Prevention of Alzheimer’s Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation

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“Alzheimer’s disease (AD) is characterized by enhanced β-amyloid peptide (βA) deposition along with glial activation in senile plaques, selective neuronal loss, and cognitive deficits.

Cannabinoids are neuroprotective agents against excitotoxicity in vitro and acute brain damage in vivo.

This background prompted us to study the localization, expression, and function of cannabinoid receptors in AD and the possible protective role of cannabinoids after βA treatment, both in vivo and in vitro.

Here, we show that senile plaques in AD patients express cannabinoid receptors CB1 and CB2, together with markers of microglial activation, and that CB1-positive neurons, present in high numbers in control cases, are greatly reduced in areas of microglial activation. In pharmacological experiments, we found that G-protein coupling and CB1 receptor protein expression are markedly decreased in AD brains. Additionally, in AD brains, protein nitration is increased, and, more specifically, CB1 and CB2 proteins show enhanced nitration. Intracerebroventricular administration of the synthetic cannabinoid WIN55,212-2 to rats prevent βA-induced microglial activation, cognitive impairment, and loss of neuronal markers.

Cannabinoids (HU-210, WIN55,212-2, and JWH-133) block βA-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor-α release; these effects are independent of the antioxidant action of cannabinoid compounds and are also exerted by a CB2-selective agonist. Moreover, cannabinoids abrogate microglia-mediated neurotoxicity after βA addition to rat cortical cocultures.

Our results indicate that cannabinoid receptors are important in the pathology of AD and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.”

“Cannabinoid receptors in AD brain.”

“Cannabinoids, the active components of marijuana and their analogs, exert a wide spectrum of central and peripheral effects by activating specific cannabinoid receptors, two of which have been well characterized to date: CB1 and CB2.”

“Cannabinoids exert neuroprotection under different experimental conditions. Thus, cannabinoid receptor activation protects hippocampal or granule cerebellar neurons from excitotoxicity”

“This background prompted us to study the characteristics and localization of cannabinoid receptors in AD brain, with particular emphasis on any relationship with microglial activation.”

“Cannabinoid treatment prevents βA-induced microglial activation and neurotoxicity in vitro.”

“Cannabinoid treatment prevents βA-induced toxic effects in vivo.”

“Because cannabinoids combine both anti-inflammatory and neuroprotective actions, our findings may set the basis for the use of these compounds as a therapeutic approach for AD.”

https://pmc.ncbi.nlm.nih.gov/articles/PMC6726060

https://www.jneurosci.org/content/25/8/1904.long

Phenylpropionamides of Cannabis sativa L. seeds exert a cytoprotective effect through modulation of the AMPK/mTOR/ULK1 autophagy pathway and attenuate apoptosis in MPP+-induced SH-SY5Y cells

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“Objective: This study aimed to investigate whether phenylpropionamides (PHS) exert therapeutic effects on Parkinson’s disease (PD) by targeting autophagy-related pathways, using network pharmacology and in vitro experiments.

Methods: Network pharmacology (NP) analysis and molecular dynamics simulation (MDS) were applied to elucidate the potential mechanisms by which PHS treats PD. Subsequently, SH-SY5Y cells were treated with MPP+ to establish a neurotoxin model. Cell viability was assessed using the CCK-8 assay. Mitochondrial membrane potential (MMP) in SH-SY5Y cells was measured using JC-1 staining. Western blot (WB) was used to detect the expression of Bax, cleaved caspase-3, caspase-3, LC3-II, p62, Beclin-1, AMPK, mTOR, and ULK1 signaling proteins in SH-SY5Y cells.

Results: NP analysis suggested that the potential anti-PD effects of PHS were associated with cleaved caspase-3, Bcl-2, mTOR, and Beclin-1. Furthermore, KEGG and PPI analyses demonstrated that PHS may exert anti-PD effects by modulating the AMPK/mTOR/ULK1 autophagy signaling pathway. Molecular docking (MolD) and MDS showed that the key PHS component (Cannabisin I) had a stable interaction with caspase-3, Bcl-2, AMPK, mTOR, ULK1, and Beclin-1. The in vitro experiments showed that PHS suppressed the expression of cleaved caspase-3 and Bax, promoted Bcl-2 expression, activated the autophagy pathway, increased the levels of LC3-II and Beclin-1, increased mitochondrial membrane potential and decreased the levels of p62. Notably, PHS promoted autophagy by increasing AMPK and ULK1 while inhibiting mTOR protein levels. Therefore, PHS may represent a promising candidate for neuroprotective intervention in neurodegenerative disorders.

Conclusion: This study suggests that PHS may exert anti-PD effects, possibly through triggering autophagy via the AMPK/mTOR/ULK1 signaling pathway.”

https://pubmed.ncbi.nlm.nih.gov/42456387

“Historically, the seeds of Cannabis sativa L. have been used in traditional Chinese medicine (TCM). They are frequently utilized in various dietary applications, including cannabis seed oil, bread, and yogurt. Because they are rich in unsaturated fatty acids (UFAs) and essential amino acids (EAAs), they have been sought after by people. In addition, they have been reported to exhibit neuroprotective and immunomodulatory effects, as well as benefits for gastrointestinal health.

Furthermore, UFAs and EAAs, the seeds of Cannabis sativa L., are abundant in a category of compounds known as phenylpropionamides (PHS). Research has demonstrated that PHS compounds possess the ability to inhibit apoptosis in the SH-SY5Y cell model of PD, which is triggered by 1-methyl−4-phenylpyridinium (MPP+), by modulating the autophagy pathway. Previous studies have identified 22 PHS in cannabis seeds and demonstrated that PHS ameliorated MPTP-induced PD symptoms by promoting autophagy.”

https://www.sciencedirect.com/science/article/abs/pii/S0040816626004490?via%3Dihub

Delta-9-tetrahydrocannabinol delineates D-galactose and aluminium chloride-induced cognitive dysfunction and neurodegeneration in the hippocampus of the Wistar rat model

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“Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by neurodegeneration and a decline in cognition and memory. D-galactose (D-gal) and aluminium chloride (AlCl3) have been used to induce cognitive deterioration in rat models that mimic the alterations observed in AD.

This study assessed the neurotherapeutic effect of Δ9-tetrahydrocannabinol (Δ9THC) on cognitive abilities, brain morphology, neurogenesis activity and neuropathological markers in Wistar rats induced by D-gal plus AlCl3.

Male albino Wistar rats received D-gal (60 mg/kg, intraperitoneally) and AlCl3 (200 mg/kg, orally) daily for 10 weeks. The rats were then treated with increasing concentrations of Δ9THC (0.75, 1.5 and 3.0 mg/kg) for 28 days. Cognitive performance was evaluated using the novel object recognition and modified elevated plus maze tests. Dentate gyrus viable granule cells, neurogenesis markers, amyloid precursor protein and phosphorylated tau (p‑tau Thr231) were assessed histologically and molecularly.

Δ9THC treatment improved cognitive performance, prevented granule cell loss in the dentate gyrus, increased neurogenesis-related markers (GFAP+, DCX+, calbindin+ and NeuN immunoreactivity), and reduced amyloid precursor protein and p‑tau Thr231 expression.

These findings suggest that Δ9THC possesses promising therapeutic potential against Alzheimer’s disease.”

https://pubmed.ncbi.nlm.nih.gov/42454694


Progressive weight loss is attenuated by THC treatment in rats with activity-based anorexia

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“Anorexia nervosa (AN) is a severe psychiatric disorder with limited effective pharmacological treatments.

Given the role of the endocannabinoid system (ECS) in regulating energy balance and its possible involvement in AN pathophysiology, cannabinoid-based interventions may hold therapeutic potential.

Using the preclinical activity-based anorexia (ABA) model, we investigated whether Δ⁹-tetrahydrocannabinol (THC) could attenuate the progression of ABA-induced weight loss.

Female rats were exposed to the ABA paradigm, which combines restricted food access (2 h/day) with unrestricted access to running wheels. After 3 days, when ABA rats had lost 10-12% of their baseline body weight, they received daily injections of either THC or vehicle. Rats were removed from the paradigm after losing 23% of their body weight or on the morning of day 8, whichever occurred first.

THC treatment significantly attenuated weight loss and prolonged survival in the paradigm.

These beneficial effects of THC were mediated by a selective suppression of excessive dark- and light-phase wheel running with no additional effects on food intake.

These findings provide the first evidence that initiating THC treatment after significant weight loss in the ABA paradigm can halt the progression of weight loss through a selective decrease in energy expenditure.

Importantly, treatment was initiated after (rather than before) the emergence of ABA-induced weight loss, thus enhancing the translational relevance of the model and our findings.

Together, these findings suggest that pharmacological activation of the ECS may represent a promising treatment for individuals with AN.”

https://pubmed.ncbi.nlm.nih.gov/42448208

“THC treatment, initiated after ∼12% body weight loss in rats with activity-based anorexia (ABA), reduced further weight loss and prolonged survival.”

“Findings support endocannabinoid-targeted therapies for anorexia nervosa.”

https://www.sciencedirect.com/science/article/abs/pii/S0031938426002313?via%3Dihub


Edible Oil-Based Extraction of Cannabis sativa L. Roots: Effect of Solvent and Temperature on Friedelin Yield and Antioxidant Activity

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“The roots of Cannabis sativa L., historically overlooked, are gaining attention as a potential source of bioactive compounds with antioxidant, antimicrobial, and anti-inflammatory properties.

While previous studies have focused on extractions using ethanol, water, or supercritical CO2, the feasibility of edible oil-based extraction remains largely unexplored.

This study evaluated the extraction of root compounds using hemp seed oil, MCT coconut oil, and grape seed oil at six temperatures (50-90 °C).

Extracts were analyzed by GC-MS for compound identification and quantification, and antioxidant activity was assessed using the DPPH assay, ABTS test and β-carotene bleaching method, with results statistically evaluated by ANOVA. Friedelin was successfully extracted with all oils, with grape seed oil yielding the highest concentration (0.810 mg/g dry roots), achieving recoveries higher than those previously reported for ethanol-based extractions.

All extracts demonstrated positive antioxidant activity, with grape seed oil, both alone and combined with extracts, showing higher values across the three methods. ANOVA revealed a significant effect of solvent type on both Friedelin concentration and antioxidant capacity.

These results demonstrate that edible oils are effective solvents for extracting bioactive compounds from C. sativa roots, supporting their potential application in cosmetic or medicinal formulations.”

https://pubmed.ncbi.nlm.nih.gov/42123839

“In conclusion, this research validates the feasibility of extracting bioactive compounds from cannabis roots using accessible edible oils, achieving Friedelin recoveries higher than those previously reported for alcoholic extractions. These findings provide an important foundation for the development of Cannabis sativa L. root-based products for cosmetic or medicinal applications.”

https://www.mdpi.com/1420-3049/31/9/1473


Cannabis sativa: A Source of Antiparasitic Compounds?

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“Cannabis sativa (hemp, marijuana, ganja) is a plant with industrial, medicinal, and recreational uses that synthesizes phytocannabinoids, a group of compounds from which tetrahydrocannabinol (THC) and cannabidiol (CBD) outstand by their known high and low psychoactive properties.

These and other cannabinoids (endocannabinoids and synthetic derivatives with modulating effects over cannabinoid receptors CB1/2) have been tested in vitro using cultured parasites and in vivo in rodent models of protozoosis affecting the central nervous system as are amoebic encephalopathy, cerebral malaria, brain toxoplasmosis as well as Chagas disease and Leishmaniasis. Helminthiasis mainly includes Nippotrongyloidosis and Schistosomiasis and even their effects on ticks as Boophilus have been reported.

The parasiticidal effect of C. sativa extracts and cannabinoids is consistently found although some points of concern arise from animal models because CB1 or CB2 inactivation/inhibition led to distinct outcomes –beneficial or deleteriousin parasite load and host survival, depending on the organism studied. Possible parasitic targets of cannabinoids include arginase, acetylcholinestherase and haemozoin, a product of hemoglobin digestion.

Collectively, these data highlight that the potential use of cannabinoids against parasitic infections should consider the effects of these compounds on their known targets at the endocannabinoid system (CB1/2) and the likely target(s) in parasites.”

“Plant-derived compounds have multiple beneficial activities for human health, including new candidates for the treatment of parasitic diseases. Among these are macrocyclic lactones terpenes and polyphenols. Unlike most plant species, C. sativa (hemp, marijuana or ganja) is a rich source of both products of industrial interest and phytomedicinal compounds as well”

“At the light of experimental evidence, the potential application of cannabinoids in parasitosis is generally promising on the basis of their parasiticidal in vitro activities”

https://biomedres.us/fulltexts/BJSTR.MS.ID.007960.php


Cannabinoids from C. sativa L.: Systematic Review on Potential Pharmacological Effects against Infectious Diseases Downstream and Multidrug-Resistant Pathogens

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“Cannabis sativa L. has garnered attention as a potential source for new antimicrobial agents, particularly due to the increased prevalence of microbial resistance to conventional antimicrobials and the emergence of multidrug-resistant pathogens.

This review, conducted according to the PRISMA 2020 statement, systematically analyzed the antimicrobial properties of C. sativa extracts and cannabinoids against various bacteria, fungi, viruses, and parasites. Data were collected from the scientific literature (102 papers) and clinical trials (5 studies) from 2014 to June 2024.

Findings revealed that cannabinoids, especially CBD, demonstrate significant antimicrobial activity against Gram-positive bacteria like MRSA, Gram-negative bacteria such as Pseudomonas aeruginosa, various Candida species, SARS-CoV-2, and HIV. Additionally, CBD showed efficacy against parasitic infections like Echinococcus granulosus and Leishmania species.

These results suggest that cannabinoids may represent a new class of antimicrobial agents with unique and diverse mechanisms of action, potentially effective in broad-spectrum therapies.

This study highlights the urgent need for further research and standardized clinical trials to validate these findings and to develop cannabinoid-based treatments.

The antimicrobial properties of C. sativa align with WHO priorities and support global health initiatives, offering promising avenues for addressing antimicrobial resistance and improving public health outcomes.”

“Cannabis sativa L., part of the natural products arsenal, has been a rich source for identifying new therapeutic agents. In recent years, there has been a growing interest in using C. sativa and understanding how its bioactive compounds—phytocannabinoids—support the prevention and treatment of various diseases and conditions. This interest is particularly relevant given the growing prevalence of microbial resistance to conventional antibiotics and the emergence of multidrug-resistant (MDR) pathogens.”

“Cannabis extracts and cannabinoids have demonstrated the capacity to inhibit the growth of certain bacterial strains at concentrations comparable to traditional antimicrobials. These findings represent a significant advancement in the battle against antimicrobial resistance, offering a perspective for future treatments.”

“The ability of Cannabis to combat antimicrobial-resistant infections, potentially in combination with traditional antimicrobials, could substantially contribute to global health by providing novel treatment avenues and reducing the burden of infectious diseases worldwide.”

https://www.mdpi.com/2673-9879/4/3/33

In vivo and in silico wound healing potential of Cannabis Sativa seed oil through inflammation mediators

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“Background: This study investigates the wound healing potential of Cannabis Sativa seed oil (CSSO), derived from the industrial hemp variety ‘NARLI’. The rich essential fatty acid profile of CSSO presents promising therapeutic opportunities; however, its specific in vivo efficacy and targeted molecular mechanisms in wound management remain underexplored. This study aimed to evaluate the in vivo tissue regeneration dynamics and the in silico anti-inflammatory mechanisms of CSSO derived from the ‘NARLI’ hemp variety in an excision wound model.

Methods: Using an excision wound model, 42 rats were divided into two groups: control (untreated) and CSSO-treated. Wound healing was assessed through clinical wound area measurement, histopathological evaluation, immunohistochemistry (IHC), and molecular docking analyses. Wound area measurements were taken on days 7, 14, and 21.

Results: On day 21, CSSO-treated animals showed a significantly higher wound closure rate (93%) compared to the control group (87.55%) (p = 0.005). Histopathological analysis revealed enhanced neovascularization, increased collagen deposition (p = 0.008), reduced inflammatory cell infiltration (p = 0.020), and increased epithelial proliferation in the CSSO group. Immunohistochemistry findings showed a marked decrease in proinflammatory cytokines TNF-α and IL-1β (p = 0.023) and TGF-β (p = 0.030), and a notable upregulation of angiogenesis and proliferation markers VEGF (p = 0.031) and Ki-67 (p = 0.001). Molecular docking analyses revealed that CSSO-derived fatty acids showed binding affinities (-5.3 to -7.5 kcal/mol) with anti-inflammatory-related proteins (COX-2 and NLRP3) and (-3.1 to -6.1 kcal/mol) binding affinities with wound healing-related proteins (SIRT1 and GSK3β), suggesting a possible mechanistic basis underlying the wound healing potential of CSSO.

Conclusions: Topical application of CSSO was associated with improved wound healing outcomes in rats, including enhanced wound closure and favourable histopathological and immunohistochemical changes. Further studies are needed to confirm these findings and clarify the mechanisms involved.”

https://pubmed.ncbi.nlm.nih.gov/42426779

https://link.springer.com/article/10.1186/s12906-026-05462-8

CBD-Containing Topical Formulation for Localized Pain in Fibromyalgia: A 12-Week Pilot Feasibility Study

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“Background: Fibromyalgia (FM) is a chronic pain condition characterized by widespread pain, fatigue, and functional impairment. Current pharmacological treatments show limited efficacy and poor tolerability. Cannabidiol (CBD) has demonstrated analgesic and anti-inflammatory properties, but evidence regarding CBD-containing topical formulations in FM remains scarce.

Objectives: To evaluate the feasibility, safety, and preliminary efficacy of a CBD-containing topical formulation for localized pain in patients with FM and to explore its potential impact on broader symptom domains.

Material and methods: This single-arm pilot study included 30 women with FM and clinically relevant localized pain due to musculoskeletal, neuropathic, or cutaneous comorbidities. Participants self-applied a commercially available CBD-containing topical formulation to a painful area every 8 h for 12 weeks. Outcomes were assessed at baseline, 4 weeks, and 12 weeks. Nonparametric repeated-measures analyses, Monte Carlo resampling, effect sizes, and minimal clinically important difference (MCID) thresholds were applied.

Results: At the 4- and 12-week follow-up visits, all participants reported full adherence to the prescribed application schedule. No adverse events or side effects were reported. Localized pain showed a significant and clinically meaningful reduction at 4 weeks, sustained at 12 weeks (60% achieving MCID). Functional capacity improved significantly, with 50% of participants exceeding the MCID at 4 weeks. Widespread Pain Index (WPI) and Symptom Severity Scale (SSS) scores decreased progressively, and a lower proportion of participants met the 2010 American College of Rheumatology (ACR) diagnostic criteria for FM at 12 weeks, while generalized pain, fatigue, anxiety, and depression did not show significant changes.

Conclusions: Topical application of a CBD-containing formulation was feasible and was associated with improvements in localized pain and functionality in this exploratory single-arm study. Changes observed in WPI and SSS, and in the proportion of participants meeting the 2010 ACR criteria at follow-up, should be interpreted cautiously and considered exploratory and hypothesis-generating, given the uncontrolled design (precluding causal inference), the symptom-based and fluctuating nature of FM, and the multicomponent composition of the product. Although limited by its uncontrolled design, this pilot study provides effect size estimates and methodological guidance to support future randomized controlled trials of topical cannabinoids in FM.”

https://pubmed.ncbi.nlm.nih.gov/42421470

https://journals.sagepub.com/doi/10.1177/25785125261468882

Evaluating the Combined Effects of Cannabinoids and Music, and Their Interactions in Mood and Emotional Regulation: An Online Survey

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“Background: While both cannabis and music have demonstrated significant independent impacts on emotional states, the synergies between these two modalities remain underexplored. This study investigates the interactions between cannabis consumption and music listening, focusing on their effects on emotional experiences, mood regulation, and sensory perceptions.

Methods: An online cross-sectional survey consisting of 176 questions was administered to 122 cannabis users. The survey captured detailed information on demographics, cannabis use patterns, music engagement behaviors, emotional responsiveness, and the interplay between cannabis and music perception.

Results: Most participants viewed the combination of cannabis and music favorably, reporting enhanced relaxation, improved mood, and increased feelings of connection. Cannabis use was also associated with altered responses to imposed music in various settings and a heightened likelihood of using music during routine activities. In addition, participants frequently reported the use of cannabis as a substitute for pharmaceutical treatments for pain, anxiety, and sleep disorders, with music further amplifying these therapeutic effects. However, no significant differences were observed in overall music reward experiences with or without cannabis, highlighting the nuanced and context-dependent nature of these interactions.

Conclusion: These findings provide novel insights into the potential for cannabis and music to act as complementary tools for emotional well-being, underscoring the need for further research to elucidate the mechanisms underlying their combined effects. This study provides a foundation for future investigations into the therapeutic integration of music as a supportive adjunct to cannabinoid-based interventions targeting emotional and psychological health.”

https://pubmed.ncbi.nlm.nih.gov/42421248

https://journals.sagepub.com/doi/10.1177/25785125261467505