Category Archives: Dementia

Acute cannabidiol (CBD), tetrahydrocannabinol (THC) and their mixture (THC:CBD) exert differential effects on brain activity and blood flow in rats: A translational neuroimaging study

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“Background: Cannabis constituents, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), show distinct pharmacological profiles with therapeutic relevance for neurological and psychiatric conditions. THC exerts euphoric effects primarily via CB1 receptor activation, while CBD displays non-euphoric properties affecting various pathways.

Aims: This study evaluated the effects of THC, CBD, and their combination on brain functional connectivity (FC) and cerebral blood flow (CBF) using multimodal neuroimaging.

Methods: Adult male Sprague Dawley rats received intraperitoneal doses of 10 mg/kg THC, 150 mg/kg CBD, 10.8:10 mg/kg THC:CBD, or vehicle. Resting-state blood oxygenation level dependent magnetic resonance imaging and arterial spin labelling assessed FC and CBF, approximately 2 h after drug administration. Graph-theory metrics and seed-based analyses identified connectivity and perfusion alterations, while plasma analyses determined cannabinoid concentrations.

Results: THC increased whole-brain FC and clustering coefficient, with elevated CBF in cortical and subcortical regions. CBD decreased FC metrics without affecting CBF, while THC:CBD induced moderate increases in both. Seed-based analysis revealed THC-driven increases in cortical-hippocampal and cortical-striatal connectivity, attenuated in the THC:CBD group. A multivariate combined analysis of FC and CBF revealed a divergent pattern of changes induced by each drug.

Conclusions: In conclusion, we show that THC and CBD induce distinct neurophysiological profiles in rats, with THC increasing both connectivity and perfusion, moderated by CBD when combined. These findings corroborate existing knowledge about the effects of cannabinoids on the brain, while also supporting the potential of preclinical functional neuroimaging to delineate cannabinoid-induced endophenotypes, offering insights for therapeutic development.”

https://pubmed.ncbi.nlm.nih.gov/40838351/

“Growing evidence supports the therapeutic potential of cannabis and its constituent phytocannabinoids in treating a range of neurological and psychiatric conditions.”

“In summary, we have demonstrated that acute THC administration resulted in increases in FC and regional CBF, acute CBD administration resulted in an overall reduction in FC with negligible effect on CBF, and the combination drug THC:CBD resulted in effects similar to, but lower than THC alone. Our application of functional neuroimaging has thus identified differential pharmacodynamic signatures for THC and CBD in anaesthetised adult male rats. Further work should encompass an investigation of the effects of sub-chronic administration of phytocannabinoids on brain activity in animal models with relevance to selected disease indications to investigate changes on FC in a perturbed system, more applicable to the disease state. “

https://journals.sagepub.com/doi/10.1177/02698811251360745

Cannabidiol improves learning and memory deficits and alleviates anxiety in 12-month-old SAMP8 mice

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“Cannabidiol (CBD) has gained a lot of interest in recent years for its purported medicinal properties. CBD has been investigated for the treatment of anxiety, depression, epilepsy, neuroinflammation, and pain.

Recently there has been an interest in CBD as a possible treatment for age-related disorders such as Alzheimer’s disease and related disorders (ADRD). Here we tested the hypothesis that chronic CBD administration would improve learning and memory in the SAMP8 mouse model of Alzheimer’s disease.

SAMP8 mice aged 11 months (at the start of the study) were administered vehicle or CBD (3 or 30 mg/Kg) daily via oral gavage for 2 months. Vehicle-treated young SAMP8 mice (age 3 months at the start of the study) served as unimpaired controls. After 30 days of treatment (4 and 12 months of age), learning and memory, activity, anxiety, strength and dexterity were assessed.

High dose CBD treatment significantly improved learning and memory of the 12-month-old mice in the T maze. Novel object recognition memory was also improved by CBD in aged CBD treated mice. Aged CBD treated mice also displayed less anxiety in the elevated plus maze test compared to controls. However, activity and strength levels were similar between groups. Biochemical analysis revealed decreased markers of oxidative stress, providing a possible mechanism by which CBD treatment impacts learning, memory, and anxiety.

These results highlight the potential use of CBD as a therapeutic for age related cognitive impairment and dementia.”

https://pubmed.ncbi.nlm.nih.gov/40811673/

“Cannabidiol (CBD) is an abundant phytocannabinoid found in the Cannabis sativa plant.”

“CBD is thought by many to have medicinal properties. Except for a few conditions including two rare forms of epilepsy and multiple-sclerosis-associate spasticity, CBD has not been approved by the FDA”

“Here, we examine the potential use of CBD in treating age- related memory loss, anxiety, strength and dexterity impairment in the Senescence-accelerated mouse -prone 8(SAMP8) mice, a polygenic model of spontaneous onset AD.”

“Our results indicate that CBD can reverse age-related changes in the SAMP8 mice. CBD reversed memory impairment in both the T-maze and NOR with a 24-hour retention interval. These results indicate that CBD is able to reverse memory impairment in both spatial and recognition tasks. Taken together therefore, there appears to be an antioxidant effect of CBD contributing to the improvement in memory in the aged mice. These results show that CBD is an attractive therapeutic warranting further investigation in AD, and other neurodegenerative diseases.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0296586

Substance Abuse and Cognitive Decline: The Critical Role of Tau Protein as a Potential Biomarker

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“Tau protein is essential for the structural stability of neurons, particularly through its role in microtubule assembly and axonal transport. However, when abnormally hyperphosphorylated or cleaved, Tau can aggregate into insoluble forms that disrupt neuronal function, contributing to the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD).

Emerging evidence suggests that similar Tau-related alterations may occur in individuals with chronic exposure to psychoactive substances. This review compiles experimental, clinical, and postmortem findings that collectively indicate a substance-specific influence on Tau dynamics.

Alcohol and opioids, for instance, promote Tau hyperphosphorylation and fragmentation through the activation of kinases such as GSK-3β and CDK5, as well as proteases like caspase-3, leading to neuroinflammation and microglial activation. Stimulants and dissociatives disrupt insulin signaling, increase oxidative stress, and impair endosomal trafficking, all of which can exacerbate Tau pathology.

In contrast, cannabinoids and psychedelics may exert protective effects by modulating kinase activity, reducing inflammation, or enhancing neuroplasticity.

Psychedelic compounds such as psilocybin and harmine have been demonstrated to decrease Tau phosphorylation and facilitate cognitive restoration in animal models. Although the molecular mechanisms differ across substances, Tau consistently emerges as a convergent target altered in substance-related cognitive disorders.

Understanding these pathways may provide not only mechanistic insights into drug-induced neurotoxicity but also identify Tau as a valuable biomarker and potential therapeutic target for the prevention or treatment of cognitive decline associated with substance use.”

https://pubmed.ncbi.nlm.nih.gov/40806766/

“Alcohol, methamphetamine, and opioids consistently elicited Tau hyperphosphorylation in cortical and subcortical regions tied to executive function, reward processing, and memory. In contrast, certain cannabinoids and psychedelics demonstrated potential neuroprotective properties, modulating Tau-related signaling in ways that reduced aberrant phosphorylation and enhanced synaptic resilience in preclinical models. “

https://www.mdpi.com/1422-0067/26/15/7638

Exploring the impact of chronic intermittent EU-GMP certified Cannabis sativa L. therapy and its relevance in a rat model of aging

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“Background: Aging is a multifaceted process marked by the progressive accumulation of cellular damage in various tissues, resulting in a decline in physiological functions. The primary aim of aging research is to identify compounds that can delay or mitigate these detrimental changes. As cannabis legalization becomes more widespread and with limited empirical studies on its effects in the aging human population, there is a pressing need for research into the impact of Cannabis and cannabinoids on healthy aging and age-related diseases.

Methods: Our study aims to evaluate the effects of chronic, intermittent exposure, defined as 6 weeks of use of EU-GMP certified Cannabis sativa L. (Cannabixir® Medium Flos) administration, dosed at 6.25 and 25 mg/kg on neurobiological changes in naturally aged rats and its potential efficacy in mitigating age-related alterations. The impact of the Cannabixir® Medium Flos was assessed through clinical, histopathological, immunohistochemical, and behavioral evaluations.

Results: Cannabixir® Medium Flos was found to be generally safe, with no significant effects on motor performance and a neutral effect on anxiety-like behavior. Histological analysis revealed that the hippocampus of aged rats treated with this compound-an area known for its abundance of endocannabinoids and cannabinoid receptor type 1-exhibited characteristics similar to those observed in young adult rats. Additionally, the study suggests that chronic, intermittent treatment with Cannabixir® Medium Flos may modulate astrocyte function, reduce neuroinflammation, and potentially influence cell proliferation and neuronal apoptosis in a dose-dependent manner. However, these preliminary findings should be interpreted with caution, as the study’s exploratory nature.

Conclusions: These preliminary findings suggest that cannabinoid therapy targeting the endocannabinoid system may offer potential neuroprotective benefits in aging.

While the study offers valuable preclinical insights into the effects of an EU-GMP-certified cannabinoid receptor ligand in reducing age-related cognitive decline, these effects are likely mediated by a combination of mechanisms. Given the complex phytochemical composition, the observed outcomes cannot be attributed exclusively to cannabinoid receptor activation. Accordingly, these findings should be interpreted with caution, and further studies employing more targeted methodologies are needed to elucidate the underlying mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/40770774/

“Targeting the ECS could be a promising strategy for developing therapies aimed at promoting healthy aging and longevity.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00313-8

Neural Signatures of Cannabis Use: Reversing Cognitive Aging via Whole-Brain Functional Network Connectivity

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“Given the growing trend toward permissive societal attitudes and the legalization of cannabis, coupled with an increasing recognition of its therapeutic potential, there has been a notable rise in cannabis consumption among older adults.

Cognitive aging, one of the most prevalent concerns in this demographic, intersects with cannabis use, which shares several neural correlates. However, the precise impact of cannabis on the aging brain and cognitive function remains poorly understood.

In this study, we leveraged large-scale data from the UK Biobank, which includes over 25,000 participants, to conduct a comprehensive examination of the relationships between cannabis use, normative aging, and cognitive function. Our focus was on how these factors correlate with brain functional network connectivity (FNC), aiming to elucidate the interactive effects underlying brain neuroimaging patterns.

Our findings reveal that cannabis usage and healthy aging are associated with overlapping brain network configurations, particularly within the FNC between subcortical and sensorimotor regions, as well as between subcortical and cerebellar areas, albeit with significantly reversed effects.

Notably, cannabis users exhibited superior performance across multiple cognitive domains, and interestingly, the effects of cannabis and cognition are presented concurrently across a range of brain systems.

In conclusion, our study offers valuable insights into the potential influence of cannabis on brain aging and cognitive performance. The results suggest that cannabis users display brain network characteristics typically associated with younger brains, along with enhanced cognitive abilities, highlighting a potential modulatory role for cannabinoids and endocannabinoids in neurodegenerative processes, as explained through neural dedifferentiation and compensation theories.”

https://pubmed.ncbi.nlm.nih.gov/40766216/

https://www.researchsquare.com/article/rs-6977015/v1

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

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

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

Emerging nano-derived therapy for the treatment of dementia: a comprehensive review

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“Dementia includes a variety of neurodegenerative diseases that affect and target the brain’s fundamental cognitive functions. It is undoubtedly one of the diseases that affects people globally. The ameliorating the disease is still not known; the symptoms, however, can be prevented to an extent. Dementia encompasses Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Lewy body dementia, mixed dementia, and various other diseases.

The aggregation of β-amyloid protein plaques and the formation of neurofibrillary tangles have been concluded as the foremost cause for the onset of the disease. As the cases climb, new neuroprotective methods are being developed in the form of new drug delivery systems that provide targeted delivery.

Herbal drugs like Ashwagandha, Brahmi, and Cannabis have shown satisfactory results by not only treating the symptoms but have also been shown to reduce and ameliorate the formation of amyloid plaque formation.

This article explores the intricate possibilities of drug delivery and the absolute use of herbal drugs to target neurodegenerative diseases. The various possibilities of nanotechnology currently available with new emerging techniques are also discussed.”

https://pubmed.ncbi.nlm.nih.gov/40268841/

https://link.springer.com/article/10.1007/s13346-025-01863-3