Differential metabolic pathways underlie THC- and CBD-mediated inhibition of B-cell activation in both young and aged mice

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“Objective: B lymphocytes play a crucial role in immunity but also contribute to the pathogenesis of various diseases. Cannabis plants produce numerous biologically active compounds, including cannabinoids. The two most studied phytocannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These cannabinoids exert diverse and potent biological effects primarily through the endocannabinoid system (ECS), which also plays a key role in mature B-cell function. Both the immune system and the ECS undergo age-related changes that lead to a clinically significant decline in function.

Methods: This study compares the effects of THC and CBD on B-cell activity in young and aged mice. Murine B lymphocytes were activated using lipopolysaccharide (LPS) and interleukin-4 (IL-4), and the impact of cannabinoid treatments was assessed in terms of cell phenotype, proliferation, antibody secretion, tumor necrosis factor-alpha (TNFα) secretion, extracellular signal-regulated kinase (ERK) phosphorylation, and the cellular metabolome.

Results: Both THC and CBD exhibited dose-dependent inhibitory effects on B-cell activation in young and aged mice. However, we show here, for the first time, that the treatments induce distinct metabolic profiles. Although some metabolites, such as glucose-6-phosphate, pentose phosphate pathway (PPP) and nucleotide metabolites, were reduced by both cannabinoids, THC selectively reduced the levels of a distinct set of amino acids, while only CBD increased the levels of Citrulline and Allantoin. Additionally, the effects of THC and CBD differed between young and aged B cells, suggesting that age-related changes in the ECS may influence cannabinoid sensitivity.

Conclusions: These findings provide insights into the distinct mechanisms by which THC and CBD regulate immune activation and may open the door for investigating the mechanisms behind cannabinoids effects on the immune system. They also highlight the need for further research into phytocannabinoid-based therapies, particularly in age-specific contexts. Given the immunoregulatory properties of cannabinoids, especially CBD, tailored therapeutic strategies may enhance their clinical applications.”

https://pubmed.ncbi.nlm.nih.gov/40599768/

“These findings emphasize the need for further investigation into phytocannabinoid-based therapies, particularly for age-specific applications. Given the immunoregulatory properties of cannabinoids, especially CBD, tailored therapeutic strategies may be developed to optimize their clinical use.”

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1605474/full

Recent Preclinical Evidence on Phytocannabinoids in Neurodegenerative Disorders: A Focus on Parkinson’s and Alzheimer’s Disease

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“The endocannabinoid system (ECS) is a vital biological network essential for maintaining homeostasis and supporting various physiological functions. It comprises cannabinoid receptors, endogenous lipid-based ligands, known as endocannabinoids, as well as metabolic enzymes and associated proteins responsible for regulating their levels within tissues. The ECS plays a central role in modulating processes involving the central nervous system (CNS). Recent studies have highlighted its antioxidant, anti-inflammatory, and neuroprotective properties.

The therapeutic potential of cannabinoids, particularly phytocannabinoids derived from plants, has attracted significant attention in medical and pharmaceutical research. This interest has grown in parallel with the increasing availability of cannabinoid-based food supplements on the pharmaceutical market. Given the complexity of the ECS and its broad range of interactions, the discovery of this system has spurred extensive investigations into the use of cannabinoids for various health conditions.

In this review, we examine recent preclinical evidence supporting the use of phytocannabinoids in the context of neurodegenerative diseases, particularly in Alzheimer’s disease and Parkinson’s disease. Targeting the ECS through phytocannabinoid-based pharmacological modulation offers a promising therapeutic strategy for these neurological disorders. Among these compounds, cannabidiol has emerged as a key focus of research due to its multifaceted effects and favorable safety profile. Nonetheless, continued investigation is necessary to clarify its mechanisms of action, and to develop effective, evidence-based clinical applications.”

https://pubmed.ncbi.nlm.nih.gov/40573285/

“Recent advances in cannabinoid research have shed light on the considerable therapeutic potential of phytocannabinoids, particularly CBD, in the treatment of neurodegenerative diseases.

The preclinical studies presented in this review demonstrate consistent neuroprotective, anti-inflammatory, antioxidant, and neuromodulator effects in models of AD, PD, or HD.

These effects are largely mediated through the complex interplay of phytocannabinoids with the ECS, as well as their interactions with non-cannabinoid targets, such as TRPV1, 5-HT1A receptors, and PPARs.The ECS emerges as a crucial modulator of CNS homeostasis, and its dysregulation appears to be closely linked with the pathophysiology of major neurodegenerative diseases.

Phytocannabinoid-mediated modulation of ECS activity has shown promising outcomes in various animal models, including reductions in neuroinflammation, attenuation of excitotoxicity, and preservation of cognitive and motor function.The evidence suggests that phytocannabinoids may contribute to neuronal preservation, attenuation of neuroinflammatory cascades, and improvement in motor and cognitive performance in disease models. Moreover, their favorable safety profile and ability to act on multiple molecular pathways position them as promising candidates for disease-modifying interventions.

As interest in cannabinoid pharmacotherapy continues to grow, phytocannabinoids represent a promising, multifaceted class of compounds with the potential to address unmet therapeutic needs in the field of neurodegeneration.”

https://www.mdpi.com/1424-8247/18/6/890

Cannabinol’s Modulation of Genes Involved in Oxidative Stress Response and Neuronal Plasticity: A Transcriptomic Analysis

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“Cannabis sativa is a remarkable source of bioactive compounds, with over 150 distinct phytocannabinoids identified to date. Among these, cannabinoids are gaining attention as potential therapeutic agents for neurodegenerative diseases.

Previous research showed that cannabinol (CBN), a minor cannabinoid derived from Δ9-tetrahydrocannabinol, exhibits antioxidant, anti-inflammatory, analgesic, and anti-bacterial effects.

The objective of this study was to assess the protective potential of 24 h CBN pre-treatment, applied at different concentrations (5 µM, 10 µM, 20 µM, 50 µM, and 100 µM), in differentiated neuroblastoma × spinal cord (NSC-34) cells. Transcriptomic analysis was performed using next-generation sequencing techniques.

Our results reveal that CBN had no negative impact on cell viability at the tested concentrations. Instead, it showed a significant effect on stress response and neuroplasticity-related processes. Specifically, based on the Reactome database, the biological pathways mainly perturbed by CBN pre-treatment were investigated.

This analysis highlighted a significant enrichment in the Reactome pathway’s cellular response to stress, cellular response to stimuli, and axon guidance.

Overall, our results suggest that CBN holds promise as an adjuvant agent for neurodegenerative diseases by modulating genes involved in neuronal cell survival and axon guidance.”

https://pubmed.ncbi.nlm.nih.gov/40563376/

“Aging and neurodegenerative diseases are characterized by a progressive decline in cellular functions, including genomic instability, epigenetic alterations, mitochondrial dysfunction, and chronic inflammation. Our study supports that CBN exerts pleiotropic effects by modulating key molecular pathways involved in oxidative stress response, DNA repair, and neuronal survival. These results suggest that CBN positively modulates the response to cellular damage, stimulating the antioxidant response through the Nrf2 pathway and reducing the sensitivity to programmed cell death, as demonstrated by the regulation of caspases and other genes related to neuronal survival. These effects indicate that CBN may be able to support neuronal health under conditions of chronic stress, a hallmark of neurodegenerative diseases. These findings pave the way for further research into CBN’s therapeutic potential, emphasizing the need for in vivo studies to validate its efficacy and safety profile in neurodegenerative disease models.”

https://www.mdpi.com/2076-3921/14/6/744

Exploring Cannabis sativa L for Anti-Alzheimer Potential: An Extensive Computational Study including Molecular Docking, Molecular Dynamics, and ADMET Assessments

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“Introduction: Cholinesterase enzymes play a pivotal role in hydrolyzing acetylcholine, a neurotransmitter crucial for memory and cognition, into its components, acetic acid, and choline. A primary approach in addressing Alzheimer’s disease symptoms is by inhibiting the action of these enzymes.

Methods: With this context, our study embarked on a mission to pinpoint potential Cholinesterase (ChE) inhibitors using a comprehensive computational methodology. A total of 49 phytoconstituents derived from Cannabis sativa L underwent in silico screening via molecular docking, pharmacokinetic and pharmacotoxicological analysis, to evaluate their ability to inhibit cholinesterase enzymes. Out of these, two specific compounds, namely tetrahydrocannabivarin and Δ-9- tetrahydrocannabinol, belonging to cannabinoids, stood out as prospective therapeutic agents against Alzheimer’s due to their potential as cholinesterase inhibitors. These candidates showcased commendable binding affinities with the cholinesterase enzymes, highlighting their interaction with essential enzymatic residues.

Results: They were predicted to exhibit greater binding affinities than Rivastigmine and Galantamine. Their ADMET assessments further classified them as viable oral pharmaceutical drugs. They are not expected to induce any mutagenic or hepatotoxic effects and cannot produce skin sensitization. In addition, these phytoconstituents are predicted to be BBB permeable and can reach the central nervous system (CNS) and exert their therapeutic effects. To delve deeper, we explored molecular dynamics (MD) simulations to examine the stability of the complex formed between the best candidate (Δ-9-tetrahydrocannabinol) and the target proteins under simulated biological conditions. The MD study affirmed that the ligand-ChE recognition is a spontaneous reaction leading to stable complexes.

Conclusion: Our research outcomes provide valuable insights, offering a clear direction for the pharmaceutical sector in the pursuit of effective anti-Alzheimer treatments.”

https://pubmed.ncbi.nlm.nih.gov/40525419/

https://www.eurekaselect.com/article/142967

Sativex (nabiximols) for the treatment of Agitation & Aggression in Alzheimer’s dementia in UK nursing homes: a randomised, double-blind, placebo-controlled feasibility trial

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“Background: Alzheimer’s Disease (ad) patients often experience clinically significant agitation, leading to distress, increased healthcare costs and earlier institutionalisation. Current treatments have limited efficacy and significant side effects. Cannabinoid-based therapies, such as the nabiximols oral spray (Sativex®; 1:1 delta-9-tetrahydrocannabinol and cannabidiol), offer potential alternatives. We aimed to explore the feasibility and safety of nabiximols as a potential treatment for agitation in ad.

Methods: The ‘Sativex® for Agitation & Aggression in Alzheimer’s Dementia’ (STAND) trial was a randomised, double-blind, placebo-controlled, feasibility study conducted in UK care homes. Participants with probable ad and predefined clinically significant agitation were randomised to receive placebo or nabiximols for 4 weeks on an up-titrated schedule, followed by a 4-week observation period. To be considered feasible, we prespecified the following thresholds that needed to be met: randomising 60 participants within 12 months, achieving a ≥ 75% follow-up rate at 4 weeks, maintaining ≥80% adherence to allocation and estimating a minimum effect size (Cohen’s d ≥ 0.3) on the Cohen-Mansfield Agitation Inventory. This trial is registered with ISRCTN 7163562.

Findings: Between October 2021 and June 2022, 53 candidates were assessed; 29 met eligibility criteria and were randomised. No participants withdrew, and adherence was high (100%) and was generally feasible to deliver. The intervention was well tolerated (0 adverse reactions), with no safety concerns reported.

Interpretation: Despite significant COVID-19 pandemic related challenges, administering nabiximols through oral mucosa to advanced ad patients with agitation demonstrated feasibility and safety. These findings support a larger confirmatory efficacy trial to evaluate the potential therapeutic efficacy of nabiximols for agitation in ad.”

https://pubmed.ncbi.nlm.nih.gov/40479610/

“In conclusion, this study demonstrates the feasibility of a pilot randomised, placebo-controlled trial of nabiximols oral spray for agitation in AD patients in care homes, with no safety concerns observed.”

“Low-dose mixed delta-9-tetrahydrocannabinol and cannabidiol showed favourable safety profile and high tolerability.”

https://academic.oup.com/ageing/article/54/6/afaf149/8158002?login=false

Cannabidiolic Acid Rescues Deficits in Hippocampal Long-Term Potentiation in Models of Alzheimer’s Disease: An Electrophysiological and Proteomic Analysis

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“In this study, we have examined the neuroprotective effects of cannabidiolic acid (CBDA) in models of Alzheimer’s disease (AD).

We used in vitro electrophysiological recording in hippocampal slices and performed proteomic analysis of cortical tissue from APPswe/PS1dE9 (APP/PS1) mice. In wild-type (WT) slices from C57BL6 mice, acute treatment with CBDA (10 μM) did not alter levels of hippocampal long-term potentiation (LTP); however, it did reverse the attenuation of LTP produced by acute beta amyloid peptide (Aβ42). We also examined the effects of CBDA or vehicle in APP/PS1 mice and WT littermates over a 5-week period at 8 months.

LTP levels recorded in slices from WT mice treated with CBDA at 1, 10, or 30 mg/kg (IP) or vehicle were similar. LTP was attenuated in slices from vehicle-treated APP/PS1 compared to vehicle-treated WT mice, while treatment of APP/PS1 mice with all doses of CBDA reversed the deficits in LTP. There was also a deficit in paired-pulse facilitation (PPF) in vehicle-treated APP/PS1 compared to WT, indicating altered synaptic function and transmitter release; this was reversed in slices from CBDA-treated APP/PS1 mice. Levels of cortical soluble Aβ42 were similar across CBDA- and vehicle-treated groups; however, the level of aggregated Aβ42 was decreased in the CBDA-treated group.

Proteomic analysis of cortical tissue from APP/PS1 cortex compared to WT revealed alterations in protein expression, with pathway enrichment analyses suggesting implicated canonical pathways, including mitochondrial dysfunction, protein sorting, and synaptogenesis; all were significantly improved by CBDA treatment. These changes likely facilitate the improvement in synaptic transmission and LTP we observed following CBDA treatment in APP/PS1 mice.

This research suggests that CBDA should be considered a novel therapy for AD.”

https://pubmed.ncbi.nlm.nih.gov/40430085/

https://www.mdpi.com/1422-0067/26/10/4944

Effects of cannabidiol (CBD) treatment on age-related cognitive decline in C57 mice

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“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

Cannabinol (CBN) alleviates age-related cognitive decline by improving synaptic and mitochondrial health

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“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

Cannabidiol as a multifaceted therapeutic agent: mitigating Alzheimer’s disease pathology and enhancing cognitive function

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“Background: Cannabidiol (CBD), the second most abundant phytocannabinoid in Cannabis sativa, has garnered significant interest due to its non-psychoactive nature and diverse receptor interactions.

Methods: This study employs in vitro and in vivo methodologies to validate CBD’s potential as a treatment for Alzheimer’s disease (AD) by addressing key hallmarks of the condition and promoting neuroprotective effects on spatial memory.

Results: Our findings demonstrate CBD’s ability to decrease pTau and Aβ aggregation and to mitigate their axonal transport between cortical and hippocampal neurons. Moreover, CBD treatment was shown to reduce neuroinflammation, as CBD was able to skew microglia towards a neuroprotective M2 phenotype while attenuating proinflammatory cytokine release in the 5xFAD AD mouse model. Notably, daily CBD injections (10 mg/Kg) for 28 days in 5xFAD mice resulted in significant improvements in both short- and long-term spatial memory. The study also reveals CBD’s capacity to partially revert neurite formation loss induced by Aβ, Tau, and pTau proteins, suggesting a potential role in promoting neuronal plasticity. Additionally, CBD treatment led to a reduction in reactive oxygen species (ROS) formation and increased neuronal viability in the presence of AD-associated protein aggregates.

Conclusions: These multifaceted effects of CBD, ranging from molecular-level modulation to behavioral improvements, underscore its potential as a comprehensive therapeutic approach for AD. The findings not only support CBD’s neuroprotective properties but also highlight its ability to target multiple pathological processes simultaneously, offering a promising avenue for future AD treatment strategies.”

https://pubmed.ncbi.nlm.nih.gov/40394655/

“These multifaceted effects of CBD, ranging from molecular-level modulation to behavioral improvements, underscore its potential as a comprehensive therapeutic approach for AD. The findings not only support CBD’s neuroprotective properties but also highlight its ability to target multiple pathological processes simultaneously, offering a promising avenue for future AD treatment strategies.”

https://alzres.biomedcentral.com/articles/10.1186/s13195-025-01756-0

In Vivo and In Vitro Crosstalk Among CBD, Aβ, and Endocannabinoid System Enzymes and Receptors

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“Cannabidiol (CBD), a non-psychotropic compound derived from Cannabis sativa, has garnered attention as a potential therapeutic agent for various neurodegenerative diseases, including Alzheimer’s disease (AD).

Despite growing interest, additional research is required to clarify the specific mechanisms by which CBD influences the pathological accumulation of β-amyloid (Aβ) associated with AD. Moreover, the interactions between CBD and the endocannabinoid system (ECS), both in the presence and absence of Aβ expression, remain a subject of active investigation.

Elucidating these mechanisms may provide valuable insights for advancing both our understanding and the development of targeted interventions in neurodegenerative disease management. Using a multifaceted approach that integrates pharmacological interventions, immunofluorescence imaging, flow cytometry, and biochemical assays, we examined the effects of CBD on Aβ40 and Aβ42. Additionally, we analyzed the modulation of cannabinoid receptor 1(CB1 receptor) and fatty acid amide hydrolase (FAAH) in the presence or absence of Aβ expression, uncovering the intricate regulatory mechanisms of CBD.

Our findings indicate a nuanced response to CBD; while it may produce side effects in non-pathological cells, it demonstrates an ability to induce autophagy and apoptosis in Aβ-expressing cells via the activation of the Microtubule-associated protein 1 light chain 3 B(LC3B) and Caspase-3 pathways. Furthermore, our investigation into faah-1 involvement highlighted its role in alleviating pharyngeal dysfunction and counteracting weight loss in Aβ-expressing Caenorhabditis elegans(C. elegans) strains. These insights advance our understanding of CBD’s therapeutic potential in addressing neurodegenerative pathologies.”

https://pubmed.ncbi.nlm.nih.gov/40350019/

https://www.sciencedirect.com/science/article/abs/pii/S0014299925004741?via%3Dihub