidate the mechanisms underlying the association between cannabis use and sinonasal symptoms.”

https://pubmed.ncbi.nlm.nih.gov/35900733/

https://jamanetwork.com/journals/jamaotolaryngology/article-abstract/2794662

“SINONASAL SYMPTOMS LESS COMMON IN REGULAR CANNABIS USERS”

https://www.physiciansweekly.com/sinonasal-symptoms-less-common-in-regular-cannabis-users

Role of 5HT1A Receptors in the Neuroprotective and Behavioral Effects of Cannabidiol in Hypoxic-Ischemic Newborn Piglets

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Frontiers announces its first partnership with a leading Chinese University | STM Publishing News

“Background: Hypoxic-ischemic (HI) insults have important deleterious consequences in newborns, including short-term morbidity with neuromotor and cognitive disturbances. Cannabidiol (CBD) has demonstrated robust neuroprotective effects and shows anxiolytic/antidepressant effects as well. These effects are thought to be related to serotonin 5-HT1A receptor (5HT1AR) activation. We hereby aimed to study the role of 5HT1AR in the neuroprotective and behavioral effects of CBD in HI newborn piglets. 

Methods: 1-day-old piglets submitted to 30 min of hypoxia (FiO2 10%) and bilateral carotid occlusion were then treated daily with vehicle, CBD 1 mg/kg, or CBD with the 5HT1AR antagonist WAY 100635 1 mg/kg 72 h post-HI piglets were studied using amplitude-integrated EEG to detect seizures and a neurobehavioral test to detect neuromotor impairments. In addition, behavioral performance including social interaction, playful activity, hyperlocomotion, and motionless periods was assessed. Then, brain damage was assessed using histology (Nissl and TUNEL staining) and biochemistry (proton magnetic resonance spectroscopy studies. 

Results: HI led to brain damage as assessed by histologic and biochemistry studies, associated with neuromotor impairment and increased seizures. These effects were not observed in HI piglets treated with CBD. These beneficial effects of CBD were not reversed by the 5HT1AR antagonist, which is in contrast with previous studies demonstrating that 5HT1AR antagonists eliminated CBD neuroprotection as assessed 6 h after HI in piglets. HI led to mood disturbances, with decreased social interaction and playfulness and increased hyperlocomotion. Mood disturbances were not observed in piglets treated with CBD, but in this case, coadministration of the 5HT1AR antagonist eliminates the beneficial effects of CBD. 

Conclusion: CBD prevented HI-induced mood disturbances in newborn piglets by acting on 5HT1AR. However, 5HT1AR activation seems to be necessary for CBD neuroprotection only in the first hours after HI.”

https://pubmed.ncbi.nlm.nih.gov/35924056/

“Postinsult CBD administration prevented HI-induced brain damage, and neuromotor deficits and behavioral disturbances. These results indicate that, in addition to its robust neuroprotective effects, CBD could be an interesting candidate to be included in the treatment of HI newborns to mitigate the consequences of stress derived from brain damage and hypothermia treatment.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.925740/full

Cannabidiol increases gramicidin current in human embryonic kidney cells: An observational study

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Plos One | Publons

“Gramicidin is a monomeric protein that is thought to non-selectively conduct cationic currents and water. Linear gramicidin is considered an antibiotic. This function is considered to be mediated by the formation of pores within the lipid membrane, thereby killing bacterial cells.

The main non-psychoactive active constituent of the cannabis plant, cannabidiol (CBD), has recently gained interest, and is proposed to possess various potential therapeutic properties, including being an antibiotic. We previously determined that CBD’s activity on ion channels could be, in part, mediated by altering membrane biophysical properties, including elasticity.

In this study, our goal was to determine the empirical effects of CBD on gramicidin currents in human embryonic kidney (HEK) cells, seeking to infer potential direct compound-protein interactions. Our results indicate that gramicidin, when applied to the extracellular HEK cell membrane, followed by CBD perfusion, increases the gramicidin current.”

https://pubmed.ncbi.nlm.nih.gov/35913948/

“One compound with amphiphilic properties is cannabidiol (CBD), the primary non-psychotropic constituent of Cannabis sativa. CBD is a clinically and experimentally substantiated therapeutic compound with efficacy against a variety of conditions, including seizure disorders (for which CBD is FDA-approved), pain, and muscle spasms. Furthermore, CBD has been suggested to have antibiotic properties.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0271801

A polarized supercell produces specialized metabolites in cannabis trichomes

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Press – The Jensen Laboratory

“For centuries, humans have cultivated cannabis for the pharmacological properties that result from consuming its specialized metabolites, primarily cannabinoids and terpenoids. Today, cannabis is a multi-billion-dollar industry whose existence rests on the biological activity of tiny cell clusters, called glandular trichomes, found mainly on flowers. Cannabinoids are toxic to cannabis cells,1 and how the trichome cells can produce and secrete massive quantities of lipophilic metabolites is not known.1 To address this gap in knowledge, we investigated cannabis glandular trichomes using ultra-rapid cryofixation, quantitative electron microscopy, and immuno-gold labeling of cannabinoid pathway enzymes. We demonstrate that the metabolically active cells in cannabis form a “supercell,” with extensive cytoplasmic bridges across the cell walls and a polar distribution of organelles adjacent to the apical surface where metabolites are secreted. The predicted metabolic role of the non-photosynthetic plastids is supported by unusual membrane arrays in the plastids and the localization of the start of the cannabinoid/terpene pathway in the stroma of the plastids. Abundant membrane contact sites connected plastid paracrystalline cores with the plastid envelope, plastid with endoplasmic reticulum (ER), and ER with plasma membrane. The final step of cannabinoid biosynthesis, catalyzed by tetrahydrocannabinolic acid synthase (THCAS), was localized in the cell-surface wall facing the extracellular storage cavity. We propose a new model of how the cannabis cells can support abundant metabolite production, with emphasis on the key role of membrane contact sites and extracellular THCA biosynthesis. This new model can inform synthetic biology approaches for cannabinoid production in yeast or cell cultures.”

https://pubmed.ncbi.nlm.nih.gov/35917819/

https://www.cell.com/current-biology/fulltext/S0960-9822(22)01115-0?

“Study defines how cannabis cells make cannabinoids”

https://www.news-medical.net/news/20220803/Study-defines-how-cannabis-cells-make-cannabinoids.aspx

Mortality risk for individuals with cannabis use disorders in relation to alcohol use disorders: Results of a follow-up study

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Psychiatry Research

“Background: There are few studies on mortality on individuals entering treatment for cannabis use disorders.

Objectives: To estimate mortality risk for individuals treated for cannabis use disorders comparing patients with concomitant alcohol use disorders to those with only cannabis use disorders.

Methods: Follow-up study on 1136 residents in Northern Italy who turned to health services following problems caused by cannabis use disorders between 2009 and 2019. Individuals with concomitant use of opioids, amphetamines, cocaine, or injecting drugs were excluded. Crude mortality rates per 1000 Person Years (CMR), and standardized mortality ratios adjusted for age, sex and calendar year (SMR) were calculated.

Results: Elevated CMRs (CMR 4.4, 3-6.4), higher among patients with concomitant alcohol use disorders (CMR 10.2, 6.6-15.6) compared to those with only cannabis use disorders (CMR 1.8, 0.9-3.6) were found. Regarding excess mortality with respect to the general population, SMRs were higher and statistically significant (SMR 5.4, 3.7-7.8), both among patients with concomitant alcohol use disorders (SMR 10.2, 6.6-15.6) and among those with only cannabis use disorders (SMR 2.3, 1.1-4.5).

Conclusions: The results of this study show that individuals with only cannabis use disorders have a lower mortality risk compared to those with both cannabis and alcohol use disorders.”

https://pubmed.ncbi.nlm.nih.gov/35908347/

“The results of our study show that individuals with only cannabis use disorders have a lower mortality risk compared to those with cannabis and alcohol use disorders.”

https://www.sciencedirect.com/science/article/abs/pii/S0165178122003365?via%3Dihub

“Daily drinking is associated with increased mortality”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214719/

[Medical cannabis]

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“Health is a human right. In order to guarantee that right, it is fundamental that all activities concerning health in different contexts (clinical, research, teaching) contribute to the construction of an efficient system that promotes excellence, equity, justice, and solidarity. In this issue, we take on alternatives regarding the use of medical cannabis from this perspective. Health research and its contribution to knowledge – in particular with respect to the development of new pharmaceuticals – represents not only a challenge related to technology and production, but also an opportunity for ensuring the autonomy of the health system.”

https://pubmed.ncbi.nlm.nih.gov/35900986/

http://revistas.unla.edu.ar/saludcolectiva/article/view/3991

Industrial hemp seed: from the field to value-added food ingredients

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figure 1

“Industrial hemp, with low levels of the intoxicating cannabinoid tetrahydrocannabinol (THC), is grown for fibre and seeds. The industrial hemp industry is poised for expansion. The legalisation of industrial hemp as an agricultural commodity and the inclusion of hemp seed in foods is helping to drive the expansion of the hemp food ingredients industry.

This paper discusses the opportunity to build an industrial hemp industry, with a focus on the prospects of hemp seed and its components in food applications. The market opportunities for industrial hemp products are examined. Various aspects of the science that underpins the development of an industrial hemp industry through the food supply chain are presented. This includes a discussion on the agronomy, on-farm and post-harvest considerations and the various types of food ingredients that can be made from hemp seed. The characteristics of hemp seed meal, hemp seed protein and hemp seed oil are reviewed. Different processes for production of value-added ingredients from hemp seed, hemp seed oil and hemp seed protein, are examined. The applicability of hemp seed ingredients in food applications is reviewed. The design of hemp seed ingredients that are fit-for-purpose for target food applications, through the selection of varieties and processing methods for production of various hemp seed ingredients, needs to consider market-led opportunities. This will require an integrated through chain approach, combined with the development of on-farm and post-farm strategies, to ensure that the hemp seed ingredients and foods containing hemp seed are acceptable to the consumer.”

https://pubmed.ncbi.nlm.nih.gov/35906681/

“Overall, the opportunity to build a whole supply chain is particularly attractive for the farm sector wishing to diversify and plant sustainable crops with potential for economic returns.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-022-00156-7