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Targeting dysfunctional endocannabinoid signaling in a mouse model of Gulf War illness

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“Gulf War Illness (GWI) is a chronic disorder characterized by a heterogeneous set of symptoms that include pain, fatigue, anxiety, and cognitive impairment. These are thought to stem from damage caused by exposure under unpredictable stress to toxic Gulf War (GW) chemicals, which include pesticides, nerve agents, and prophylactic drugs.

We hypothesized that GWI pathogenesis might be rooted in long-lasting disruption of the endocannabinoid (ECB) system, a signaling complex that serves important protective functions in the brain.

Using a mouse model of GWI, we found that tissue levels of the ECB messenger, anandamide, were significantly reduced in the brain of diseased mice, compared to healthy controls. In addition, transcription of the Faah gene, which encodes for fatty acid amide hydrolase (FAAH), the enzyme that deactivates anandamide, was significant elevated in prefrontal cortex of GWI mice and brain microglia.

Behavioral deficits exhibited by these animals, including heightened anxiety-like and depression-like behaviors, and defective extinction of fearful memories, were corrected by administration of the FAAH inhibitor, URB597, which normalized brain anandamide levels. Furthermore, GWI mice displayed unexpected changes in the microglial transcriptome, implying persistent dampening of homeostatic surveillance genes and abnormal expression of pro-inflammatory genes upon immune stimulation.

Together, these results suggest that exposure to GW chemicals produce a deficit in brain ECB signaling which is associated with persistent alterations in microglial function. Pharmacological normalization of anandamide-mediated ECB signaling may offer an effective therapeutic strategy for ameliorating GWI symptomology.”

https://pubmed.ncbi.nlm.nih.gov/39241906/

“A mouse model for Gulf War Illness (GWI) displays deficits in brain anandamide.

Normalization of endocannabinoid signaling may offer a therapeutic strategy for GWI.”

https://www.sciencedirect.com/science/article/pii/S0028390824003113?via%3Dihub

“FDA-approved cannabidiol [Epidiolex®] alleviates Gulf War Illness-linked cognitive and mood dysfunction, hyperalgesia, neuroinflammatory signaling, and declined neurogenesis”

https://pubmed.ncbi.nlm.nih.gov/39169440/

“CBD formulation improves energetic homeostasis in dermal fibroblasts from Gulf War Illness patients.  Our data provide new evidence that will validate the potential of cannabinoids as a therapeutic strategy to mitigate energy imbalance that may contribute to detrimental symptomatology (i.e., chronic fatigue, brain fog, cognitive dysfunction, etc.) in GWI patients.”

https://pubmed.ncbi.nlm.nih.gov/35560565/

Cannabidiol suppresses silica-induced pulmonary inflammation and fibrosis through regulating NLRP3/TGF-β1/Smad2/3 pathway

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“Silica-induced pulmonary fibrosis is an irreversible and progressive lung disease with limited treatments available. In this work, FDA-approved cannabidiol (CBD) was studied for its potential medical use in silicosis.

In silicosis female C57BL/6 mice model, oral CBD or pirfenidone (PFD) on day 1 after intratracheal drip silica (150 mg/mL) and continued for 42 days. Lung inflammatory and fibrotic changes were studied using ELISA kits, H&E staining and Masson staining. Osteopontion (OPN) and α-smooth muscle actin (α-SMA) expression in lung tissues was determined using immunohistochemical staining.

The results indicated that CBD attenuated silica-induced pulmonary inflammation and fibrosis.

Human myeloid leukemia mononuclear cells (THP-1) were treated with silica (200 μg/mL) to induce cell damage, then CBD (10 μM, 20 μM) and PFD (100 μM) were incubated. In vitro experiments showed that CBD can effectively reduce the expression of NLRP3 inflammasome in THP-1 cells and subsequently block silica-stimulated transformation of fibromuscular-myofibroblast transition (FMT) by culturing human embryonic lung fibroblasts (MRC-5) in conditioned medium of THP-1 cells.

Therefore, CBD exhibited the potential therapy for silicosis through inhibiting the silica-induced pulmonary inflammation and fibrosis via the NLRP3/TGF-β1/Smad2/3 signaling pathway.”

https://pubmed.ncbi.nlm.nih.gov/39244899/

“CBD ameliorates silica-induced pulmonary inflammation and fibrosis.”

https://www.sciencedirect.com/science/article/abs/pii/S1567576924016096?via%3Dihub

“Silica compounds are found throughout the environment in rocks, sand, clay, soil, air, and water. Silica is used in many commercial products, such as bricks, glass and ceramics, plaster, granite, concrete, cleansers, skin care products, and talcum powder. Some forms of amorphous silica are used as food additives, food wrappings, toothpaste and cosmetics. The general population is exposed to silica through air, certain types of indoor dust (such as from concrete), food, water, soil, and some consumer products. The exposure of greatest concern is through air.”

https://wwwn.cdc.gov/TSP/ToxFAQs/ToxFAQsDetails.aspx?faqid=1492&toxid=290#:~:text=Silica%20is%20used%20in%20many,food%20wrappings%2C%20toothpaste%20and%20cosmetics.

Pharmacology of Non-Psychoactive Phytocannabinoids and Their Potential for Treatment of Cardiometabolic Disease

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“The use of Cannabis sativa by humans dates back to the third millennium BC, and it has been utilized in many forms for multiple purposes, including production of fibre and rope, as food and medicine, and (perhaps most notably) for its psychoactive properties for recreational use. The discovery of Δ9-tetrahydrocannabinol (Δ9-THC) as the main psychoactive phytocannabinoid contained in cannabis by Gaoni and Mechoulam in 1964 (J Am Chem Soc 86, 1646-1647), was the first major step in cannabis research; since then the identification of the chemicals (phytocannabinoids) present in cannabis, the classification of the pharmacological targets of these compounds and the discovery that the body has its own endocannabinoid system (ECS) have highlighted the potential value of cannabis-derived compounds in the treatment of many diseases, such as neurological disorders and cancers. Although the use of Δ9-THC as a therapeutic agent is constrained by its psychoactive properties, there is growing evidence that non-psychoactive phytocannabinoids, derived from both Cannabis sativa and other plant species, as well as non-cannabinoid compounds found in Cannabis sativa, have real potential as therapeutics. This chapter will focus on the possibilities for using these compounds in the prevention and treatment of cardiovascular disease and related metabolic disturbances.”

https://pubmed.ncbi.nlm.nih.gov/39235486/

https://link.springer.com/chapter/10.1007/164_2024_731

Cannabis sativa L. essential oil: chemical characterisation and antimicrobial activity against methicillin-resistant Staphylococcus pseudintermedius

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“Cannabis sativa L. essential oil has attracted the interest of the scientific community thanks to its numerous biological activities. Several studies have evaluated EOs as alternative therapeutic approaches to limit the use of antibiotics; the present study aimed to evaluate the in vitro inhibitory and bactericidal activity of the essential oils obtained from the leaves and inflorescences of two hemp genotypes against twenty-one multidrug-resistant, methicillin-resistant Staphylococcus pseudintermedius strains isolated from canine clinical samples.

Both EOs were mainly represented by sesquiterpene hydrocarbons, with a prevalence of β-caryophyllene and α-humulene. However, different relative amounts of phytocannabinoids were also detected. Microbiological results evidenced better outcomes for the EO characterised by the highest content of phytocannabinoids, which in turn showed no differences among the tested strains. Nevertheless, both the EOs showed better inhibitory and bactericidal activities than their main constituent, β-caryophyllene, tested individually, highlighting the presence of synergistic effects among the EO compounds.”

https://pubmed.ncbi.nlm.nih.gov/39229937/

https://www.tandfonline.com/doi/full/10.1080/14786419.2024.2398733

Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models

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“Mutations in mitochondrial energy-producing genes lead to a heterogeneous group of untreatable disorders known as primary mitochondrial diseases (MD). Leigh syndrome (LS) is the most common pediatric MD and is characterized by progressive neuromuscular affectation and premature death.

Here, we show that daily cannabidiol (CBD) administration significantly extends lifespan and ameliorates pathology in two LS mouse models, and improves cellular function in fibroblasts from LS patients. CBD delays motor decline and neurodegenerative signs, improves social deficits and breathing abnormalities, decreases thermally induced seizures, and improves neuropathology in affected brain regions.

Mechanistically, we identify peroxisome proliferator-activated receptor gamma (PPARγ) as a key nuclear receptor mediating CBD’s beneficial effects, while also providing proof of dysregulated PPARγ expression and activity as a common feature in both mouse neurons and fibroblasts from LS patients.

Taken together, our results provide the first evidence for CBD as a potential treatment for LS.”

https://pubmed.ncbi.nlm.nih.gov/39231983/

“Here we report that daily CBD administration significantly extends lifespan and improves clinical signs in mouse models of two distinct LS phenotypic presentations, identifying downstream targets for the beneficial effects of CBD and paving the way for novel therapeutic avenues for LS.”

“CBD prolongs lifespan and improves fitness in Ndufs4-deficient mice”

https://www.nature.com/articles/s41467-024-51884-8


Anti-inflammatory effects of phytocannabinoids and terpenes on inflamed Tregs and Th17 cells in vitro

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“Aims: Phytocannabinoids and terpenes from Cannabis sativa have demonstrated limited anti-inflammatory and analgesic effects in several inflammatory conditions. In the current study, we test the hypothesis that phytocannabinoids exert immunomodulatory effects in vitro by decreasing inflammatory cytokine expression and activation.

Key methods: CD3/CD28 and lipopolysaccharide activated peripheral blood mononuclear cells (PBMCs) from healthy donors (n = 6) were treated with phytocannabinoid compounds and terpenes in vitro. Flow cytometry was used to determine regulatory T cell (Treg) and T helper 17 (Th17) cell responses to treatments. Cell pellets were harvested for qRT-PCR gene expression analysis of cytokines, cell activation markers, and inflammation-related receptors. Cell culture supernatants were analysed by ELISA to quantify IL-6, TNF-α and IL-10 secretion.

Main findings: In an initial screen of 20 μM cannabinoids and terpenes which were coded to blind investigators, cannabigerol (GL4a), caryophyllene oxide (GL5a) and gamma-terpinene (GL6a) significantly reduced cytotoxicity and gene expression levels of IL6, IL10, TNF, TRPV1, CNR1, HTR1A, FOXP3, RORC and NFKΒ1. Tetrahydrocannabinol (GL7a) suppression of T cell activation was associated with downregulation of RORC and NFKΒ1 gene expression and reduced IL-6 (p < 0.0001) and IL10 (p < 0.01) secretion. Cannabidiol (GL1b) significantly suppressed activation of Tregs (p < 0.05) and Th17 cells (p < 0.05) in a follow-on in vitro dose-response study. IL-6 (p < 0.01) and IL-10 (p < 0.01) secretion was significantly reduced with 50 μM cannabidiol.

Significance: The study provides the first evidence that cannabidiol and tetrahydrocannabinol suppress extracellular expression of both anti- and pro-inflammatory cytokines in an in vitro PBMC model of inflammation.”

https://pubmed.ncbi.nlm.nih.gov/39208564/

https://www.sciencedirect.com/science/article/pii/S0014480024000431?via%3Dihub


Cannabinoids in Integumentary Wound Care: A Systematic Review of Emerging Preclinical and Clinical Evidence

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“This systematic review critically evaluates preclinical and clinical data on the antibacterial and wound healing properties of cannabinoids in integument wounds.

Comprehensive searches were conducted across multiple databases, including CINAHL, Cochrane library, Medline, Embase, PubMed, Web of Science, and LILACS, encompassing records up to May 22, 2024. Eighteen studies met the inclusion criteria. Eleven were animal studies, predominantly utilizing murine models (n = 10) and one equine model, involving 437 animals. The seven human studies ranged from case reports to randomized controlled trials, encompassing 92 participants aged six months to ninety years, with sample sizes varying from 1 to 69 patients. The studies examined the effects of various cannabinoid formulations, including combinations with other plant extracts, crude extracts, and purified and synthetic cannabis-based medications administered topically, intraperitoneally, orally, or sublingually.

Four animal and three human studies reported complete wound closure. Hemp fruit oil extract, cannabidiol (CBD), and GP1a resulted in complete wound closure in twenty-three (range: 5-84) days with a healing rate of 66-86% within ten days in animal studies. One human study documented a wound healing rate of 3.3 cm2 over 30 days, while three studies on chronic, non-healing wounds reported an average healing time of 54 (21-150) days for 17 patients by oral oils with tetrahydrocannabinol (THC) and CBD and topical gels with THC, CBD, and terpenes. CBD and tetrahydrocannabidiol demonstrated significant potential in reducing bacterial loads in murine models. However, further high-quality research is imperative to fully elucidate the therapeutic potential of cannabinoids in the treatment of bacterial skin infections and wounds. Additionally, it is crucial to delineate the impact of medicinal cannabis on the various phases of wound healing.”

https://pubmed.ncbi.nlm.nih.gov/39204426/

“This systematic review methodically evaluates the current evidence on the wound healing and antibacterial properties of medicinal cannabis (MC) in treating integumentary wounds and infections, whether used alone or in combination with other agents. The findings demonstrate that MC possesses significant antibacterial properties and promotes wound healing, showing promising results in both animal models and human studies.”

https://www.mdpi.com/1999-4923/16/8/1081

Chronic Cannabidiol Administration Mitigates Excessive Daytime Sleepiness and Fatigue in Patients with Primary Hypertension: Insights from a Randomized Crossover Trial

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“Background: The chronic effects of cannabidiol (CBD) supplementation on factors that could impact the quality of life (anxiety, sleeping quality, memory, etc.) are poorly explored. Hence, the aim of this study was to establish whether chronic CBD supplementation will improve self-reported outcomes related to quality of life. 

Methods: In this randomized crossover trial, 64 patients with primary hypertension were assigned to receive CBD (225-450 mg) for 5 weeks followed by 5 weeks of placebo or vice versa, with a 2-week washout in-between the two. Self-reported outcomes were assessed using short form-36 (SF-36), Pittsburgh sleep quality index (PSQI), Epworth sleepiness scale (ESS), memory complaint questionnaire (MAC-Q), and state-trait anxiety inventory (STAI). 

Results: Five-week administration of CBD, but not of placebo, resulted in improvement of ESS score (F = 6.738, p = 0.011), as well as fatigue/vitality (ΔCBD = 5.0, p < 0.001) and psychological well-being dimensions of SF-36 (ΔCBD = 7.4, p = 0.039). No overall benefit of CBD on quality of life was noted (p = 0.674). No changes were seen in total scores of MAC-Q, PSQI, or STAI (p = 0.151, p = 0.862, p = 0.702, respectively). No significant correlations were found between plasma CBD concentrations and any of the scores. 

Conclusions: Chronic CBD administration reduced excessive daytime sleepiness, despite the fact that no change was observed in self-reported quality of sleep. Furthermore, self-reported fatigue and psychological well-being dimensions of quality of life also improved following chronic CBD use.”

https://pubmed.ncbi.nlm.nih.gov/39187263/

https://www.liebertpub.com/doi/10.1089/can.2024.0028

Successful use of cannabidiol in nonconvulsive status epilepticus in Angelman syndrome

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“Angelman syndrome (AS) is a rare neurogenetic disorder characterized by developmental delay, epileptic seizures, cognitive impairment, electroencephalographic epileptiform and slow interictal abnormalities, and motor dysfunction.1

In AS, nonconvulsive status epilepticus (NCSE) is frequent, is characterized by period of decreased responsiveness which may last hours to days, and it occur in about 20% of patients.2 Treatment of NCSE in AS is challenging and no specific drugs are approved with this purpose.

Epidyolex® is approved by EMA up to a dose of 20 mg/kg/d for individuals >2 years with Lennox–Gastaut Syndrome (LGS) or Dravet Syndrome (DS), and with a higher maximum dose of 25 mg/kg/d in those with tuberous sclerosis complex (TSC) (EMA).3

We recently treated an 8-year-old boy with AS expressing deletion of 15q11.2q13 (6.23 Mb). At the age of 2 years, he started to present with asynchronous bilateral upper limbs myoclonia. He was treated with clonazepam and ethosuximide with good effects, being almost seizure-free until the age of 5 years, when myoclonia associated with poor responsiveness reappeared consistently.

At the age of 8 years, he was receiving ethosuximide (20.5 mg/kg/d) and clonazepam (0.08 mg/kg/d), he presented with marked drowsiness and an increase of myoclonia (Figure 1A). He was admitted in our Department of Neurology (Bambino Gesù Children Hospital – Rome, Italy). Long-term EEG monitoring showed a NCSE pattern (Figure 1A,B), clinically characterized by a reduction in motor initiative and an increase in tremor. This pattern resolved only intermittently during intravenous Midazolam administration. Intravenous valproate (bolus at 30 mg/kg/d and then continuous infusion at 2 mg/kg/d) (Figure 1C) and levetiracetam (bolus at 60 mg/kg/d) (Figure 1D), were ineffective and therefore stopped.

We added Epidyolex® CBD, with a faster titration than usual, starting with 10 mg/kg/d up to 20 mg/kg/d in 8 days. After 1 week, he became more responsive (Figure 1E,F), and after 1 month, he was seizure-free, and the EEG was significantly improved (Figure 1G,H). Epidyolex® was added to ethosuximide and clobazam which were not effective alone. After 4 months of follow-up, no clinical-EEG modifications were observed. The patients did not present adverse events both in the acute phase of administration and during the follow-up.

This case has shown the potential benefits given by Epidyolex® CBD for the treatment of NCSE in a patient with AS. The faster titration was well tolerated.

Given the need for innovative treatments, especially for drug-resistant epilepsies, Epidyolex® CBD may be a promising anti-seizure medication and has been given “off label” to people with epilepsy syndromes outside LGS, DS, and TSC.4 Interestingly, acute CBD (100 mg/kg) treatment attenuated hyperthermia- and acoustically induced seizures in a mouse model of AS supporting the hypothesis that CBD may alleviate seizures and EEG abnormalities in AS, putting the basis for a rational development of CBD as treatment for epilepsy in AS.5 The use of CBD in refractory status epilepticus has been recently reviewed, and in 9 out of 11 treated patients the outcome was favorable.6

We believe this is the first report of the use of CBD in the acute treatment of NCSE in patients with AS. Although anecdotal, this observation ought to encourage further trials and confirmation from future studies.”

https://onlinelibrary.wiley.com/doi/10.1002/epi4.12948

Bioelectronic sensing platform emulating the human endocannabinoid system for assessing and modulating of cannabinoid activity

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“Cannabinoids are involved in physiological and neuromodulatory processes through their interactions with the human cannabinoid receptor-based endocannabinoid system. Their association with neurodegenerative diseases and brain reward pathways underscores the importance of evaluating and modulating cannabinoid activity for both understanding physiological mechanisms and developing therapeutic drugs. The use of agonists and antagonists could be strategic approaches for modulation.

In this study, we introduce a bioelectronic sensor designed to monitor cannabinoid binding to receptors and assess their agonistic and antagonistic properties. We produced human cannabinoid receptor 1 (hCB1R) via an Escherichia coli expression system and incorporated it into nanodiscs (NDs). These hCB1R-NDs were then immobilized on a single-walled carbon nanotube field-effect transistor (swCNT-FET) to construct a bioelectronic sensing platform. This novel system can sensitively detect the cannabinoid ligand anandamide (AEA) at concentrations as low as 1 fM, demonstrating high selectivity and real-time response. It also successfully identified the hCB1R agonist Δ9-tetrahydrocannabinol and observed that the hCB1R antagonist rimonabant diminished the sensor signal upon AEA binding, indicating the antagonism-based modulation of ligand interaction. Consequently, our bioelectronic sensing platform holds potential for ligand detection and analysis of agonism and antagonism.”

https://pubmed.ncbi.nlm.nih.gov/39173339/

https://www.sciencedirect.com/science/article/abs/pii/S0956566324006924?via%3Dihub