This study deals with the comprehensive phytochemical composition and antiviral activity against SARS-CoV-2 of acidic (non-decarboxylated) and neutral (decarboxylated) ethanolic extracts from seven high-cannabidiol (CBD) and two high-Δ9-tetrahydrocannabinol (Δ9-THC) Cannabis sativa L. genotypes. Their secondary metabolite profiles, phytocannabinoid, terpenoid, and phenolic, were determined by LC-UV, GC-MS, and LC-MS/MS analyses, respectively. All three secondary metabolite profiles, cannabinoid, terpenoid, and phenolic, varied significantly among cannabinoid extracts of different genotypes. The dose-response analyses of their antiviral activity against SARS-CoV-2 showed that only the single predominant phytocannabinoids (CBD or THC) of the neutral extracts exhibited antiviral activity (all IC50 < 10.0 μM). The correlation matrix between phytoconstituent levels and antiviral activity revealed that the phenolic acids, salicylic acid and its glucoside, chlorogenic acid, and ferulic acid, and two flavonoids, abietin, and luteolin, in different cannabinoid extracts from high-CBD genotypes are implicated in the genotype-distinct antagonistic effects on the predominant phytocannabinoid. On the other hand, these analyses also suggested that the other phytocannabinoids and the flavonoid orientin can enrich the extract's pharmacological profiles. Thus, further preclinical studies on cannabinoid extract formulations with adjusted non-phytocannabinoid compositions are warranted to develop supplementary antiviral treatments.
Background: Activation of cannabinoid receptor 1 (CB1R) in the nervous system modulates the processing of acute and chronic pain. CB1R activity is regulated by desensitization and internalization. SH3-containing GRB2-like protein 3-interacting protein 1 (SGIP1) inhibits the internalization of CB1R. This causes increased and prolonged association of the desensitized receptor with G protein-coupled receptor kinase 3 (GRK3) and beta-arrestin on the cell membrane and results in decreased activation of extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Genetic deletion of SGIP1 in mice leads to altered CB1R-related functions, such as decreased anxiety-like behaviors, modified cannabinoid tetrad behaviors, reduced acute nociception, and increased sensitivity to analgesics. In this work, we asked if deletion of SGIP1 affects chronic nociception and analgesic effect of Δ9-tetrahydrocannabinol (THC) and WIN 55,212-2 (WIN) in mice. Methods: We measured tactile responses of hind paws to increasing pressure in wild-type and SGIP1 knock-out mice. Inflammation in the paw was induced by local injection of carrageenan. To determine the mechanical sensitivity, the paw withdrawal threshold (PWT) was measured using an electronic von Frey instrument with the progression of the applied force. Results: The responses to mechanical stimuli varied depending on the sex, genotype, and treatment. SGIP1 knock-out male mice exhibited lower PWT than wild-type males. On the contrary, the female mice exhibited comparable PWT. Following THC or WIN treatment in male mice, SGIP1 knock-out males exhibited PWT lower than wild-type males. THC treatment in SGIP1 knock-out females resulted in PWT higher than after THC treatment of wild-type females. However, SGIP1 knock-out and wild-type female mice exhibited similar PWT after WIN treatment. Conclusions: We provide evidence that SGIP1, possibly by interacting with CB1R, is involved in processing the responses to chronic pain. The absence of SGIP1 results in enhanced sensitivity to mechanical stimuli in males, but not females. The antinociceptive effect of THC is superior to that of WIN in SGIP1 knock-out mice in the carrageenan-induced model of chronic pain.
- MeSH
- Benzoxazines * pharmacology MeSH
- Hyperalgesia * genetics MeSH
- Morpholines pharmacology MeSH
- Mice, Inbred C57BL MeSH
- Mice, Knockout * MeSH
- Mice MeSH
- Naphthalenes MeSH
- Nociception drug effects MeSH
- Receptor, Cannabinoid, CB1 * genetics metabolism MeSH
- Dronabinol * pharmacology MeSH
- Inflammation * MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Mitochondria are central to cellular energy metabolism, contributing to synaptic transmission and plasticity. The mitochondrial membranes present the cannabinoid type-1 receptor (mito-CB1R), which has been functionally linked to neuronal energy supply and cognitive processing. Prenatal exposure to Δ9-tetrahydrocannabinol (pTHC) has been associated with cognitive impairments associated with molecular cellular and functional abnormalities in several brain regions, including the hippocampus. This study aims at assessing whether, besides the memory impairment, pTHC exposure may result in mitochondrial molecular and functional alterations in the hippocampus of the offspring. Moreover, the assessment of CB1R expression is also carried out as a proxy of CB1 signalling in pTHC-exposed offspring. THC (2 mg/Kg), or vehicle, was administered to the dams from gestational day (GD) 5 to GD20, and the offspring were tested for declarative memory using the Novel Object Recognition test in the L-maze. We also assessed: mitochondrial respiration by high-resolution respirometry; mitochondrial respiratory complex-I subunit NDUFS1 protein levels, and mito-CB1R expression by ELISA. Our results revealed: significant memory impairment in pTHC-exposed offspring; attenuated mitochondrial respiration in the hippocampus alongside a marked reduction in complex-I-subunit NDUFS1; a significant increase in mito-CB1R expression. This is the first evidence of pTHC exposure-induced impairment in memory processing in the offspring that suggests a functional link between an attenuation in mitochondrial bioenergetics and abnormal CB1R signalling in the hippocampus.
- MeSH
- Maze Learning drug effects MeSH
- Cell Respiration drug effects MeSH
- Hippocampus * metabolism drug effects MeSH
- Rats MeSH
- Mitochondria * metabolism drug effects MeSH
- Memory drug effects MeSH
- Memory Disorders * metabolism chemically induced MeSH
- Rats, Wistar MeSH
- Receptor, Cannabinoid, CB1 * metabolism MeSH
- Pregnancy MeSH
- Dronabinol * toxicity MeSH
- Prenatal Exposure Delayed Effects * metabolism chemically induced MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Alterations in the excitability of dorsal root ganglion (DRG) neurons are critical in the pathogenesis of acute and chronic pain. Neurotransmitter release from the terminals of DRG neurons is regulated by cannabinoid receptor 1 (CB1) and transient receptor potential vanilloid 1 (TRPV1), both activated by anandamide (AEA). In our experiments, the AEA precursor N-arachidonoylphosphatidylethanolamine (20:4-NAPE) was used to study the modulation of nociceptive DRG neurons excitability using K+-evoked Ca2+ transients. Intrathecal administration was used to evaluate in vivo effects. Application of 20:4-NAPE at lower concentrations (10 nM - 1 μM) decreased the excitability of DRG neurons, whereas the higher (10 μM) increased it. Both effects of 20:4-NAPE were blocked by the N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor LEI-401. Similarly, lower concentrations of externally applied AEA (1 nM - 10 nM) inhibited DRG neurons, whereas higher concentration (100 nM) did not change it. High AEA concentration (10 μM) evoked Ca2+ transients dependent on TRPV1 activation in separate experiments. Inhibition of the CB1 receptor by PF514273 (400 nM) prevented the 20:4-NAPE- and AEA-induced inhibition, whereas TRPV1 inhibition by SB366791 (1 μM) prevented the increased DRG neuron excitability. In behavioral tests, lower 20:4-NAPE concentration caused hyposensitivity, while higher evoked mechanical allodynia. Intrathecal LEI-401 prevented both in vivo effects of 20:4-NAPE. These results highlight anti- and pro-nociceptive effects of 20:4-NAPE mediated by CB1 and TRPV1 in concentration-dependent manner. Our study underscores the complexity of endocannabinoid signaling in pain transmission modulation and highlights 20:4-NAPE as a potential therapeutic target, offering new insights for developing analgesic strategies.
- MeSH
- Endocannabinoids pharmacology metabolism MeSH
- Phosphatidylethanolamines * pharmacology MeSH
- Phospholipase D * metabolism antagonists & inhibitors MeSH
- TRPV Cation Channels metabolism MeSH
- Rats MeSH
- Arachidonic Acids * pharmacology MeSH
- Neurons * drug effects metabolism MeSH
- Polyunsaturated Alkamides pharmacology MeSH
- Rats, Sprague-Dawley MeSH
- Receptor, Cannabinoid, CB1 metabolism MeSH
- Ganglia, Spinal * drug effects metabolism cytology MeSH
- Calcium metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The semi-synthetic cannabinoid hexahydrocannabinol (HHC) has become a highly discussed topic in forensic toxicology since 2022 due to its legal availability at this time and its psychoactive effects. This study aimed to investigate the pharmacokinetics, effects, and immunological detectability of HHC after oral (25 mg HHC fruit gum) and inhalative (three puffs from HHC vape) consumption with three participants per group. Serum (up to 48 h), urine (up to five days), and saliva (up to 48 h) samples were collected at different relevant time points and analyzed by HPLC-MS/MS for (9R)/(9S)-HHC, 11-hydroxy-HHC, and (9R)/(9S)-HHC carboxylic acid with a fully validated method. Additionally, immunological detectability was investigated with three different commercially available tests. To address the psychoactive effects, the subjective "high" feeling (scale 0-10) was monitored and different psychophysical tests (e.g. modified Romberg test, walk and turn) were conducted. Overall, the pharmacokinetics and effects of HHC were comparable to tetrahydrocannabinol (THC). However, the route of administration as well as inter-individual factors played a crucial role regarding maximum concentrations, pharmacokinetic profiles, and psychoactive effects.
- MeSH
- Cannabinoid Receptor Agonists pharmacokinetics pharmacology MeSH
- Administration, Inhalation * MeSH
- Administration, Oral * MeSH
- Adult MeSH
- Emotions drug effects MeSH
- Pharmacokinetics * MeSH
- Immunologic Tests MeSH
- Cannabinoids * analysis blood pharmacokinetics pharmacology urine MeSH
- Liquid Chromatography-Mass Spectrometry MeSH
- Humans MeSH
- Psychophysiology * MeSH
- Psychotropic Drugs * analysis blood pharmacokinetics pharmacology urine MeSH
- Saliva chemistry MeSH
- Dronabinol pharmacokinetics pharmacology MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Konopí seté (Cannabis sativa) je rostlina, která byla do 19. století v Čechách i na Moravě zdrojem suroviny pro výrobu textilního materiálu kanafasu. S rozvojem výzkumu endokanabinoidního systému se tato rostlina dostává opět do popředí zájmu. Endokanabinoidní systém ovlivňuje homeostázu celého organismu na bázi modulace aktivity jiných neurotransmiterů, např. nocicepci, kognici, spasticitu, spánek aj. Kanabinoidní receptory se nachází v periferním (CB2) i centrálním nervovém systému (CB1), ale i v pojivových tkáních a imunitním systému. Nejznámějšími účinnými molekulami je delta-9-tetrahydrokanabinol (THC) a kanabidiol (CBD). Prezentuji kazuistiku pacienta s chronickými vertebrogenními obtížemi a polyneuropatií dolních končetin doprovázenou neuropatickou bolestí. Léčebné konopí v monoterapii nebo kombinované terapii může být dobrou volbou pro pacienty při léčbě neuropatické bolesti v individualizované léčbě.
Hemp (Cannabis sativa) is a herb which was used for the production of canvas until the 19th century in Bohemia and Moravia. The progress in research focused on endocanabinoid system brings this herb into the focus again. Endocanabinoid system influences homeostasis of the whole organism due to modulation of neurotransmiter activity and subsequently the nociception, cognition, spasticity, sleep etc. Cannabinoid receptors are situated in the peripheral (CB2) and central nervous system (CB1), as well as in the connective tissue and immune system. The best-known effective molecules are delta-9-tetrahydrocanabinol (THC) and cannabidiol (CBD). I present a case report of a patient with chronic vertebrogenic problems and polyneuropathy of the lower extremities accompanied by neuropathic pain. Medical cannabis in monotherapy or in combination therapy can be a good choice for patients with neuropathic pain in individualized treatment.
- MeSH
- Cannabis * MeSH
- Endocannabinoids pharmacology therapeutic use MeSH
- Cannabidiol metabolism therapeutic use MeSH
- Case Reports as Topic MeSH
- Humans MeSH
- Medical Marijuana * pharmacology therapeutic use MeSH
- Neuralgia diagnosis drug therapy MeSH
- Receptors, Cannabinoid MeSH
- Dronabinol metabolism therapeutic use MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Review MeSH
Hlavním cílem tohoto textu je představit nové psychoaktivní látky zahrnující širokou a různorodou skupinu látek, většinou syntetického původu, zejména se stimulačními, sedativními a halucinogenními účinky. Tyto látky byly vyvinuty nebo znovu uvedeny na trh, aby na jedné straně nahradily tradiční návykové látky, jejichž výroba a zejména distribuce často cílí na obcházení legislativy. Na druhé straně se jedná o velký obchodní potenciál pro výrobce a distributory těchto látek. V textu jsou představeny různé podskupiny těchto látek, jako jsou syntetické kanabinoidy a opioidy, a jejich závažná zdravotní rizika, včetně neurotoxických a kardiovaskulárních komplikací. Dále se zaměřuje na specifické skupiny uživatelů, které tyto látky preferují, na jejich důvody pro užívání, včetně snahy vyhnout se detekci drog nebo zlepšit sexuální prožitek. Zvláštní pozornost je věnována i novým psychedelickým látkám a kratomu, včetně jejich farmakologických vlastností a zdravotních rizik. Článek zdůrazňuje složitost fenoménu nových psychoaktivních látek a nutnost zvýšené pozornosti zdravotnických pracovníků při identifikaci a léčbě intoxikací těmito látkami.
The main objective of this text is to introduce new psychoactive substances, which encompass a broad and diverse group of substances, mostly of synthetic origin, with primarily stimulating, sedative, and hallucinogenic effects. These substances were developed or reintroduced to the market to replace traditional addictive substances, and their production often aims to circumvent legislation. The text discusses various subgroups of these substances, such as synthetic cannabinoids and opioids, and their serious health risks, including neurotoxic and cardiovascular complications. It also focuses on specific user groups who prefer these substances and their reasons for use, including attempts to avoid drug detection or enhance sexual experiences. Special attention is also given to new psychedelic substances and kratom, including their pharmacological properties and health risks. The article emphasizes the complexity of the phenomenon of new psychoactive substances and the need for increased attention from healthcare professionals in identifying and treating intoxications with these substances.
- MeSH
- Dimethoxyphenylethylamine administration & dosage pharmacology MeSH
- Cannabinoids pharmacology adverse effects MeSH
- Ketamine administration & dosage pharmacology adverse effects MeSH
- Humans MeSH
- Mitragyna chemistry adverse effects MeSH
- Analgesics, Opioid adverse effects MeSH
- Psychotropic Drugs * pharmacology classification adverse effects MeSH
- Wakefulness-Promoting Agents pharmacology adverse effects MeSH
- Drug Users MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
BACKGROUND: The rapid increase in cannabis use during pregnancy-up by 170 % between 2009 and 2016-raises pressing concerns about its effects on fetal health, particularly on the delicate monoamine system within the fetoplacental unit, which is crucial for placental function and neurodevelopment. OBJECTIVE: This systematic review explores the impact of prenatal cannabinoid exposure on the monoamine system within the fetoplacental unit, with a focus on its implications for fetal development through the lens of the Developmental Origins of Health and Disease (DOHaD) framework. METHODS: A comprehensive search across multiple databases initially retrieved 18,252 papers. After rigorous screening, only 16 animal studies and 4 human studies met the inclusion criteria. Findings were synthesized to evaluate the effects of prenatal cannabis exposure on neurotransmitter regulation, receptor function, and gene expression. RESULTS: Although no studies directly addressed the monoamine system in the placenta, animal models revealed significant disruptions in neurotransmitter regulation and neurodevelopmental changes following prenatal cannabis exposure. Human studies suggested potential cognitive and behavioral risks for offspring exposed in utero. CONCLUSION: This review exposes a critical gap in the literature on cannabis' effects on the placental monoamine system. While evidence points to notable neurodevelopmental risks, the scarcity of focused research underscores the need for further investigation to fully understand the implications of prenatal cannabis exposure.
- MeSH
- Biogenic Monoamines metabolism MeSH
- Cannabinoids * metabolism MeSH
- Humans MeSH
- Placenta * metabolism drug effects MeSH
- Pregnancy MeSH
- Fetal Development drug effects MeSH
- Prenatal Exposure Delayed Effects * metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Systematic Review MeSH
Quorum sensing, a bacterial cell-to-cell communication mechanism, plays a key role in bacterial virulence and biofilm formation. Targeting quorum-sensing pathways represents a promising strategy for the development of novel antibacterial agents. This study evaluated the anti-quorum-sensing activities of 18 natural compounds, including cannabinoids, arylbenzofurans, flavonoids, caffeine, and chlorogenic acid, using the luminescent biosensor strain Vibrio harveyi MM30. V. harveyi MM30, a mutant strain deficient in the production of autoinducer-2 (AI-2) but responsive to exogenous AI-2, was used to assess the activity of test compounds on the AI-2 receptor pathway. Test compounds were incubated in AI-2-containing media, and luminescence was measured to evaluate quorum-sensing inhibition. Comparisons were made in the absence of AI-2 to determine AI-2-independent inhibitory activity. The most active compounds were further tested on methicillin-resistant Staphylococcus aureus (MRSA 7112) to determine their effects on AI-2 production in spent media. Among the tested compounds, the non-prenylated arylbenzofuran moracin M and the prenylated arylbenzofuran moracin C exhibited significant quorum-sensing inhibitory activity in the AI-2-mediated pathway. None of the test compounds significantly inhibited quorum sensing in the absence of AI-2. Five compounds (cannabigerol, cannabidiol, cannabigerolic acid, moracin M, and moracin C) were selected for further investigation in MRSA 7112 cultures. The spent media from MRSA 7112 cultures treated with moracin M (16, 32, 64 μg/mL) and cannabigerolic acid (16 μg/mL) showed significant inhibition of AI-2 production when transferred to V. harveyi MM30 cultures. Moracin M and cannabigerolic acid demonstrated potential as quorum-sensing inhibitors by targeting AI-2 production and signalling pathways in MRSA 7112 and V. harveyi. These findings suggest their potential for further development as antibacterial agents targeting quorum-sensing mechanisms.
- Publication type
- Journal Article MeSH
Introduction: The use of Cannabis sativa L. in health care requires stringent care for the optimal production of the bioactive compounds. However, plant phenotypes and the content of secondary metabolites, such as phytocannabinoids, are strongly influenced by external factors, such as nutrient availability. It has been shown that phytocannabinoids can exhibit selective cytotoxicity against various cancer cell lines while protecting healthy tissue from apoptosis. Research Aim: This study aimed to clarify the cytotoxic effect of cannabis extracts on colorectal cell lines by identifying the main active compounds and determining their abundance and activity across all developmental stages of medical cannabis plants cultivated under hydroponic conditions. Materials and Methods: Dimethyl sulfoxide extracts of medical cannabis plants bearing the genotype classified as chemotype I were analyzed by high-performance liquid chromatography, and their cytotoxic activity was determined by measuring cell viability by methylthiazolyldiphenyl-tetrazolium bromide assay on the human colon cancer cell lines, Caco-2 and HT-29, and the normal human epithelial cell line, CCD 841 CoN. Results: The most abundant phytocannabinoid in cannabis extracts was tetrahydrocannabinolic acid (THCA). Its maximum concentrations were reached from the 7th to the 13th plant vegetation week, depending on the nutritional cycle and treatment. Almost all extracts were cytotoxic to the human colorectal cancer (CRC) cell line HT-29 at lower concentrations than the other cell lines. The phytocannabinoids that most affected the cytotoxicity of individual extracts on HT-29 were cannabigerol, Δ9-tetrahydrocannabinol, cannabidiol, cannabigerolic acid, and THCA. The tested model showed almost 70% influence of these cannabinoids. However, THCA alone influenced the cytotoxicity of individual extracts by nearly 65%. Conclusions: Phytocannabinoid extracts from plants of the THCA-dominant chemotype interacted synergistically and showed selective cytotoxicity against the CRC cell line, HT-29. This positive extract response indicates possible therapeutic value.
- MeSH
- Caco-2 Cells MeSH
- Cannabis * chemistry MeSH
- Hydroponics MeSH
- Humans MeSH
- Medical Marijuana * MeSH
- Dronabinol analysis MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
