“Aging is associated with cognitive decline, and currently, there are no approved medications that can prevent these impairments.

Recently, cannabinoids derived from Cannabis sativa have emerged as promising therapeutic compounds with neuroprotective, anti-inflammatory, and cognitive-enhancing properties. Despite their benefits, further research is needed to fully understand their efficacy across various conditions.

This study investigates the effects of cannabidiol (CBD) on memory impairment and brain inflammation in aging mice.

Fourteen-month-old C57 mice were administered CBD orally for 7 months and subsequently evaluated between 19 and 21 months of age using behavioral tasks that are sensitive to dysfunction of the perirhinal cortex, hippocampus, amygdala, and various brain regions that are crucial for motor control and coordination.

The findings of this study indicate that CBD reduces inflammatory response in the brain and improves cognitive decline associated with aging.”

https://pubmed.ncbi.nlm.nih.gov/40416734/

“The findings of this study show that CBD targets inflammatory responses in the brain and can improve cognitive decline associated with aging. It is possible that the effects of CBD treatment can be enhanced if an extract with THC and terpenoids is used.”

https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2025.1567650/full

“Age-related cognitive decline and neurodegenerative diseases, such as Alzheimer’s disease, represent major global health challenges, particularly with an aging population. Mitochondrial dysfunction appears to play a central role in the pathophysiology of these conditions by driving redox dysregulation and impairing cellular energy metabolism. Despite extensive research, effective therapeutic options remain limited.

Cannabinol (CBN), a cannabinoid previously identified as a potent inhibitor of oxytosis/ferroptosis through mitochondrial modulation, has demonstrated promising neuroprotective effects.

In cell culture, CBN targets mitochondria, preserving mitochondrial membrane potential, enhancing antioxidant defenses and regulating bioenergetic processes. However, the in vivo therapeutic potential of CBN, particularly in aging models, has not been thoroughly explored.

To address this gap, this study investigated the effects of CBN on age-associated cognitive decline and metabolic dysfunction using the SAMP8 mouse model of accelerated aging.

Our results show that CBN significantly improves spatial learning and memory, with more pronounced cognitive benefits observed in female mice. These cognitive improvements are accompanied by sex-specific changes in metabolic parameters, such as enhanced oxygen consumption and energy expenditure. Mechanistically, CBN modulates key regulators of mitochondrial dynamics, including mitofusin 2 (MFN2) and dynamin-related protein 1 (DRP1), while upregulating markers of mitochondrial biogenesis including mitochondrial transcription factor A (TFAM) and translocase of outer mitochondrial membrane 20 (TOM20). Additionally, CBN upregulates key synaptic proteins involved in vesicle trafficking and postsynaptic signaling suggesting that it enhances synaptic function and neurotransmission, further reinforcing its neuroprotective effects.

This study provides in vivo evidence supporting CBN’s potential to mitigate age-related cognitive and metabolic dysfunction, with notable sex-specific effects, highlighting its promise for neurodegenerative diseases and cognitive decline.”

https://pubmed.ncbi.nlm.nih.gov/40412024/

“CBN shows promise as a therapeutic agent for age-related cognitive decline and metabolic dysfunction.”

https://www.sciencedirect.com/science/article/pii/S2213231725002058?via%3Dihub

“Alzheimer’s disease (AD) is the most common form of dementia, characterized by β-amyloid (Aβ) plaques and neurofibrillary tangles, leading to neuronal loss and cognitive impairments. Recent studies have reported the dysregulation of RNA splicing in AD pathogenesis.

Our previous transcriptomic study demonstrated the neuroprotective effect of the phytocannabinoid cannabinerol (CBNR) against the cell viability loss induced by Aβ in differentiated SH-SY5Y cells. This study also highlighted the deregulation of genes involved in mRNA splicing after Aβ exposure or CBNR pre-treatment.

Here, we investigated whether CBNR could restore the splicing defects induced by Aβ in an AD in vitro model.

Using the rMATS computational tool for detecting differential alternative splicing events (DASEs) from RNA-Seq data, we obtained 96 DASEs regulated in both conditions and, remarkably, they were all restored by CBNR pre-treatment. The pathway analysis indicated an over-representation of the “Alzheimer’s disease-amyloid secretase pathway”. Additionally, we observed that Aβ exposure increased the frequency of retained introns (RIs) among the shared DASEs, and that this frequency returned to normality by CBNR pre-treatment. Interestingly, most of these RIs contain a premature in-frame stop codon within the RNA sequence. Finally, analyzing the DASE regions for miRNA hybridization, we found 33 potential DASE/miRNA interactions that were relevant in AD pathogenesis.

These findings revealed a novel trans-gene regulation by CBNR, potentially explaining part of its neuroprotective role. This is the first study demonstrating the involvement of a cannabinoid in the regulation of mRNA splicing in an AD model.”

https://pubmed.ncbi.nlm.nih.gov/40243843/

“In conclusion, we documented for the first time that a cannabinoid, CBNR, is able to regulate AS in an in vitro AD model. CBNR pre-treatment restored the splicing defects produced by Aβ exposure, involving genes also highly associated with AD. Moreover, thanks to this mechanism, CBNR probably counteracts the Aβ-induced mis-regulation of genes, due to premature stop codons and miRNA or lncRNA targeting. This work improves our knowledge of the molecular mechanisms that can be potentially useful in treating AD, corroborating the fact that drugs targeting post-transcriptional splicing processes could be considered novel and valid choices in neuroprotection and prevention issues.”

https://www.mdpi.com/1422-0067/26/7/3113

“Background: Alzheimer’s disease (AD) is a prevalent, incurable, and chronic neurodegenerative condition characterized by the accumulation of amyloid-β protein (Aβ), disrupting various bodily systems. Despite the lack of a cure, phenolic compounds like cannabidiol (CBD), a non-psychoactive component of cannabis, have emerged as potential therapeutic agents for AD.

Objective: This systematic review explores the impact of different types of cannabidiol on AD, unveiling their neuroprotective mechanisms.

Methods: The research used PubMed, Scopus, and Web of Science databases with keywords like “Alzheimer’s disease” and “Cannabidiol.” Studies were evaluated based on title, abstract, and relevance to treating AD with CBD. No restrictions on research type or publication year. Excluded were hypothesis papers, reviews, books, unavailable articles, etc.

Results: Microsoft Excel identified 551 articles, with 92 included in the study, but only 22 were thoroughly evaluated. In-vivo and in-silico studies indicate that CBD may disrupt Aβ₄₂, reduce pro-inflammatory molecule release, prevent reactive oxygen species formation, inhibit lipid oxidation, and counteract Aβ-induced increases in intracellular calcium, thereby protecting neurons from apoptosis.

Conclusions: In summary, the study indicates that CBD and its analogs reduce the production of Aβ₄₂. Overall, these findings support the potential of CBD in alleviating the underlying pathology and symptoms associated with AD, underscoring the crucial need for further rigorous scientific investigation to elucidate the therapeutic applications and mechanisms of CBD in AD.”

https://pubmed.ncbi.nlm.nih.gov/40034365/

“In conclusion, the finding of this study indicates that cannabidiol/derivatives inhibit AD progression through various mechanisms and key hypotheses regarding AD pathology. Nave CBD can reduce Aβ, IL-6 expression in peripheral leukocytes, and retarded cognitive decline. Compare with other CBD derivatives, CBD carbamate derivatives notably reduced Aβ1–42 levels, restored cognitive function to a normal state, and exhibited superior behavioral performance when compared to donepezil. CBD decreases Caspase 9, Caspase 3, and cleaved PARP1 protein levels and shows Antiapoptotic effects during cognitive decline. It also shows anti-cholinergic activity by inhibiting AChE and BuChE. As a result, the expression of ChAT can be normalized. In terms of the neuroinflammatory process, the expression of proinflammatory miRNAs (miR-146a, miR-155, and miR-34a) associated with TLR and NF-κB signaling is reduce. Therefore, continued research efforts should focus on elucidating the precise mechanisms of action, exploring potential synergies with other AD medications, and optimizing CBD formulations and derivatization to maximize therapeutic benefits in AD patients. These observations underscore the significance of further research and exploration into the therapeutic applications of CBD in the context of AD.”

https://journals.sagepub.com/doi/10.1177/25424823241284464