Author Archives: David Worrell

Selected cannabis cultivars modulate glial activation: in vitro and in vivo studies

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“Introduction: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by neuroinflammation, demyelination and axonal loss. Cannabis, an immunomodulating agent, is known for its ability to treat MS effectively. However, due to variations in the profile of secondary metabolites, especially cannabinoids, among cannabis cultivars, the effectiveness of cannabis treatment can vary, with significant variability in the effects on different biological parameters. For screening available cultivars, cellular in vitro as well as pre-clinical in vivo assays, are required to evaluate the effectiveness of the wide range of chemical variability that exists in cannabis cultivars. This study evaluated comparatively three chemically diverse cannabis cultivars, CN2, CN4 and CN6, containing different ratios of phytocannabinoids, for their neuroinflammatory activity in MS model.

Materials and methods: In vitro experiments were performed with lipopolysaccharide (LPS)-activated BV-2 microglia and primary glial cells to evaluate the effect of different cannabis cultivars on nitric oxide (NO) and inflammatory cytokines, as well as inducible nitric oxide synthase (iNOS) protein expression. An in vivo experiment using the experimental autoimmune encephalomyelitis (EAE) MS model was conducted using Myelin oligodendrocyte glycoprotein (MOG) as the activating peptide. The cannabis extracts of the cultivars CN2, CN4, CN6 or vehicle, were intraperitoneally injected with clinical scores given based on observed symptoms over the course of study. At the end of the experiment, the mice were sacrificed, and splenocyte cytokine secretion was measured using ELISA. Lumbar sections from the spinal cord of treated MS mice were evaluated for microglia, astrocytes and CD4+ cells.

Results: Extracts of the CN2 cultivar contained tetrahydrocannabinolic acid (THCA) and tetrahydrocannabinol (THC) without cannabidiol (CBD), and a number of monoterpenes. CN4 contained cannabidiolic acid (CBDA) and tetrahydrocannabidiolic acid (THCA), with significant amounts of THC: CBD in a 1:1 ratio, as well as sesquiterpenes and some monoterpenes; and CN6 contained primarily CBDA and THCA, as well as THC and CBD in a 2:1 ratio, with some sesquiterpenes and no monoterpenes. All extracts were not cytotoxic in glial cells up to 50 µg/ml. Dose dependent inhibition of LPS-induced BV2 as well as primary microglial NO secretion confirmed the anti-inflammatory and anti-oxidative activity of the three cannabis cultivars. CN2 but not CN4 reduced both astrocytosis and microglial activation in lumbar sections of EAE mice. In contrast, CN4 but not CN2 significantly decreased the secretion of TNFα and Interferon γ (IFNγ) in primary splenocytes extracted from EAE mice.

Conclusions: While both cannabis cultivars, CN2 and CN4, significantly reduced the severity of the clinical signs throughout the course of the study, they modulated different inflammatory mediators and pathways, probably due to differences in their phytocannabinoid composition. This demonstrates the differential potential of cannabis cultivars differing in chemotype to regulate neuroinflammation and their potential to treat MS.”

https://pubmed.ncbi.nlm.nih.gov/38778343/

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-024-00232-0

The Potential of Cannabichromene (CBC) as a Therapeutic Agent

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“There is a growing interest in the use of medicinal plants to treat a variety of diseases, and one of the most commonly used medicinal plants globally is Cannabis sativa 

The two most abundant cannabinoids (Δ9-tetrahydrocannabinol and cannabidiol) have been governmentally approved to treat selected medical conditions; however, the plant produces over 100 cannabinoids, including cannabichromene (CBC). While the cannabinoids share a common precursor molecule, cannabigerol, they are structurally and pharmacologically unique. These differences may engender differing therapeutic potentials.

In this review, we will examine what is currently known about CBC with regards to pharmacodynamics, pharmacokinetics, and receptor profile. We will also discuss the therapeutic areas that have been examined for this cannabinoid, notably antinociceptive, antibacterial, and anti-seizure activities. Finally, we will discuss areas where new research is needed and potential novel medicinal applications for CBC. 

Significance Statement Cannabichromene (CBC) has been suggested to have disparate therapeutic benefits such as anti-inflammatory, anticonvulsant, antibacterial, and antinociceptive effects. Most of the focus on the medical benefits of cannabinoids has been focused on THC and CBD. The preliminary studies on CBC indicate that this phytocannabinoid may have unique therapeutic potential that warrants further investigation. Following easier access to hemp, CBC products are commercially available over-the-counter and are being widely utilized with little or no evidence of their safety or efficacy.”

https://pubmed.ncbi.nlm.nih.gov/38777605/

https://jpet.aspetjournals.org/content/early/2024/05/22/jpet.124.002166

[Cannabinoid Drugs in the Treatment of Psychiatric Disorders – Data from the German Federal Institute for Drugs and Medical Devices]

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“Background: Since 2017 physicians in Germany can prescribe cannabis based medicines or medical cannabis with subsequent funding by the statutory health insurance system.

Methods: Physicians prescribing cannabinoid drugs were legally required to take part in a survey conducted by the Federal Institute for Drugs and Medical Devices. This study analyses data from 16.809 case reports that were collected from 30.3.2017 to 31.12.2021.

Results: There were 5582 cases documenting the use of cannabinoid drugs in psychiatric disorders. More than half of the prescriptions were Dronabinol. 80% of the treatments concerned somatoform disorders. Most of the treatments for other psychiatric disorders also targeted pain. Doctors reported a positive effect on symptoms in at least 75% of the cases.

Discussion: Most patients with psychiatric disorders received cannabinoid drugs for pain. The evidence from randomized controlled clinical trials for the use of cannabinoid drugs in psychiatric indications is weak.”

https://pubmed.ncbi.nlm.nih.gov/38749455/

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2296-1358

The Use of Cannabidiol in Treating Psychiatric Disorders: A Systematic Review

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“Cannabidiol (CBD) has been used as a pharmacological treatment for psychiatric disorders in many studies, but few of good quality at the moment. Our objective was to assess the effect of CBD in mono/add-on therapy on symptom severity in psychiatric disorders. We performed a systematic review of clinical trials and randomized controlled trials that used CBD as treatment for psychiatric disorders. PRISMA criteria have been used for methodological purposes. Two assessors individually examined the results based on title and abstract, and decided which papers warranted full read. We included studies in English that measured disease severity as primary outcome. Out of 226 studies returned from the search, 9 warranted full read. There were 4 studies using CBD in schizophrenia, 3 studies of substance use disorder and 2 studies of social anxiety. CBD has a good safety profile even in higher doses, but results are inconclusive regarding improvements in disease severity.”

https://pubmed.ncbi.nlm.nih.gov/38765233/

https://psychiatry-psychopharmacology.com/en/the-use-of-cannabidiol-in-treating-psychiatric-disorders-a-systematic-review-133107

Cannabidiol improves nonmotor symptoms, attenuates neuroinflammation and favors hippocampal newborn neuronal maturation in a rat model of Parkinsonism

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“Objective: To investigate the effects of cannabidiol (CBD) on emotional and cognitive symptoms in rats with intra-nigral 6-hydroxydopamine (6-OHDA) lesions.

Methods: Adult male Wistar rats received bilateral intranigral 6-OHDA infusions and were tested in a battery of behavioral paradigms to evaluate nonmotor symptoms. The brains were obtained to evaluate the effects of CBD on hippocampal neurogenesis.

Results: 6-hydroxydopamine-lesioned rats exhibited memory impairments and despair-like behavior in the novelty-suppressed feeding test and forced swim test, respectively. The animals also exhibited dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), striatum, and ventral tegmental area and a reduction of hippocampal neurogenesis. Cannabidiol decreased dopaminergic neuronal loss in the SNpc, reduced the mortality rate and decreased neuroinflammation in 6-OHDA-lesioned rats. In parallel, CBD prevented memory impairments and attenuated despair-like behavior that were induced by bilateral intranigral 6-OHDA lesions. Repeated treatment with CBD favored the neuronal maturation of newborn neurons in the hippocampus in Parkinsonian rats.

Conclusion: The present findings suggest a potential beneficial effect of CBD on nonmotor symptoms induced by intra-nigral 6-OHDA infusion in rats.”

https://pubmed.ncbi.nlm.nih.gov/38770713/

https://www.cambridge.org/core/journals/acta-neuropsychiatrica/article/abs/cannabidiol-improves-nonmotor-symptoms-attenuates-neuroinflammation-and-favors-hippocampal-newborn-neuronal-maturation-in-a-rat-model-of-parkinsonism/76995CF9AE1A7A6188A327F29DA10440

Perioperative Cannabinoids Significantly Reduce Postoperative Opioid Requirements in Patients Undergoing Coronary Artery Bypass Graft Surgery

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“Background Opioids, commonly used to control pain associated with surgery, are known to prolong the duration of mechanical ventilation and length of hospital stay. A wide range of adjunctive strategies are currently utilized to reduce postoperative pain, such as local and regional nerve blocks, nerve cryoablation, and adjunctive medications. We hypothesized that dronabinol (a synthetic cannabinoid) in conjunction with standard opioid pain management will reduce opioid requirements to manage postoperative pain. Methods Sixty-eight patients who underwent isolated first-time coronary artery bypass graft surgery were randomized to either the control group, who received only standard opioid-based analgesia, or the dronabinol group, who received dronabinol (a synthetic cannabinoid) in addition to standard opioid-based analgesia. Dronabinol was given in the preoperative unit, before extubation in the ICU, and after extubation on the first postoperative day. Preoperative, intraoperative, and postoperative parameters were compared under an IRB-approved protocol. The primary endpoints were the postoperative opioid requirement, duration of mechanical ventilation, and ICU length of stay, and the secondary endpoints were the duration of inotropic support needed, left ventricular ejection fraction (LVEF), and the change in LVEF. This study was undertaken at Northwest Medical Center, Tucson, AZ, USA. Results Sixty-eight patients were randomized to either the control group (n = 37) or the dronabinol group (n = 31). Groups were similar in terms of demographic features and comorbidities. The total postoperative opioid requirement was significantly lower in the dronabinol group [39.62 vs 23.68 morphine milligram equivalents (MMEs), p = 0.0037], representing a 40% reduction. Duration of mechanical ventilation (7.03 vs 6.03h, p = 0.5004), ICU length of stay (71.43 vs 63.77h, p = 0.4227), and inotropic support requirement (0.6757 vs 0.6129 days, p = 0.7333) were similar in the control and the dronabinol groups. However, there was a trend towards lower durations in each endpoint in the dronabinol group. Interestingly, a significantly better preoperative to postoperative LVEF change was observed in the dronabinol group (3.51% vs 6.45%, p = 0.0451). Conclusions Our study found a 40% reduction in opioid use and a significantly greater improvement in LVEF in patients treated with adjunctive dronabinol. Mechanical ventilation duration, ICU length of stay, and inotropic support requirement tended to be lower in the dronabinol group, though did not reach statistical significance. The results of this study, although limited by sample size, are very encouraging and validate our ongoing investigation.”

https://pubmed.ncbi.nlm.nih.gov/38765405/

https://www.cureus.com/articles/243644-perioperative-cannabinoids-significantly-reduce-postoperative-opioid-requirements-in-patients-undergoing-coronary-artery-bypass-graft-surgery#!/

The antitumor action of endocannabinoids in the tumor microenvironment of glioblastoma

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“Approximately 80% of all malignant brain tumors are gliomas, which are primary brain tumors. The most prevalent subtype of glioma, glioblastoma multiforme (GBM), is also the most deadly. Chemotherapy, immunotherapy, surgery, and conventional pharmacotherapy are currently available therapeutic options for GBM; unfortunately, these approaches only prolong the patient’s life by 5 years at most. Despite numerous intensive therapeutic options, GBM is considered incurable.

Accumulating preclinical data indicate that overt antitumoral effects can be induced by pharmacologically activating endocannabinoid receptors on glioma cells by modifying important intracellular signaling cascades. The complex mechanism underlying the endocannabinoid receptor-evoked antitumoral activity in experimental models of glioma may inhibit the ability of cancer cells to invade, proliferate, and exhibit stem cell-like characteristics, along with altering other aspects of the complex tumor microenvironment. The exact biological function of the endocannabinoid system in the development and spread of gliomas, however, is remains unclear and appears to rely heavily on context.

Previous studies have revealed that endocannabinoid receptors are present in the tumor microenvironment, suggesting that these receptors could be novel targets for the treatment of GBM. Additionally, endocannabinoids have demonstrated anticancer effects through signaling pathways linked to the classic features of cancer. Thus, the pharmacology of endocannabinoids in the glioblastoma microenvironment is the main topic of this review, which may promote the development of future GBM therapies.”

https://pubmed.ncbi.nlm.nih.gov/38720772/

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1395156/full

Anticancer effect of minor phytocannabinoids in preclinical models of multiple myeloma

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“Multiple myeloma (MM) is a blood cancer caused by uncontrolled growth of clonal plasmacells. Bone disease is responsible for the severe complications of MM and is caused by myeloma cells infiltrating the bone marrow and inducing osteoclast activation. To date, no treatment for MM is truly curative since patients relapse and become refractory to all drug classes.

Cannabinoids are already used as palliative in cancer patients. Furthermore, their proper anticancer effect was demonstrated in many cancer models in vitro, in vivo, and in clinical trials. Anyway, few information was reported on the effect of cannabinoids on MM and no data has been provided on minor phytocannabinoids such as cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), and cannabidivarin (CBDV). Scientific literature also reported cannabinoids beneficial effect against bone disease.

Here, we examined the cytotoxic activity of CBG, CBC, CBN, and CBDV in vitro in MM cell lines, their effect in modulating MM cells invasion toward bone cells and the bone resorption. Subsequently, according to the in vitro results, we selected CBN for in vivo study in a MM xenograft mice model.

Results showed that the phytocannabinoids inhibited MM cell growth and induced necrotic cell death. Moreover, the phytocannabinoids reduced the invasion of MM cells toward osteoblast cells and bone resorption in vitro. Lastly, CBN reduced in vivo tumor mass.

Together, our results suggest that CBG, CBC, CBN, and CBDV can be promising anticancer agents for MM.”

https://pubmed.ncbi.nlm.nih.gov/38760945/

https://iubmb.onlinelibrary.wiley.com/doi/10.1002/biof.2078

Cannabidiol prevents LPS-induced inflammation by inhibiting the NLRP3 inflammasome and iNOS activity in BV2 microglia cells via CB2 receptors and PPARγ

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“Neuroinflammation stands as a critical player in the pathogenesis of diverse neurological disorders, with microglial cells playing a central role in orchestrating the inflammatory landscape within the central nervous system.

Cannabidiol (CBD) has gained attention for its potential to elicit anti-inflammatory responses in microglia, offering promising perspectives for conditions associated with neuroinflammation.

Here we investigated whether the NLRP3 inflammasome and inducible nitric oxide synthase (iNOS) are involved in the protective effects of CBD, and if their modulation is dependent on cannabinoid receptor 2 (CB2) and PPARγ signalling pathways.

We found that treatment with CBD attenuated pro-inflammatory markers in lipopolysaccharide (LPS)-challenged BV2 microglia in a CB2- and PPARγ-dependent manner. At a molecular level, CBD inhibited the LPS-induced pro-inflammatory responses by suppressing iNOS and NLRP3/Caspase-1-dependent signalling cascades, resulting in reduced nitric oxide (NO), interleukin-1β (IL-1β), and tumour necrosis factor-alpha (TNF-α) concentrations.

Notably, the protective effects of CBD on NLRP3 expression, Caspase-1 activity, and IL-1β concentration were partially hindered by the antagonism of both CB2 receptors and PPARγ, while iNOS expression and NO secretion were dependent exclusively on PPARγ activation, with no CB2 involvement. Interestingly, CBD exhibited a protective effect against TNF-α increase, regardless of CB2 or PPARγ activation.

Altogether, these findings indicate that CB2 receptors and PPARγ mediate the anti-inflammatory effects of CBD on the NLRP3 inflammasome complex, iNOS activity and, ultimately, on microglial phenotype. Our results highlight the specific components responsible for the potential therapeutic applications of CBD on neuroinflammatory conditions.”

https://pubmed.ncbi.nlm.nih.gov/38761855/

https://www.sciencedirect.com/science/article/abs/pii/S0197018624000962?via%3Dihub

Cannabidiol ameliorates PTSD-like symptoms by inhibiting neuroinflammation through its action on CB2 receptors in the brain of male mice

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“Post-traumatic stress disorder (PTSD) is a debilitating mental health disease related to traumatic experience, and its treatment outcomes are unsatisfactory.

Accumulating research has indicated that cannabidiol (CBD) exhibits anti-PTSD effects, however, the underlying mechanism of CBD remains inadequately investigated. Although many studies pertaining to PTSD have primarily focused on aberrations in neuronal functioning, the present study aimed to elucidate the involvement and functionality of microglia/macrophages in PTSD while also investigated the modulatory effects of CBD on neuroinflammation associated with this condition.

We constructed a modified single-prolonged stress (SPS) mice PTSD model and verified the PTSD-related behaviors by various behavioral tests (contextual freezing test, elevated plus maze test, tail suspension test and novel object recognition test). We observed a significant upregulation of Iba-1 and alteration of microglial/macrophage morphology within the prefrontal cortex and hippocampus, but not the amygdala, two weeks after the PTSD-related stress, suggesting a persistent neuroinflammatory phenotype in the PTSD-modeled group.

CBD (10 mg/kg, i.p.) inhibited all PTSD-related behaviors and reversed the alterations in both microglial/macrophage quantity and morphology when administered prior to behavioral assessments. We further found increased pro-inflammatory factors, decreased PSD95 expression, and impaired synaptic density in the hippocampus of the modeled group, all of which were also restored by CBD treatment. CBD dramatically increased the level of anandamide, one of the endocannabinoids, and cannabinoid type 2 receptors (CB2Rs) transcripts in the hippocampus compared with PTSD-modeled group.

Importantly, we discovered the expression of CB2Rs mRNA in Arg-1-positive cells in vivo and found that the behavioral effects of CBD were diminished by CB2Rs antagonist AM630 (1 mg/kg, i.p.) and both the behavioral and molecular effects of CBD were abolished in CB2Rs knockout mice. These findings suggest that CBD would alleviate PTSD-like behaviors in mice by suppressing PTSD-related neuroinflammation and upregulation and activation of CB2Rs may serve as one of the underlying mechanisms for this therapeutic effect.

The present study offers innovative experimental evidence supporting the utilization of CBD in PTSD treatment from the perspective of its regulation of neuroinflammation, and paves the way for leveraging the endocannabinoid system to regulate neuroinflammation as a potential therapeutic approach for psychiatric disorders.”

https://pubmed.ncbi.nlm.nih.gov/38759736/

“Cannabidiol alleviated all PTSD-like behaviors in mice by suppressing PTSD-related neuroinflammation.”

https://www.sciencedirect.com/science/article/abs/pii/S0889159124004045?via%3Dihub