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SELECTED CANNABIS TERPENES SYNERGIZE WITH THC TO PRODUCE INCREASED CB1 RECEPTOR ACTIVATION

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Biochemical Pharmacology

“The cannabis plant exerts its pharmaceutical activity primarily by the binding of cannabinoids to two G protein-coupled cannabinoid receptors, CB1 and CB2. The role that cannabis terpenes play in this activation has been considered and debated repeatedly, based on only limited experimental results. In the current study we used a controlled in-vitro heterologous expression system to quantify the activation of CB1 receptors by sixteen cannabis terpenes individually, by tetrahydrocannabinol (THC) alone and by THC-terpenes mixtures. The results demonstrate that all terpenes, when tested individually, activate CB1 receptors, at about 10-50% of the activation by THC alone. The combination of some of these terpenes with THC significantly increases the activity of the CB1 receptor, compared to THC alone. In some cases, several fold. Importantly, this amplification is evident at terpene to THC ratios similar to those in the cannabis plant, which reflect very low terpene concentrations. For some terpenes, the activation obtained by THC- terpene mixtures is notably greater than the sum of the activations by the individual components, suggesting a synergistic effect. Our results strongly support a modulatory effect of some of the terpenes on the interaction between THC and the CB1 receptor. As the most effective terpenes are not necessarily the most abundant ones in the cannabis plant, reaching “whole plant” or “full spectrum” composition is not necessarily an advantage. For enhanced therapeutic effects, desired compositions are attainable by enriching extracts with selected terpenes. These compositions adjust the treatment for various desired medicinal and personal needs.”

https://pubmed.ncbi.nlm.nih.gov/37084981/

https://www.sciencedirect.com/science/article/pii/S0006295223001399?via%3Dihub

Endocannabinoid System: Chemical Characteristics and Biological Activity

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“The endocannabinoid system (eCB) has been studied to identify the molecular structures present in Cannabis sativa. eCB consists of cannabinoid receptors, endogenous ligands, and the associated enzymatic apparatus responsible for maintaining energy homeostasis and cognitive processes.

Several physiological effects of cannabinoids are exerted through interactions with various receptors, such as CB1 and CB2 receptors, vanilloid receptors, and the recently discovered G-protein-coupled receptors (GPR55, GPR3, GPR6, GPR12, and GPR19). Anandamide (AEA) and 2-arachidoylglycerol (2-AG), two small lipids derived from arachidonic acid, showed high-affinity binding to both CB1 and CB2 receptors.

eCB plays a critical role in chronic pain and mood disorders and has been extensively studied because of its wide therapeutic potential and because it is a promising target for the development of new drugs. Phytocannabinoids and synthetic cannabinoids have shown varied affinities for eCB and are relevant to the treatment of several neurological diseases.

This review provides a description of eCB components and discusses how phytocannabinoids and other exogenous compounds may regulate the eCB balance. Furthermore, we show the hypo- or hyperfunctionality of eCB in the body and how eCB is related to chronic pain and mood disorders, even with integrative and complementary health practices (ICHP) harmonizing the eCB.”

https://pubmed.ncbi.nlm.nih.gov/37017445/

“The roles of cannabinoid receptors and their agonists in multiple conditions have been addressed in this review. Since research with derivatives of Cannabis has started and the biological functions of isolated compounds in experimental and human diseases have shown promising outcomes, it is evident that selective ligands of specific Cannabis receptors could induce beneficial outcomes, depending on the clinical condition. More research on the biological function of each Cannabis derivative should be encouraged.”

https://www.mdpi.com/1424-8247/16/2/148

Cannabidiol Treatment Shows Therapeutic Efficacy in a Rodent Model of Social Transfer of Pain in Pair-Housed Male Mice

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“Introduction: Prosocial behavior refers to sharing emotions and sensations such as pain. Accumulated data indicate that cannabidiol (CBD), a nonpsychotomimetic component of the Cannabis sativa plant, attenuates hyperalgesia, anxiety, and anhedonic-like behavior. Nevertheless, the role of CBD in the social transfer of pain has never been evaluated. In this study, we investigated the effects of acute systemic administration of CBD in mice that cohabited with a conspecific animal suffering from chronic constriction injury. Furthermore, we assessed whether repeated CBD treatment decreases hypernociception, anxiety-like behavior, and anhedonic-like responses in mice undergoing chronic constriction injury and whether this attenuation would be socially transferred to the partner. 

Materials and Methods: Male Swiss mice were Housed in pairs for 28 days. On the 14th day of living together, animals were then divided into two groups: cagemate nerve constriction (CNC), in which one animal of each partner was subjected to sciatic nerve constriction; and cagemate sham (CS), subjected to the same surgical procedure but without suffering nerve constriction. In Experiments 1, 2, and 3 on day 28 of living together, the cagemates (CNC and CS) animals received a single systemic injection (intraperitoneally) of vehicle or CBD (0.3, 1, 10, or 30 mg/kg). After 30 min, the cagemates were subjected to the elevated plusmaze followed by exposure to the writhing and sucrose splash tests. For chronic treatment (Exp. 4), sham and chronic constriction injury animals received a repeated systemic injection (subcutaneous) of vehicle or CBD (10 mg/kg) for 14 days after the sciatic nerve constriction procedure. On days 28 and 29 sham and chronic constriction injury animals and their cagemates were behaviorally tested. 

Results and Conclusion: Acute CBD administration attenuated anxiety-like behavior, pain hypersensitivity, and anhedonic-like behavior in cagemates that cohabited with a pair in chronic pain. In addition, repeated CBD treatment reversed the anxiety-like behavior induced by chronic pain and enhanced the mechanical withdrawal thresholds in Von Frey filaments and the grooming time in the sucrose splash test. Moreover, repeated CBD treatment effects were socially transferred to the chronic constriction injury cagemates.”

https://pubmed.ncbi.nlm.nih.gov/37074109/

https://www.liebertpub.com/doi/10.1089/can.2022.0300

Effects of Cannabidiol, Hypothermia, and Their Combination in Newborn Rats With Hypoxic-Ischemic Encephalopathy

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eNeuro

“Therapeutic hypothermia is well-established as a standard treatment for infants with hypoxic-ischemic encephalopathy but it is only partially effective. The potential for combination treatments to augment hypothermic neuroprotection has major relevance.

Our aim was to assess the effects of treating newborn rats following hypoxic-ischemic (HI) injury with cannabidiol (CBD) at 0.1 or 1 mg/kg i.p., in normothermic (37.5°C) and hypothermic (32.0°C) conditions, from 7 (neonatal phase) to 37 days old (juvenile phase).

Placebo or CBD were administered at 0.5, 24 and 48 h after HI injury. Two sensorimotor (rotarod and cylinder rearing), and two cognitive (novel object recognition and T-maze) tests were conducted 30 days after HI. The extent of brain damage was determined by magnetic resonance imaging, histological evaluation, magnetic resonance spectroscopy, amplitude-integrated electroencephalography and Western blotting. At 37 days, the HI insult produced impairments in all neurobehavioral score (cognitive and sensorimotor tests), brain activity (electroencephalography), neuropathological score (temporoparietal cortexes and CA1 layer of hippocampus), lesion volume, magnetic resonance biomarkers of brain injury (metabolic dysfunction, excitotoxicity, neural damage and mitochondrial impairment), oxidative stress and inflammation (TNFα).

We observed that CBD or hypothermia (to a lesser extent than CBD) alone improved cognitive and motor functions, as well as brain activity. When used together, CBD and hypothermia ameliorated brain excitotoxicity, oxidative stress and inflammation, reduced brain infarct volume, lessened the extent of histological damage, and demonstrated additivity in some parameters. Thus, coadministration of CBD and hypothermia could complement each other in their specific mechanisms to provide neuroprotection.

Significance StatementCannabidiol and hypothermia act on some common processes related to hypoxic-ischemic brain damage, modulating excitotoxicity, inflammation and oxidative stress. The two therapies in combination do not compete against each other in modulating these processes, but rather produce additive neuroprotective effects. Furthermore, in the instances where there was not an additive effect, combination of cannabinoid with hypothermia often resulted in a significantly superior profile compared to hypothermia alone, being a promising observation for the clinic. These results justify interest in cannabidiol for developing a combined treatment with hypothermia to increase the number of hypoxic-ischemic infants that benefit from treatment.”

https://pubmed.ncbi.nlm.nih.gov/37072177/

https://www.eneuro.org/content/early/2023/04/12/ENEURO.0417-22.2023


Cannabidiol reduces LPS-induced nociception via endocannabinoid system activation

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“Bacterial infections are often accompanied by fever and generalized muscle pain. However, the treatment of pain with an infectious etiology has been overlooked. Thus, we investigated the impact of cannabidiol (CBD) in bacterial lipopolysaccharide (LPS)-induced nociception.

Male Swiss mice received intrathecal (i.t.) LPS injection, and the nociceptive threshold was measured by the von Frey filaments test. Spinal involvement of the cannabinoid CB2 receptor, toll-like receptor 4 (TLR4), microglia and astrocytes were evaluated by i.t. administration of their respectively antagonists or inhibitors. Western blot, immunofluorescence, ELISA and liquid chromatography-mass spectrometry were used to assess Cannabinoid CB2 receptors and TLR4 spinal expression, proinflammatory cytokines and endocannabinoid levels. CBD was administered intraperitoneally at 10 mg/kg.

The pharmacological assay demonstrated TLR4 participation in LPS-induced nociception. In addition, spinal TLR4 expression and proinflammatory cytokine levels were increased in this process.

CBD treatment prevented LPS-induced nociception and TLR4 expression.

AM630 reversed antinociception and reduced CBD-induced endocannabinoids upregulation. Increased spinal expression of the cannabinoid CB2 receptor was also found in animals receiving LPS, which was accompanied by reduced TLR4 expression in CBD-treated mice.

Taken together, our findings indicated that CBD is a potential treatment strategy to control LPS-induced pain by attenuating TLR4 activation via the endocannabinoid system.”

https://pubmed.ncbi.nlm.nih.gov/37076976/

https://onlinelibrary.wiley.com/doi/10.1111/bcpt.13876

The Effects of Endogenous Cannabinoids on the Mammalian Respiratory System: A Scoping Review of Cyclooxygenase-Dependent Pathways

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“Introduction: The endogenous cannabinoid (endocannabinoid) system is an emerging target for the treatment of chronic inflammatory disease with the potential to advance treatment for many respiratory illnesses. The varied effects of endocannabinoids across tissue types makes it imperative that we explore their physiologic impact within unique tissue targets. The aim of this scoping review is to explore the impact of endocannabinoid activity on eicosanoid production as a measure of human airway inflammation. 

Methods: A scoping literature review was conducted according to PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) guidelines. Search strategies using MeSH terms related to cannabinoids, eicosanoids, cyclooxygenase (COX), and the respiratory system were used to query Medline, Embase, Cochrane, CINAHL, Web of Science, and Biosis Previews in December 2021. Only studies that investigated the relationship between endocannabinoids and the eicosanoid system in mammalian respiratory tissue after 1992 were included. 

Results: Sixteen studies were incorporated in the final qualitative review. Endocannabinoid activation increases COX-2 expression, potentially through ceramide-dependent or p38 and p42/44 Mitogen-Activated Protein Kinase pathways and is associated with a concentration-dependent increase in prostaglandin (PG)E2. Inhibitors of endocannabinoid hydrolysis found either an increase or no change in levels of PGE2 and PGD2 and decreased levels of leukotriene (LT)B4, PGI2, and thromboxane A2 (TXA2). Endocannabinoids increase bronchial epithelial cell permeability and have vasorelaxant effects in human pulmonary arteries and cause contraction of bronchi and decreased gas trapping in guinea pigs. Inhibitors of endocannabinoid hydrolysis were found to have anti-inflammatory effects on pulmonary tissue and are primarily mediated by COX-2 and activation of eicosanoid receptors. Direct agonism of endocannabinoid receptors appears to play a minor role. 

Conclusion: The endocannabinoid system has diverse effects on the mammalian airway. While endocannabinoid-derived PGs can have anti-inflammatory effects, endocannabinoids also produce proinflammatory conditions, such as increased epithelial permeability and bronchial contraction. These conflicting findings suggest that endocannabinoids produce a variety of effects depending on their local metabolism and receptor agonism. Elucidation of the complex interplay between the endocannabinoid and eicosanoid pathways is key to leveraging the endocannabinoid system as a potential therapeutic target for human airway disease.”

https://pubmed.ncbi.nlm.nih.gov/37074668/

https://www.liebertpub.com/doi/10.1089/can.2022.0277

Risk of Motor Vehicle Collisions and Culpability among Older Drivers Using Cannabis: A Meta-Analysis

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“Limited studies have investigated the effects of cannabis use on driving among older adults, who represent the fastest growing segment of drivers globally. We conducted a systematic review and meta-analysis to evaluate the effects of delta-9-tetrahydrocannabinol (THC) exposure on risks of (1) motor vehicle collisions (MVC) and (2) culpability for MVCs among adults 50 years and older. Three reviewers screened 7022 studies identified through MEDLINE, EMBASE, CENTRAL, and PsycINFO. Odds Ratios (OR) were calculated using the Mantel-Haenszel method in Review Manager 5.4.1. Heterogeneity was assessed using I2. The National Heart, Lung, and Blood Institute tool was used to assess the quality of each study. Seven cross-sectional studies were included. Three studies evaluated culpability while four evaluated MVC.

The pooled risk of MVC was not significantly different between THC-positive and THC-negative older drivers (OR, 95% CI 1.15 [0.40, 3.31]; I2 = 72%). In culpability studies, THC exposure was not significantly associated with an increased risk of being culpable for MVC among adults over the age of 50 (OR, 95% CI 1.24 [0.95, 1.61]; I2 = 0%). Inspection of funnel plots did not indicate publication bias.

Our review found that THC exposure was not associated with MVC involvement nor with culpability for MVCs.”

https://pubmed.ncbi.nlm.nih.gov/36979231/

https://www.mdpi.com/2076-3425/13/3/421

A Comprehensive Review on Cannabis sativa Ethnobotany, Phytochemistry, Molecular Docking and Biological Activities

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“For more than a century, Cannabis was considered a narcotic and has been banned by lawmakers all over the world. In recent years, interest in this plant has increased due to its therapeutic potential, in addition to a very interesting chemical composition, characterized by the presence of an atypical family of molecules known as phytocannabinoids. With this emerging interest, it is very important to take stock of what research has been conducted so far on the chemistry and biology of Cannabis sativa.

The aim of this review is to describe the traditional uses, chemical composition and biological activities of different parts of this plant, as well as the molecular docking studies. Information was collected from electronic databases, namely SciFinder, ScienceDirect, PubMed and Web of Science. 

Cannabis is mainly popular for its recreational use, but it is also traditionally used as remedy for the treatment of several diseases, including diabetes, digestive, circulatory, genital, nervous, urinary, skin and respiratory diseases.

These biological proprieties are mainly due to the presence of bioactive metabolites represented by more than 550 different molecules. Molecular docking simulations proved the presence of affinities between Cannabis compounds and several enzymes responsible for anti-inflammatory, antidiabetic, antiepileptic and anticancer activities.

Several biological activities have been evaluated on the metabolites of Cannabis sativa, and these works have shown the presence of antioxidant, antibacterial, anticoagulant, antifungal, anti-aflatoxigenic, insecticidal, anti-inflammatory, anticancer, neuroprotective and dermocosmetic activities. This paper presents the up-to-date reported investigations and opens many reflections and further research perspectives.”

https://pubmed.ncbi.nlm.nih.gov/36986932/

“At present, more than 545 phytochemicals have been described in the different parts of the Cannabis plant. The most represented metabolite class is the phytocannabinoids and they exhibit enormous structural diversity and bioactivities. Cannabis sativa is found in a wide variety of forms and environments on all continents and its pharmacological properties seem to go far beyond psychotic effects, with the ability to address needs such as the treatment and relief of many symptoms and diseases.”

https://www.mdpi.com/2223-7747/12/6/1245

Special Issue: Therapeutic Potential for Cannabis and Cannabinoids

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“The number of patients reporting the use of cannabis for medical purposes, whether through state-regulated medical marijuana programs or through over-the-counter hemp extracts, continues to grow. The growth in medicinal use of cannabis has in many ways surpassed the scientific data on the benefits and hazards of cannabis, and the scientific community has largely been left playing catch-up. Since 1996, when California became the first jurisdiction to legalize medical cannabis, the number of states following suit has grown and is currently at 37, while nearly 50 countries have legalized medical cannabis (and even more have decriminalized the plant) including Canada, Austria, Uruguay, Australia, South Korea, and Lesotho.

Cannabis sp. produces a number of phytochemicals with potential medical benefits including terpenes, flavonoids, and a unique class of molecules called cannabinoids, of which Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two most studied. Amazingly, the plant produces over 100 different cannabinoids with different potential therapeutic targets and activities, and these remain understudied.

The therapeutic benefits of cannabinoids are due, in large part, to the endocannabinoid system that exists in the human body, in addition to the ability of cannabinoids to interact and signal through a large number of disparate receptor molecules.”

“Cannabis is a complicated plant that produces over 100 cannabinoids in addition to terpenes and flavonoids. Adding to the complexity of trying to address the mechanism of action for cannabis is the fact that the cannabinoids that have been studied have been reported to exhibit activity at a number of different receptors.

This makes cannabinoids (and cannabis) a promiscuous drug. While typically viewed as a negative, promiscuous drugs do offer some advantages, most notably the ability to target different pathways of a disease with one medication.

The field of medical cannabis is growing rapidly, and as patients continue to use this plant to treat their conditions, there will remain a growing need for the scientific and medical communities to better understand how cannabis can impact the body.”

https://www.mdpi.com/2227-9059/11/3/902

Cannabidiol as a Promising Therapeutic Option in IC/BPS: In Vitro Evaluation of Its Protective Effects against Inflammation and Oxidative Stress

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“Several animal studies have described the potential effect of cannabidiol (CBD) in alleviating the symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic inflammatory disease of the urinary bladder. However, the effects of CBD, its mechanism of action, and modulation of downstream signaling pathways in urothelial cells, the main effector cells in IC/BPS, have not been fully elucidated yet. Here, we investigated the effect of CBD against inflammation and oxidative stress in an in vitro model of IC/BPS comprised of TNFα-stimulated human urothelial cells SV-HUC1. Our results show that CBD treatment of urothelial cells significantly decreased TNFα-upregulated mRNA and protein expression of IL1α, IL8, CXCL1, and CXCL10, as well as attenuated NFκB phosphorylation. In addition, CBD treatment also diminished TNFα-driven cellular reactive oxygen species generation (ROS), by increasing the expression of the redox-sensitive transcription factor Nrf2, the antioxidant enzymes superoxide dismutase 1 and 2, and hem oxygenase 1. CBD-mediated effects in urothelial cells may occur by the activation of the PPARγ receptor since inhibition of PPARγ resulted in significantly diminished anti-inflammatory and antioxidant effects of CBD. Our observations provide new insights into the therapeutic potential of CBD through modulation of PPARγ/Nrf2/NFκB signaling pathways, which could be further exploited in the treatment of IC/BPS.”

https://pubmed.ncbi.nlm.nih.gov/36902479/

https://www.mdpi.com/1422-0067/24/5/5055