Category Archives: Alzheimer’s Disease (AD)

Cannabidiol as a Neuroprotective Agent in Acrylamide-Induced Neurotoxicity: Effects on Oxidative Stress, Inflammation, and Cholinergic Function in Male Mice

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“The neuroprotective potential of cannabidiol (CBD) was assessed in a mouse model of acrylamide-induced neurotoxicity.

Acrylamide (AA), an environmental and dietary pollutant, is known to cross the blood-brain barrier and induce oxidative stress, inflammation and neurotoxic effects.

Male C57BL/6 mice were randomly assigned to four groups: Control (Con), Acrylamide (AA), Cannabidiol (CBD), and a combination treatment (AA + CBD). The AA group received acrylamide (10 mg/kg, i.p.) daily for 5 days. CBD was administered (10 mg/kg, i.p.) for 10 days in the CBD and AA + CBD groups. In the AA + CBD group, acrylamide (10 mg/kg, i.p.) was co-administered during the last 5 days of CBD treatment.

Behavioral outcomes were analyzed using the open field test, revealing that CBD mitigated anxiety-like behavior induced by acrylamide, enhancing movement and center exploration. Further, CBD treatment modulated oxidative stress responses, reducing MDA levels and partially restoring antioxidant markers (GSH, SOD, and CAT) in the hippocampus and striatum. Inflammatory markers were also assessed, revealing that acrylamide elevated pro-inflammatory cytokines TNF-α and IL-6.

Notably, CBD co-treatment reduced TNF-α levels in the hippocampus and cortex and attenuated IL-6 levels in the cortex and striatum, suggesting an anti-inflammatory effect. Additionally, CBD modulated neuroplasticity by increasing BDNF levels in the hippocampus, counteracting the reduction caused by acrylamide. CBD also influenced cholinergic activity by restoring Ach levels and altering AChE activity across brain regions.

Findings suggest that CBD exhibits neuroprotective properties by reducing oxidative stress, inflammation and cholinergic dysregulation, thereby offering a promising therapeutic approach for mitigating pollutant-induced neurotoxicity and potentially treating neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/41395773

“By improving behavioral outcomes, reducing oxidative stress, modulating inflammation, enhancing neuroplasticity and preserving cholinergic function, CBD shows promise as a potential therapeutic approach for neurotoxic and neurodegenerative conditions. “

https://onlinelibrary.wiley.com/doi/10.1002/jnr.70098

Treatment with a botanical mixture of cannabidiol:Δ9-tetrahydrocannabinol enhances microglial phagocytosis and shapes amyloid plaques in a mouse model of Alzheimer’s disease

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“The potential use of phytocannabinoids in neurodegenerative disorders is currently under intense investigation based on their potential anti-inflammatory, antioxidant, and neuroprotective effects.

Here, we tested the effects of chronic (28 days) treatment with a complex botanical mixture of purified cannabidiol:Δ9-tetrahydrocannabinol (CBD:THC, 99:1) in male 5xFAD mice, a murine model of Alzheimer’s disease that recapitulates amyloid pathology. Effects of exposure to this cannabinoid mixture were evaluated using behavioral tests (elevated plus maze for anxiety, tail suspension for depression-like behavior, rotarod for motor coordination, open field for locomotor activity, and novel object recognition for memory), quantification of protein expression (IL-1β, CD40, TREM2, COX2), assessment of functional parameters (microglial phagocytic activity by flow cytometry), and in vivo multiphoton microscopy (time-course of changes of neuritic plaque structural features). Twice daily dosing with 50 mg/kg subcutaneously (s.c.) significantly reduced locomotion, increased anxiety- and depression-like behaviors and had no effect on memory and motor coordination.

In vivo imaging experiments suggest that the CBD:THC treatment enhanced microglial phagocytic activity on amyloid plaques; this effect was observed both in plaque features (multiphoton microscopy measurements) as well as in microglia (flow cytometry data). Exposure to CBD:THC induced significant changes in in vivo microglia-amyloid interactions, increasing phagocytic activity and reducing the amyloid peptide accumulation in the neuritic plaques.

Thus, CBD:THC (99:1) may be a promising treatment to reduce amyloid pathology, though caution should be noted due to the behavioral alterations observed, i.e., increased anxiety- and depression-like behaviors as well as decreased locomotion.”

https://pubmed.ncbi.nlm.nih.gov/41389629

https://www.sciencedirect.com/science/article/pii/S0753332225010960?via%3Dihub


Lifetime Cannabis Use Is Associated with Brain Volume and Cognitive Function in Middle-Aged and Older Adults

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“Objective: Cannabis use has increased among older adults, yet the neurocognitive effects in this demographic remain unclear. Prior work has suggested cannabis may increase brain volume in areas rich in cannabinoid (CB1) receptors, though negative effects are often reported in adolescents. This study sought to clarify the relationship between cannabis use and brain health among middle-aged and older adults.

Method: Using data from the UK Biobank, which includes health information from over 500,000 adults, associations between cannabis use, regional brain volume, and cognition in participants aged 40-70 years (mean age = 54.5) were evaluated.

Results: Lifetime cannabis use was positively associated with regional brain volume in CB1-rich regions, including the caudate, putamen, hippocampus, and amygdala. Greater lifetime use was also linked to better performance in learning, processing speed, and short-term memory. Individuals reporting use limited to adolescence also showed larger regional volumes and better cognitive performance than non-users. Sex differences in cannabis effects on brain volume and cognition were also observed.

Conclusions: Results highlight that cannabis may influence brain health differently across the lifespan, potentially offering protective effects in older age while posing risks earlier in development. Protective effects may result from endocannabinoid-mediated modulation of inflammation, immune function, and neurodegeneration. Observed sex differences likely reflect variation in the endocannabinoid system and underscore the importance of considering sex as a biological variable in studies of cannabis and brain health.”

https://pubmed.ncbi.nlm.nih.gov/41379083

https://www.jsad.com/doi/10.15288/jsad.25-00346

Molecular Modeling and Analysis of Cannabinoid and Cannabinoid-like Molecules Combining K-Means Clustering with Pearson Correlation and PCA

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“More recently, cannabinoid molecules have been widely studied for their potential to treat various diseases.

We used a multidisciplinary approach, combining molecular docking and machine learning tools, to identify cannabinoid-based molecules as potential acetylcholinesterase inhibitors.

We brought together molecules from the classes of cannabinoids, stilbenoids, isoflavones, and other natural products, along with their electronic structure and absorption, distribution, metabolism, excretion and tolerable toxicity (ADMET) data. A novel machine learning framework (MolSimEx, Molecular Similarity Explorer) combining K-means clustering,

Pearson correlation, and principal component analysis was developed to address the similarities of these groups. From the dataset, 30 molecules were selected based on docking scores below -11 kcal/mol. The K-means clustering yielded high classification accuracy on the dataset, correctly grouping the cannabinoid analogues. Additionally, these analogues clustered with classical acetylcholinesterase inhibitors such as huprine-X, huprine-W, and donepezil when considering ADMET and electronic descriptor data.

Radulanin J showed the highest correlation (0.41) with donepezil’s profile, suggesting the potential of cannabinoid-derived compounds as acetylcholinesterase inhibitors.”

https://pubmed.ncbi.nlm.nih.gov/41373674

“We have identified a set of 30 molecules, out of 253 derived from phytocannabinoids, flavonoids, and terpenoids, as potential new inhibitors against the hAChE (6O4W) enzyme.”

https://www.mdpi.com/1422-0067/26/23/11520

“Acetylcholinesterase inhibitors (AChEIs) are drugs that block the enzyme acetylcholinesterase, preventing the breakdown of the neurotransmitter acetylcholine, thus increasing its levels in the brain to improve nerve cell communication. They are used primarily to treat symptoms of Alzheimer’s disease”

“Provides a blueprint for developing new treatments for Alzheimer’s by targeting AChE, a key enzyme in neurotransmission.”

Evaluation of long-term safety profile of an EU-GMP certified Cannabis sativa L. strain in a naturally aging preclinical model

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“Aging is characterized in part by chronic, low-grade inflammation, a major driver of cognitive decline, metabolic imbalance and organ dysfunction. Despite its central role in age-related morbidity, pharmacological strategies with well-defined long-term safety profiles remain limited.

Phytocannabinoids have been proposed as modulators of neuroinflammatory and metabolic pathways, but their chronic safety during natural aging is poorly characterized.

Our team has previously reported the acute and 28-day repeated-dose toxicity profile of an EU-GMP certified Cannabis sativa L. strain (Cannabixir® Medium Flos). Here, we extend this work by assessing its long-term safety in a naturally aging preclinical model. Mature to older mice received chronic, intermittent administration of Cannabixir® Medium Flos (2.5, 5, and 10 mg/kg), defined as daily weekday dosing for 3 or 6 months. Clinical and histopathological evaluations were conducted with a focus on systemic and central nervous system safety.

Chronic administration was well tolerated across all doses and durations.

Body weight remained stable despite increased food intake. Respiratory quotient values were preserved and close to 1 across all groups. Histological analyses confirmed preserved neuronal and glial architecture with no evidence of central nervous system injury or other organ-level toxicity. Long-term, intermittent Cannabixir® Medium Flos administration was well tolerated in naturally aged mice, with no adverse effects on systemic physiology or central nervous system integrity.

Together with prior acute and sub-chronic toxicity data, these findings provide robust evidence supporting the long-term safety of EU-GMP certified Cannabis sativa L. strain in the context of aging.”

https://pubmed.ncbi.nlm.nih.gov/41357885

“Importantly, the endocannabinoid system itself undergoes profound remodeling with aging, including reduced endocannabinoid tone, altered receptor expression and impaired signaling efficiency, changes that correlate with increased vulnerability to inflammation, metabolic imbalance, and neurodegeneration. These age-related alterations highlight the importance of evaluating the long-term safety of cannabinoid-based interventions in naturally aging bodies.”

“These findings suggest the potential for phytocannabinoid-mediated neuroprotection via modulation of the endocannabinoid system, although the precise molecular pathways remain to be elucidated.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1716366/full

Evaluation of two different Cannabis sativa L. extracts as antioxidant and neuroprotective agents

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“Cannabis sativa L. is a plant that contains numerous chemically active compounds including cannabinoids such as trans-Δ-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), and flavone derivatives, such as luteolin-7-O-glucuronide and apigenin glucuronide.”

“These extracts could be a source of compounds with potential benefit on human health, especially related to neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/36176449

“In conclusion, this study provided new insights into the biological activities of two different extracts of C. sativa. It was revealed that these extracts constitute a valuable and interesting natural source of bioactive molecules with great antioxidant properties, potentially capable of preventing neurodegenerative diseases.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.1009868/full

 

A Randomized Controlled Trial of the Safety and Efficacy of Dronabinol for Agitation in Alzheimer’s Disease

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“Importance: Agitation in Alzheimer’s disease (AD) is a great source of distress for patients and caregivers and a major public health burden. Current treatments are only modestly effective and many have safety issues including mortality risk. Novel therapeutic options are needed.

There is preliminary evidence for the safety and efficacy of dronabinol (tetrahydrocannabinol, THC) for agitation in AD.

Objective: Assess the safety and efficacy of dronabinol (THC) to decrease agitation in AD.

Design: THC-AD was a 3-week randomized parallel double-blind placebo-controlled clinical trial, conducted between 2017 and 2024.

Setting: 5 inpatient and outpatient academic clinical research centers in the Eastern U.S.

Participants: Volunteer sample of 75 participants meeting inclusion criteria for agitation of AD (International Psychogeriatric Association Provision Criteria) with Neuropsychiatric Inventory Clinician Version Agitation or Aggression (NPI-C A/A) domains total score of 4 or greater. Major exclusion criteria included seizure disorder, delirium, and non-AD dementia.

Interventions: 3 weeks dronabinol vs. placebo titrated up to target dose of 10 mg daily in divided twice-daily.

Main outcomes and measures: Prespecified co-primary agitation outcomes were the Pittsburgh Agitation Scale (PAS) and NPI-C A/A total score.

Results: The majority of participants were female and were taking concomitant psychotropic medications (antidepressants and antipsychotics) at baseline. Study participants were moderately agitated at baseline, were diverse in ethnic background (9% Black, 11% Hispanic/Latina/Latino), and had severe cognitive impairment evidenced by MMSE or SIB-8. 84% completed the 3-week trial.

Dronabinol decreased agitation on both primary outcomes greater than placebo to a clinically relevant extent. The fitted between-arm difference in PAS decline/week was -0.74 (SE 0.3, p = 0.015, effect size = 0.53) and for NPI-C A/A the decline was not significant at -1.26 (SE 0.67, p = 0.094, effect size = 0.36). No secondary outcomes differed between treatment arms including sleep, activities of daily living, Cohen-Mansfield Agitation Inventory (CMAI), cognition, intoxication, or use of ‘as-needed’ lorazepam or trazodone. Dronabinol treatment was not associated with greater intoxication nor with other adverse events (AEs) except for somnolence.

Conclusions and relevance: Adjunctive dronabinol treatment was safe and effective for treating agitation in AD.”

https://pubmed.ncbi.nlm.nih.gov/41350162

“Highlights

•What is the primary question addressed by this study?

Is dronabinol (synthetic THC) a safe and effective treatment for reducing agitation in individuals with Alzheimer’s disease?

•What is the main finding of this study?

In a 3-week randomized, placebo-controlled trial of 75 participants with moderate to severe Alzheimer’s disease, dronabinol significantly reduced agitation as measured by the Pittsburgh Agitation Scale (effect size = 0.53) and showed a trend toward improvement on the NPI-C Agitation/Aggression domain. The medication was well tolerated, with somnolence as the only notable side effect and no increased risk of delirium, falls, or intoxication.

•What is the meaning of the finding?

These results suggest that dronabinol may be a relatively safe and effective pharmacologic option for managing agitation in Alzheimer’s disease.”

https://www.ajgponline.org/article/S1064-7481(25)00506-8/abstract

A Balanced Cannabinoids Mixture Protects Neural Stem/progenitor Cells from CoCl2 Induced Injury by Regulating Autophagy and Inflammation: An in Vitro Study

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“Although tetrahydrocannabinol (THC) and cannabidiol (CBD) have been individually studied for their neuroprotective roles, few studies have addressed the effects of their balanced 1:1 formulation Satinex (STX) under pathologic conditions like hypoxia. Moreover, the effect of STX on embryonic neural stem/progenitor cells (ENS/PCs) derived from the rat embryonic brain, which are highly vulnerable during early development, remains unexplored.

Considering the pivotal role of hypoxia in numerous neuropathological situations, this study examined the impact of STX on rat ENS/PCs exposed to chemically induced hypoxia.

ENS/PCs were isolated from rat embryos and subjected to hypoxia using 100 µM cobalt (II) chloride hexahydrate (CoCl₂0.6 H₂O) for 48 h. Cytotoxic activity of STX andCoCl2was assessed using the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2 H-tetrazolium (MTT) assay, while stem cell identity was confirmed via flow cytometry (Nestin, SOX2). STX (0.1 and 0.5 µM) was applied under both normoxic and hypoxic conditions. Expression levels of hypoxia-inducible factor 1-alpha (Hif1α) mRNA, autophagy markers (Beclin-1, microtubule-associated protein 1 light chain 3-II [LC3-II]), and pro-inflammatory proteins nuclear factor kappa B [NF-κB], Toll-like receptor 2 [TLR2], Toll-like receptor 4 [TLR4]) were assessed using reverse transcription polymerase chain reaction (RT-PCR) and western blot techniques following STX treatment.

Based on flow cytometric assays, over 70% of cultivated cells were positive for Nestin and SOX2. Hypoxia significantly reduced cell viability and proliferation, accompanied by increased Hif1α mRNA expression. Treatment with STX (0.1 µM and 0.5 µM) significantly reversed these changes, restoring cell viability and proliferation while reducing Hif1α levels. Hypoxia also elevated autophagy markers (Beclin-1, LC3-II) and pro-inflammatory proteins (NF-κB, TLR2, TLR4), which STX suppressed in a dose-dependent manner.

This study provides novel evidence that STX mitigates hypoxia-induced neural damage by downregulating Hif1α and its downstream inflammatory and autophagic signaling pathways. The use of a clinically relevant cannabinoids mixture and a developmentally sensitive cell model underline the translational potential of balanced THC/CBD formulations in the treatment of hypoxia-related neurodegenerative and neurodevelopmental conditions.”

https://pubmed.ncbi.nlm.nih.gov/41240218

https://link.springer.com/article/10.1007/s12640-025-00770-2

History of cannabis use and cognitive function in older adults: findings from the UK biobank

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“Background: Cannabis is a commonly used psychoactive drug, but its cognitive effects remain unclear, particularly in older adults. This study examined associations between past and present cannabis use and cognitive function among dementia-free older adults.

Methods: Cross-sectional and longitudinal data were drawn from the UK Biobank, including adults aged ≥60 years. Cannabis use patterns were self-reported, and cognitive function was assessed via computerized tests of attention, executive function, processing speed, visual memory and working memory. Multivariable linear regression models adjusted for demographic, health and lifestyle-related covariates.

Results: Cross-sectional analyses included 67 713 participants; longitudinal analyses included 52 002 participants with two cognitive assessments (mean age 67.2 ± 4.4 years; 46.1% male). Lifetime cannabis users (17%) performed better across all cognitive domains: attention (B = 0.071), executive function (B = 0.047), processing speed (B = 0.363), visual (B = 0.062) and working memory (B = 0.181). Current use was associated with better working memory (B = 0.169). Mixed and contradictory results were found for early onset, duration and frequency of use with cognitive outcomes. Longitudinally, past use was associated with less decline in executive function, while longer duration of use predicted steeper decline in processing speed.

Conclusions: Cannabis use is not uniformly harmful to cognition in older adults. Past use was linked to better performance and slower decline in some cognitive domains. However, specific usage patterns, such as longer duration, were associated with poorer outcomes in other domains. These findings highlight the need for further research to clarify underlying mechanisms and guide evidence-based recommendations regarding cannabis use in aging populations.”

https://pubmed.ncbi.nlm.nih.gov/41189327/

“Cannabis use in older adults is not uniformly associated with cognitive decline; former users showed better cognitive perform.”

“These results offer preliminary evidence that cannabis use may not be uniformly detrimental to cognitive health in aging.”

https://academic.oup.com/ageing/article/54/11/afaf319/8313927?login=false

A randomized clinical trial of low-dose cannabis extract in Alzheimer’s disease

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“Preclinical and clinical evidence suggest that low-dose cannabinoids could ameliorate Alzheimer’s disease (AD) signs and symptoms.

We designed this trial to evaluate the safety and efficacy of low-dose THC-CBD balanced cannabinoid extract in the treatment of patients with AD-associated dementia.

The objective of this phase 2 trial was to evaluate the safety and efficacy of a balanced THC-CBD cannabinoid extract for symptomatic patients with AD.

A Phase 2, randomized, double-blind, placebo-controlled, clinical trial including patients between 60 and 80 years-old diagnosed with AD-associated dementia. For 26 weeks, participants orally received either placebo or THC-CBD extract (0.350 mg/THC and 0.245 mg/CBD), daily.

At week 26, Mini-Mental State Exam total score was significantly higher in cannabis- when compared to placebo-treated patients, which was assessed using the mixed model analysis. No significant difference was detected between placebo and cannabis groups in terms of secondary outcomes and adverse events incidence.

To this date, this is the longest clinical trial evaluating cannabinoids effects on AD patients. We initially demonstrate that low-dose THC-CBD potentially can be an effective and safe therapeutic option for AD-related dementia. Nonetheless, larger and longer trials are necessary to confirm this finding and establish cannabinoid administration as therapy for AD dementia.”

https://pubmed.ncbi.nlm.nih.gov/41160460/

https://journals.sagepub.com/doi/10.1177/13872877251389608