Category Archives: Alzheimer’s Disease (AD)

The effects of chronic cannabidiol administration on brain pathology and behavioral deficits found in the tau P301s-line PS19 mouse model of Alzheimer’s disease

Posted on by

“Compounds derived from the plant Cannabis demonstrate many therapeutic properties suggesting that they could delay the onset and progression of Alzheimer’s disease (AD).

The goal of the present experiment was to observe the effects of chronic cannabidiol (CBD) administration on the behavior and brain pathology of an AD tauopathy mouse model, Tau P301S-Line PS19 mice.MethodsMice were orally given CBD (20 mg/kg) or vehicle, daily, beginning around 3 months of age. At 6 months old, mice were tested on a battery of tasks to assess object recognition, motor function, and spatial learning and memory. The mice were retested at 9 months old on the behavioral tasks and the fear conditioning paradigm was added. Following completion of behavioral testing, the mice were perfused for histological analysis.

Results Chronic CBD treatments did not appear to affect the behavior nor restore the reduced hippocampal volume of Tau P301S mice. However, a deeper assessment of the changes in inflammatory markers showed a treatment effect on a measure of microglia reactivity. Robust sex differences were revealed with Tau P301S males showing more severe pathology relative to females. Finally, daily treatments of CBD did not negatively impact the behavior or brain of any of the experimental groups suggesting that its chronic administration was relatively safe.

Conclusions Taken together, the results suggested that CBD can have beneficial effects on some of the pathology associated with AD, even in an aggressive model of this neurodegenerative disease, but the impacts on impaired behavior were minimal.”

https://pubmed.ncbi.nlm.nih.gov/41736228

“Cannabidiol (CBD) is a safe, readily available, and relatively inexpensive treatment option that has been shown to improve pathologies associated with AD.”

https://journals.sagepub.com/doi/10.1177/13872877261421654


Efficacy and Safety of Cannabinoids for Neuropsychiatric Symptoms of Dementia: A Systematic Review with Meta-analysis

Posted on by

“Background and objective: Neuropsychiatric symptoms (NPS) are highly prevalent in persons with dementia and have been associated with adverse health outcomes. Neuropsychiatric symptoms can impose major physical, psychosocial, and financial burdens on caregivers while contributing to additional pressure on healthcare systems. Although atypical antipsychotics have received regulatory approval for treating specific NPS, such as agitation, their use in older adults has been linked to higher risks of mortality, cardiovascular events, and falls. Cannabinoids have emerged as promising pharmacological treatments for NPS in dementia, including agitation, anxiety, and depressive symptoms, owing to their behavior-modulating effects. The objective of this study was to provide a comprehensive assessment of the efficacy and safety of cannabinoids for NPS in dementia, which may help refine evidence-based guidelines for their use.

Methods: We systematically reviewed studies from MEDLINE, Embase, PsycINFO, CINAHL, Cochrane Library, and ClinicalTrials.gov from inception to August 2025. Search terms relevant to cannabinoids and dementia were used. Randomized controlled trials on the use of cannabinoids for treating NPS in dementia with published results were included. Participant characteristics, including age, sex, and baseline cognition, were collected. Random-effects meta-analyses were conducted to examine standardized mean differences in NPS scores between cannabinoid and placebo groups. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool (RoB 2) for randomized trials. Heterogeneity between studies was analyzed through I2 statistics. Additionally, subgroup analyses and meta-regressions were performed for variables of interest. Last, risk ratios for outcomes related to adverse events were calculated to evaluate the safety of cannabinoids in this population.

Results: Of the ten included studies (328 participants), eight assessed total NPS and nine reported on agitation in persons with dementia. Our results indicated that cannabinoids did not decrease total NPS (standardized mean difference [SMD]: – 0.18, 95% confidence interval [CI] – 0.48 to 0.12; p = 0.2) compared to placebo, but reduced agitation (SMD: – 0.52, 95% CI – 1.00 to – 0.05, p = 0.03) with high heterogeneity (I2 = 77.2%). However, after removing studies rated as high risk (RoB 2) for a sensitivity analysis, the result was no longer statistically significant (SMD: – 0.35, 95% CI – 0.79 to 0.10, p = 0.1). Subgroup analyses demonstrated that cannabinoids were beneficial with doses higher than 10 mg of tetrahydrocannabinol-equivalent (SMD: – 0.63, 95% CI – 0.98 to – 0.28, p < 0.01), and in patients with severe dementia (SMD: – 0.96, 95% CI – 1.75 to – 0.16, p < 0.01). The risk of overall adverse events did not differ significantly between cannabinoid and placebo treatments, though cannabinoids were associated with an increased risk of sedation (risk ratio = 2.09, 95% CI = 1.22 to 3.57, p < 0.01).

Conclusions: This review provides up-to-date evidence that cannabinoids are efficacious for alleviating dementia-related agitation and are generally well tolerated in this population, though sedation was more commonly reported in the cannabinoid group. However, the data remained scarce for other NPS and requires further research.”

https://pubmed.ncbi.nlm.nih.gov/41748849

https://link.springer.com/article/10.1007/s40263-026-01277-w

Discovery and structure-activity relationship of cannabidiol aminoquinones as anti-Alzheimer’s agents via dual modulation of Nrf2/HO-1 and TLR4/NF-κB pathways

Posted on by

“Neuroinflammation and oxidative stress are recognized as key drivers of neuronal death and the progression of neurodegenerative diseases. At the same time, they serve as central hubs linking the major pathological hallmarks of Alzheimer’s disease (AD), including Aβ aggregation, tau protein hyperphosphorylation, neurofibrillary tangle formation, and neuronal injury.

In this study, we screened natural active molecules of cannabidiol (CBD) and its derivatives, and conducted molecular docking simulations. A class of CBD aminoquinone scaffolds with potential anti-AD activity was identified, and 32 CBD aminoquinone derivatives were synthesized for comprehensive in vitro and in vivo evaluation.

Among them, compound G-12 with p-F-aniline moiety exhibited potent anti-inflammatory activity (IC50 = 1.39 μM), outstanding neuroprotective effects (IC50 = 1.29 μM), and prominent behavioral manifestations. In addition, G-12 displayed acceptable in vivo pharmacokinetic (PK) properties. The superior performance of G-12 indicated that through the Nrf2/HO-1 oxidative stress pathway, it affected the TLR4/NF-κB inflammatory pathway, inhibited neuroinflammation, and thereby influenced Aβ aggregation, protecting neurons.

This strategy that links several major pathological features of AD is effective in combating AD.

G-12 is also a lead compound with the potential to be developed into a multifunctional drug for AD.”

https://pubmed.ncbi.nlm.nih.gov/41643512

“Cannabidiol (CBD) is one of non-psychoactive cannabinoids derived from cannabis plants. CBD and its structural analogues modulate a broad spectrum of pharmacological targets, including multiple orphan receptors, GPCRs, 5-HT1A receptors, and PPARγ and TRPV1 channels, thus show potential therapeutic effects such as neuroprotection, anti-epilepsy, anti-inflammation, antioxidation. CBD exhibits neuroprotective properties through multiple mechanisms in the treatment of neurodegenerative disorders, including AD, multiple sclerosis, epilepsy, Parkinson’s disease. Currently, CBD has been approved as an orphan drug by the FDA for the treatment of Lennox-Gastaut syndrome and Dravet.”

https://www.sciencedirect.com/science/article/abs/pii/S0045206826001264?via%3Dihub

Involvement of Keap1/Nrf2 and the antioxidant defence in cytoprotective effects induced by cannabis polyphenols in SH-SY5Y neuronal cells

Posted on by

“Oxidative stress (OS) is widely recognized as a central promoter to the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS).

Cannabis sativa L. synthesizes a complex array of bioactive compounds that extends well beyond the well-known cannabinoids to include a diverse suite of polyphenols, terpenes, fatty acids, tocopherols, and proteins. The non-cannabinoid polyphenolic fraction is composed primarily of flavonoids, stilbenoids, lignans, and lignanamides, which contribute substantially to the plant’s antioxidant, anti-inflammatory, and neuroprotective properties.

This study investigates the redox-modulating and cytoprotective properties of a polyphenolic fraction derived from Cannabis sativa L. in SH-SY5Y neuroblastoma cells.

Neurons were treated with various concentrations of the aqueous polyphenolic cannabis extract and exposed to oxidative stress using hydrogen peroxide (100 µM). Protein and gene expression related to redox signalling were analyzed via Western blot and qPCR, and molecular docking studies were performed in silico. Furthermore, antioxidant enzymes activity was measured by spectrophotometry.

Results revealed that the phenolic fraction significantly activated the Keap1/Nrf2 pathway, increased expression of PRDX1 and PRDX3, and enhanced endogenous antioxidant defences. Simultaneously, it reduced endoplasmic reticulum stress-induced apoptosis (via Bax/Bcl-2 modulation) and attenuated inflammatory markers, including NO, NF-κB2, IL-6, and IL-8. In silico docking studies identified Leu583 as a key residue in Nrf2-ligand interactions.

These findings suggest that Cannabis sativa L. polyphenols are key bioactive compounds modulating redox homeostasis and inflammation, and offering neuroprotective benefits with potential relevance in diseases involving mitochondrial dysfunction and oxidative damage.”

https://pubmed.ncbi.nlm.nih.gov/41643607

“Collectively, these results position phenolic compounds present in Cannabis sativa as promising and essential key candidates for targeting mitochondrial dysfunction and oxidative neurotoxicity, although further studies are needed to fully the therapeutic and clinical potential.”

https://www.sciencedirect.com/science/article/pii/S0753332226000806?via%3Dihub

Synergistic Neuroprotection by Cannabis sativa and Tilia × viridis: Attenuation of Hippocampal Neurons Glutamate-Induced Oxidative Stress and LPS-Driven Microglial Inflammation

Posted on by

“Throughout history, Cannabis sativa has been linked to the therapeutic management of epilepsy and Tilia × viridis has a tradition of use as a sedative.

This study aimed to evaluate the protective effect of an ethanolic extract of C. sativa (CSRD), an aqueous extract of T. × viridis (TE), and their combination against oxidative stress induced by glutamate in a murine hippocampal neuronal (HT-22) cell line, as well as their anti-inflammatory activity in male Wistar rats’ microglial cells stimulated with LPS.

A phytochemical analysis was also conducted. Glutamate-induced reactive oxygen species (ROS) were quantified using 2′,7′-dichlorodihydrofluorescein diacetate via fluorescence microscopy. Cell viability was assessed using the MTT assay. Distinct microglial cell phenotypes were identified via immunofluorescence.

Extracts partially reversed glutamate-induced loss of cell viability (52% to 200% for CSRD; 22% to 82% for TE). Their combination produced a greater effect, reversing glutamate-induced toxicity by 133% to 284% and fully restoring cell viability to control levels. Moreover, the combined treatment reduced intracellular ROS levels (52% to 58%).

Notably, the combination also exhibited the most pronounced anti-inflammatory effects, significantly reducing the proportion of reactive phenotype 1 cells, while increasing the population of anti-inflammatory phenotype 2 cells and preserving the trophic phenotype 3 subpopulation.

In conclusion, this study not only validates the ethnobotanical uses of C. sativa and T. × viridis but also reveals a potent synergy when combined. This provides a strong foundation for the development of phytomedicines with translational potential for managing complex pathologies like epilepsy or neuroinflammation associated with neurodegenerative diseases.”

https://pubmed.ncbi.nlm.nih.gov/41628619

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2751-0171

The role of the endocannabinoid system in managing neuropsychiatric symptoms in Alzheimer’s disease

Posted on by

“The endocannabinoid system comprises cannabinoid receptors (CBRs) 1 & 2, endocannabinoids (eCBs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the enzymes that regulate their production and degradation.

ECS plays a significant role in both health and disease.

It influences neuronal and glial communications, neurotransmitter regulations, neuroinflammation, and behavioral alterations. Neuropsychiatric symptoms (NPS) are commonly seen in neurodegenerative conditions like Alzheimer’s disease (AD), apart from the core clinical diagnosis of dementia.

NPS consists of various disturbing symptoms, including anxiety, agitation, apathy, hallucinations, delusions, sleeping problems, appetite problems, and depression. In AD, up to 97% exhibit one or more NPS.

Emerging evidence from preclinical and clinical studies suggests that ECS is both a contributor to and a potential therapeutic target for managing NPS. This review explores ECS’s role in NPS and its therapeutic implications.”

https://pubmed.ncbi.nlm.nih.gov/41608471

“ECS is essential for regulating a range of behaviors and undergoes notable changes during the progression of AD, particularly through modulation of the CB1R and CB2Rs and their endocannabinoids. Further placebo-controlled, randomized clinical trials are needed to confirm the efficacy of cannabinoid receptor-targeting therapies in managing NPS in AD.”

https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2025.1709266/full


Exploring cannabinoid modulation on autophagy mechanisms in Alzheimer’s disease: a review

Posted on by

“Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of toxic protein aggregates in the brain, leading to brain cell death and cognitive impairment. Central to AD pathogenesis is the autophagy pathway, a crucial cellular self-digestion process.

Cannabinoids, the fundamental phytochemical compounds derived from the Cannabis sativa plant, have been demonstrated to exhibit neuroprotective qualities when used as a treatment at microdoses.

However, the impact of multi-cannabinoid treatments on autophagy induction and subsequent cell survival in AD in vitro models remains uncertain. This review seeks to explore the potential of a multi-cannabinoid treatment strategy in enhancing neuronal cell survival through autophagy activation within an AD in vitro model.

The proposed approach involves a combination of cannabinoids in their potential to upregulate autophagy mechanisms, potentially supporting neuronal cell resilience. By unravelling the mechanistic link between autophagy, cannabinoid treatment, and neuronal viability, this review aims to elucidate how cannabinoids influence neuronal function and survival at a cellular and molecular level. By offering insights into the exploitation of the endocannabinoid system, this review contributes to the development of novel cannabinoid-based treatment avenues for AD. This pursuit aligns with the broader objective of addressing the debilitating effects of AD on the quality of life for those affected.”

https://pubmed.ncbi.nlm.nih.gov/41601969

“Emerging evidence, including a recent case report, suggests that cannabinoid microdosing may offer a potential strategy for reducing AD-related symptoms while minimizing adverse effects.”

“Pharmacokinetic data further indicate that multi-cannabinoid formulations, particularly those combining THC and CBD, add additional minor cannabinoids, may provide enhanced therapeutic efficacy and improved safety profiles compared to monotherapy.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1748368/full


Age differences in endocannabinoid tone are ameliorated after recent cannabis use

Posted on by

“An age-related decline in endocannabinoid system (ECS) activity may contribute to conditions such as chronic pain and Alzheimer’s disease. Although cannabis is increasingly used by older adults to alleviate age-related conditions, it remains unclear how cannabinoids affect ECS activity across the lifespan.

The present study assayed levels of seven endocannabinoids (AEA, 2-AG, DEA, LEA, PEA, SEA, and OEA) in a sample of adults (N = 142; younger 21-24 years, n = 38; midlife 25-54, n = 73; older 55-71, n = 31) assayed before cannabis use (baseline [pre-use]) and ~ 1 h after flower or ~ 2 h after edible cannabis use.

At baseline, older adults exhibited lower AEA and DEA than younger adults, and lower LEA than midlife adults.

Acute cannabis use increased AEA, DEA, LEA, PEA, SEA, and OEA across all age groups (all p < .001). 2-AG showed no increase. For AEA and DEA, increases were larger in older adults (Time×Age).

These findings indicate broad endocannabinoid elevations after cannabis use regardless of age, alongside age-related differences at baseline and in acute responses.”

https://pubmed.ncbi.nlm.nih.gov/41580496

https://www.nature.com/articles/s41598-025-27618-1

Cannabidiol Enhances SIRT1 and Autophagy for the Maintenance of Human Mesenchymal Stem Cells

Posted on by

“Background/aim: Mesenchymal stem cells (MSCs) are used to treat various degenerative diseases. However, their therapeutic potential is limited by cellular aging during in vitro cultivation. This study aimed to explore whether cannabidiol (CBD) can delay MSC aging by enhancing the expression of Sirtuin 1 (SIRT1) and autophagy, two key anti-aging regulators.

Materials and methods: CBD, the most important non-psychotomimetic phytocannabinoid derived from the Cannabis sativa plant, was used to up-regulate SIRT1 and autophagy in order to maintain MSC stemness. MSCs were treated with CBD and assessed for cell viability, doubling time, key gene/protein expression, relative senescence-associated β-galactosidase (SA-β-gal) assay, relative telomere length, and telomerase expression.

Results: CBD significantly increased the expression of SIRT1 and autophagy-related markers in MSCs. Furthermore, CBD preserved MSC stemness by promoting the deacetylation of SRY-box transcription factor 2 (SOX2) through SIRT1, and delayed cellular senescence by enhancing autophagy, reducing SA-β-gal activity, maintaining proliferation capacity, and supporting telomere function.

Conclusion: CBD promotes MSC stemness and delays cellular senescence, potentially through the activation of SIRT1 and autophagy. These findings suggest that CBD may serve as a promising agent for preserving MSC function in regenerative medicine.”

https://pubmed.ncbi.nlm.nih.gov/41482390

“Cannabidiol (CBD) is the major non-psychotomimetic phytocannabinoid derived from the Cannabis sativa plant. Numerous studies have demonstrated its broad pharmacological effects, including antidepressant, anti-inflammatory, antiemetic, neuroprotective, analgesic, antibacterial, anticonvulsant, anxiolytic, antipsychotic, antitumor, and immunomodulatory activities. Recently, CBD has been shown to extend lifespan and improve health span in various models”

“This study demonstrates that an optimal concentration of CBD enhances MSC proliferation and promotes SIRT1 activation, thereby inducing autophagy and maintaining stemness through the regulation of SOX2. Moreover, CBD was found to delay cellular senescence and preserve replicative potential in MSCs. Collectively, these findings highlight CBD as a promising modulatory agent for improving MSC longevity and therapeutic quality, with potential implications for regenerative and anti-aging applications.”

https://iv.iiarjournals.org/content/40/1/222

Unveiling Neurological Benefits: A Review of Hemp Leaf, Flower, Seed Oil Extract, and Their Phytochemical Properties in Neurological Disorders

Posted on by

“Neurological disorders such as epilepsy, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis present significant global health care challenges, with complex pathophysiology and limited therapeutic options that often carry substantial side effects.

Hemp-derived compounds, particularly from Cannabis sativa seeds, leaves, and flowers, have gained attention for their potential neuroprotective properties.

This review aims to synthesize the current evidence surrounding the therapeutic benefits of hemp-derived compounds, focusing on their bioactive phytochemical profiles, mechanisms of action, and therapeutic efficacy in treating neurological disorders.

A comprehensive review of pre-clinical and clinical studies was conducted, analyzing the phytochemical composition of hemp extracts, including cannabinoids (such as cannabidiol, CBD), terpenes, flavonoids, and polyunsaturated fatty acids. We explored their mechanisms of action through interactions with the endocannabinoid system, neurotransmitter receptors, inflammatory pathways, and oxidative stress mechanisms.

The review highlights the therapeutic potential of hemp-derived extracts in mitigating various neurological conditions. Pre-clinical and clinical studies have demonstrated their efficacy in reducing seizure frequency in epilepsy, protecting dopaminergic neurons in Parkinson’s disease, alleviating neuroinflammation and oxidative stress in Alzheimer’s disease, and promoting remyelination in multiple sclerosis.

The entourage effect, where cannabinoids, terpenes, and flavonoids work synergistically, enhances these therapeutic effects. Innovations in extraction technologies have optimized yield and preserved bioactivity, further enhancing clinical relevance.

Hemp-derived compounds exhibit significant neuroprotective and therapeutic potential for managing neurological disorders. However, challenges such as product standardization, safety profiles, and regulatory frameworks must be addressed for clinical translation. Further research is essential to optimize dosing, establish safety parameters, and develop standardized formulations, which will be crucial for fully harnessing the therapeutic potential of hemp-derived products in treating neurological conditions.”

https://pubmed.ncbi.nlm.nih.gov/41468178

https://www.liebertpub.com/doi/10.1177/25785125251410822