“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

“Alzheimer’s disease (AD) has traditionally been associated with amyloid-β plaques, but growing evidence underscores the role of neuroinflammation in disease progression. The autoinflammatory hypothesis of AD suggests chronic immune dysfunction contributes to neuronal damage, making immune modulation a promising therapeutic strategy.Cannabidiol (CBD), a phytocannabinoid with anti-inflammatory properties, may offer therapeutic potential.

This study investigates how CBD independently influences two key neuroinflammatory regulators in AD: the Indoleamine 2,3-dioxygenase (IDO) pathway and the cyclic GMP-AMP synthase (cGAS) pathway.

Though mechanistically distinct, both shape CNS immune responses. Targeting these immune-metabolic axes provides a mechanistic alternative to amyloid- or tau-based approaches by addressing upstream drivers of neuroinflammation and immune dysregulation. Using the male 5XFAD transgenic AD mouse model, we administered CBD via inhalation and assessed IDO and cGAS expression using flow cytometry, immunofluorescence, and gene expression analysis. We evaluated cytokine levels and used STRING-based bioinformatics to identify CBD-target interactions.

CBD treatment significantly reduced IDO and cGAS expression, correlating with decreased pro-inflammatory cytokines, including TNF-α, IL-1β, and IFN-γ. Bioinformatics identified potential interactions between CBD and immune targets such as AKT1, TRPV1, and GPR55. These targets were prioritized based on their roles in neuroinflammatory signaling and high-confidence interactions with CBD. AKT1 regulates inflammatory signaling and cell survival, TRPV1 modulates nociception and neuroinflammation, and GPR55 influences immune cell activation.

These findings support CBD as a potential monotherapy or adjunctive treatment for AD by targeting distinct neuroinflammatory pathways, including IDO and cGAS. Further studies are warranted to fully explore its therapeutic potential.

Significance statement This study highlights the therapeutic potential of cannabidiol (CBD) in targeting neuroinflammation, a major driver of Alzheimer’s disease (AD) progression. By modulating the IDO and cGAS pathways-critical regulators of CNS immune responses-CBD reduces pro-inflammatory cytokines and ameliorates immune dysfunction. These findings support the emerging autoinflammatory hypothesis of AD, which posits that chronic inflammation underlies neuronal damage. The IDO/cGAS signaling axis, located at the intersection of innate immunity and metabolic regulation, remains underexplored in AD and represents a key intervention point to disrupt neuroinflammatory loops. This study positions CBD as a promising mono- or adjunctive therapy and reinforces the need to consider multi-targeted strategies that address upstream immune mechanisms in neurodegenerative disease.”

https://pubmed.ncbi.nlm.nih.gov/41052930/

https://www.eneuro.org/content/early/2025/09/26/ENEURO.0114-25.2025

“Introduction: Alzheimer’s disease (AD) is a common neurodegenerative condition involving a complex blend of disturbances in synaptic development and maintenance, neurovascular cross-talk, ionic and nutrient transport, and mitochondrial metabolism. The precise molecular profile of AD onset with insight for major pathological contributors remains unclear with corresponding impedances in therapeutic development. The current study sought two objectives, as (i) to resolve the molecular pathogenesis from cognitive impairment to the onset of AD-like neuropathology and (ii) whether the novel agent cannabidiol (CBD), noted for its neuroprotective effects, influences the molecular transition associated with AD onset.

Methods: Dietary CBD was administered daily (80-100 mg/kg/day) in male 3xTg-AD mice and wild-type B6129SF2/J animals from 4.5 to 6.5 mo of age with inclusion of vehicle controls. RNA sequencing encompassed longitudinal and cross-sectional blood and brain samples, respectively. Metabolomics and behavioral analyses examined brain regions (cortex, hippocampus) and associated integrated neurocircuitry.

Results and discussion: There were >1,000 differentially expressed markers of AD onset, whereby >75% were either eliminated or reversed in the direction of expression in response to CBD. Signaling pathways encompassed synaptic development and plasticity (e.g., Foxp2), neurovascular interactions (Smad9, Angptl6), receptors and ion channels (Gria4, Chrna2, Rgs7/Rgs7bp), mitochondrial genes (Ndufa7, Cox7a2), immunity (Ncr1), oxidation-reduction (Esr1), lipid synthesis (Fasn, ApoE), and carbohydrate metabolism (Mafa, Mlxipl). As potentially addressable with CBD treatment, AD onset represents molecular integration of neurovascular interactions, channelopathies, metabolic disturbances, and aberrations in developmental genes with involvement of major pathological contributors such as inflammation, oxidative signaling, dyslipidemia, and insulin resistance.”

https://pubmed.ncbi.nlm.nih.gov/40979532/

“Altogether, with all details enclosed in the primary manuscript and Supplementary Files, we hereby conclude that the onset of Alzheimer’s disease represents a molecular integration of neurovascular interactions, channelopathies, metabolic disturbances, and developmental genes gone awry with notable overlap among other neurological (e.g., Parkinson’s and frontotemporal dementia) and non-neurological (e.g., cancer) conditions. Remarkably, chronic cannabidiol treatment has the potential to widely address and almost completely disrupt molecular signatures of the onset of Alzheimer’s disease.”

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1667585/full

“Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment, synaptic dysfunction, and neuronal loss. Neuroinflammation, driven by the activation of microglia and astrocytes, is a key contributor to AD pathology, amplifying oxidative stress and amyloid-β toxicity. Modulation of neuroinflammatory pathways thus represents a promising therapeutic strategy.

In this study, we evaluated the effects of a food-grade hempseed protein hydrolysate (HPH20A) on hippocampal inflammation and glial activation in a scopolamine-induced mouse model of AD.

Mice were orally supplemented with HPH20A (10 mg/kg/day) for 12 weeks. Hippocampal tissue was analyzed by RT-qPCR and immunohistochemistry to assess the expression of glial and inflammatory markers. To identify peptides capable of reaching the brain, we employed a double transwell in vitro system simulating intestinal and blood-brain barrier (BBB) transport, followed by LC-TIMS-MS/MS peptidomics, in silico bioactivity prediction, and molecular docking. HPH20A supplementation significantly attenuated the expression of pro-inflammatory markers, including GFAP, IBA1, TREM2, CD68, iNOS, COX2, and IL-6, and increased the anti-inflammatory cytokine IL-10. Peptidomic analysis identified two peptides, NVDTELAHKL and DSETVKRL, consistently present across intestinal, systemic, and brain compartments. These peptides were predicted to exhibit anti-inflammatory activity and demonstrated high-affinity binding to AD-related targets (APP, TREM2, and AChE) in docking simulations.

Taken together, these findings suggest that HPH20A exerts neuroprotective effects by modulating hippocampal inflammation inflammation, potentially through specific bioactive peptides capable of crossing the BBB.

Our results support the potential of hempseed-derived peptides as dietary modulators of neuroinflammation in early stages of neurodegenerative disease.”

https://pubmed.ncbi.nlm.nih.gov/40916308/

https://www.sciencedirect.com/science/article/pii/S0753332225006328?via%3Dihub

“A long-term high-fat diet (HFD) intake causes obesity, disrupting the gut microbiota and body metabolite balance, and increasing the risk of Alzheimer’s disease (AD).

Fermented hempseed may restore microbiota balance, improve metabolism, and reduce neuroinflammation, potentially protecting against cognitive decline.

This study investigates the protective effects and mechanisms of action of Pediococcus acidilactici KCTC 15831BP-fermented hempseed (FHS) against AD-like symptoms induced by obesity in high-fat diet-fed mice.

Nine-week-old male C57BL/6 mice were fed an HFD and supplemented with either orlistat, raw hempseed, FHS, or live Pediococcus acidilactici KCTC 15831BP (PA) for 15 weeks. At the end of the experiment, the impacts of supplementation on obesity- and AD-related markers, brain and blood metabolites, and fecal microbiota were assessed.

HFD-fed mice exhibited obesity markers, such as increased body weight, altered serum lipids, insulin resistance, high leptin but low adiponectin levels, fatty liver, and enlarged adipose tissue. They also showed AD-related disorders, including cognitive decline, oxidative stress, neuroinflammation, and beta-amyloid accumulation. HFD feeding also led to gut microbiota dysbiosis and unfavorable changes in serum and brain metabolites.

FHS intervention reversed most adverse effects, restoring gut microbiome balance, improving the Firmicutes/Bacteroidetes ratio, and normalizing disrupted serum and brain metabolites, including increasing protective compounds like L-tryptophan and trans-cinnamic acid. The beneficial changes in the gut microbiota and metabolite profiles caused by FHS positively correlated with improvements in obesity and AD markers.

These findings highlight the interconnection between the diet, gut, and brain, emphasizing the role of the diet-microbiota-gut-brain axis in mitigating neurodegenerative diseases.”

https://pubmed.ncbi.nlm.nih.gov/40878211/

https://pubs.rsc.org/en/content/articlelanding/2025/fo/d5fo01921d

“Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a set of multifactorial conditions that progressively impair memory processing and cognitive function. The study of this pathology is particularly challenging due to its complex etiology, which involves several pathological hallmarks, including amyloid plaque formation, tau protein hyperphosphorylation, neuroinflammation, oxidative stress, and other contributing factors-all leading to neuronal loss. The primary therapeutic approach for AD involves the use of anticholinesterase agents; however, these treatments are associated with adverse effects, and their efficacy has been increasingly questioned.

Against this backdrop, researchers have investigated cannabidiol (CBD) as a potential complementary treatment for AD. This study compiles and synthesizes current evidence regarding the therapeutic effects of CBD in the context of AD, examining its impact on the amyloid cascade, tau phosphorylation, neuroinflammation, oxidative stress, the cholinergic pathway, glucose and lipid metabolism, behavioral alterations, and physiological changes. In addition, an in silico analysis was conducted based on studies that identified differential gene expression in response to CBD.

Through this analysis, we mapped the gene network and biological pathways involved in CBD’s mechanism of action in AD, contributing to the identification of potential gene targets for further research and providing deeper insight into its therapeutic potential.”

https://pubmed.ncbi.nlm.nih.gov/40859865/

“In summary, the combination of literature review and in silico analysis brings together classical and contemporary data analysis methods, promoting a rich understanding of a complex disease such as AD. This combination of methodologies, capable of bringing together the effects and pathways of action associated with genetic modulation promoted by CBD treatment, demonstrates the enabling potential of this cannabinoid for the development of a complementary therapeutic method for AD.”

https://onlinelibrary.wiley.com/doi/10.1111/ejn.70229