There are inconclusive claims in the scientific literature that the species Trema micranthum, widely distributed throughout the Brazilian territory, may produce phytocannabinoids, potentially serving as an alternative to Cannabis sativa. In this study, we conducted a comprehensive investigation to assess the presence of phytocannabinoids in two Trema micranthum samples collected in the Midwest region of Brazil. In trying to detect cannabinoids in T. micranthum, a recommended cannabis screening test was employed, the Fast Blue BB Salt (FBBBS) colorimetric assay, followed by thin-layer chromatography (TLC) and instrumental techniques: high-performance liquid chromatography coupled to diode array detector (HPLC-DAD) and gas chromatography coupled to mass spectrometry (GC-MS). When employed without chloroform extraction, the FBBBS reagent yielded positive results for extracts from all parts of T. micranthum (leaves, branches, fruits, and inflorescences). However, these initial positive results from the FBBBS test, suggesting the presence of cannabinoids, were not corroborated by FBBBS followed by chloroform extraction, TLC, or the instrumental techniques used in this study. These additional outcomes suggest that the positive FBBBS test results were likely due to the presence of other phenolic compounds rather than phytocannabinoids. For example, the presence of vitexin-like compounds in T. micranthum extracts might explain the positive FBBBS test results. Therefore, new assertions that T. micranthum produces cannabinoids will require the support of more selective experiments to avoid false-positive claims based on less selective screening tests.

Cannabielsoin (CBE) is primarily recognized as an oxidation byproduct of cannabidiol (CBD) and a minor mammalian metabolite of CBD. The pharmacological interactions between CBE and cannabinoid receptors remain largely unexplored, particularly with respect to cannabinoid receptor type 1 (CB1). The present study aimed to elucidate the interaction dynamics of CBE in relation to CB1 by employing cyclic adenosine monophosphate (cAMP) and β-arrestin assays to assess its role as an agonist, antagonist, and positive allosteric modulator (PAM). To our knowledge, this is the first publication to investigate CBE\'s receptor activity in vitro. Our findings reveal that S-CBE acts as an agonist to CB1 with EC50 = 1.23 µg/mL (3.7 µM) in the cAMP assay. No agonist activity was observed in the β-arrestin assay in concentrations up to 12 µM, suggesting a noteworthy affinity towards G-protein activation and the cAMP signaling pathway. Furthermore, in silico molecular docking simulations were conducted to provide a structural basis for the interaction between CBE and CB1, offering insights into the molecular determinants of its receptor affinity and functional selectivity.

The relationship between nuclear factor erythroid 2-related factor 2 (Nrf2) and phytocannabinoids/endocannabinoids (pCBs/eCBs) has been investigated in a variety of models of peripheral illnesses, with little clarification on their interaction within the central nervous system (CNS). In this context, evidence suggests that the Nrf2-pCBs/eCBS interaction is relevant in modulating peroxidation processes and the antioxidant system. Nrf2, one of the regulators of cellular redox homeostasis, appears to have a protective role toward damaging insults to neurons and glia by enhancing those genes involved in the regulation of homeostatic processes. Specifically in microglia and macroglia cells, Nrf2 can be activated, and its signaling pathway modulated, by both pCBs and eCBs. However, the precise effects of pCBs and eCBs on the Nrf2 signaling pathway are not completely elucidated yet, making their potential clinical employment still not fully understood.

Cannabidiol (CBD) is a safe and non-psychotropic phytocannabinoid with a wide range of potential therapeutic anti-inflamatory and antioxidant activities. Due to its lipophilicity, it is normally available dissolved in oily phases. The main aim of this work was to develop and characterize a new formulation of a microemulsion with potential anti-inflammatory and antioxidant activity for the topical treatment of inflammatory skin disorders. The microemulsion system was composed of a 20% CBD oil, which served as the hydrophobic phase; Labrasol/Plurol Oleique (1:1), which served as surfactant and cosurfactant (S/CoS), respectively; and an aqueous vegetal extract obtained from Sambucus ebulus L. (S. ebulus) ripe fruits, which has potential anti-oxidant and anti-inflammatory activity and which served as the aqueous phase. A pseudo-ternary phase diagram was generated, leading to the selection of an optimal proportion of 62% (S/CoS), 27% CBD oil and 11% water and, after its reproducibility was tested, the aqueous phases were replaced by the vegetal hydrophilic extract. The defined systems were characterized in terms of conductivity, droplet size (by laser scattering), compatibility of components (by differential scanning calorimetry) and rheological properties (using a rotational rheometer). The designed microemulsion showed good stability and slight pseudo-plastic behavior. The release properties of CBD from the oil phase and caffeic acid from the aqueous phase of the microemulsion were studied via in vitro diffusion experiments using flow-through diffusion cells and were compared to those of a CBD oil and a microemulsion containing only CBD as an active substance. It was found that the inclusion of the original oil in microemulsions did not result in a significant modification of the release of CBD, suggesting the possibility of including hydrophilic active compounds in the formulation and establishing an interesting strategy for the development of future formulations.

Neurodegenerative disorders are affecting millions of people worldwide, impacting the healthcare system of our society. Among them, Alzheimer\'s disease (AD) is the most common form of dementia, characterized by severe cognitive impairments. Neuropathological hallmarks of AD are β-amyloid (Aβ) plaques and neurofibrillary tangles, as well as endoplasmic reticulum and mitochondria dysfunctions, which finally lead to apoptosis and neuronal loss. Since, to date, there is no definitive cure, new therapeutic and prevention strategies are of crucial importance. In this scenario, cannabinoids are deeply investigated as promising neuroprotective compounds for AD. In this study, we evaluated the potential neuroprotective role of cannabinerol (CBNR) in an in vitro cellular model of AD via next-generation sequencing. We observed that CBNR pretreatment counteracts the Aβ-induced loss of cell viability of differentiated SH-SY5Y cells. Moreover, a network-based transcriptomic analysis revealed that CBNR restores normal mitochondrial and endoplasmic reticulum functions in the AD model. Specifically, the most important genes regulated by CBNR are related mainly to oxidative phosphorylation (COX6B1, OXA1L, MT-CO2, MT-CO3), protein folding (HSPA5) and degradation (CUL3, FBXW7, UBE2D1), and glucose (G6PC3) and lipid (HSD17B7, ERG28, SCD) metabolism. Therefore, these results suggest that CBNR could be a new neuroprotective agent helpful in the prevention of AD dysfunctions.

UVA exposure disturbs the metabolism of skin cells, often inducing oxidative stress and inflammation. Therefore, there is a need for bioactive compounds that limit such consequences without causing undesirable side effects. The aim of this study was to analyse in vitro the effects of the phytocannabinoids cannabigerol (CBG) and cannabidiol (CBD), which differ in terms of biological effects. Furthermore, the combined use of both compounds (CBG+CBD) has been analysed in order to increase their effectiveness in human skin fibroblasts and keratinocytes protection against UVA-induced alternation. The results obtained indicate that the effects of CBG and CBD on the redox balance might indeed be enhanced when both phytocannabinoids are applied concurrently. Those effects include a reduction in NOX activity, ROS levels, and a modification of thioredoxin-dependent antioxidant systems. The reduction in the UVA-induced lipid peroxidation and protein modification has been confirmed through lower levels of 4-HNE-protein adducts and protein carbonyl groups as well as through the recovery of collagen expression. Modification of antioxidant signalling (Nrf2/HO-1) through the administration of CBG+CBD has been proven to be associated with reduced proinflammatory signalling (NFκB/TNFα). Differential metabolic responses of keratinocytes and fibroblasts to the effects of the UVA and phytocannabinoids have indicated possible beneficial protective and regenerative effects of the phytocannabinoids, suggesting their possible application for the purpose of limiting the harmful impact of the UVA on skin cells.

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The Cannabis species is one of the potent ancient medicinal plants acclaimed for its medicinal properties and recreational purposes. The plant parts are used and exploited all over the world for several agricultural and industrial applications. For many years Cannabis spp. has proven to present a highly diverse metabolomic profile with a pool of bioactive metabolites used for numerous pharmacological purposes ranging from anti-inflammatory to antimicrobial. Cannabis sativa has since been an extensive subject of investigation, monopolizing the research. Hence, there are fewer studies with a comprehensive understanding of the composition of bioactive metabolites grown in different environmental conditions, especially C. indica and a few other Cannabis strains. These pharmacological properties are mostly attributed to a few phytocannabinoids and some phytochemicals such as terpenoids or essential oils which have been tested for antimicrobial properties. Many other discovered compounds are yet to be tested for antimicrobial properties. These phytochemicals have a series of useful properties including anti-insecticidal, anti-acaricidal, anti-nematicidal, anti-bacterial, anti-fungal, and anti-viral properties. Research studies have reported excellent antibacterial activity against Gram-positive and Gram-negative multidrug-resistant bacteria as well as methicillin-resistant Staphylococcus aureus (MRSA). Although there has been an extensive investigation on the antimicrobial properties of Cannabis, the antimicrobial properties of Cannabis on phytopathogens and aquatic animal pathogens, mostly those affecting fish, remain under-researched. Therefore, the current review intends to investigate the existing body of research on metabolomic profile and anti-microbial properties whilst trying to expand the scope of the properties of the Cannabis plant to benefit the health of other animal species and plant crops, particularly in agriculture.

It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat different types of seizures related to Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and more recently tuberous sclerosis complex (TSC). During this time, 39 randomized clinical trials (RCTs) and 13 meta-analyses on the efficacy and safety of CBD treatment have been published. Each of the meta-analyses had its own criteria for the RCTs\' inclusion and, therefore, slightly different interpretations of the analyzed data. Each of them contributed in its own way to the understanding of CBD pharmacology, mechanisms of therapeutic action, development of adverse reactions, and drug-drug interactions. Hence, it seemed reasonable to gather the most relevant data in one article and present all the current knowledge on the use of CBD in epilepsy. The results of the 13 meta-analyses presented herein confirmed the effectiveness and safety of CBD in children and adolescents with DREs. In adults, reliable conclusions cannot be drawn due to insufficient data.

Phytocannabinoids, a diverse group of naturally occurring compounds extracted from the Cannabis plant, have attracted interest due to their potential pharmacological effects and medicinal uses. This comprehensive review presents the intricate pharmacological profiles of phytocannabinoids while exploring the diverse impacts these substances have on biological systems. From the more than one hundred cannabinoids which were identified in the Cannabis plant so far, cannabidiol (CBD) and tetrahydrocannabinol (THC) are two of the most extensively studied phytocannabinoids. CBD is a non-psychoactive compound, which exhibits potential anti-inflammatory, neuroprotective, and anxiolytic properties, making it a promising candidate for a wide array of medical conditions. THC, known for its psychoactive effects, possesses analgesic and antiemetic properties, contributing to its therapeutic potential. In addition to THC and CBD, a wide range of additional phytocannabinoids have shown intriguing pharmacological effects, including cannabichromene (CBC), cannabigerol (CBG), and cannabinol (CBN). The endocannabinoid system, made up of the enzymes involved in the production and breakdown of endocannabinoids, cannabinoid receptors (CB1 and CB2), and endogenous ligands (endocannabinoids), is essential for preserving homeostasis in several physiological processes. Beyond their effects on the endocannabinoid system, phytocannabinoids are studied for their ability to modify ion channels, neurotransmitter receptors, and anti-oxidative pathways. The complex interaction between phytocannabinoids and biological systems offers hope for novel treatment approaches and lays the groundwork for further developments in the field of cannabinoid-based medicine. This review summarizes the state of the field, points out information gaps, and emphasizes the need for more studies to fully realize the therapeutic potential of phytocannabinoids.