“Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that requires therapeutic agents capable of targeting multiple pathological pathways.

In this study, a series of cannabidiol (CBD)-like hydrazone derivatives (3a–i) was synthesized and characterized by NMR, HRMS, and single-crystal X-ray diffraction for compound 3i.

In silico ADME analysis predicted favorable drug-like properties, including compliance with Lipinski’s Rule of Five, oral bioavailability, and blood-brain barrier permeability. The compounds were evaluated for cholinesterase inhibition, antioxidant activity, cytotoxicity in neuronal cell lines, and binding interactions with human butyrylcholinesterase (hBChE) by molecular docking. Biological evaluation revealed a marked preference for BChE over acetylcholinesterase (AChE).

Compound 3f was the most potent BChE inhibitor (IC₅₀ = 1.67 ± 0.11 μM), while compounds 3b and 3f demonstrated high selectivity toward BChE. Antioxidant assays (DPPH, ABTS, FRAP, and FTC) indicated moderate, mechanism-dependent activity. Compounds 3b and 3e showed the strongest ABTS radical-scavenging effects, whereas compounds 3b and 3f provided the greatest protection against lipid peroxidation, surpassing CBD under the tested conditions. Several derivatives, particularly 3a, 3b, 3f, 3h, and 3i, exhibited favorable safety profiles in SH-SY5Y and Neuro-2a cells. Molecular docking supported the experimental findings.

Overall, compounds 3b and 3f emerged as promising multifunctional leads for the development of multitarget-directed anti-Alzheimer agents.”

https://pubmed.ncbi.nlm.nih.gov/42588505

“Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has emerged as a promising multitarget neuroprotective agent for Alzheimer’s disease (AD).”

https://www.mdpi.com/1420-3049/31/15/2657

“Alzheimer’s disease (AD) initiates with subtle neuroimmune alterations that precede overt synaptic loss and neuronal death, yet the early sequence linking Aβ exposure to glial activation remains incompletely understood.

To capture early neuroimmune dynamics with greater physiological relevance, we employed primary mixed neuron-glia cultures derived from the hippocampi of postnatal day 1 (P1) mice. Unlike conventional coculture systems, these hippocampal mixed cultures preserve intrinsic neuron-astrocyte-microglia communication and recapitulate key features of the in vivo hippocampal microenvironment.

Using this model, we investigated whether cannabidiol (CBD) modulates the initial pathogenic events triggered by Aβ_25-35 during a 24h simultaneous cotreatment in cell culture.

Aβ exposure induced robust hippocampal glial activation, oxidative stress, and elevated levels of proinflammatory mediators, particularly IL-1β, IL-6, and TNF-α. Notably, hippocampal synaptic and neurogenic markers (5HT₁A, Gria1, GRIN1, DCX, PSD-95) remained largely unaltered at this early stage, revealing a temporal dissociation in which glial-driven inflammation precedes synaptic dysfunction.

CBD significantly attenuated inflammatory and oxidative responses and prevented Aβ-induced cellular damage, indicating engagement of endocannabinoid-related mechanisms that constrain early hippocampal glial reactivity. Although CBD did not fully normalize all glial alterations, it preserved hippocampal synaptic integrity and halted progression toward neuronal dysfunction.

Together, these findings identify early hippocampal glial inflammation as a primary target of CBD and provide mechanistic insight into the temporal sequence linking Aβ exposure to neuroimmune activation.

These results highlight early glial responses as a critical window for therapeutic intervention and support cannabinoid-based strategies to modulate the initial stages of Alzheimer’s disease pathogenesis.”

https://pubmed.ncbi.nlm.nih.gov/42331352

https://onlinelibrary.wiley.com/doi/10.1111/ejn.70588

“Objective: Agitation and related neuropsychiatric symptoms are common in Alzheimer’s disease (AD) and contribute to caregiver burden, functional decline, and institutionalization. Cannabinoid-based therapies have been investigated as potential symptomatic interventions, but evidence remains limited by small trials, heterogeneous formulations, and variable outcome reporting. We aimed to evaluate the efficacy, cognitive outcomes, and safety of cannabinoid-based therapies in AD.

Methods: This systematic review and meta-analysis were prospectively registered in PROSPERO and conducted following PRISMA 2020 guidelines. PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched through April 2025 for randomized placebo-controlled trials evaluating cannabinoid-based therapies for agitation or neuropsychiatric symptoms in AD. One nonrandomized open-label study was retained as supplementary evidence for sensitivity analyses. Primary efficacy analyses were restricted to randomized between-group contrasts. Outcomes included Neuropsychiatric Inventory (NPI) total score, Cohen-Mansfield Agitation Inventory-Short Form (CMAI-SF), NPI agitation/aggression, Mini-Mental State Examination (MMSE), and safety outcomes. Random-effects meta-analyses were complemented by Bayesian models and Trial Sequential Analysis.

Results: Seven studies met the inclusion criteria, including six randomized trials and one open-label prospective cohort, with 221 participants enrolled. Cannabinoid-based therapies showed lower neuropsychiatric symptom and agitation scores than placebo in randomized between-group analyses: NPI total score (standardized mean difference [SMD], -0.31; 95% confidence intervals [CI], -0.47 to -0.15; k = 4), CMAI-SF (SMD, -0.40; 95% CI, -0.69 to -0.10; k = 3), and NPI agitation/aggression (SMD, -0.47; 95% CI, -0.69 to -0.25; k = 3). Bayesian posterior probabilities for lower symptom scores exceeded 95%. MMSE findings did not support a consistent cognitive benefit. Somnolence was the principal safety signal (risk ratios, 2.25; 95% CI, 1.43-3.54), with Trial Sequential Analysis suggesting sufficient accrued information for this outcome. Falls and fatigue were imprecisely estimated.

Conclusions: Cannabinoid-based therapies showed lower agitation and neuropsychiatric symptom scores than placebo in AD, with somnolence as the main safety concern. Interpretation remains limited by few trials, heterogeneous formulations and outcome instruments, short follow-up, and concentrated statistical weight. Larger randomized trials with formulation-specific protocols, longer follow-up, active comparators, and systematic safety monitoring are needed.”

https://pubmed.ncbi.nlm.nih.gov/42315374

https://www.ajgponline.org/article/S1064-7481(26)00400-8/abstract

“Pathogenic tau hyperphosphorylation, together with reduced protein phosphatase 2 A (PP2A) expression, is associated with neurofibrillary tangle formation and cognitive deterioration in Alzheimer’s disease (AD).

Cannabidiol (CBD), a non-psychotropic phytocannabinoid, remains insufficiently studied for its potential to modulate the PP2A-tau axis in experimental AD.

This study evaluated whether CBD improves hippocampus-dependent spatial cognition in a D-galactose/AlCl₃ rat model of AD and whether these effects are associated with restoration of PP2A expression and attenuation of tau hyperphosphorylation.

AD-like pathology was induced in male Wistar rats by D-galactose (60 mg/kg i.p.) and AlCl₃ (200 mg/kg oral gavage) for 10 weeks, followed by CBD (20, 40 or 80 mg/kg) or donepezil (1 mg/kg) for three weeks. The Morris water maze, Jess Simple Western, and ELISA were used to assess cognition, PP2A expression, and p-tau levels, respectively.

CBD significantly improved spatial learning and memory. PP2A expression increased across all tested doses, with the highest mean level observed at 80 mg/kg. Hippocampal p-tau levels were significantly increased in the model group and significantly reduced by all CBD doses and donepezil (all p < 0.0001 vs. model). The inverse relationship between PP2A expression and p-tau levels suggests possible involvement of the PP2A-tau axis.

CBD attenuated cognitive deficits and tau hyperphosphorylation alongside restoration of PP2A expression, suggesting that the PP2A-tau axis may be a relevant therapeutic target in AD-related tauopathy.”

https://pubmed.ncbi.nlm.nih.gov/42240860

https://link.springer.com/article/10.1007/s11011-026-01894-w