Search Results (1,948)

Naturally occurring psychoactive substances, such as opioids, cocaine, and cannabinoids, affect not only the central nervous system but also the functioning of the microbiota–gut–brain axis. Available evidence indicates that their use is associated with changes in the gut microbiota and modulation of immune responses. Escherichia coli, a permanent component of the gut microbiota under conditions favoring dysbiosis, can enhance inflammatory responses and influence neuroimmunological mechanisms related to the development of addiction. This study aims to review and analyze the available literature concerning the effects of selected naturally derived psychoactive substances on E. coli and on the functioning of the microbiota–gut–brain axis, with particular emphasis on inflammatory processes and their potential significance in the pathogenesis of addiction. Full article

Central nervous system disorders drive disability, yet many neuroactive candidates fail because the brain is a hard compartment to dose. Plant-derived molecules spanning polyphenols, alkaloids, terpenoids, and cannabinoids are attractive because their pleiotropic actions can engage oxidative stress, neuroinflammation, and circuit dysfunction. In practice, the blood–brain barrier (BBB) restricts most native phytochemicals through tight-junction selectivity, rapid metabolism, low solubility, and transporter-mediated efflux. Key gaps include poor standardization of exposure metrics, limited human-relevant BBB models, and few head-to-head studies that compare delivery platforms on the same payload and outcome. This review tackles the mismatch between mechanistic promise and reliable brain exposure that stalls translation. The objectives are to link phytochemical liabilities to enabling strategies in nanomedicine, alternative routes, and transporter-targeted prodrugs, and to propose decision-grade endpoints for translation. We synthesize evidence on BBB transport logic, nanocarrier families, targeting ligands, intranasal delivery, focused ultrasound-mediated opening, and prodrug approaches that hijack influx transporters, while foregrounding safety and chemistry, manufacturing, and controls (CMC) constraints. Here we highlight that effective neurotherapeutics emerge when chemistry, carrier, route, and measurement are co-designed rather than optimized in isolation. This framework can guide platform selection, de-risk first in-human studies, and sharpen trial endpoints. More broadly, it offers a transferable playbook for barrier-limited drug development across neurology, psychiatry, and oncology. Full article

Biostimulants represent a sustainable strategy to enhance the therapeutic potential of medicinal plants, which often exhibit low and variable levels of bioactive compounds. Cannabis sativa, a medicinally important species, produces diverse cannabinoids, such as THC, CBD, CBG, and CBC, whose profiles depend on plant chemotype and determine pharmacological activity. We developed a novel plant-based biostimulant, Tricostimulant™, to optimize cannabinoid production in Cannabis sativa. Field trials demonstrated increased biomass and selective enhancement of cannabinoid content. In high-CBD chemotypes, Tricostimulant™ was associated with higher CBD and CBG without relevant changes in THC levels, whereas in high-THC chemotypes, higher THC values were observed without evident variation in CBD. The most pronounced differences were observed when the biostimulant was applied during the vegetative stage, highlighting the importance of application timing. These results indicate the potential of Tricostimulant™ to modulate cannabinoid profiles, contributing to improved optimization and standardization of cannabis-based therapeutics. Further research is required to confirm these findings and elucidate the underlying mechanisms of biostimulant action. Full article

Cannabis is the most-used psychoactive drug in Aotearoa—New Zealand (NZ); recreational use remains illegal, while medicinal use was legalized in 2020. Cannabis use is associated with increased risk of injury; however, there is little known on the causes and circumstances of cannabis-related fatal injuries. This retrospective population study utilized coronial case files to describe the contribution and circumstances of cannabis-related fatal injuries in NZ. Between 2012 and 2016, cannabis was reported in 273 of 3599 unintentional/assault injury deaths (1.32 deaths per 100,000 person-years, 95% CI 1.17, 1.49). High-risk groups included males aged 15–44 years, Indigenous Māori, and those in deprived areas, for whom higher rates of post mortem testing were conducted. Cannabis-related fatalities mainly resulted from road crashes and multi-drug poisonings with concomitant alcohol use common, especially in traffic crashes on public roads (49% of concomitant use). Cannabis use was mainly observed in the decedent (n = 256, 94%). One in five deaths involved a worker, either as a user or as a bystander to another’s use. Coronial files identified important opportunities for safety countermeasures targeting cannabis use among drivers and its concomitant use with alcohol. Improved coverage of post mortem testing could address data limitations, including biased testing patterns and missing medical use. Full article

Atrial septal defect (ASD) affects 1:11.3 children in some US states; however, the antecedents of these trends are yet to be identified. A total of 1882 ASD rates (ASDRs) for 2003–2020 were sourced from the National Birth Defects Prevention Network reports. A total of 406,893 ASDs are reported. Substance (cigarettes, binge alcohol, cannabis, cannabinoids, analgesics, cocaine) exposure data were taken from the National Survey of Drug Use and Health. Income and ethnicity data were derived from the US Census. Adjustment was performed by mixed effects, survey and generalized additive regression. Causal analysis was by inverse probability weighting and E-values. Data were analyzed in RStudio. The highest ASDR of 884/10,000 live births was amongst Non-Hispanic Asians and Pacific Islanders in Nevada in 2016–2020. The 2005–2018 median ASDR rose >12-fold in Nevada and New Mexico, >6-fold in New York, and 4.2-fold nationally 1989–2020; it doubled in NY from 2012–2016 to 2016–2020. The average state ASDR rose supra-exponentially (p = 0.0075) and was associated with higher cannabis use states (p = Zero, Cohen’s D = 1.24), apparently driven by cannabis legalization (p = Zero). Estimated exposures to Δ9THC, cannabidiol and cannabigerol were implicated (from p = 2.67 × 10^–68). Cannabis-legal states were compared with others (mean ASDR (C.I.) 178.15 (131.68, 224.62) vs. 74.28 (70.60, 77.96), p = Zero; O.R. 1.82 (1.81, 1.84), E-values 3.04 (lower C.I. 3.02), Cohen’s D 1.29 (0.96, 1.62)). Overall, 29/39 (74.4%) E-value estimates were >4; 39/39 (100%) were >1.25. Cannabis, cannabinoids and cannabis legalization are strong candidates for driving the US ASDR supra-exponentially. Estimates of many cannabinoids, including cannabidiol, Δ9THC, and cannabigerol, are implicated. The results are consistent with other large epidemiological studies. The importance of the results is magnified by the increasing legalization and penetration of cannabinoids into the US population. Since therapeutic abortion is not practiced for ASD, it may be used as a bellwether index of heritable transgenerational cannabinoid genotoxicity and epigenotoxicity associated with cannabinoid exposure. Full article

Background: Prenatal cannabinoid exposure (PCE) causes neurodevelopmental impairments affecting learning and memory; however, the receptor-level interactions underlying these cognitive deficits remain poorly understood. This study investigated whether a moderate dose of prenatal Δ⁹-tetrahydrocannabinol (THC) exposure alters the biophysical properties of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which are critical mediators of excitatory neurotransmission and synaptic plasticity. Methods: Pregnant Sprague-Dawley rats received a moderate dose (5 mg/kg) of THC or vehicle control via oral gavage throughout gestation and early postnatal development. Single-channel electrophysiological activity of the AMPA receptors (AMPARs) was recorded using patch-clamp techniques on synaptosomal AMPARs reconstituted into artificial lipid bilayers from adolescent offspring. Western blot analysis of GluA1- and GluA2-containing AMPAR subunits and the postsynaptic scaffold protein postsynaptic density 95 (PSD95) was conducted to assess protein levels. Results: Prenatal THC exposure decreased AMPAR open-channel probability, reduced mean open time, increased mean closed time, and altered burst channel activity significantly, without altering GluA1, GluA2, or PSD95 protein levels. Furthermore, the interactive channel-gating activity observed in control synaptosomes was absent in synaptosomes derived from THC-exposed offspring. Conclusions: Prenatal cannabinoid exposure induces early alterations in glutamatergic synaptic function primarily mediated by changes in AMPAR channel kinetics rather than receptor abundance. By identifying AMPAR single-channel dysfunction as a sensitive marker of PCE-induced synaptic disruption, this work provides a mechanistic framework linking prenatal THC exposure to long-term alterations in learning and memory. Full article

Cannabinoids are of considerable current interest for use in pharmaceutical and non-medical consumer products. While there have been significant efforts to understand their chemical stability under ambient conditions, only sparse attention has been paid to characterising their photostability. Here, we present UVA (365 nm) and UVB (280 nm) photolysis measurements of eight representative cannabinoids, including natural compounds (THC, CBD, THCA, CBDA), metabolites (THC-COOH, THC-OH), and synthetic analogues (JWH-018, MDMB-FUBINACA). Measurements were performed using a novel online-electrospray mass spectrometry (MS) approach, where online photolysis of cannabinoid solutions was conducted with laser light-emitting diodes. MS detection was used to monitor precursor compound decay and photoproduct formation. Complementary results obtained via UV–Vis spectroscopy of photolysed cannabinoid solutions are also presented. For THC, CBD, THC-COOH, THC-OH, THCA and CBDA, significant photodegradation was observed with 280 nm photolysis, both through the appearance of photoproducts detected by MS and via time-dependent changes in the solution UV–Vis absorption profiles. In contrast, the synthetic cannabinoids (JWH-018 and MDMB-FUBINACA) showed negligible degradation with UVB photolysis, consistent with their relatively low absorbance propensity through the mid-UV region. No significant photodegradation was observed for UVA (365 nm) photolysis of any of the cannabinoids. The results presented here constitute the first directly comparable set of photolysis measurements for key phytocannabinoids. Full article

Myofibroblasts derived from retinal pigment epithelial (RPE) cells play a key role in the pathogenesis of retinal fibrotic conditions such as proliferative vitreoretinopathy (PVR). Upon exposure to growth factors and cytokines such as TNF-α and TGF-β (TNT), RPE cells undergo epithelial-mesenchymal transition and subsequent transdifferentiation to contractile myofibroblasts. In this study, the effects of JD5037, a peripherally restricted CB1 antagonist, on myofibroblast transdifferentiation of primary cultures of human RPE cells were assessed. JD5037 significantly reduced TNT-induced, RPE cell-mediated collagen gel contraction, an indicator of myofibroblast function, in a concentration-dependent manner. Western blot analysis showed that JD5037 attenuated TNT-induced expression of α-SMA and fibronectin, two molecular markers of myofibroblasts. Furthermore, siRNA knockdown of CB1 cannabinoid receptor partially inhibited TNT-induced myofibroblast transdifferentation of human RPE cells and eliminated the inhibitory effects of JD5037 on myofibroblast transdifferentiation. These data demonstrate, for the first time, that peripherally restricted antagonists, such as JD5037, targeting the CB1 cannabinoid receptor have therapeutic potential for PVR and other retinal fibrotic conditions. Full article

Cannabis use is generally restricted worldwide because it contains the narcotic compound Δ⁹-tetrahydrocannabinol (Δ⁹-THC). Although cannabis is detected at crime scenes using color-based primary screening methods, the details of the reaction mechanism have not yet been elucidated. In this study, we isolated the products generated during the color reaction between the diazonium salt prepared from para-nitroaniline and nine cannabinoids and determined their structures. Azo compounds 6, 11, 16, and 17 were produced from cannabidiol, cannabigerol, cannabichromene, and cannabidiolic acid, respectively, while quinoneimines 7–10 and 12–15, which contained positional isomers, were produced from cannabinol, Δ⁹-THC, and hexahydrocannabinol. The reaction barely proceeded with Δ⁹-THC acetate and HHC acetate. Full article

Current treatments for breast cancer (BC) include surgery, radiation, chemotherapy, targeted therapy, hormonal therapy, and immunotherapy. However, adverse effects such as pain, nausea, cardiotoxicity, and neuropathy have prompted interest in complementary approaches. Cannabinoids (CBS), particularly cannabidiol and delta-9-tetrahydrocannabinol, are already used by cancer patients for symptom relief, and preclinical studies in cell culture and mouse models suggest additional therapeutic potential at the cellular level: combining CBS with chemotherapy may sensitize tumour cells to chemotherapeutic agents, inhibit tumour proliferation, and increase apoptosis. In murine models, such combinations may also mitigate chemotherapy-induced cardiotoxicity by enhancing antioxidant activity, modulating cannabinoid receptor signalling to reduce pro-inflammatory markers, and restoring mitochondrial function in myocytes. In addition, CBS may augment hormonal therapy in estrogen receptor-positive (ER+) BC cells, primarily via aromatase inhibition and modulation of ER and EGR3 signalling. Notably, evidence on combining CBS with targeted therapies in BC is lacking, while studies of CBS–immunotherapy combinations have been conducted in non-BC cancers; in BC, they are scarce and limited to in vitro models. This represents a key area for future research, particularly given the heterogeneity across non-BC cancers, where CBS–immunotherapy combinations have demonstrated mixed effects, both beneficial and detrimental (e.g., reduced response rates and overall survival), with the underlying mechanisms remaining unclear. Translation of these findings into clinical practice faces several challenges. Although over 120 CBS have been identified, only a few are well-characterized. CBS exhibit diverse mechanisms and effects, including potential adverse outcomes and interactions with conventional therapies (e.g., effects on chemotherapeutic drug metabolism). Variability among BC cells may also result in differing responses to the same therapeutic combinations. Future research should delineate the effects of individual CBS in combination strategies and prioritize well-controlled, standardized clinical studies to build on in vitro and animal data, while also exploring genetically informed personalized approaches. Ultimately, clinical guidelines specifying CBS type, formulation, and delivery are needed. Full article

Salicylic acid (SA) is a key signaling molecule regulating secondary metabolism and stress responses in plants, but its preharvest role as a low-cost elicitor in cannabis remains underexplored. This study evaluated the effects of preharvest foliar SA application at different concentrations and application intervals on pigments, antioxidants, and cannabinoids in Cannabis sativa L. leaves and inflorescences. In leaves, moderate SA (0.1 M) significantly enhanced total phenolic content, total flavonoid content, and antioxidant activity (%DPPH inhibition), while higher concentrations suppressed these responses, reflecting a regulated metabolic trade-off rather than irreversible tissue damage. A significant interaction between SA concentration and preharvest time was observed for chlorophyll a (p < 0.01), whereas chlorophyll b and total chlorophyll were not significantly influenced by the interaction. In inflorescences, short-term application of 0.1 M SA (1 h preharvest) maximized phenolics, flavonoids, antioxidant capacity, and pigment accumulation, whereas the untreated controls showed the lowest levels. Cannabinoids exhibited distinct responses: Δ⁹-tetrahydrocannabinol (Δ⁹-THC), total tetrahydrocannabinol (Total THC), and tetrahydrocannabinolic acid (THCA) peaked at 0.1 M SA applied 1 h preharvest, while cannabidiol (CBD) was less concentration-dependent, with maximum accumulation observed at 1.0 M SA applied 24 h preharvest. Preharvest SA elicitation strongly modulated cannabis secondary metabolism. Short-term application of moderate SA promoted total phenolic, total flavonoid, antioxidant, pigment, and THC-group cannabinoid accumulation, while CBD displayed broader tolerance to concentration and application timing. These findings highlighted the potential of SA as a preharvest elicitor to improve cannabis phytochemical quality. Full article

Background: SARS-CoV-2 infection during pregnancy has been associated with systemic inflammatory responses and placental pathology; however, the molecular mechanisms underlying placental involvement remain incompletely understood. The endocannabinoid system plays a critical role in placental development, immune regulation, and vascular homeostasis. Materials and Methods: Placental tissues were obtained from 20 healthy pregnant women and 20 women with confirmed SARS-CoV-2 infection who had recovered by the time of delivery. Demographic and laboratory parameters were recorded. Histopathological evaluation was performed using hematoxylin and eosin staining. Immunohistochemical analysis of cannabinoid receptor 1 (CNR1) and cannabinoid receptor 2 (CNR2) expression was conducted, supported by quantitative digital image analysis using QuPath. Network-based protein–protein interaction and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to explore potential molecular mechanisms. Results: COVID-19-positive placentas exhibited prominent histopathological alterations, including increased fibrinoid deposition, syncytial knot formation, vascular congestion, and intervillous inflammatory cell infiltration. Systemic inflammatory and coagulation markers, particularly neutrophil percentage, C-reactive protein, D-dimer, and fibrinogen levels, were significantly elevated in the COVID-19 group. CNR1 and CNR2 expressions were markedly increased across multiple placental compartments, including decidual cells, trophoblastic layers, syncytial knots, and Hofbauer cells. Quantitative digital analysis confirmed significant upregulation of both receptors. Bioinformatic analysis revealed enrichment of endocannabinoid signaling, cAMP-related pathways, and inflammatory mediator regulation of TRP channels. Conclusions: The findings indicate that SARS-CoV-2 infection is associated with coordinated inflammatory, structural, and molecular alterations in the placenta. Upregulation of CB1 and CB2 suggests an active involvement of the endocannabinoid system in placental immune and vascular responses to COVID-19, highlighting its potential relevance for understanding placental pathology associated with maternal viral infections Full article

In the search for new therapeutic strategies for the treatment of skin cancer, cannabinoids have become the focus of scientific interest. The present study investigated the effects of the phytocannabinoids Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) on the viability, apoptosis, and mitochondrial function of human melanoma (A375) and cutaneous squamous cell carcinoma (SCC) cells (A431). Both cannabinoids caused a time- and concentration-dependent loss of viability and an upregulation of caspase-3/7 activity, associated with the induction of initiator caspases-8 and -9, PARP cleavage, and an increase in the autophagy marker LC3A/B-II. Inspired by the latest work on the dual role of heme oxygenase-1 (HO-1) in cell fate, the expression of this enzyme was examined and found to be upregulated at the mRNA and protein level by THC and CBD. Inhibition of HO-1 activity by tin protoporphyrin IX (SnPPIX) reduced the loss of viability caused by both cannabinoids, suggesting a cytotoxic rather than cytoprotective mediator role for this enzyme here. At the mitochondrial level, THC and CBD caused a reduction in membrane potential, a release of cytochrome c into the cytosol, and electron microscopically detectable mitochondrial damages. A more detailed functional analysis revealed an inhibition of mitochondrial oxygen consumption rate, accompanied by a decrease in various subunits of mitochondrial oxidative phosphorylation complexes. In conclusion, our data demonstrate a strong cytotoxic effect of THC and CBD on melanoma and cutaneous SCC cells involving mitochondrial apoptosis and mitochondrial dysfunction. Full article

The G-protein-coupled receptor cannabinoid receptor 2 (CB₂R) initiates a key signaling pathway in mammalian physiology and pathophysiology. CB₂R signaling holds significant therapeutic potential in ameliorating many pathologies, particularly in inflammatory conditions, neurodegenerative disorders, fibroproliferative and ocular diseases. CB2 modulators have been studied for their anti-inflammatory and tissue protective effects in preclinical animal models of cardiovascular, gastrointestinal, liver, kidney, lung and neurodegenerative disorders with numerous compounds undergoing clinical evaluation. Existing ligands can be classified as endocannabinoids, cannabinoid-like natural products and synthetic CB₂R ligands. A genetically encoded G-protein-coupled receptor activation-based (GRAB) sensor for CB₁R—GRAB_eCB2.0 was developed recently. This current study extends the sensor’s development to allow for a GPCR activation-based sensor for CB₂R. The sensor, GRAB-CB2, will facilitate the evaluation of pharmacological characteristics and responses of various functionally selective and indiscriminate cannabinoid ligands acting on CB2. Full article

Background/Objectives: Cannabinoids are increasingly recognised for their therapeutic potential beyond well-established indications such as chronic pain, multiple sclerosis, and specific epileptic syndromes. Recent advances have highlighted their possible role in less-common or orphan diseases, opening new avenues for pharmaceutical research and clinical application. Methods: This review provides a critical synthesis of the most recent evidence (2020–2025), available in PubMed and Scopus, regarding the use of cannabinoids in conditions including refractory epilepsies beyond Dravet and Lennox–Gastaut syndromes, movement disorders such as dystonia and Tourette syndrome, rare dermatological diseases like epidermolysis bullosa, and emerging data in Crohn’s disease. Results: Negative outcomes, such as those reported in Fragile X syndrome trials, are also discussed as instructive examples of methodological and pharmacological challenges. Particular attention is given to the optimisation of pharmaceutical formulations and advanced separation technologies, including oromucosal sprays, transdermal gels, and novel nanocarrier systems, which aim to overcome issues of bioavailability and variability in patient response. Finally, safety concerns, regulatory aspects, and the need for robust clinical trials are addressed. Conclusions: Overall, cannabinoids represent a promising yet underexplored therapeutic option in rare and complex disorders, warranting further investigation supported by innovative pharmaceutical approaches. Full article