Therapeutic potentials of cannabidiol: Focus on the Nrf2 signaling pathway

Posted on November 6, 2024 by David

“Cannabidiol (CBD), a cannabinoid that does not create psychoactive activities, has been identified as having a multitude of therapeutic benefits.

This study delves into the chemical properties, pharmacokinetics, safety and toxicity, pharmacological effects, and most importantly, the association between the therapeutic potential of CBD and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway.

The relationship between Nrf2 and CBD is closely linked to certain proteins that are associated with cardiovascular dysfunctions, cancers, and neurodegenerative conditions. Specifically, Nrf2 is connected to the initiation and progression of diverse health issues, including nephrotoxicity, bladder-related diseases, oral mucositis, cancers, obesity, myocardial injury and angiogenesis, skin-related inflammations, psychotic disorders, neuropathic pain, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, neuroinflammation, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis.

The association between CBD and Nrf2 is a zone of great interest in the medical field, as it has the potential to significantly impact the treatment and prevention of wide-ranging health conditions. Additional investigation is necessary to entirely apprehend the mechanisms underlying this crucial interplay and to develop effective therapeutic interventions.”

https://pubmed.ncbi.nlm.nih.gov/39491419/

“CBD plays a protective role in cardiovascular dysfunctions, cancers, and neurodegenerative conditions by targeting the Nrf2 signaling pathway.”

https://www.sciencedirect.com/science/article/pii/S0753332223016037?via%3Dihub

Treatment of Neuropsychiatric Symptoms in Alzheimer’s Disease with a Cannabis-Based Magistral Formulation: An Open-Label Prospective Cohort Study

Posted on October 30, 2024 by David

“Introduction: Neuropsychiatric symptoms (NPS) may be disruptive and problematic for patients with Alzheimer’s disease (AD) and for their caregivers. Cannabidiol (CBD) may be a safer alternative. The objective was to evaluate whether CBD-rich oil was effective, and safe in adults with NPS secondary to AD.

Methods: An open-label, prospective cohort, single-center study in patients with AD onset after the age of 65 with untreated NPS. A CBD-rich oil was administrated 0.1 mL sublingually every 8-12 h, up-titrated weekly. The primary outcome was to establish a reduction in the NPI-Q severity score of >30% at 12 weeks compared with the baseline. A p value of <0.05 was statistically significant.

Results: Between July 2020 and July 2023, 59 (93.5%) patients completed ≥3 months of follow-up. The patients were under treatment for a mean of 23.2 months, the median dose of CBD was 111 mg/day. The median NPI-Q severity and caregiver’s distress scores at baseline were 24 and 29, respectively. At 3 months, the median NPI-Q severity score shifted to 12 (p < 0.001) and 14 (p < 0.001), respectively. The proportion of patients who achieved a reduction in the NPI-Q severity score of >30% was 94.9%, while a reduction of >50% was achieved by 54.2%. The improvement was maintained for up to 24 months.

Conclusion: This study shows that CBD-rich oil is an effective and safe therapy for treating NPS in AD patients, while also reducing the caregivers’ distress.”

https://pubmed.ncbi.nlm.nih.gov/39474242/

“There is a need for an alternative treatment to significantly improve NPS in AD and decrease the caregiver’s stress as well as the financial burden resulting from polypharmacy and institutionalization. Any promising treatment should be safe and reduce the risk of adverse effects. This study evaluated the efficacy of a CBD-rich oil in treating NPS in a cohort of 59 patients with AD over a follow-up of more than 1 year, with a specific focus on its impact on caregiver burden. The study showed a significant reduction in the NPI-Q severity and caregiver’s distress scores after 3 months of intervention, and sustained for up to 24 months of follow-up. Notably, the effectiveness was independent of age, sex, years with AD, type of acetylcholinesterase inhibitors, and NPI-Q severity score before CBD treatment. A low CBD dose and a slow dose titration improve tolerance. These results may indicate that alleviating NPS in people with AD facilitates daily caregiving and improves caregivers’ emotional and physical distress.”

https://karger.com/mca/article/7/1/160/913137/Treatment-of-Neuropsychiatric-Symptoms-in

Unveiling the Potential of Phytocannabinoids: Exploring Marijuana’s Lesser-Known Constituents for Neurological Disorders

Posted on October 27, 2024 by David

“Cannabis sativa is known for producing over 120 distinct phytocannabinoids, with Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD) being the most prominent, primarily in their acidic forms.

Beyond Δ⁹-THC and CBD, a wide array of lesser-known phytocannabinoids, along with terpenes, flavonoids, and alkaloids, demonstrate diverse pharmacological activities, interacting with the endocannabinoid system (eCB) and other biological pathways. These compounds, characterized by phenolic structures and hydroxyl groups, possess lipophilic properties, allowing them to cross the blood-brain barrier (BBB) effectively.

Notably, their antioxidant, anti-inflammatory, and neuro-modulatory effects position them as promising agents in treating neurodegenerative disorders. While research has extensively examined the neuropsychiatric and neuroprotective effects of Δ⁹-THC, other minor phytocannabinoids remain underexplored. Due to the well-established neuroprotective potential of CBD, there is growing interest in the therapeutic benefits of non-psychotropic minor phytocannabinoids (NMPs) in brain disorders.

This review highlights the emerging research on these lesser-known compounds and their neuroprotective potential. It offers insights into their therapeutic applications across various major neurological conditions.”

https://pubmed.ncbi.nlm.nih.gov/39456229/

“In summary, the therapeutic potential of cannabis sativa extends well beyond the widely studied CBD, encompassing a diverse range of lesser-known phytocannabinoids that show promise in addressing various neurological disorders. The neuroprotective functions of these NMPs, particularly their antioxidant, anti-inflammatory, and immune-modulating properties, offer new avenues for research and treatment. While the pharmacological mechanisms of many NMPs remain underexplored, emerging studies suggest their potential to develop novel therapies for brain disorders. As research continues to unfold, these findings could pave the way for innovative cannabinoid plant-based treatments that go beyond the scope of traditional approaches, offering new hope in neuroprotection and disease management.”

https://www.mdpi.com/2218-273X/14/10/1296

Decoding the Therapeutic Potential of Cannabis and Cannabinoids in Neurological Disorders

Posted on October 16, 2024 by David

“For millennia, Cannabis sativa has served diverse roles, from medicinal applications to recreational use. Despite its extensive historical use, only a fraction of its components have been explored until recent times.

The therapeutic potential of Cannabis and its constituents has garnered attention, with suggestions for treating various conditions such as Parkinson’s disease, epilepsy, Alzheimer’s disease, and other Neurological disorders.

Recent research, particularly on animal experimental models, has unveiled the neuroprotective properties of cannabis. This neuroprotective effect is orchestrated through numerous G protein-coupled receptors (GPCRs) and the two cannabinoid receptors, CB1 and CB2.

While the capacity of cannabinoids to safeguard neurons is evident, a significant challenge lies in determining the optimal cannabinoid receptor agonist and its application in clinical trials. The intricate interplay of cannabinoids with the endocannabinoid system, involving CB1 and CB2 receptors, underscores the need for precise understanding and targeted approaches. Unravelling the molecular intricacies of this interaction is vital to harness the therapeutic potential of cannabinoids effectively.

As the exploration of cannabis components accelerates, there is a growing awareness of the need for nuanced strategies in utilizing cannabinoid receptor agonists in clinical settings. The evolving landscape of cannabis research presents exciting possibilities for developing targeted interventions that capitalize on the neuroprotective benefits of cannabinoids while navigating the complexities of receptor specificity and clinical applicability.”

https://pubmed.ncbi.nlm.nih.gov/39410886/

https://www.eurekaselect.com/article/143747

Cannabidiol ameliorates cognitive decline in 5×FAD mouse model of Alzheimer’s disease through potentiating the function of extrasynaptic glycine receptors

Posted on October 13, 2024 by David

“Emerging evidence supports the therapeutic potential of cannabinoids in Alzheimer’s disease (AD), but the underlying mechanism upon how cannabinoids impact brain cognition and AD pathology remains unclear.

Here we show that chronic cannabidiol (CBD) administration significantly mitigates cognitive deficiency and hippocampal β-amyloid (Aβ) pathology in 5×FAD mouse model of AD. CBD achieves its curative effect mainly through potentiating the function of inhibitory extrasynaptic glycine receptor (GlyR) in hippocampal dentate gyrus (DG).

Based on the in vitro and in vivo electrophysiological recording and calcium imaging, CBD mediated anti-AD effects via GlyR are mainly accomplished by decreasing neuronal hyperactivity of granule cells in the DG of AD mice. Furthermore, the AAV-mediated ablation of DG GlyRα1, or the GlyRα1^S296A mutation that exclusively disrupts CBD binding, significantly intercepts the anti-AD effect of CBD.

These findings suggest a GlyR dependent mechanism underlying the therapeutic potential of CBD in the treatment of AD.”

https://pubmed.ncbi.nlm.nih.gov/39396064/

https://www.nature.com/articles/s41380-024-02789-x

Cannabidiol, a plant-derived compound, is an emerging strategy for treating cognitive impairments: comprehensive review of randomized trials

Posted on September 26, 2024 by David

“Background: Finding new strategies to treat cognitive disorders is a challenging task. Medication must defeat the blood-brain barrier. Cannabidiol (CBD), a non-intoxicating compound of the cannabis plant, has gained recognition as a nutraceutical for its potential effectiveness in treating anxiety, oxidative stress, convulsions, and inflammation. However, the dose, tolerable upper intake, formulation, administration routes, comorbidities, diet, and demographic factors to reverse cognitive impairments have not been completely explored. Trials using CBD as a primary intervention have been conducted to alleviate cognitive issues. This review evaluates the benefits of CBD supplementation, research design, formulations, and outcomes reported in randomized clinical trials.

Methods: An evidence-based systematic literature review was conducted using PUBMED and the Florida International University Research Library resources. Fourteen randomized trials were selected for review, and their designs and outcomes were compared conceptually and in the form of resume tables.

Results: CBD showed improvement in anxiety and cognitive impairments in 9 out of 16 analyzed trials. However, the variability could be justified due to the diversity of the trial designs, underpowered studies, assayed population, uncontrolled results for comorbidities, medications, severity of drug dependence, compliances, and adherences. Overall, oral single doses of 200 mg-1,500 mg or vaporized 13.75 mg of CBD were shown to be effective at treating anxiety and cognition with a good safety profile and no drug addiction behaviors. Conversely, results that did not have a significant effect on treating cognitive impairments can be explained by various factors such as THC or other abuse drugs masking effect, low dose, and unknown purity of CBD. Furthermore, CBD shows potential properties that can be tested in the future for Alzheimer’s disease.

Conclusion: As medical cannabis becomes more accessible, it is essential to understand whether medication rich in CBD exerts a beneficial effect on cognitive disorders. Our study concludes that CBD is a promising candidate for treating neurocognitive disorders; however, more studies are required to define CBD as a therapeutic candidate for managing cognitive disorders.”

https://pubmed.ncbi.nlm.nih.gov/39323633/

“Cannabidiol (CBD), a phytocannabinoid, is derived from the cannabis plant.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1403147/full

Bidirectional Effect of Long-Term Δ9-Tetrahydrocannabinol Treatment on mTOR Activity and Metabolome

Posted on September 19, 2024 by David

“Brain aging is associated with cognitive decline, reduced synaptic plasticity, and altered metabolism. The activity of mechanistic target of rapamycin (mTOR) has a major impact on aging by regulating cellular metabolism. Although reduced mTOR signaling has a general antiaging effect, it can negatively affect the aging brain by reducing synaptogenesis and thus cognitive functions. Increased mTOR activity facilitates aging and is responsible for the amnestic effect of the cannabinoid receptor 1 agonist Δ⁹-tetrahydrocannabinol (THC) in higher doses.

Long-term low-dose Δ⁹-THC had an antiaging effect on the brain by restoring cognitive abilities and synapse densities in old mice.

Whether changes in mTOR signaling and metabolome are associated with its positive effects on the aging brain is an open question. Here, we show that Δ⁹-THC treatment has a tissue-dependent and dual effect on mTOR signaling and the metabolome.

In the brain, Δ⁹-THC treatment induced a transient increase in mTOR activity and in the levels of amino acids and metabolites involved in energy production, followed by an increased synthesis of synaptic proteins. Unexpectedly, we found a similar reduction in the mTOR activity in adipose tissue and in the level of amino acids and carbohydrate metabolites in blood plasma as in animals on a low-calorie diet.

Thus, long-term Δ⁹-THC treatment first increases the level of energy and synaptic protein production in the brain, followed by a reduction in mTOR activity and metabolic processes in the periphery.

Our study suggests that a dual effect on mTOR activity and the metabolome could be the basis for an effective antiaging and pro-cognitive medication.”

https://pubmed.ncbi.nlm.nih.gov/39296258/

https://pubs.acs.org/doi/10.1021/acsptsci.4c00002

The Endocannabinoid System in Alzheimer’s Disease: A Network Meta-Analysis

Posted on September 9, 2024 by David

“The findings concerning the association between endocannabinoid system (ECS) and Alzheimer’s disease (AD) exhibited inconsistencies when examining the expression levels of endocannabinoids. This study aimed to provide a comprehensive summary of the studies regarding alterations of the ECS in AD.

Six databases were thoroughly searched for literature to select relevant studies investigating the ECS in AD, including changes in cannabinoid receptors (CB1R and CB2R), endocannabinoids (2-AG and AEA), and their associated enzymes (FAAH and MAGL). Traditional meta-analysis evaluated the expression levels of the ECS in AD, and the results showed no significant differences in ECS components between healthy controls and AD patients. However, subgroup analysis revealed significantly lower expression levels of CB1R in AD than in controls, particularly in studies using western blot (SMD = -0.88, p < 0.01) and in studies testing CB1R of frontal cortex (SMD = -1.09, p < 0.01). For studies using HPLC, the subgroup analysis indicated significantly higher 2-AG levels in AD than in controls (SMD = 0.46, p = 0.02). Network meta-analysis examined the rank of ECS alterations in AD compared to controls, and the findings revealed that 2-AG and MAGL exhibited the largest increase and CB1R showed the largest decrease relative to the control group.

Based on the findings of traditional meta-analysis and network meta-analysis, we proposed that AD patients may present decreased expression levels of CB1R and increased expression levels of 2-AG and its degrading enzyme MAGL.

Our results may contribute to the growing body of research supporting the therapeutic potential of ECS modulation in the management of AD.”

https://pubmed.ncbi.nlm.nih.gov/39245959/

https://onlinelibrary.wiley.com/doi/10.1002/jnr.25380

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

Posted on September 8, 2024 by David

“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 Aβ_1-42-induced cytotoxicity was assessed using the thiazolyl blue tetrazolium bromide (MTT) assay. Transmission electron microscopy was used to visualise phytocannabinoid effects on Aβ_1-42 aggregation and fluorescence microscopy.

Results: Tetrahydrocannabinol (THC)/tetrahydrocannabinolic acid (THCA)-predominant cannabis extracts demonstrated the most significant overall neuroprotection against Aβ_1-42-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 Aβ_1-42 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

Posted on September 6, 2024 by David

“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

www.thctotalhealthcare.com

Category Archives: Alzheimer’s Disease (AD)