Category Archives: Endocannabinoid System

Innovations in Cannabis Delivery Systems: A Patent Review (2012-2024)

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“Introduction: Cannabis sativa has been cultivated for over 11,700 years, originating in Central and Southeast Asia, and has been used for medical, recreational, and religious purposes. Among its therapeutic potentials, it is notable for its capacity to alleviate pain, nausea, anxiety, and more. The plant’s primary secondary metabolites are cannabinoids, which interact with the endocannabinoid system to produce these effects. However, due to the dosage variability and the secondary effects associated with a lack of targeted action, their medical use is limited, creating the need for effective delivery systems.

Methodology: This systematic patent review on cannabis drug delivery systems was conducted using patents retrieved from the Espacenet database. The search employed the keywords “Cannabis” and “Delivery,” along with the IPC classification code A61, to filter patents filed between 2012 and 2024. This initial search yielded 99 patents, which were further screened to identify 15 patents that met the inclusion criteria.

Results: Of the selected patents, most originated from the United States, followed by Canada, international patents (WIPO), and China. A notable increase in patent filings occurred in 2022, coinciding with the peak in scientific publications on the topic. This trend indicates a growing interest in the design of cannabis delivery systems.

Discussion: The historical importance and therapeutic potential of Cannabis sativa are welldocumented, yet modern medical use remains restricted due to pharmacokinetic limitations. Delivery systems such as extracellular vesicles, microneedles, and emulsions have been developed to improve the bioavailability and stability of cannabinoids. Extracellular vesicles facilitate targeted, noninvasive delivery of cannabinoids to the central nervous system. Microneedles offer a painless method for transdermal administration, overcoming skin barrier limitations. Emulsions improve the solubility and bioavailability of lipophilic cannabinoids, making them suitable for various administration routes.

Conclusion: Since 2012, there has been considerable growth in patents and publications related to cannabis drug delivery systems, driven by the therapeutic potential of cannabinoids. Innovations in delivery systems like emulsions, microneedles, and extracellular vesicles aim to improve the pharmacokinetics and therapeutic efficacy of cannabis-derived compounds, representing a shift towards medical cannabis applications.”

https://pubmed.ncbi.nlm.nih.gov/40454502/

https://www.eurekaselect.com/article/148648

Role of Endocannabinoids in Glaucoma: A Review

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“Aims: A review of the published literature was done to understand the role of endocannabinoids in glaucoma.

Background: As evidence mounts that intraocular pressure (IOP) is not the only factor in the pathogenesis and progression of glaucoma, a look into other aspects is the need of the hour. From the first instance of a drop in IOP linked to marijuana in the 1970s to the present, research has been ongoing, mostly in animals and in vitro models, with a scarcity of human studies, to delve into the world of the endocannabinoid system (ECS).

Methods: PubMed, ScienceDirect, and Google Scholar were searched for studies relating to endocannabinoids and their role in glaucoma.

Results: The ECS comprises ligands, receptors, and the synthesizing and degrading enzymes and is ubiquitous throughout the human body, including the visual system, from the eye to the occipital lobe. Apart from the IOP-lowering effect of the system, another property being investigated and implicated as an attribute of its receptors is neuroprotection. This neuroprotection seems to be mediated by excitotoxicity reduction and changes in vascular tone by acting on cannabinoid receptors.

Conclusion: The possibilities are indeed immense, and further research into the complex relationship between ECS and glaucoma is imperative to enable us to develop therapies for this otherwise chronic, progressive neuropathy, where the only armament in our hands is early diagnosis and maintenance therapy.

Clinical significance: We still do not have drugs for the prevention of retinal ganglion cell loss and for neuroprotection in glaucoma. Drugs that target cannabinoid receptors can revolutionize glaucoma management owing to their IOP-lowering action and neuroprotective effects. Based on the findings, we argue that further studies on the ECS and its implications in glaucoma are warranted to develop newer, effective, and better-targeted treatment strategies.”

https://pubmed.ncbi.nlm.nih.gov/40417140/

“Currently, no drugs can target the loss of RGCs in glaucoma.
Therefore, drugs that can target CB1 receptors can change the
course of glaucoma treatment, as they can exert hypotensive
and neuroprotective effects in conjunction.”

https://www.jocgp.com/doi/pdf/10.5005/jp-journals-10078-1467

The endocannabinoid system regulates both ependymoglial and neuronal cell responses to a tail amputation in the axolotl

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“Background: The endocannabinoid system is a neuromodulatory system implicated in cellular processes during both development and regeneration. The Mexican axolotl, one of only a few vertebrates capable of central nervous system regeneration, was used to examine the role of the endocannabinoid system in the regeneration of the tail and spinal cord following amputation.

Results: The endocannabinoid receptor CB1 was upregulated in the regenerating axolotl spinal cord by 4 hours following tail amputation, and this upregulation persisted for at least 14 days. The endocannabinoid receptor CB2 was upregulated later, between 7 and 14 days after tail amputation. Both CB1 and CB2 were located in ependymoglia and neurons within the regenerating spinal cord. Treatment with inverse agonists to inhibit CB1 (AM251) or CB2 (AM630) inhibited spinal cord and tail regeneration. During the first 7 days after injury, CB1 and CB2 expression was also necessary for the proliferation of ependymoglial cells and the regeneration of axons into the newly regenerated tail tissue. However, only CB1 was necessary for the differentiation of ependymoglia into immature neurons.

Conclusions: These studies are the first to examine the role of the endocannabinoid system during spinal cord regeneration in a regeneration-competent vertebrate.”

https://pubmed.ncbi.nlm.nih.gov/40377265/

“In summary, we provide evidence that CB1 and CB2 receptors are present in both ependymoglia and neurons of the regenerating axolotl spinal cord, and may play an essential role in creating a permissive environment for spinal cord regeneration in this vertebrate species. More specifically, the endocannabinoid receptors may regulate the proliferation and differentiation of ependymoglial cells into immature neurons, prevent glial scar formation, and promote regenerating axon elongation. In the future, it will be important to examine the role of the endocannabinoid system in interactions between neurons and the ependymoglia and in conjunction with other important signaling pathways important for the ependymoglial responses to trauma, and/or their regulation of microglia in the regenerating axolotl spinal cord.”

https://anatomypubs.onlinelibrary.wiley.com/doi/10.1002/dvdy.70035

Targeting the Gut-Brain Axis with Plant-Derived Essential Oils: Phytocannabinoids and Beyond

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“Background: The gut-brain axis (GBA) is a complex bidirectional communication system that links the gastrointestinal tract and the central nervous system. Essential oils (EOs) have emerged as promising natural compounds capable of modulating this axis. 

Methods: A comprehensive analysis of the recent literature was conducted, focusing on studies investigating the effects of EOs on the GBA.

Particular attention was given to the endocannabinoid system, the role of cannabis-derived EOs, and other plant-based EOs with potential neuroprotective and gut microbiota-modulating effects. 

Results: Among the EOs analyzed, cannabis essential oil (CEO) gained attention for its interaction with cannabinoid receptors (CBR1 and CBR2), modulating gut motility, immune responses, and neurotransmission. While acute administration of the CEO reduces inflammation and gut permeability, chronic use has been associated with alterations in gut microbiota composition, potentially impairing cognitive function. Other EOs, such as those from rosemary, lavender, eucalyptus, and oregano, demonstrated effects on neurotransmitter modulation, gut microbiota balance, and neuroinflammation, supporting their potential therapeutic applications in GBA-related disorders. 

Conclusions: EOs demonstrate promising potential in modulating the GBA through mechanisms including neurotransmitter regulation, gut microbiota modulation, and anti-inflammatory activity. At the same time, phytocannabinoids offer therapeutic value; their long-term use warrants caution due to potential impacts on microbiota. Future research should aim to identify EO-based interventions that can synergistically restore GBA homeostasis and mitigate neurodegenerative and gastrointestinal disorders.”

https://pubmed.ncbi.nlm.nih.gov/40362887/

https://www.mdpi.com/2072-6643/17/9/1578

The Impact of Major and Minor Phytocannabinoids on the Maintenance and Function of INS-1 β-Cells Under High-Glucose and High-Lipid Conditions

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“Type 2 diabetes mellites (T2DM) is the most common form of diabetes and affects a significant portion of the population. Obesity-related increases in free fatty acids and glucose in the diet contribute to β-cell dysfunction and loss, ultimately leading to the onset of T2DM.

The endocannabinoid system, which is present throughout the body, plays a vital role in regulating various physiological processes, including those in the pancreas. This system has been implicated in metabolic disorders like obesity and diabetes, as it helps to regulate appetite, food intake, and fat production.

Phytocannabinoids from Cannabis sativa have the potential to influence the endocannabinoid system, offering a promising therapeutic approach for diabetes and its complications.

Using high-glucose-high-lipid (HGHL)-induced INS-1 β-cells, we investigated the protective effects of two major (THC and CBD) and three minor (THCV, CBC, and CBG) phytocannabinoids on high glucose-high lipid (HGHL)-induced apoptosis, cell cycle disruption, and impaired function of beta-cells.

Our results showed that all five phytocannabinoids reduced HGHL-induced apoptosis, likely by decreasing TXNIP protein levels. Additionally, THC and all three minor phytocannabinoids provided protective effects against functional impairments caused by HGHL exposure.”

https://pubmed.ncbi.nlm.nih.gov/40363798/

“Our findings demonstrate that all five phytocannabinoids tested effectively mitigate high-glucose–high-lipid (HGHL)-induced apoptosis in INS-1 β-cells, primarily through their mitigatory effects on thioredoxin-interacting protein (TXNIP). Among the tested compounds, THC exhibited the most pronounced impact on reducing TXNIP levels and apoptotic biomarkers, suggesting that THC may be the most promising candidate for counteracting oxidative stress and apoptosis in HGHL-induced β-cells.”

https://www.mdpi.com/1420-3049/30/9/1991

In Vitro Immunomodulatory Effects of Equine Adipose Tissue-Derived Mesenchymal Stem Cells Primed with a Cannabidiol-Rich Extract

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“Cell-based therapy using mesenchymal stem cells (MSCs) shows promise for treating several diseases due to their anti-inflammatory and immunomodulatory properties. To enhance the therapeutic potential of MSCs, in vitro priming strategies have been explored.

Cannabidiol (CBD), a non-psychoactive compound derived from cannabis, may influence MSC proliferation, differentiation, and immunomodulatory properties. This study evaluates the immunomodulatory potential of equine adipose tissue-derived MSCs (EqAT-MSCs) primed with a CBD-rich cannabis extract.

EqAT-MSCs (P3) were primed with CBD concentrations of 5 µM and 7 µM for 24 h. Morphological analysis, MTT assay, β-galactosidase activity, apoptosis assays, and gene expression of interleukins IL-1β, IL-6, IL-10, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) were conducted. Additionally, cannabinoid receptor 1 (CB1) and 2 (CB2) expression were evaluated in naïve EqAT-MSCs (P2-P5). The naïve EqAT-MSCs expressed CB1 and CB2 receptors. Priming with 5 µM significantly increased the expression of IL-10, TNF-α, and IFN-γ, while 7 µM decreased IL-1β and IL-6 expression. No significant changes were observed in other cytokines, MTT, β-galactosidase activity, or apoptosis.

These findings demonstrate that naïve EqAT-MSCs express CB1 and CB2 receptors and priming with the extract modulates the expression of pro- and anti-inflammatory cytokines, highlighting its potential immunomodulatory role in EqAT-MSC-based therapies.”

https://pubmed.ncbi.nlm.nih.gov/40362445/

https://www.mdpi.com/1422-0067/26/9/4208

Adult Neurogenesis Is Regulated by the Endocannabinoid and Kisspeptin Systems

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“Neurogenesis is considered the most robust form of plasticity in the adult brain. To better decipher this process, we evaluated the potential crosstalk of Kisspeptin and Endocannabinoid Systems (KPS and ECS, respectively) on hippocampal neurogenesis.

Male adolescent rats were exposed to kisspeptin-10 (KP10) and the endocannabinoid anandamide (AEA) administered alone or in combination with the type 1 cannabinoid receptor (CB1R) antagonist SR141716A. The expression of Kiss1 and Kisspeptin receptor (Kiss1R) has been characterized for the first time in rat hippocampus together with the expression of the CB1R and the Transient Receptor Potential Vanilloid 1 ion channel receptor (TRPV1).

Results show that both systems inhibit neurogenesis by reducing the extracellular signal-regulated kinase (ERK) signaling. Despite little differences in the expression of Kiss1R and CB1R, TRPV1 is enhanced by both KP10 and AEA treatments, suggesting TRPV1 as a common thread. KP10 administration reduces CB1R expression in the dentate gyrus, while AEA does not. KPS, unlike ECS, promotes the expression of estrogen receptor α (ER-α) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), also upregulating sirtuin 1 (SIRT1), brain-derived-neurotrophic factor (BDNF), and c-Jun.

These findings suggest that the interaction between ECS and KPS could be involved in the fine-tuning of neurogenesis, highlighting a novel role for KPS.”

https://pubmed.ncbi.nlm.nih.gov/40362219/

https://www.mdpi.com/1422-0067/26/9/3977

Nucleolar sequestration of cannabinoid type-2 receptors in triple-negative breast cancer cells

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“Multiple investigations have shown that the different types of cannabinoids, phytocannabinoids, synthetic cannabinoids, and endocannabinoids, possess antiproliferative and anticancer properties.

The cannabinoid type-2 receptor (CB2R) has been proposed as a central player in tumor progression and has been correlated with the aggressiveness of breast cancer. Using immunocytochemistry and confocal microscopy, in the present work, we studied the expression level and subcellular localization of CB2R in two human triple-negative breast cancer (TNBC) cell lines, corresponding to early (stage I, HCC-1395) and metastatic (MDA-MB-231) stages, and they were compared with a non-tumoral mammary epithelial cell line (MCF-10A).

We found that although CB2R was detected at the plasma membrane, it was mainly localized intracellularly, with ~40-fold higher expression in both TNBC cell lines than in MCF-10A (P < 0.0001). Notably, double staining with DAPI or with the nucleoli-specific fluorescent marker (3xnls-mTurquoise2) showed that most of the CB2R overexpressed in the nucleoli of cancer cells.

This finding is supported by the fact that CB2R expression was markedly lower in mitotic cells compared to interphase cells (P < 0.0001). Interestingly, exposure of cancer cells to the specific agonist HU-308 reversed the nucleolar sequestration of CB2R while increasing the presence of the receptor in the nucleoplasm and cytoplasm (P < 0.0001). In addition, we found that this agonist reduced both the cell migration (P < 0.05-0.0001) and proliferation (P < 0.001) of TNBC cells. It remains to determine the function and signaling ability of CB2R in the nucleolus.

Although our study only includes cell lines (tumoral and non-tumoral), we consider that this feature of nucleolar sequestration of CB2R could be a potential diagnostic marker for TNBC from the early stage.”

https://pubmed.ncbi.nlm.nih.gov/40359210/

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0323554

In Vivo and In Vitro Crosstalk Among CBD, Aβ, and Endocannabinoid System Enzymes and Receptors

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“Cannabidiol (CBD), a non-psychotropic compound derived from Cannabis sativa, has garnered attention as a potential therapeutic agent for various neurodegenerative diseases, including Alzheimer’s disease (AD).

Despite growing interest, additional research is required to clarify the specific mechanisms by which CBD influences the pathological accumulation of β-amyloid (Aβ) associated with AD. Moreover, the interactions between CBD and the endocannabinoid system (ECS), both in the presence and absence of Aβ expression, remain a subject of active investigation.

Elucidating these mechanisms may provide valuable insights for advancing both our understanding and the development of targeted interventions in neurodegenerative disease management. Using a multifaceted approach that integrates pharmacological interventions, immunofluorescence imaging, flow cytometry, and biochemical assays, we examined the effects of CBD on Aβ40 and Aβ42. Additionally, we analyzed the modulation of cannabinoid receptor 1(CB1 receptor) and fatty acid amide hydrolase (FAAH) in the presence or absence of Aβ expression, uncovering the intricate regulatory mechanisms of CBD.

Our findings indicate a nuanced response to CBD; while it may produce side effects in non-pathological cells, it demonstrates an ability to induce autophagy and apoptosis in Aβ-expressing cells via the activation of the Microtubule-associated protein 1 light chain 3 B(LC3B) and Caspase-3 pathways. Furthermore, our investigation into faah-1 involvement highlighted its role in alleviating pharyngeal dysfunction and counteracting weight loss in Aβ-expressing Caenorhabditis elegans(C. elegans) strains. These insights advance our understanding of CBD’s therapeutic potential in addressing neurodegenerative pathologies.”

https://pubmed.ncbi.nlm.nih.gov/40350019/

https://www.sciencedirect.com/science/article/abs/pii/S0014299925004741?via%3Dihub

Efficacy of a Neuroimmune Therapy Including Pineal Methoxyindoles, Angiotensin 1-7, and Endocannabinoids in Cancer, Autoimmune, and Neurodegenerative Diseases

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“Purpose: Recent advancements in psycho-neuro-endocrine-immunology indicate that numerous noncommunicable diseases (NCDs) originate from disruptions in the cytokine immune network, resulting in chronic inflammatory responses. This persistent low-degree inflammation is attributed to deficiencies in crucial endogenous anti-inflammatory neuroendocrine systems, including the pineal gland, the endocannabinoid system, and the angiotensin-converting enzyme 2 / angiotensin 1-7 axis.

The administration of pineal methoxyindoles (melatonin, 5-methoxytryptamine), cannabinoids, and angiotensin 1-7 may entail potential therapeutic benefits for NCDs, particularly for patients who do not respond to conventional treatments.

Patients and methods: This study evaluates the safety and efficacy of a neuroimmune regimen comprising melatonin (100 mg/day at night), 5-methoxytryptamine (30 mg in the early afternoon), angiotensin 1-7 (0.5 mg twice daily), and cannabidiol (20 mg twice daily) in 306 patients with NCDs, including advanced cancer, autoimmune diseases, neurodegenerative disorders, depression, and cardiovascular disease.

Results: The neuroimmune regimen successfully halted cancer progression in 68% of cancer patients, who also reported improvements in mood, sleep, and relief from anxiety, pain, and fatigue. In patients with autoimmune diseases, the treatment effectively controlled the disease process, remarkable in cases of multiple sclerosis. Additionally, positive outcomes were observed in patients with Parkinson’s disease, Alzheimer’s disease, and depression.

Conclusion: Randomized controlled trials are required to assess this therapeutic approach for NCDs that includes endogenous neuroendocrine molecules regulating immune responses in an anti-inflammatory manner.”

https://pubmed.ncbi.nlm.nih.gov/40330271/

“This study highlights the potential of leveraging endogenous molecules to treat NCDs by modulating cell proliferation, inflammation, immune responses, metabolism, and neurological functions. The findings suggest that a neuroimmune regimen incorporating melatonin, angiotensin 1–7, and other bioactive compounds could offer a low-cost, minimally toxic therapeutic approach.”

https://www.dovepress.com/efficacy-of-a-neuroimmune-therapy-including-pineal-methoxyindoles-angi-peer-reviewed-fulltext-article-CIA