Disease-Modifying Symptomatic Treatment (DMST) Potential of Cannabinoids in Patients with Multiple Sclerosis

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“With the recent introduction of a number of highly effective disease-modifying treatments (DMTs) and the resulting almost complete prevention of acute relapses in many patients with multiple sclerosis (MS), the interest of MS clinicians has gradually shifted from relapse prevention to counteraction of disease progression and the treatment of residual symptoms.

Targeting the cannabinoid system with nabiximols is an approved and effective strategy for the treatment of spasticity secondary to MS.

Recently, the concept of spasticity plus syndrome (SPS) was introduced to account for the evidence that spasticity often appears in MS patients in clusters with other symptoms (such as pain, bladder dysfunction, sleep, and mood disorders), where cannabinoids can also be effective due to their broader action on many immune and neuronal functions. Interestingly, outside these symptomatic benefits, extensive pre-clinical and clinical research indicated how the modulation of the cannabinoid system results in significant anti-inflammatory and neuroprotective effects, all potentially relevant for MS disease control.

This evidence makes nabiximols a potential disease modifying symptomatic treatment (DMST), a concept introduced in an attempt to overcome the often artificial distinction between DMTs and symptomatic therapies (STs).”

https://pubmed.ncbi.nlm.nih.gov/39279696/

https://www.eurekaselect.com/article/143047

Effectiveness of Cannabinoids Treatment in Pain Management and Other Fibromyalgia-Associated Symptoms: A Case Series

“Pharmacological therapies for FM are still ineffective in many patients, involving adverse effects that hinder their long-term use.

We aimed to assess the effectiveness of cannabinoids (Tilray Dried Flower THC18) in the management of chronic pain and other FM-associated symptoms according to patient-reported outcomes, in a series of three FM patients. 

We observed improvements after one and three months of cannabinoids treatment in Brief Pain Inventory (BPI), Visual Analogue Scale (VAS), Insomnia Severity Index (ISI), SF-36 Health Survey, and Fibromyalgia Impact Questionnaire (FIQ) allowing pain relief, and improvements in sleep quality, performance of daily life activities, and quality of life.

In conclusion, although more studies are needed, in our series of FM patients, cannabinoids treatment showed promising results in the management of chronic pain and other FM-associated symptoms, improving the quality of life of these patients.”

https://www.heraldopenaccess.us/openaccess/effectiveness-of-cannabinoids-treatment-in-pain-management-and-other-fibromyalgia-associated-symptoms-a-case-series

Cannabinoids in the Inflamed Synovium Can Be a Target for the Treatment of Rheumatic Diseases

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“The management of rheumatic diseases has noticeably changed in recent years with the development of targeted therapeutic agents, namely, biological disease-modifying antirheumatic drugs. Identifying essential signaling pathways and factors crucial for the development and progression of these diseases remains a significant challenge.

Therapy could be used to delay the onset or reduce harm. The endocannabinoid system’s presence within the synovium can be identified as a suggested target for therapeutic interventions due to its role in modulating pain, inflammation, and joint metabolism.

This review brings together the most pertinent information concerning the actions of the endocannabinoid system present in inflamed synovial tissue and its interaction with phytocannabinoids and synthetic cannabinoids, which can be used from a therapeutic perspective to minimize the inflammatory and pain processes typical of osteoarthritis and rheumatoid arthritis.”

https://pubmed.ncbi.nlm.nih.gov/39273304/

https://www.mdpi.com/1422-0067/25/17/9356

Changes in health-related quality of life over the first three months of medical marijuana use

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“Background: The psychosocial impact of medical marijuana use is not yet known. This study evaluated short-term changes in health-related quality of life (HRQoL) over the first three months of medical marijuana use.

Methods: This prospective, observational, longitudinal study followed adults newly recommended for medical marijuana by a physician for any of the more than 20 qualifying medical conditions in Pennsylvania. Participants (N = 438) provided their clinical status and demographic information, and completed semi-structured interviews prior to medical marijuana initiation (baseline) and at three months. HRQoL was assessed by the Short Form-36 (SF-36). Paired-samples t-tests evaluated changes in HRQoL over time.

Results: Participants (M age = 46.4 years [15.6]; 66.4% female) were mostly commonly referred for medical marijuana to treat anxiety disorders (61.9%) or severe chronic or intractable pain (53.6%). Participants reported rapid and significant improvements in all of the domains of HRQoL from baseline to three months after initiating medical marijuana use (physical functioning, role limitations due to physical health problems, emotional well-being, role limitations due to emotional problems, bodily pain, social functioning, energy/fatigue and general health, P < .001 for all). Age was negatively predictive of level of improvement over time for the physical functioning (P < .0001), role limitations due to physical health problems (P < .001), and pain (P < .0001) domains after controlling for baseline, with older participants displaying less improvement than younger participants.

Conclusions: Gains were observed in all HRQoL domains assessed after three months of medical marijuana use. In several domains, age was a significant predictor of degree of improvement.”

https://pubmed.ncbi.nlm.nih.gov/39256884/

“In conclusion, the use of medical marijuana for three months was associated with improvements in physical, social, emotional and pain-related HRQoL. Ongoing surveillance of HRQoL in individuals with physical and mental health conditions can help to treat the “whole person” and to capture any collateral impact of selected therapeutic approaches as treatment initiates and progresses. Results from this study can help patients, their caregivers, and their providers to make more informed and evidence-based decisions on whether to incorporate medical marijuana into their treatment regimens.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-024-00245-9

Cannabinoids elicit antidepressant-like behavior and activate serotonergic neurons through the medial prefrontal cortex

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“Preclinical and clinical studies show that cannabis modulates mood and possesses antidepressant-like properties, mediated by the agonistic activity of cannabinoids on central CB1 receptors (CB1Rs). The action of CB1R agonists on the serotonin (5-HT) system, the major transmitter system involved in mood control and implicated in the mechanism of action of antidepressants, remains however poorly understood.

In this study, we demonstrated that, at low doses, the CB1R agonist WIN55,212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate] exerts potent antidepressant-like properties in the rat forced-swim test (FST).

This effect is CB1R dependent because it was blocked by the CB1R antagonist rimonabant and is 5-HT mediated because it was abolished by pretreatment with the 5-HT-depleting agent parachlorophenylalanine. Then, using in vivo electrophysiology, we showed that low doses of WIN55,212-2 dose dependently enhanced dorsal raphe nucleus 5-HT neuronal activity through a CB1R-dependent mechanism.

Conversely, high doses of WIN55,212-2 were ineffective in the FST and decreased 5-HT neuronal activity through a CB1R-independent mechanism. The CB1R agonist-induced enhancement of 5-HT neuronal activity was abolished by total or medial prefrontocortical, but not by lateral prefrontocortical, transection. Furthermore, 5-HT neuronal activity was enhanced by the local microinjection of WIN55,212-2 into the ventromedial prefrontal cortex (mPFCv) but not by the local microinjection of WIN55,212-2 into the lateral prefrontal cortex. Similarly, the microinjection of WIN55,212-2 into the mPFCv produced a CB1R-dependent antidepressant-like effect in the FST.

These results demonstrate that CB1R agonists possess antidepressant-like properties and modulate 5-HT neuronal activity via the mPFCv.”

“These results establish that low doses of a CB1R agonist elicit potent antidepressant-like behavior and enhance 5-HT neurotransmission, mediated by CB1R activation in the mPFCv. Conversely, high doses nullify antidepressant-like behavior and markedly attenuate 5-HT neurotransmission, an effect that appears to be instigated by a non-CB1R mechanism.”

https://pubmed.ncbi.nlm.nih.gov/17959812/

Medicinal cannabis extracts are neuroprotective against Aβ1-42-mediated toxicity in vitro

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“Background: Phytocannabinoids inhibit the aggregation and neurotoxicity of the neurotoxic Alzheimer’s disease protein β amyloid (Aβ). We characterised the capacity of five proprietary medical cannabis extracts, heated and non-heated, with varying ratios of cannabidiol and Δ9-tetrahydrocannabinol and their parent carboxylated compounds to protect against lipid peroxidation and Aβ-evoked neurotoxicity in PC12 cells.

Methods: Neuroprotection against lipid peroxidation and Aβ1-42-induced cytotoxicity was assessed using the thiazolyl blue tetrazolium bromide (MTT) assay. Transmission electron microscopy was used to visualise phytocannabinoid effects on Aβ1-42 aggregation and fluorescence microscopy.

Results: Tetrahydrocannabinol (THC)/tetrahydrocannabinolic acid (THCA)-predominant cannabis extracts demonstrated the most significant overall neuroprotection against Aβ1-42-induced loss of PC12 cell viability. These protective effects were still significant after heating of extracts, while none of the extracts provided significant neuroprotection to lipid peroxidation via tbhp exposure. Modest inhibition of Aβ1-42 aggregation was demonstrated only with the non-heated BC-401 cannabis extract, but overall, there was no clear correlation between effects on fibrils and conferral of neuroprotection.

Conclusions: These findings highlight the variable neuroprotective activity of cannabis extracts containing major phytocannabinoids THC/THCA and cannabidiol (CBD)/cannabidiolic acid (CBDA) on Aβ-evoked neurotoxicity and inhibition of amyloid β aggregation. This may inform the future use of medicinal cannabis formulations in the treatment of Alzheimer’s disease and dementia.”

https://pubmed.ncbi.nlm.nih.gov/39243211/

“With access to approved pathways increasing globally, medicinal cannabis formulations are increasingly being used to treat neuropsychiatric conditions. With laboratory and animal studies now showing benefits of cannabis and cannabinoids in treating neurodegenerative diseases, this study investigated whether whole cannabis extracts could protection neuronal cells against the toxicity of a signature Alzheimer’s disease protein, beta (β) amyloid.

We found that cannabis extracts afforded neuronal cells protection against amyloid β toxicity, mostly in extracts with the major phytocannabinoid, Δ9-THC, or its parent compound, Δ9-THC-COOH. These results suggest that medicinal cannabis may have potential in the further treatment of dementia.”

https://onlinelibrary.wiley.com/doi/10.1111/bcpt.14078


A combination of Δ9-tetrahydrocannabinol and cannabidiol modulates glutamate dynamics in the hippocampus of an animal model of Alzheimer’s disease

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“A combination of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) at non-psychoactive doses was previously demonstrated to reduce cognitive decline in APP/PS1 mice, an animal model of Alzheimer’s disease (AD). However, the neurobiological substrates underlying these therapeutic properties of Δ9-THC and CBD are not fully understood.

Considering that dysregulation of glutamatergic activity contributes to cognitive impairment in AD, the present study evaluates the hypothesis that the combination of these two natural cannabinoids might reverse the alterations in glutamate dynamics within the hippocampus of this animal model of AD.

Interestingly, our findings reveal that chronic treatment with Δ9-THC and CBD, but not with any of them alone, reduces extracellular glutamate levels and the basal excitability of the hippocampus in APP/PS1 mice.

These effects are not related to significant changes in the function and structure of glutamate synapses, as no relevant changes in synaptic plasticity, glutamate signaling or in the levels of key components of these synapses were observed in cannabinoid-treated mice. Our data instead indicate that these cannabinoid effects are associated with the control of glutamate uptake and/or to the regulation of the hippocampal network.

Taken together, these results support the potential therapeutic properties of combining these natural cannabinoids against the excitotoxicity that occurs in AD brains.”

https://pubmed.ncbi.nlm.nih.gov/39232876/

https://www.neurotherapeuticsjournal.org/article/S1878-7479(24)00126-0/fulltext

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

The effects of Cannabis sativa and cannabinoids on the inhibition of pancreatic lipase – An enzyme involved in obesity

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“Introduction: Obesity is a chronic noncommunicable disease characterized by excessive body fat that can have negative health consequences. Obesity is a complex disease caused by a combination of genetic, environmental, and lifestyle factors. It is characterized by a discrepancy between caloric intake and expenditure. Obesity increases the risk of acquiring major chronic diseases, including heart disease, stroke, cancer, and Type 2 diabetes mellitus (T2DM). Currently, the inhibition of pancreatic lipases (PL) is a promising pharmacological therapy for obesity and weight management. In this study, the inhibition of pancreatic lipase by Cannabis sativa (C. sativa) plant extract and cannabinoids was investigated.

Methods: The inhibitory effect was assessed using p-nitrophenyl butyrate (pNPB), and the results were obtained by calculating the percentage relative activity and assessed using one-way analysis of variance (ANOVA). Kinetic studies and spectroscopy techniques were used to evaluate the mode of inhibition. Diet-induced; and diabetic rat models were studied to evaluate the direct effects of C. sativa extract on PL activity.

Results: Kinetic analyses showed that the plant extracts inhibited pancreatic lipase, with tetrahydrocannabinol (THC) and cannabinol (CBN) being the potential cause of the inhibition noted for the C. sativa plant extract. CBN and THC inhibited the pancreatic lipase activity in a competitive manner, with the lowest residual enzyme activity of 52 % observed at a 10 μg/mL concentration of CBN and 39 % inhibition at a 25 μg/mL concentration of THC. Circular dichroism (CD) spectroscopy revealed that the inhibitors caused a change in the enzyme’s secondary structure. At low concentrations, THC showed potential for synergistic inhibition with orlistat. C.sativa treatment in an in vivo rat model confirmed its inhibitory effects on pancreatic lipase activity.

Conclusion: The findings in this study provided insight into the use of cannabinoids as pancreatic lipase inhibitors and the possibility of using these compounds to develop new pharmacological treatments for obesity.”

https://pubmed.ncbi.nlm.nih.gov/39232382/

https://www.sciencedirect.com/science/article/pii/S0753332224012423?via%3Dihub

Mechanistic Insights into the Impact of WIN 55, 212-2, a Synthetic Cannabinoid, on Adhesion Molecules PECAM-1 and VE-cadherin in HeLa Cells: Implications on Cancer Processes

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“The endocannabinoid (eCB) system comprises endogenous ligands, cannabinoid receptors (CBRs) and proteins involved in their regulation; its alteration leads to many diseases including cancer. Thus, becomes a therapeutic target for synthetic cannabinoids aimed to control cancer cell proliferation, migration, adhesion and invasion. However, little is known about adhesion molecules regulation through CBRs activation.

Consequently, the aim of this study was to evaluate the effects of a CB1/CB2 agonist, WIN-55, 212-2 (WIN), on the regulation of adhesion molecules PECAM-1 and VE-cadherin in HeLa cells. CBRs expression was evaluated by immunofluorescence staining in HeLa cells. Cell viability by MTT, cell adhesion by crystal violet, adhesion molecules expression and location by Western blot and immunofluorescence staining assays were assessed on cells treated with different WIN concentrations.

Results show that CB1, CB2 and GPR55 receptors are expressed in HeLa cells. Additionally, biphasic effects were observed in their metabolic activity and adhesive properties: low WIN concentrations significantly increased them, in contrast, were decreased at high ones as compared to controls (p < 0.0001), demonstrating that WIN elicits opposite effects depending on the concentration and exposure time. PECAM-1 was detected in cytoplasm, membrane and perinuclear region of HeLa cells, whereas VE-cadherin had a nuclear distribution. There were not significant differences in PECAM-1 and VE-cadherin expression and location, suggesting that WIN does not modulate these proteins.

These findings support the potential use of WIN due to its anticancer properties without dysregulating adhesion molecules. WIN possible contribution to inhibit cancer progression should be further investigated.”

https://pubmed.ncbi.nlm.nih.gov/39228102/

https://www.tandfonline.com/doi/full/10.1080/15376516.2024.2399132