The endocannabinoidomes: Pharmacological redundancy and promiscuity, and multi-kingdom variety of sources and molecular targets

Posted on by
Reply
pubmed logo

“The endocannabinoid system (eCB) is a complex signaling network discovered in mammals during the 1980s-1990s.

It conventionally revolves around two arachidonic acid-derived mediators, N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoyl-glycerol; their main receptors, the cannabinoid receptors of type 1 (CB1) and type 2 (CB2), and the transient receptor potential vanilloid-1 channels; and the enzymes responsible for their biosynthesis and degradation. However, drawing on these discoveries, numerous eCB-like signaling lipids beyond the classical eCBs, have been unveiled, together with their receptors and metabolic enzymes, thus forming a more complex signaling network known as the endocannabinoidome (eCBome).

This review explores the physiology, pharmacological complexity, and molecular targets of the mammalian eCBome, highlighting its versatility and redundancy in the context of global health. Emerging mediators, metabolic pathways and mechanisms, receptors, and their implications in human physiology and pathology are described, particularly concerning metabolic disorders, pain, inflammation, neurodegenerative diseases, and cancer.

The importance of other “eCBomes” in nonmammalian forms of life that constitute the external and internal environments of mammals is also discussed for the first time in this context. The overarching objective of this article is to gain insights into the potential of eCBome-based therapeutic strategies aimed at enhancing both human and environmental well-being.

SIGNIFICANCE STATEMENT: Lipid-based signaling molecules are ubiquitous in nature, yet their study remains challenging due to intricate regulatory mechanisms. Among lipid signaling pathways, the endocannabinoid (eCB) system and its extended version, the endocannabinoidome (eCBome), are particularly remarkable. Comprising hundreds of mediators, and dozens of receptors and metabolic enzymes, the eCBome regulates critical physiological processes not only in mammals but also across diverse organisms, including plants, fungi, and bacteria. This article examines the evolutionary and functional diversity of eCBomes and highlights their untapped potential as multikingdom therapeutic targets to address pressing challenges in global health.”

https://pubmed.ncbi.nlm.nih.gov/40554266/

https://pharmrev.aspetjournals.org/article/S0031-6997(25)07478-2/abstract

Graphical abstract undfig1

Δ9-Tetrahydrocannabinol and cannabidiol selectively suppress toll-like receptor (TLR) 7- and TLR8-mediated interleukin-1β production by human CD16+ monocytes by inhibiting its post-translational maturation

Posted on by
Reply
pubmed logo

“Monocytes are innate immune cells that release inflammatory factors upon detection of infectious and injurious stimuli. CD16+ monocytes, a subset of the total monocyte population, are associated with acute and chronic inflammation in human immunodeficiency virus-associated neurocognitive disorder and rheumatoid arthritis. Given the role monocytes play in regulating the host immune response, this investigation explored the effects of cannabinoids on the monocyte secretome for potential therapeutic applications.

Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are major cannabis-derived compounds established to have immune-modulating properties. Despite a rise in medical cannabis use, the specific mechanism by which THC and CBD modulate the inflammatory response, including by human monocytes remains poorly understood.

We hypothesized that THC and CBD suppress toll-like receptor (TLR) 7- or TLR8-induced inflammatory profiles by CD16+ and CD16– monocytes, specifically interleukin (IL) 1β maturation. Cannabinoid receptor 2 selective agonist, JWH-015, was used to deduce whether cannabinoid receptor 2 signaling alone can mimic immune-modulating properties of THC. Primary human CD16+ and CD16– monocytes were pretreated with THC, CBD, or JWH-015 and then activated through TLR7 or TLR8. Activated monocytes mainly produced IL-1β, tumor necrosis factor-⍺, and IL-6.

We show that THC and CBD, but not JWH-015, exert anti-inflammatory effects on primary human monocyte apoptosis-associated speck-like protein-incorporating inflammasome formation and subsequent caspase-1 activity, contributing to suppressed IL-1β production. In addition, mRNA expression of IL1B, CASP1, NLRP3, and PYCARD were unaffected by THC. Minimal THC effects were observed on TLR8-mediated AIM2 mRNA expression.

Collectively, results from these studies suggest THC and CBD may be useful in mitigating IL-1β-mediated acute or chronic inflammation.

SIGNIFICANCE STATEMENT: This current investigation aimed to understand the role of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in mediating virally activated CD16+ monocyte inflammatory cytokine production. Further, the results indicated that THC and CBD selectively suppress monocyte interleukin 1β production, though THC is more efficacious, through its maturation, as evidenced by suppressed caspase-1 activity and apoptosis-associated speck-like protein-incorporating inflammasome formation.

This work provides evidence to support that THC, and to an extent CBD, exert anti-inflammatory effects that could be useful in mitigating monocyte interleukin 1β-mediated chronic inflammation.”

https://pubmed.ncbi.nlm.nih.gov/40553974/

https://jpet.aspetjournals.org/article/S0022-3565(25)39828-9/abstract

Effect of Cannabidiol and Δ9-tetrahydrocannabinol on Anti-Inflammatory Lipid Mediator Synthesis in Humans

Posted on by
Reply
pubmed logo

“Background: Eicosanoids-lipid mediators derived from polyunsaturated fatty acids such as arachidonic acid-have a notable role in inflammatory signaling. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) have been shown in preclinical studies to modulate inflammatory pathways the modulating the enzymes that generate eicosanoids, namely lipoxygenase (LOX), cyclooxygenase (COX), and cytochrome P450 (CYP450). 

Methods: This present study aimed to investigate how CBD and THC effect plasma levels of eicosanoids generated through LOX, COX, and cytochrome P450 (CYP450) pathways. Using plasma sample data from multiple clinical studies, we tested the hypothesis that high-CBD cannabis use would increase eicosanoid levels compared with high-THC cannabis. 

Results: Following cannabis use, high-CBD cannabis led to a rise in plasma eicosanoids, particularly lipoxins, while high-THC cannabis did not. 

Conclusions: CBD promoted anti-inflammatory eicosanoid production via the 15-LOX pathway, therefore supporting the potential role of CBD as a therapeutic candidate for inflammatory diseases.”

https://pubmed.ncbi.nlm.nih.gov/40552985/

https://www.liebertpub.com/doi/10.1089/can.2024.0175

Is highly purified cannabidiol a treatment opportunity for drug-resistant epilepsy in subjects with typical Rett syndrome and CDKL5 deficiency disorder?

Posted on by
Reply
pubmed logo

“Objective: This study aimed to evaluate the efficacy and safety of adjunctive, highly purified Cannabidiol (Epidiolex®) in individuals with drug-resistant epilepsy (DRE) due to genetically determined typical Rett Syndrome (RTT) and CDKL5 Deficiency Disorder (CDD).

Methods: We recruited subjects with genetically confirmed typical RTT and CDD with drug-resistant seizures who received add-on treatment with highly purified Cannabidiol (CBD) through a national collaboration group. CBD treatment was titrated from 5 to 20 mg/kg/day; concurrent antiseizure medications (ASMs) could have been adjusted as clinically indicated.

Results: We enrolled 27 subjects (26 females), carrying a MECP2 genetic variant (14 subjects, 51.9%) or a CDKL5 genetic variant (13 subjects, 48.1%). Median age [IRQ] of individuals was 10.5 [7.9, 18.5] years. The median dose of CBD [IRQ] at last follow-up was 15 [11.12, 18.8] mg/kg/day, in association with a mean of 3 ASMs (range 2-4). The median duration of treatment was 14 [8.5, 20] months. Although not reaching a significant statistical effect, CBD reduced the incidence of seizures with respect to the baseline in 18/27 (66.6%) subjects, with 7 (25.9%) showing a seizure reduction >75%, and 11 (40.7%) >50%. The most relevant adverse events were somnolence seen in 3 subjects, irritability/agitation in 2 subjects, loss of appetite in 2 subjects, and insomnia in 1 individual. Caregivers reported an improvement in attention and reactivity in 12 subjects (44.4%), in sleep quality in 5 subjects (18.5%), and in motor aspects in 3 patients (11.1%).

Significance: CBD resulted effective in reducing seizure frequency in 66.6% of the study sample, regardless of the pathogenic variant; side effects were mild, and caregivers reported an improvement in behavioral and motor features.

Plain language summary: This study explored the use of highly purified Cannabidiol (CBD, Epidiolex®) as an add-on therapy for individuals with drug-resistant epilepsy due to Rett Syndrome (RTT) or CDKL5 Deficiency Disorder (CDD). Twenty-seven participants received CBD alongside their usual ASMs. After a median treatment duration of 14 months, 66.6% experienced fewer seizures, with some showing over 75% reduction. Side effects were generally mild, mainly sleepiness or irritability. Notably, caregivers reported improvements in attention, responsiveness, sleep, and motor function. While results were not statistically significant, they suggest CBD may benefit seizure control and quality of life in RTT and CDD patients.”

https://pubmed.ncbi.nlm.nih.gov/40543048/

“Many caregivers observed positive changes beyond seizure control, including better attention, improved sleep, and enhanced motor function.”

https://onlinelibrary.wiley.com/doi/10.1002/epi4.70078

The effect of cannabidiol on neurometabolite levels in alcohol use disorder

Posted on by
Reply
pubmed logo

“Background and aims: Preclinical research demonstrates that cannabidiol (CBD) attenuates alcohol-seeking behaviour and may have a neuroprotective effect against adverse alcohol consequences on the brain. This preliminary clinical study aimed to examine the effect of CBD on modulating neurometabolites in individuals with Alcohol Use Disorder (AUD).

Methods: Twenty-two non-treatment seeking participants were randomized to receive 800 mg CBD or matched placebo/day in a crossover double-blind, randomized trial. Presence of GABA+, NAA, Glx, Cho, and glutathione (GSH) in the dorsal anterior cingulate cortex was measured using in vivo proton magnetic resonance spectroscopy (1H-MRS) in each session.

Results: There were no significant treatment effects across each of the neurometabolites (p’s ≥ .28) but post hoc analyses revealed significant treatment effects when considering recent alcohol consumption. Specifically, CBD sessions were associated with significantly higher GSH (P < .001) and GLx (p = .001) concentrations relative to placebo sessions for participants who consumed alcohol the previous day while this effect was not observed in those who were abstinent. Similarly, GABA concentrations were significantly higher during CBD sessions and lower during placebo sessions for participants who consumed alcohol the previous day and this relationship was not observed for individuals who were abstinent the previous day (P = .0024).

Conclusion: The effect of CBD on modulating levels of neurometabolites may be contingent on recent alcohol consumption. These preliminary results suggest that CBD may regulate abnormal neurometabolite concentrations the day following alcohol consumption and thus may have a role in management of AUD.”

https://pubmed.ncbi.nlm.nih.gov/40551671/

Perceptions, Uses, and Information Sources of Medical Cannabis Among Patients With Cancer

Posted on by
Reply
pubmed logo

“Purpose: Although medical cannabis (MC) has been shown to relieve cancer- and treatment-related symptoms, there is increasing misinformation regarding its antitumor efficacy. We aimed to identify opportunities for oncologists to communicate evidence-based guidance to patients regarding its use.

Methods and materials: Patients with cancer seen in radiation oncology clinic between June 2022 and July 2023 were surveyed with a questionnaire regarding their perceptions and information sources of MC. Associations between survey responses and demographic and disease variables were evaluated. Qualitative thematic analysis was performed on narrative responses in search of common themes.

Results: Eighty-four patients (84% completion rate) were included in the analysis. Most (83.3%) strongly agreed or agreed that MC can provide symptom relief, whereas a subset of patients (15.5%) strongly agreed or agreed that MC can cure cancer. This latter subcohort was significantly more likely to identify as Hispanic/Latino (38.5% vs 9.9%, P = .009) and less likely to be up to date on COVID-19 vaccinations (30.8% vs 8.5%, P = 0.044). Identifying as Hispanic/Latino remained significantly associated with strongly agreeing or agreeing that MC can cure cancer on bivariate analysis (odds ratio, 6.528; 95% CI, 1.477-28.715; P = .012). Education level, other sociodemographic characteristics, and sources for information about MC were not significantly different between these patients. Thematic analysis revealed that patients hoped to learn more about MC from their oncologists but perceived them to be unknowledgeable on the subject.

Conclusions: Although most patients consider MC to be a valuable addition to conventional therapies for managing refractory symptoms, a subset believed it had potential as an anticancer therapy. Many patients rely on unregulated sources, highlighting the need for providers to address misinformation, bridge knowledge gaps, and clarify its use.”

https://pubmed.ncbi.nlm.nih.gov/40546850/

“Most patients (83.3%) strongly agreed or agreed that MC can provide symptom relief for cancer and treatment-related symptoms, whereas 15.5% strongly agreed or agreed that MC can cure cancer.”

https://www.advancesradonc.org/article/S2452-1094(24)00241-0/fulltext

Cannabidiol (CBD) as a potential therapeutic agent for liver cancer: a comprehensive review of current evidence

Posted on by
Reply
pubmed logo

“Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality with limited treatment options. Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has shown anticancer properties.

This review analyzes CBD’s therapeutic potential in HCC, focusing on mechanisms, preclinical/clinical findings, and integration into treatment strategies. A systematic search (PubMed, Scopus, Web of Science, Google Scholar) up to March 2025 identified 16 relevant studies (in vitro, in vivo, clinical).

CBD exerts antitumor effects via multiple pathways, including apoptosis, autophagy regulation, metastasis suppression, and tumor microenvironment modulation. CBD interacts with the endocannabinoid system (ECS), inhibits oncogenic signaling (PI3K/AKT/mTOR), and enhances chemotherapeutic efficacy (sorafenib, cabozantinib).

Studies show CBD induces pyroptosis via caspase-3/GSDME, and modulates autophagy by inhibiting the PI3K/Akt/mTOR pathway. It also sensitizes HCC cells to sorafenib and cabozantinib. Preclinical results are promising, but clinical studies are limited. Challenges like bioavailability and potential hepatotoxicity require investigation. Future research should optimize formulations, determine dosing, and conduct clinical trials to validate CBD’s efficacy/safety in HCC patients.

Validated CBD could offer an innovative HCC management option.”

https://pubmed.ncbi.nlm.nih.gov/40533744/

“Overall, while preclinical findings strongly support the therapeutic potential of CBD in HCC, robust clinical trials are urgently needed to confirm its efficacy, safety, optimal dosing strategies, and long-term effects. If validated, CBD could represent an innovative and complementary approach in the management of hepatocellular carcinoma.”

https://cancerci.biomedcentral.com/articles/10.1186/s12935-025-03870-3

Effectiveness of Full Spectrum Cannabis Extracts in the Treatment of Chronic Pain: An Open Label Study

Posted on by
Reply
pubmed logo

“The aim of this work was to assess the effectiveness of full-spectrum cannabis (THC and CBD) extracts as adjuvants in the treatment of chronic pain. This is a prospective, open label, longitudinal study.

Major cannabinoids were analyzed in herbal preparations using high performance liquid chromatography (HPLC). Subjects were included when chronic pain diagnosis criteria was met according to physicians’ diagnosis. A patient stratification protocol was developed using a visual analogue scale to measure pain, a numerical scale for life quality parameters and a self-administered health survey. Eighty-eight patients aged between 35 and 88 years were included.

A significant decrease in both pain and other life quality parameters was observed between time zero and subsequent time intervals, excepting the “appetite” variable.

Overall, 51 individuals reported a decrease in pain, 38 a decrease in anxiety and 48 in insomnia, with “decrease” defined as symptom reduction of 50% or more between the first and last consultation. In addition, 23 subjects reduced or discontinued other analgesics and/or anti-inflammatory drugs during the trial. Adverse effects were mild and reversible.

These results are consistent with previous studies, supporting effectiveness and safety of cannabis extracts as adjuvants in the treatment of chronic pain.”

https://pubmed.ncbi.nlm.nih.gov/40526158/

https://www.tandfonline.com/doi/full/10.1080/15360288.2025.2517778

Exploring Cannabis sativa L for Anti-Alzheimer Potential: An Extensive Computational Study including Molecular Docking, Molecular Dynamics, and ADMET Assessments

Posted on by
Reply
pubmed logo

“Introduction: Cholinesterase enzymes play a pivotal role in hydrolyzing acetylcholine, a neurotransmitter crucial for memory and cognition, into its components, acetic acid, and choline. A primary approach in addressing Alzheimer’s disease symptoms is by inhibiting the action of these enzymes.

Methods: With this context, our study embarked on a mission to pinpoint potential Cholinesterase (ChE) inhibitors using a comprehensive computational methodology. A total of 49 phytoconstituents derived from Cannabis sativa L underwent in silico screening via molecular docking, pharmacokinetic and pharmacotoxicological analysis, to evaluate their ability to inhibit cholinesterase enzymes. Out of these, two specific compounds, namely tetrahydrocannabivarin and Δ-9- tetrahydrocannabinol, belonging to cannabinoids, stood out as prospective therapeutic agents against Alzheimer’s due to their potential as cholinesterase inhibitors. These candidates showcased commendable binding affinities with the cholinesterase enzymes, highlighting their interaction with essential enzymatic residues.

Results: They were predicted to exhibit greater binding affinities than Rivastigmine and Galantamine. Their ADMET assessments further classified them as viable oral pharmaceutical drugs. They are not expected to induce any mutagenic or hepatotoxic effects and cannot produce skin sensitization. In addition, these phytoconstituents are predicted to be BBB permeable and can reach the central nervous system (CNS) and exert their therapeutic effects. To delve deeper, we explored molecular dynamics (MD) simulations to examine the stability of the complex formed between the best candidate (Δ-9-tetrahydrocannabinol) and the target proteins under simulated biological conditions. The MD study affirmed that the ligand-ChE recognition is a spontaneous reaction leading to stable complexes.

Conclusion: Our research outcomes provide valuable insights, offering a clear direction for the pharmaceutical sector in the pursuit of effective anti-Alzheimer treatments.”

https://pubmed.ncbi.nlm.nih.gov/40525419/

https://www.eurekaselect.com/article/142967

Hemp-Derived Iron Oxide Nanoparticles for Biomedical Applications: Synthesis, Characterization, and Therapeutic Potential

Posted on by
Reply
pubmed logo

“Iron oxide nanoparticles (IONPs) have emerged as the most widely synthesized metal nanoparticles in sustainable chemistry due to their unique magnetic properties, excellent biocompatibility, biodegradability, and non-toxicity.

In this study, IONPs are successfully synthesized via a rapid, sustainable, and environmentally friendly green synthesis approach using Cannabis sativa L. leaf extract. X-ray diffraction analysis determined that the synthesized NPs had an average particle size of 18.8 nm, while transmission electron microscopy images reveal a spherical morphology with sizes ranging from 12 to 21 nm.

Fourier-transform infrared spectroscopy analysis confirmed the presence of cannabinoids, terpenoids, and flavonoids, which are believed to play a crucial role in the formation and stabilization of IONPs. Its photocatalytic potential is demonstrated through the degradation of bromophenol blue dye.

Additionally, the NPs exhibited significant antibacterial and antifungal activity against various microbial species, along with promising anticancer effects on cancer cell lines.

In conclusion, this study provides a promising foundation for advancing the large-scale, commercial production of IONPs through green synthesis methods. By offering an eco-friendly and efficient alternative to conventional nanoparticle synthesis, the findings contribute significantly to the growing body of research in sustainable nanotechnology.”

https://pubmed.ncbi.nlm.nih.gov/40525672/

“In this study, IONPs were successfully synthesized via a single-step green approach using C. sativa leaf extract as the sole reducing and stabilizing agent, eliminating the need for secondary chemicals. Collectively, these findings underscore the potential of eco-friendly IONPs for biomedical and environmental applications, aligning with sustainable nanotechnology paradigms.”

https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/open.202500189