“The crosstalk between the endocannabinoid system (ECS) and reactive nitrogen species (RNS) has emerged as an important area of investigation in recent years.
Although many aspects of this interaction remain elusive, accumulating evidence demonstrates that the ECS plays a critical role in regulating RNS-mediated signaling under physiological conditions. This modulation can be either inhibitory or stimulatory, depending on the specific receptor subtype, cell type, and tissue location involved.
While ECS-RNS interactions support normal cellular homeostasis, their dysregulation contributes to various disease states, particularly neurodegenerative disorders. Studies in both rodent models and human subjects show that ECS modulation can reduce anxiety, attenuate neuroinflammatory responses, and slow disease progression in neurodegenerative conditions.
This review examines how cannabinoid-based interventions modulate nitrosative stress and neuroinflammation in Alzheimer’s disease (AD) and Parkinson’s disease (PD), highlighting their potential as targeted therapeutics that address multiple pathological mechanisms simultaneously and may offer advantages over conventional treatment approaches.”
“cannabinoid treatment offers a promising alternative to conventional treatments by addressing symptomology and the underlying molecular mechanisms of these diseases. Cannabinoid treatment uniquely addresses AD and PD pathology via crosstalk between the RNS and ECS, which provides hope for disease modification as an alternative to/supplement to conventional treatments.”
“We have previously demonstrated that the endocannabinoid system is dysregulated in the synaptic terminals of the cerebral cortex in aged rats. Specifically, the availability of the neuroprotective endocannabinoid 2-arachidonoylglycerol (2-AG) is reduced due to impairments in the enzymes involved in its metabolism, a deficit only partially compensated by the binding of cannabinoid receptor ligands.
Given that ∆9-tetrahydrocannabinol (THC) acts as a ligand for cannabinoid receptors (CBR), we designed the present study to investigate the effects of a full-spectrum cannabis extract with a high THC content, the THC-free fraction of this cannabis extract, and pure THC on the previously mentioned aging model. Thus, 2-AG metabolic enzymes were assayed incubating synaptosomes from aged and adult rat cerebral cortex, with ethanolic cannabis extract, the THC-free fraction of this cannabis extract or pure THC, and the corresponding radiolabeled substrates.
Our key findings indicate that the age-related decline in 2-AG bioavailability: (a) is exacerbated in the presence of either the THC-free fraction from the cannabis extract or pure THC, primarily due to a significant decrease in 2-AG synthesis; and (b) is partially mitigated by the inhibition of 2-AG hydrolysis when the extract contains THC.
These results provide compelling evidence for the regulation of 2-AG metabolism by a full-spectrum cannabis extract with high THC content, supporting the theory of the entourage effect among cannabis phytochemicals.
This highlights the potential of high THC content extracts as therapeutic agents for restoring the decreased 2-AG levels observed in the aging brain.”
“Alzheimer’s disease (AD) is characterized by progressive synaptic failure, neuroinflammation, amyloid and tau pathology, yet effective disease-modifying therapies remain limited.
Cannabidiol (CBD) has shown neuroprotective potential in AD, but its direct molecular targets and signaling mechanisms remain unclear. Here, we demonstrate that CBD ameliorates cognitive and emotional deficits in 3×Tg-AD mice by restoring synaptic integrity and plasticity.
At the mechanistic level, CBD activated TrkB signaling independently of BDNF, leading to suppression of tau hyperphosphorylation via the PI3K/AKT/GSK3β pathway and attenuation of neuroinflammation and amyloid pathology through inhibition of the JAK2/STAT3/SOCS1 axis. Using isothermal shift assays combined with biophysical binding analyses, we identified FRS2, a core adaptor protein of TrkB, as a direct molecular target of CBD.
Molecular dynamics simulations further revealed that CBD stabilizes the FRS2-TrkB interface, thereby facilitating TrkB activation. Importantly, genetic knockdown of FRS2 abolished CBD-induced TrkB signaling and its downstream neuroprotective effects in both cellular and in vivo AD models.
Together, these findings identify FRS2 as a critical signaling node mediating BDNF-independent TrkB activation by CBD and establish a mechanistic framework linking CBD to disease-modifying pathways in AD.”
“Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and frequently co-occurs with chronic pain. Worldwide, over 55 million people are affected by AD, with nearly half experiencing persistent pain. Chronic pain has been linked to accelerated memory deterioration and an increased risk of dementia, but the interplay between these conditions remains poorly understood. Existing therapies for AD and chronic pain are limited in efficacy, highlighting the need for interventions targeting multiple pathological pathways. The endocannabinoid system, which is altered in both AD and chronic pain, represents a potential therapeutic target, though its role in AD patients with comorbid pain remains unexplored.
Methods: The study evaluated the effects of an EU-GMP certified Cannabis sativa L. strain (5 mg/kg, Cannabixir® Medium Flos) on neurobiological alterations in a rat model designed to explore mechanistic interactions between scopolamine-induced transient cognitive impairment and chronic neuropathic pain induced by unilateral sciatic nerve ligation. Treatment outcomes were assessed through nociceptive tests, clinical monitoring and tissue analyses to examine cognitive and pain-related effects.
Results: Cannabixir® Medium Flos induced robust, time-dependent analgesia in thermal nociceptive tests, with the combination of the Cannabis sativa L. strain, donepezil and tramadol producing significantly longer response latencies than tramadol alone. Mechanical sensitivity was minimally affected across treatments. Immunohistochemical analyses revealed that Cannabixir® Medium Flos, either alone or in combination with donepezil or tramadol, produced the most pronounced neuroprotective effects, reducing astrocytic (GFAP) and microglial (Iba1) activation, lowering Caspase-3 and IL-6 expression, and preserving both hippocampal neuronal integrity as well as peripheral nerve structure.
Conclusion: These findings indicate that Cannabixir® Medium Flos, particularly when combined with donepezil and tramadol, provides superior analgesic and neuroprotective effects compared to tramadol alone. Its multi-target action – alleviating thermal nociception, reducing neuroinflammation, limiting apoptosis and preserving neuronal and peripheral nerve integrity-supports its potential as an adjunct therapy in managing dementia with comorbid chronic neuropathic pain. Future studies should explore the molecular mechanisms underlying these effects and assess long-term safety and efficacy across diverse models of neurodegeneration and chronic pain.”
“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.”
“Cannabidiol (CBD) is a safe, readily available, and relatively inexpensive treatment option that has been shown to improve pathologies associated with AD.”
“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.”
“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.”
“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.”
“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.”
“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.”
“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.”
“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.”
“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.”
