Category Archives: Alzheimer’s Disease (AD)

Evaluation of the effect of cannabidiol treatment on [18F]FDG and [11C]PK11195 uptake in an animal model for Alzheimer’s disease

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“Background: Cannabidiol (CBD) has well-described anti-inflammatory and neuroprotective properties. Emerging preclinical research has explored the potential of this cannabinoid as a therapeutic agent to delay or prevent the onset of symptoms and pathophysiological features of neurodegenerative processes, such as Alzheimer’s disease (AD). Therefore, the aim of this study was to evaluate the effect of CBD treatment during aging of an animal model for AD using positron emission tomography (PET).

Method: Male and female 3xTg-AD mice (ethics committee 1811/2022) were divided into control and CBD groups. At 7 months-old, the animals were treated with CBD (20 mg/kg) or vehicle for 30 days. At 4, 8, 12 and 18 months-old, [18F]FDG and [11C]PK11195 PET images were acquired to assess brain metabolism and neuroinflammation. The standardized uptake value (SUV) was calculated for the whole brain. The behavioral tests of novel object recognition (NOR) and elevated plus maze (EPM) were performed to assess memory, exploratory behavior and anxiety.

Result: There was a sex effect on [18F]FDG uptake, with vehicle-males showing higher uptake than vehicle-females at 4 (p = 0.02), 8 (p = 0.007), and 18 months (p <0.0001). Vehicle-females had reduced [18F]FDG uptake at 18 months compared to all other ages (18 months vs: 4: p = 0.045; 8: p = 0.001; 12: p <0.0001). In the CBD group, [18F]FDG uptake was higher in males than in females at 8 months (p = 0.002). CBD-males also had increased uptake from 4 to 8 months (p <0.0001) and to 12 months (p = 0.002). In addition, CBD-females had higher [18F]FDG uptake than vehicle-females at 18 months (p = 0.024). No sex effect was observed for [11C]PK11195. Increased uptake was observed in the control group at 18 months compared to 4 months (p = 0.004) and 12 months (p = 0.02). No significant differences were observed in the behavioral assessments.

Conclusion: Our study demonstrated prominent sex differences in brain metabolism and provided evidence of a possible neuroprotective role of CBD in mitigating neuroinflammatory events associated with aging. Furthermore, PET proved to be a more sensitive tool for detecting aging-induced changes in the 3xTg-AD model compared to behavioral assessments.”

https://pubmed.ncbi.nlm.nih.gov/41442268

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70856_100426

Exploring the synergistic effects of physical exercise and cannabidiol treatment in a mouse model of Down syndrome using positron emission tomography

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“Background: Down Syndrome (DS) is considered a genetic form of Alzheimer’s disease (AD) as it increases the expression of AD-related genes, leading to precocious neuroinflammation and cell death. Given the increasing longevity of the DS population, it is essential to look for alternatives to delay AD development and improve quality of life. Considering that physical exercise and cannabidiol (CBD) have recognized neuroprotective properties, the aim of this study was to evaluate the effects of these interventions alone and in combination, in a model of DS using positron emission tomography (PET).

Method: Ts65Dn trisomic mice (ethical approval: 1292/2019, 1811/2022, 2065/2024) were divided into four groups: control (no treatment); exercise; CBD; and exercise+CBD. The exercise group was subjected to physical exercise on a treadmill from 2 to 8 months of age, 3 times/week, and the CBD group was treated at 7 months of age for 30 days (20 mg/kg, ip). The exercise+CBD group received both treatments as described above. PET images with [11C]PK11195 and [18F]FDG were acquired to assess brain metabolism and neuroinflammation at 4 and 8 months of age using a small animal PET scanner. The average standardized uptake value (SUV) was calculated considering the whole brain (WB) and the hippocampus.

Result: At 4 months, exercise+CBD had higher [11C]PK11195 uptake in the WB and hippocampus compared to the other groups (control: p = 0.0006 in both; exercise: p = 0.009 and p = 0.005; CBD: p = 0.0007 and p = 0.0006). At 8 months, CBD and CBD+exercise had higher radiotracer uptake compared to the control (WB: p = 0.0005 and p = 0.0003, respectively; hippocampus: p = 0.0002 and p = 0.0003, respectively) and exercise groups (WB: p = 0.0009 and p = 0.0005, respectively; hippocampus: p <0.0001 for both). The CBD group showed increased [11C]PK11195 uptake in the WB (p <0.0001) and hippocampus (p <0.0001) at 8 months of age. Regarding [18F]FDG, the exercise+CBD group had an increase in uptake from 4 to 8 months in both regions (WB: p = 0.03; hippocampus: p = 0.04).

Conclusion: Our data suggest that CBD treatment induced a higher glial response that was not present when CBD was associated with physical exercise. Indeed, this association increased brain metabolism, suggesting a neuroprotective mechanism.”

https://pubmed.ncbi.nlm.nih.gov/41447104

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70856_099067

Natural cannabinoids effects on glutamatergic and dopaminergic neurotransmission in a transgenic model of Alzheimer’s disease

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“Background: Previous results demonstrated that chronic treatment with a combination of two natural cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), at non-psychotropic doses reduces cognitive decline, as well as the extracellular glutamate levels and the basal excitability in the hippocampus of APP/PS1 mice. In the present study, we aimed to elucidate whether this modulation of hippocampal excitability exerted by natural cannabinoids could affect the dopaminergic activity in limbic areas related to non-cognitive symptoms of Alzheimer’s disease (AD) in our animal model.

Method: We used glutamate and dopamine biosensors, along with fiber photometry techniques, to evaluate the levels of these neurotransmitters in the hippocampus and nucleus accumbens (NAcc), respectively. Experiments were conducted in anaesthetized animals for recording under an electrical hippocampal stimulation protocol, or in awake animals for recording during behavioral evaluations (novel object recognition, open field, sociability and prepulse inhibition tests).

Result: Chronic treatment with THC and CBD reversed the increased prominence and frequency of glutamate peaks observed in the hippocampus of APP/PS1 animals during the novel object recognition test at early stages of the AD-like process. At more advanced stages, APP/PS1 mice exhibited alterations in dopamine dynamics in the NAcc, which were compatible with psychotic-like traits observed in this animal model of AD. Interestingly, these alterations were partially modulated by chronic treatment with these natural cannabinoids.

Conclusion: Our results reveal that the combination of THC and CBD modulates glutamatergic activity in the hippocampus at early stages of the AD process and that, likely related to this, reduces dopaminergic alterations in limbic areas at advanced stages. Thus, these natural cannabinoids may alleviate both cognitive and non-cognitive symptoms occurring in AD, supporting their clinical development as a pleiotropic therapeutic alternative for this neurodegenerative disease.”

https://pubmed.ncbi.nlm.nih.gov/41454444

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70855_102846

Therapeutic potential of chronic CBD:THC co-treatment on disease-relevant behaviors of female TAU58/2 mice

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“Background: Limited therapeutic success and side effect profile of traditional but also novel antibody-based therapies for Alzheimer’s disease (AD) underline the need for alternatives. Cannabinoids have anti-inflammatory effects, are easily accessible and generally well tolerated. A dosage-dependent “entourage” effect has been described for phytocannabinoids such as cannabidiol (CBD) administered in combination with delta-9-tetrahydrocannabinol (THC). The effects of cannabinoid combination treatment on tau pathology, one of the major neuropathological hallmarks of AD, is poorly understood. Here, the effects of chronic treatment with CBD and THC on disease-relevant behaviors of female TAU58/2 transgenic mice were evaluated for the first time.

Method: Six-month-old TAU58/2 transgenic females (n = 28) and wild type-like control littermates (n = 22) were chronically treated with CBD+THC (50:3 mg/kg/day, i.p.) or vehicle for five weeks. Behavioral testing started after three weeks of treatment and included assessment of motor function, spatial and social recognition memory, anxiety and sensorimotor gating.

Result: Treatment and genotype effects on individual behavioral tests are summarized in Table 1. TAU58/2 transgenic females exhibited pronounced deficits in motor function, sensorimotor gating impairments, a prominent anxiolytic-like phenotype and subtle spatial memory deficits. Chronic CBD:THC co-treatment significantly improved aspects of motor function in pole test and accelerod. Moreover, anxiolytic-like behavior of TAU58/2 mice was partially reduced by cannabinoid treatment. Cannabinoids also showed the potential to improve spatial memory impairment of transgenic mice, though not confirmed by a significant treatment effect. Social recognition memory and sensorimotor gating were not affected by the treatment.

Conclusion: Here, long-term CBD:THC treatment at 50:3 mg/kg/day shows subtle but promising therapeutic effects in middle-aged TAU58/2 mice. Thereby, this study is the first to provide evidence for the therapeutic potential of CBD:THC co-treatment on tauopathy-related behavioral symptoms. Since CBD alone did not improve deficits of adult TAU58/2 mice in a previous study, these findings underline the potential of multi-cannabinoid therapy for the treatment of AD and contribute to the evaluation of the most efficient cannabinoid ratio. Ongoing tissue analysis addressing tau and inflammatory markers will reveal further insights into the underlying molecular mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/41447176

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70859_099683

Therapeutic Potential of INM-901 in Mitigating Alzheimer’s Disease Pathology: Insights from a Long-term 5xFAD Mouse Model Study

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“Background: Alzheimer’s Disease (AD) is a neurodegenerative condition characterized by cognitive and sensorimotor deficits, affecting over 6.9 million people in the US, with an annual economic impact of over $700 billion in direct and indirect healthcare costs. While current treatments such as donepezil, and memantine manage symptoms, they do not halt disease progression. Moreover, amyloid beta (Aβ) antibody therapy faces challenges, including limited efficacy in advanced disease stages, infusion-related reactions, and high treatment costs. Cannabinoids have shown potential in alleviating Aβ toxicity, reducing tau phosphorylation, and suppressing inflammation via CB1 and CB2 receptors, supporting neuronal viability. Therefore, in this study, we investigated the effects of a novel synthetic cannabinoid analogue INM-901 on Aβ-induced toxicity and disease progression using the 5xFAD mice.

Method: Male 5xFAD mice, which exhibit AD-like pathology, including accelerated Aβ-plaque accumulation, inflammation, neurodegeneration, and deficits in cognitive and motor functions, were treated (intra-peritoneally) with INM-901 at 15 or 30 mg/kg twice-weekly for 7 months. Control groups, including non-transgenic and 5xFAD mice, received vehicle-treatment. Behavioral tests, including the Open-field (OFT), Zero Maze, Barnes Maze, and Acoustic Startle Response, were conducted post-treatment. Brain tissue and plasma samples were collected and analyzed via RNAseq, immunohistochemistry, western blotting, and multiplex assay to assess the effects of INM-901 on AD-related genes and protein expression.

Result: INM-901 treatment reversed changes in anxiety-like behavior in the Zero Maze and OFT, as well as improved spatial learning and memory in the Barnes Maze. INM-901 treated mice also exhibited improved acoustic startle response (%PPI), indicating enhanced auditory function. RNAseq showed decreased expression of several inflammatory genes that were upregulated in the 5xFAD mice, while multiplex assays revealed reduced levels of pro-inflammatory cytokines and neurodegeneration marker neurofilament light chain (NfL). Immunohistochemistry demonstrated a reduction in Aβ-aggregation, as well as changes in CB2R expression, highlighting the neuroprotective and anti-inflammatory effects of INM-901.

Conclusion: INM-901 treatment reversed several behavioral changes, improved auditory deficits, decreased Aβ-aggregation, and modulated inflammatory and neuritogenesis markers in 5xFAD mice. These findings highlight the potential of INM-901 as a therapeutic candidate for AD and provide a basis for further evaluation in tauopathy and inflammatory neurodegenerative models.”

https://pubmed.ncbi.nlm.nih.gov/41449949

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70859_103609

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