“The endocannabinoid system (ECS) is a complex signaling network essential for regulating various physiological processes in the body. Selective cannabinoid receptor ligands have been developed to modulate specific ECS signaling pathways, offering potential therapeutic benefits. These ligands, with high selectivity and affinity for cannabinoid receptors, demonstrate potential in managing diverse medical conditions. Standardizing dosing is crucial to ensure reliable therapeutic effects, as cannabinoids may exhibit biphasic effects. Combination strategies involving both CB1 and CB2 receptor modulation show promise in managing complex conditions, including chronic pain, autoimmune disorders, and neurodegenerative diseases.”
“Objective: B lymphocytes play a crucial role in immunity but also contribute to the pathogenesis of various diseases. Cannabis plants produce numerous biologically active compounds, including cannabinoids. The two most studied phytocannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These cannabinoids exert diverse and potent biological effects primarily through the endocannabinoid system (ECS), which also plays a key role in mature B-cell function. Both the immune system and the ECS undergo age-related changes that lead to a clinically significant decline in function.
Methods: This study compares the effects of THC and CBD on B-cell activity in young and aged mice. Murine B lymphocytes were activated using lipopolysaccharide (LPS) and interleukin-4 (IL-4), and the impact of cannabinoid treatments was assessed in terms of cell phenotype, proliferation, antibody secretion, tumor necrosis factor-alpha (TNFα) secretion, extracellular signal-regulated kinase (ERK) phosphorylation, and the cellular metabolome.
Results: Both THC and CBD exhibited dose-dependent inhibitory effects on B-cell activation in young and aged mice. However, we show here, for the first time, that the treatments induce distinct metabolic profiles. Although some metabolites, such as glucose-6-phosphate, pentose phosphate pathway (PPP) and nucleotide metabolites, were reduced by both cannabinoids, THC selectively reduced the levels of a distinct set of amino acids, while only CBD increased the levels of Citrulline and Allantoin. Additionally, the effects of THC and CBD differed between young and aged B cells, suggesting that age-related changes in the ECS may influence cannabinoid sensitivity.
Conclusions: These findings provide insights into the distinct mechanisms by which THC and CBD regulate immune activation and may open the door for investigating the mechanisms behind cannabinoids effects on the immune system. They also highlight the need for further research into phytocannabinoid-based therapies, particularly in age-specific contexts. Given the immunoregulatory properties of cannabinoids, especially CBD, tailored therapeutic strategies may enhance their clinical applications.”
“These findings emphasize the need for further investigation into phytocannabinoid-based therapies, particularly for age-specific applications. Given the immunoregulatory properties of cannabinoids, especially CBD, tailored therapeutic strategies may be developed to optimize their clinical use.”
“Aim: Cannabis has historically been used for medicinal and industrial purposes, but is strictly regulated worldwide due to the psychoactive effects of THC. In Japan, cannabis is frequently labeled a “gateway drug,” yet strong causal evidence for progression to other substances is limited. This study investigates whether cannabis acts as a gateway drug among Japanese users.
Methods: An anonymous online survey was conducted in January 2021 with 3900 individuals reporting lifetime cannabis use in Japan. Participants were recruited via social media. The survey gathered data on demographics, cannabis and other substance use history, order of substance initiation, psychiatric background, and criminal records. A Sankey diagram visualized substance use progression, and odds ratios were calculated to assess the likelihood of using other substances following cannabis use.
Results: Of all respondents, 81.5% were male, with the largest age group being 20-24. Tobacco and alcohol were the most common initial substances, while cannabis was typically the third. Odds for subsequent use of alcohol, tobacco, methamphetamine, and other illicit drugs after cannabis use were 1.25, 0.77, 0.08, and 0.78, respectively, suggesting low probabilities of progression. Nearly half of those who reported cannabis as their third drug did not use other substances afterward.
Conclusion: Cannabis use in Japan typically follows alcohol and tobacco, and rarely leads to further drug use. These findings challenge the gateway hypothesis in the Japanese context. Shared vulnerabilities and strict drug policies may shape these patterns. Further research is warranted to explore the impact of legal changes on drug use behavior.”
“Currently, there are reservations regarding the medicinal use of Cannabis sativa extract and its potential to impact fertility. Certain cannabinoids, such as Δ9-tetrahydrocanabinol (THC), can modulate both male and female sex hormones, potentially leading to alterations in fertilization viability.
This study aims to evaluate the effects of standardized Cannabis sativa extract (CSE) and its respective placebos on fertility and early embryonic development in Wistar rats, including both male and female subjects.
The animals were divided into 7 groups, each consisting of 20 animals, and different doses of a Cannabis sativa extract (160.32mg/mL) were administered to assess fertility outcomes. Male and female fertility assessments were conducted according to the guidelines outlined in the “Guide for the Conduct of Non-Clinical Toxicology and Pharmacological Safety Studies Required for Drug Development,” including clinical exams, biochemical analyses, macroscopic evaluations, relative organ weight measurements, sperm production, and morphology assessments, as well as morphometric and histopathological analyses of the testes.
The results indicated that none of the tested doses (0.28, 2.8, 28, or 56mg/kg/bw) significantly affected sex hormone levels in either male or female rats. Additionally, no alterations were observed in male organ morphology and sperm characteristics. In female rats, fertility was unaffected, and blastocyst implantation was not impaired across all doses, even up to 7 days post-pregnancy confirmation.
No direct toxic effects on the embryo were observed.
In conclusion, treatment with Cannabis sativa extract did not result in any significant changes in fertility or pregnancy feasibility in either male or female rats.”
“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.”
“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.”
“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.”
“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.”
“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.”
“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.”
“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.”
