Category Archives: Alzheimer’s Disease (AD)

The proof is in the pudding: patient engagement in studying cannabidiol in mild cognitive impairment

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“Background: Patient engagement (PE) in clinical trials has gained importance yet remains uncommon, particularly in patients with mild cognitive impairment (MCI), a critical precursor to Alzheimer’s disease (AD). Cannabidiol (CBD) shows potential in slowing MCI progression due to its neuroprotective and anti-inflammatory properties. In CBD research, PE is underutilized too. To design a study on CBD for MCI, we administered an online survey to individuals with MCI to better understand their preferences for trial setup and outcomes.

Methods: We asked 209 individuals with MCI to complete an online survey assessing (i) willingness to participate in a trial using CBD; (ii) importance of improvements in various domains; (iii) acceptance of adverse events (AEs); (iv) reasons for AE-related dropout; (v) willingness to undergo blood sampling and lumbar puncture to assess AD pathology; and (vi) willingness to participate in a trial with a 50% chance of receiving a placebo. Data were analyzed with descriptive statistics.

Results: N = 118 agreed to participate and N = 88 completed the survey. Participants prioritized improvement in cognitive abilities (87.5%), followed by quality of life (63.6%), daily activities (55.7%), sleep (55.7%), pain (52.3%), mood (52.3%), behavior (48.9%), and anxiety (43.2%). Headache (55.7%) was the least accepted AE followed by nausea (46.6%), fatigue (35.2%), and diarrhea (35.2%). Persistent diarrhea (90.9%) and severe fatigue (84.1%) were the main reasons for potential dropout. While most would undergo blood sampling (67.0%), only a minority (21.6%) would accept lumbar puncture. One-third were ready to participate (34.1%), while 54.5% were interested pending details. Among those in favor of participation, 71.6% would participate even with a 50% chance of placebo.

Conclusions: Our study identified cognitive improvement as highly relevant for patients, indicating cognitive assessment tools as primary endpoints in MCI research. Given concerns about AEs, dose titration should be carefully considered to enhance acceptance and prevent AEs. Blood sampling seems well-accepted for AD biomarker assessment. Despite potential AEs, participation in a trial using CBD for MCI is seen as attractive, even under placebo-controlled conditions. This cross-sectional study emphasizes the importance of patient engagement in designing high-quality trials for using CBD to treat MCI.”

https://pubmed.ncbi.nlm.nih.gov/39844123/

“In summary, this study is the first to incorporate PE into a trial on the use of CBD for MCI, as there are currently no existing PE activities in this area. It provides valuable insights into the concerns, aims, and needs of people with MCI and offers initial implications for planning and conducting future studies involving this population. Our main message is to encourage the incorporation of PE activities in the drug research process, not only to reflect the goals and needs of patients but also to improve the quality of research.”

https://bmccomplementmedtherapies.biomedcentral.com/articles/10.1186/s12906-025-04753-w

Cannabinoids: Role in Neurological Diseases and Psychiatric Disorders

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“An impact of legalization and decriminalization of marijuana is the gradual increase in the use of cannabis for recreational purposes, which poses a potential threat to society and healthcare systems worldwide. However, the discovery of receptor subtypes, endogenous endocannabinoids, and enzymes involved in synthesis and degradation, as well as pharmacological characterization of receptors, has led to exploration of the use of cannabis in multiple peripheral and central pathological conditions.

The role of cannabis in the modulation of crucial events involving perturbed physiological functions and disease progression, including apoptosis, inflammation, oxidative stress, perturbed mitochondrial function, and the impaired immune system, indicates medicinal values.

These events are involved in most neurological diseases and prompt the gradual progression of the disease. At present, several synthetic agonists and antagonists, in addition to more than 70 phytocannabinoids, are available with distinct efficacy as a therapeutic alternative in different pathological conditions. The present review aims to describe the use of cannabis in neurological diseases and psychiatric disorders.”

https://pubmed.ncbi.nlm.nih.gov/39796008/

“Cannabis sativa L. (marijuana), an ancient plant with medicinal values, has been used for medicinal, recreational, and spiritual purposes for a long time worldwide.”

“The discovery of the ECS has sparked the interest of many researchers worldwide due to its potential therapeutic contribution to some of the incurable neurodegenerative diseases such as AD, PD, HD, and psychological abnormalities. To date, studies have uncovered the expression, location, structures, and mechanism of cannabinoid receptors.

When the endocannabinoid system’s associations with other biochemical pathways are fully elucidated, many medical and political changes will be seen, such as the legalization of marijuana and new therapeutic approaches to neurodegenerative diseases.

Recent developments regarding crystal structure and cryoEM open the door to understanding the structural complexity and future therapeutic implication of cannabinoids in neurological and psychiatric disorders. Most genes associated with neurological diseases have been defined; however, the molecular details of other changes are largely elusive and are of immense interest to be explored. At this stage, it will be interesting to elucidate the role of CB2R as a neuroprotective strategy in addition to other proteins that are modulated following cannabis administration.

Neuroinflammation, oxidative stress, and disrupted cell organelles, specifically mitochondria, are intimately associated with compelling causative factors for disease progression and are potential therapeutic avenues to explore in neurodegeneration, along with psychological disturbances; therefore, they should be the prime objective for future studies on cannabinoids to develop novel therapeutic chimeric molecules with minimum side effects and maximum benefits.”

https://www.mdpi.com/1422-0067/26/1/152

Pharmacological characterization of cannabidiol as a negative allosteric modulator of the 5-HT2A receptor

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“Promising clinical evidence suggests that psychedelic compounds, like lysergic acid diethylamide (LSD), have therapeutic value for treatment of psychiatric disorders. However, they often produce hallucinations and dissociative states, likely mediated by the serotonin (5-HT) receptor 5-HT2A, raising challenges regarding therapeutic scalability.

Given the reported antipsychotic effects of cannabidiol (CBD) and its promiscuous binding at many receptors, we assessed whether CBD could modulate 5-HT2A signaling.

Activation of the 5-HT2A intracellular signaling events were assessed using resonance energy transfer- or fluorescence-based biosensors in HEK 293 cells and in rat primary cortical neurons. In 5-HT2A-transfected HEK 293 T cells, CBD antagonized LSD-mediated Gq activation in a saturable way, while leaving β-arrestin2 recruitment unaffected. CBD decreased Gq activation mediated by the 5-HT2A-specific agonist DOI as well as LSD-mediated activity in primary rat neonatal cortical neurons. Using Site Identification by Ligand Competitive Saturation (SILCS) simulations, we also predicted that the putative binding site of CBD overlapped with that of oleamide, a positive allosteric modulator of 5-HT2A, and could displace the binding of orthosteric ligands toward the external binding pocket.

Based on these findings, we propose that CBD acts as a negative allosteric modulator of 5-HT2A.”

https://pubmed.ncbi.nlm.nih.gov/39761844/

“Based on these findings, we propose that CBD acts as a negative allosteric modulator of 5-HT2A.”

https://www.sciencedirect.com/science/article/abs/pii/S0898656825000014?via%3Dihub

“Efficacy and safety of negative allosteric modulators of 5-hydroxytryptamine 2A receptors in the treatment of Alzheimer’s disease psychosis: A systematic review and meta-analysis. Our results suggest that negative modulators of 5-HT2A receptors are beneficial and well-tolerated in the treatment of ADP.”

https://pubmed.ncbi.nlm.nih.gov/37166012/

Cannabidiol induces autophagy via CB1 receptor and reduces α-synuclein cytosolic levels

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“Numerous studies have explored the role of cannabinoids in neurological conditions, chronic pain and neurodegenerative diseases. Restoring autophagy has been proposed as a potential target for the treatment of neurodegenerative diseases.

In our study, we used a neuroblastoma cell line that overexpresses wild-type α-synuclein to investigate the effects of cannabidiol on autophagy modulation and reduction in the level of cytosolic α-synuclein.

Our results demonstrated that cannabidiol enhances the accumulation of LC3-II- and GFP-LC3-positive vesicles, which indicates an increase in autophagic flux. In addition, cannabidiol-treated cells showed a reduction in cytosolic α-synuclein levels. These effects were inhibited when the cells were treated with a CB1 receptor-selective antagonist, which indicates that the biological effects of cannabidiol are mediated via its interaction with CB1 receptor. Additionally, we also observed that cannabinoid compounds induce autophagy and α-synuclein degradation after they interact with the CB1 receptor.

In summary, our data suggest that cannabidiol induces autophagy and reduces cytosolic α-synuclein levels. These biological effects are mediated preferentially through the interaction of cannabidiol with CB1 receptors, and therefore, cannabinoid compounds that act selectively on this receptor could represent a new approach for autophagy modulation and degradation of protein aggregates.”

https://pubmed.ncbi.nlm.nih.gov/39710053/

https://www.sciencedirect.com/science/article/pii/S0006899324006693?via%3Dihub

Current and Potential Use of Biologically Active Compounds Derived from Cannabis sativa L. in the Treatment of Selected Diseases

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“Cannabis sativa L. contains numerous compounds with antioxidant and anti-inflammatory properties, including the flavonoids and the cannabinoids, particularly Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

Cannabinoids have an effect on the endocannabinoid system (ECS), a cellular communication network, and are, hence, widely studied for medical applications.

Epidiolex®, a 99% pure oral CBD extract, has been approved by the FDA for the treatment of epilepsy. Nabiximols (Sativex) is an oromucosal spray containing equal volume of THC and CBD, and it is commonly used as an add-on treatment for unresponsive spasticity in multiple sclerosis (MS) patients.

Several in vitro and in vivo studies have also shown that cannabinoids can be used to treat various types of cancer, such as melanoma and brain glioblastoma; the first positive clinical trials on the anticancer effect of a THC:CBD blend with temozolomide (TMZ) in the treatment of highly invasive brain cancer are very promising.

The cannabinoids exert their anticancer properties in in vitro investigations by the induction of cell death, mainly by apoptosis and cytotoxic autophagy, and the inhibition of cell proliferation. In several studies, cannabinoids have been found to induce tumor regression and inhibit angiogenic mechanisms in vitro and in vivo, as well as in two low-numbered epidemiological studies.

They also exhibit antiviral effects by inhibiting ACE2 transcription, blocking viral replication and fusion, and acting as anti-inflammatory agents; indeed, prior CBD consumption (a study of 93,565 persons in Chicago) has also been associated with a much lower incidence of SARS-CoV-2 infections.

It is postulated that cannabis extracts can be used in the treatment of many other diseases such as systemic lupus erythematosus, type 1 diabetes, or various types of neurological disorders, e.g., Alzheimer’s disease.

The aim of this review is to outline the current state of knowledge regarding currently used medicinal preparations derived from C. sativa L. in the treatment of selected cancer and viral diseases, and to present the latest research on the potential applications of its secondary metabolites.”

https://pubmed.ncbi.nlm.nih.gov/39684447/

“C. sativa L. is an extraordinary plant that provides a valuable raw material for medical applications. Its secondary metabolites, cannabinoids, have attracted growing interest in the fight against illness, mainly due to their effect on CB1 and CB2 cannabinoid receptors.”

https://www.mdpi.com/1422-0067/25/23/12738

The synthetic cannabinoid WIN 55,212-2 attenuates cognitive and motor deficits and reduces amyloid load in 5XFAD Alzheimer mice

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“Background: Alzheimer’s disease (AD) is characterized by cognitive decline, with pathological features including amyloid β (Aβ) plaques and inflammation. Despite recent approvals of anti-amyloid antibodies, there remains a need for disease-modifying and easily accessible therapies. The endocannabinoid system presents a promising target for AD treatment, as it regulates various processes implicated in AD pathogenesis.

Aims: This study assesses the effects of the synthetic cannabinoid WIN 55,212-2 on AD pathology and behavior deficits in aged 5XFAD mice, a well-established AD model.

Methods: Male 9-month-old 5XFAD mice received either 0.2 mg/kg WIN 55,212-2 or a vehicle solution for 42 days. Memory, anxiety, and motor tests were conducted at 10 months to identify potential changes in behavior and cognition following WIN 55,212-2 treatment. Additionally, the effects of prolonged WIN 55,212-2 treatment on Aβ pathology and neuroinflammation in the brain were quantified immunohistochemically.

Results: Therapeutic WIN 55,212-2 treatment improved the motor performance of 5XFAD mice on the rotarod and rescued memory deficits in the water maze. However, WIN 55,212-2 treatment did not significantly affect anxiety-like behavior in 5XFAD mice. Additionally, prolonged treatment with WIN 55,212-2 reduced Aβ plaque pathology and astrogliosis in the cortex and hippocampus.

Conclusions: This study highlights the therapeutic potential of WIN 55,212-2 in AD by ameliorating cognitive and motor deficits and reducing neuropathology. These findings support a cannabinoid-based therapy as a promising strategy for AD treatment, with WIN 55,212-2 emerging as a potential candidate.”

https://pubmed.ncbi.nlm.nih.gov/39675388/

“Natural and synthetic cannabinoids exhibit anti-inflammatory, anti-oxidative, anti-proliferative and analgesic properties. The synthetic cannabinoid WIN 55,212-2, an agonist of both CB1 and CB2 receptors, has been shown to possess neuroprotective, anti-inflammatory, and antinociceptive properties. Furthermore, it has been shown to promote neurogenesis, reduce beta-amyloid and tau in vitro and in vivo“

https://www.sciencedirect.com/science/article/abs/pii/S0091305724002387?via%3Dihub

Cannabidiol, a Strategy in Aging to Improve Redox State and Immunity in Male Rats

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“Aging is characterized by oxidative stress and immune function impairment, and is associated with increased morbidity. Cannabidiol (CBD) has anti-oxidant properties, but its role in aging has been scarcely studied.

This work aims to test the effect of CBD on the redox state and immunity during aging in rats. In this study, 15-month-old male Long Evans rats received 10 mg/kg b.w/day of CBD in their diet for 10 weeks and were compared with same-age control and 2-month-old rats serving as a young control group, both following a standard diet.

After treatment, they were sacrificed, and the spleen, thymus, and total blood cells were collected. Redox parameters such as glutathione reductase and peroxidase activities, reduced (GSH) and oxidized (GSSG) glutathione concentration, GSSG/GSH ratio, and lipid peroxidation were evaluated. Moreover, immune functions (chemotaxis, natural killer activity, and lymphoproliferation) were analyzed in the spleen.

Results show that the 15-month-old control rats exhibited increased oxidative stress and immunosenescence compared to the 2-month-old rats. However, the CBD-treated animals showed higher anti-oxidant defenses, lower oxidants in the spleen, thymus, and blood cells, and better immunity in the spleen than the corresponding age-matched controls.

Therefore, CBD administration neutralizes oxidative stress and improves immunity, suggesting it is a strategy for achieving healthy aging.”

https://pubmed.ncbi.nlm.nih.gov/39596353/

“CBD could be suggested as a candidate to slow down aging and achieve a healthier longevity.”

https://www.mdpi.com/1422-0067/25/22/12288

Cannabis Use and Age-Related Changes in Cognitive Function From Early Adulthood to Late Midlife in 5162 Danish Men

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“Introduction: Cannabis is by far the most widely used and abused drug listed on the Drug Enforcement Administration’s Schedule I, which includes drugs with a high potential for abuse. There is evidence of short-term negative effects of cannabis use on cognition, but only a limited number of studies have explored the association between cannabis use and age-related cognitive decline. The aim of the present study was to investigate the relationship between cannabis use and age-related cognitive decline from early adulthood to late midlife.

Methods: The study population consisted of 5162 men who had participated in Danish follow-up studies on cognitive aging. These studies included scores on the military intelligence test Børge Prien’s Prøve from both the conscription assessment (mean age = 20 years; p1 and p99: 18 and 26 years) and from the follow-up (mean age = 64 years; p1 and p99: 55 and 72 years) as well as extensive data on lifestyle and health from the follow-up questionnaires. The association between cannabis use and age-related cognitive decline was investigated in linear regression models.

Results: Men with a history of cannabis use had less cognitive decline from early adulthood to late midlife compared to men without a history of cannabis use. Among cannabis users, neither age of initiation of cannabis use nor frequent use was significantly associated with a greater age-related cognitive decline.

Discussion and conclusions: In a sample of more than 5000 men followed for a mean of 44 years, we found no significant harmful effects of cannabis use on age-related cognitive decline.”

https://pubmed.ncbi.nlm.nih.gov/39508467/

“In the present study, we aimed to investigate the relationship between cannabis use and age-related cognitive decline from early adulthood to late midlife. This study contributes to the sparse knowledge on this subject and aligns with most existing studies, suggesting no association between cannabis use and greater cognitive decline. More specifically, in the present study, cannabis users experienced slightly less cognitive decline compared to nonusers, and the association remained significant when controlling for potential confounders. Among cannabis users, no significant association was found with cognitive decline for either age of initiation of cannabis use or frequent cannabis use. Further studies are needed to investigate whether these findings reflect that there are no adverse effects on cognitive decline or that the effects of cannabis are temporary and disappear after a prolonged period of time.”

https://onlinelibrary.wiley.com/doi/10.1002/brb3.70136

Identification of Cannabidiolic and Cannabigerolic Acids as MTDL AChE, BuChE, and BACE-1 Inhibitors Against Alzheimer’s Disease by In Silico, In Vitro, and In Vivo Studies

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“Cannabidiolic (CBDA) and cannabigerolic (CBGA) acids are naturally occurring compounds from Cannabis sativa plant, previously identified by us as dual PPARα/γ agonists. Since the development of multitarget-directed ligands (MTDL) represents a valuable strategy to alleviate and slow down the progression of multifactorial diseases, we evaluated the potential ability of CBDA and CBGA to also inhibit enzymes involved in the modulation of the cholinergic tone and/or β-amyloid production.

A multidisciplinary approach based on computational and biochemical studies was pursued on selected enzymes, followed by behavioral and electrophysiological experiments in an AD mouse model. The β-arrestin assay on GPR109A and qPCR on TRPM7 were also carried out.

CBDA and CBGA are effective on both acetyl- and butyryl-cholinesterases (AChE/BuChE), as well as on β-secretase-1 (BACE-1) enzymes in a low micromolar range, and they also prevent aggregation of β-amyloid fibrils. Computational studies provided a rationale for the competitive (AChE) vs. noncompetitive (BuChE) inhibitory profile of the two ligands.

The repeated treatment with CBDA and CBGA (10 mg/kg, i.p.) improved the cognitive deficit induced by the β-amyloid peptide. A recovery of the long-term potentiation in the hippocampus was observed, where the treatment with CBGA and CBDA also restored the physiological expression level of TRPM7, a receptor channel involved in neurodegenerative diseases. We also showed that these compounds do not stimulate GPR109A in β-arrestin assay.

Collectively, these data broaden the pharmacological profile of CBDA and CBGA and suggest their potential use as novel anti-AD MTDLs.”

https://pubmed.ncbi.nlm.nih.gov/39510547/

“In summary, we have shown that both CBDA and CBGA are endowed with a multitarget ligand profile, acting not only as dual PPARα/γ agonists but also as inhibitors of both cholinesterase and BACE-1 enzymes, and molecular targets are currently used in the AD therapy to show down the cognitive impairment associated to the disease, thus providing a rationale for their in vivo activity.”

https://onlinelibrary.wiley.com/doi/10.1002/ptr.8369

Boosting Acetylcholine Signaling by Cannabidiol in a Murine Model of Alzheimer’s Disease

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“Alzheimer’s disease (AD) is a challenging medical issue that requires efficacious treatment options to improve long-term quality of life.

Cannabidiol (CBD) is a cannabis-derived phytocannabinoid with potential health benefits, including reports from our laboratory and others showing a therapeutic role in the pre-clinical treatment of AD; however, the mechanisms whereby CBD affects AD progression remain undefined.

Innate lymphoid cells (ILCs) are recently discovered immune cells that initiate and orchestrate inflammatory responses. ILC2, a sub-class of ILCs, is proposed to have a role in cognitive function via unknown mechanisms. In this present study, we explored whether CBD ameliorates AD symptoms via the enhancement of acetylcholine (ACh), a cholinergic neurotransmitter involved in cognition that may regulate ILC2. 5xFAD mice were chronically treated by inhalation of a formulation of broad-spectrum CBD for seven months. ACh production, ILC2s profile, brain histopathology, and long-term behavior were assessed.

Together, our studies showed that long-term inhalation of CBD improved cognitive function and reduced senile plaques in a murine AD model, effects that were associated with enhanced ACh production and altered ILC2s distribution within the CNS.

These findings indicate that inhaled CBD could offer a cost-effective, non-invasive, and effective treatment for managing AD. The beneficial effects of CBD inhalation may be linked to increased ACh production and an altered distribution of ILC2s, highlighting the need for further research in this area.”

https://pubmed.ncbi.nlm.nih.gov/39519315/

https://www.mdpi.com/1422-0067/25/21/11764