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Real-Time Optical Control of CB1 Receptor Signaling In Vitro with Tethered Photoswitchable (-)- trans-Δ9-Tetrahydrocannabinol Derivatives

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“Understanding the intricacies of the endocannabinoid system is hindered by the lack of tools to target specific pools of CB1 receptors (CB1Rs) across diverse neural circuits associated with mood, motor function, cognition, and other physiological processes.

Herein, we introduce the first photoswitchable, orthogonal remotely tethered cannabinoid ligand, PORTL-THC24, designed to achieve cell-specific and reversible control of CB1R signaling with high spatial and temporal resolution, thereby overcoming the limitations of conventional freely diffusible ligands.

PORTL-THC24 was selectively tethered to membrane-anchored SNAP-tags expressed in live cells, and provided reversible optical control of CB1R signaling when photoswitched by UV-A irradiation. We validated the functionality of PORTL-THC24 in live Neuro2a cells using a novel real-time cAMP imaging assay, demonstrating light-dependent and reversible modulation of endogenously expressed CB1R activity. Additionally, we demonstrated that SNAP-tethered PORTL-THC24 does not induce CB1R internalization, distinguishing it from conventional, freely diffusible agonists.

Our results establish PORTL-THC24 as a powerful tool for optical control of CB1R in a spatially restricted manner, setting the stage for dissecting CB1R function in complex settings and advancing the study of cannabinoid signaling across various physiological and pathological contexts.”

https://pubmed.ncbi.nlm.nih.gov/40586440/

https://pubs.acs.org/doi/10.1021/jacs.4c18379

Persistent cannabis use and ocular health in midlife

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“Introduction: Cannabis is widely used and becoming legal in many countries. While some acute ocular effects of cannabis are well-known (e.g., reduced intraocular pressure, vasodilation), little is known about the consequences of long-term cannabis use for ocular health. The aim of this study was to examine the association between persistent cannabis use across adulthood and measures of ocular health in midlife.

Methods: Participants were members of the Dunedin Study (n=1037), a longitudinal cohort followed since birth. Cannabis use has been measured by self-report at every assessment from age 18 to 45. Ocular health data were collected as part of a larger assessment at age 45 (2017-2019). Statistical analysis was performed in 2022.

Results: Cannabis use and ocular health data were obtained from 887 Study members. Generalised estimating equation analysis showed higher cannabis use was associated with poorer visual acuity, wider retinal arterioles and venules, and a thicker inferior hemifield of the ganglion cell-inner plexiform layer (GC-IPL). However, when controlling for tobacco smoking and socioeconomic status (known to be associated with these ocular health domains), the associations with visual acuity, arterioles, and venules were no longer significant. The association with GC-IPL remained significant in this adjusted model.

Conclusions: Persistent cannabis use appears to be neither harmful nor beneficial to the eye at age 45, although the thicker inferior GC-IPL hemifield in users of cannabis suggests biologically plausible neuroprotection. Further assessments as this cohort ages will illuminate the relationship between persistent cannabis use and ocular neuroprotection.”

https://pubmed.ncbi.nlm.nih.gov/40570990/

https://www.ajpmonline.org/article/S0749-3797(25)00446-5/abstract

Omega-3 Fatty Acids Mitigate Long-Lasting Disruption of the Endocannabinoid System in the Adult Mouse Hippocampus Following Adolescent Binge Drinking

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“Adolescent binge drinking has lasting behavioral consequences by disrupting the endocannabinoid system (ECS) and depleting brain omega-3.

The natural accumulation of omega-3 fatty acids in cell membranes is crucial for maintaining the membrane structure, supporting interactions with the ECS, and restoring synaptic plasticity and cognition impaired by prenatal ethanol (EtOH) exposure. However, it remains unclear whether omega-3 supplementation can mitigate the long-term effects on the ECS, endocannabinoid-dependent synaptic plasticity, and cognition following adolescent binge drinking.

Here, we demonstrated that omega-3 supplementation during EtOH withdrawal increases CB1 receptors in hippocampal presynaptic terminals of male mice, along with the recovery of receptor-stimulated [35S]GTPγS binding to Gαi/o proteins. These changes are associated with long-term potentiation (LTP) at excitatory medial perforant path (MPP) synapses in the dentate gyrus (DG), which depends on anandamide (AEA), transient receptor potential vanilloid 1 (TRPV1), and N-methyl-D-aspartate (NMDA) receptors. Finally, omega-3 intake following binge drinking reduced the time and number of errors required to locate the escape box in the Barnes maze test.

Collectively, these findings suggest that omega-3 supplementation restores Barnes maze performance to levels comparable to those of control mice after adolescent binge drinking. This recovery is likely mediated by modulation of the hippocampal ECS, enhancing endocannabinoid-dependent excitatory synaptic plasticity.”

https://pubmed.ncbi.nlm.nih.gov/40564971/

“In summary, omega-3 intake mitigates some of the adverse effects of adolescent binge drinking on Barnes maze performance.”

“Omega-3 supplementation has also been shown to reverse synaptic plasticity impairments caused by prenatal EtOH exposure.”

https://www.mdpi.com/1422-0067/26/12/5507

“Hemp (Cannabis sativa L.) is a valuable source of omega-3 fatty acids.”

Assisted Extraction of Hemp Oil and Its Application to Design Functional Gluten-Free Bakery Foods

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“Cannabis sativa L. is known for its high-value compounds, like Cannabidiol (CBD) and Cannabidiolic Acid (CBDA). It is widely used in the pharmaceutical and food industries.

Different extraction methods, like Soxhlet and maceration, are commonly employed to obtain its extracts. High temperature and long extraction time can influence the yield and the purity of the extracts, affecting the quality of the final product.

This study focused on optimizing CBD oil extraction from hemp inflorescences and its incorporation into a gluten-free bakery product for functionalization.

Dynamic maceration (DME), assisted by ultrasound and microwave irradiation, was used. Our study explored the impact of varying sonication times (three distinct durations) and microwave powers (three levels, applied for two different irradiation times) on the resulting extracts. HPLC analysis was performed on these extracts. Subsequently, we used hemp flour and hemp oil to bake gluten-free cupcakes, which were fortified with the extracted CBD oil. Rheological characterization was used to investigate the cupcake properties, along with stereoscopic, color and puncture analysis performed on the baked samples.

The most effective extraction parameters identified were 30 s of microwave irradiation at 700 W, yielding 45.2 ± 2.0 g of CBD extract, and 15 min of sonication, which resulted in 53.2 ± 2.5 g. Subsequent rheological characterization indicated that the product exhibited mechanical properties and a temperature profile comparable to a benchmark, evidenced by a height of 4.1 ± 0.2 cm and a hardness of 1.9 ± 0.2 N.

These promising values demonstrate that hemp oil and hemp flour are viable ingredients for traditional cakes and desserts, notably contributing increased nutritional value through the CBD-enriched hemp oil and the beneficial profile of hemp flour.”

https://pubmed.ncbi.nlm.nih.gov/40572627/

“In conclusion, our findings demonstrate that dynamic maceration assisted by ultrasound and microwave irradiation is an efficient method for extracting CBD-rich oil. Furthermore, hemp oil presents a viable alternative to traditional oils and fats for creating functional foods.”

https://www.mdpi.com/1420-3049/30/12/2665

[Cannabidiol inhibits neuronal endoplasmic reticulum stress and apoptosis in rats with multiple concussions by regulating the PERK-eIF2α-ATF4-CHOP pathway]

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“Objectives: To explore the effects of cannabidiol on endoplasmic reticulum stress and neuronal apoptosis in rats with multiple concussions (MCC).

Methods: SD rats were randomized into sham group, MCC group, 1% tween20 (TW) treatment group, and low-dose (10 mg/kg) and high-dose (40 mg/kg) cannabidiol treatment groups. In all but the sham group, MCC models were established using a metal pendulum percussion device, after which the rats received daily intraperitoneal injections of the corresponding agents for 2 weeks. The expressions of PERK, eIF2α, ATF4, CHOP, TRIB3, p-Akt and pro-caspase-3 in the brain tissue of the rats were detected with qRT-PCR, Western blotting and immunofluorescence staining. The core targets of cannabidiol in treatment of traumatic brain injury (TBI) were identified by network pharmacology analysis, and molecular docking was carried out to simulate the interaction of cannabidiol with the factors related to endoplasmic reticulum stress and apoptosis.

Results: Compared with the sham-operated rats, the rat models of MCC showed significantly increased mRNA expressions of PERK, eIF2α and CHOP and protein expressions of PERK, eIF2α, ATF4, CHOP, TRIB3, p-AKT and pro-caspase-3 in the cerebral cortex. CBD treatment, especially at the high dose, obviously increased the expression of p-Akt and lowered the expression levels of the other factors tested in the rat models. Network pharmacology analysis indicated interactions of the core targets of CBD with the factors related to endoplasmic reticulum stress and TBI, and molecular docking study showed a high binding energy of CBD with multiple factors pertaining to endoplasmic reticulum stress and apoptosis.

Conclusions: MCC induce endoplasmic reticulum stress and apoptosis in rat brain tissues, for which CBD, especially at a high dose, provides neuroprotective effects by inhibiting endoplasmic reticulum stress and cell apoptosis.”

https://pubmed.ncbi.nlm.nih.gov/40579137/

Cannabidiol Is a Potential Inhibitor of Ferroptosis in Human Articular Chondrocytes

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“The present study investigates the effects of cannabidiol (CBD), the major non-psychoactive compound of Cannabis sativa L. extracts, on ferroptotic cell death in human articular chondrocytes.

Exposure to known ferroptosis inducers RSL3, erastin and its analogue IKE, FINO2 and FIN56 led to a varying extent of reduced cell viability in two chondrocyte cell lines (in C-28/I2, T/C-28/A2) and primary chondrocytes, suggesting different sensitivity and defence mechanisms towards the respective substances. The cytotoxic effects were aggravated by additional exposure to iron and inhibited by the specific ferroptosis inhibitor ferrostatin-1 (Fer-1), proving the occurrence of ferroptosis.

Strikingly, co-treatment of ferroptosis inducers with CBD clearly restored cell viability in a dose-dependent manner (10 nM to 1 μM CBD) in both cell lines and primary chondrocytes. Moreover, CBD restored the activity of GPX4, a major anti-oxidative enzyme, to varying degrees when combined with IKE or RSL3. Increasing evidence has emerged for an important role of iron dyshomeostasis and ferroptosis in the onset and progression of various orthopaedic diseases, including osteoarthritis.

Therefore, the here demonstrated and previously unreported cytoprotective and anti-oxidative effects of CBD in the context of ferroptosis have highly promising therapeutic implications.”

https://pubmed.ncbi.nlm.nih.gov/40576283/

https://onlinelibrary.wiley.com/doi/10.1111/jcmm.70592

In vitro antimicrobial activity of Thai stick cannabis Hang Kra Rog Phu Phan (Cannabis sativa L.), sugar leaves extract against pathogenic bacteria

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“Objective: Cannabis sativa L. is aware of a rich source of bioactive substances with various structures that exhibit pharmacological activity in the central nervous system, cardiovascular, cerebrovascular, respiratory, reproductive, and gastrointestinal systems.

Materials and methods: In this study, cannabis sugar leaves were soaked in 99% ethanol, followed by evaporation. The antibacterial effect of the cannabis sugar leaf extract was then evaluated using the disc diffusion method. The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) were determined using broth dilution.

Results: The results of this study indicated that the cannabis sugar leaf extract inhibited Bacillus cereus, Vibrio cholerae, Escherichia coli, Staphylococcus aureus, and Staphylococcus epidermidis when compared to tetracycline, but it did not inhibit Pseudomonas aeruginosa. The MIC and MBC of the cannabis sugar leaves extract against B. cereus, V. cholerae, E. coli, S. aureus, and S. epidermidis were 0.977, 1.953, 31.25, 62.5, 125, 250, 250, 500, 250, and 500 mg/ml, respectively. The bioactive compounds in cannabis sugar leaf extract were identified using high-performance liquid chromatography.

Conclusion: The results indicated that the major bioactive compounds were Δ-9- tetrahydrocannabinol (THC) and cannabidiol (CBD). While minor bioactive compounds included gallic acid and tannic acid. These results support the benefits of cannabis sugar leaf extract, which has been used for its pharmacological properties and may be useful as an alternative antimicrobial agent in medicine.”

https://pubmed.ncbi.nlm.nih.gov/40568500/

https://www.ejmanager.com/mnstemps/39/39-1729498509.pdf?t=1750936743

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

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“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

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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

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“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

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“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