Dietary Lutein and Cognitive Function in Adults: A Meta-Analysis of Randomized Controlled Trials

Emerging literature suggests that dietary lutein may have important functions in cognitive health, but there is not enough data to substantiate its effects in human cognition. The current study was intended to determine the overall effect of lutein on the main domains of cognition in the adult population based on available placebo randomized-controlled trials. Literature searches were conducted in PubMed, AGRICOLA, Scopus, MEDLINE, and EMBASE on 14 November 2020. The effect of lutein on complex attention, executive function and memory domains of cognition were assessed by using an inverse-variance meta-analysis of standardized mean differences (SMD) (Hedge’s g method). Dietary lutein was associated with slight improvements in cognitive performance in complex attention (SMD 0.02, 95% CI −0.27 to 0.31), executive function (SMD 0.13, 95% CI −0.26 to 0.51) and memory (SMD 0.03, 95% CI −0.26 to 0.32), but its effect was not significant. Change-from-baseline analysis revealed that lutein consumption could have a role in maintaining cognitive performance in memory and executive function. Although dietary lutein did not significantly improve cognitive performance, the evidence across multiple studies suggests that lutein may nonetheless prevent cognitive decline, especially executive function. More intervention studies are needed to validate the role of lutein in preventing cognitive decline and in promoting brain health.     

Cannabinoids—Characteristics and Potential for Use in Food Production

Scientific demonstrations of the beneficial effects of non-psychoactive cannabinoids on the human body have increased the interest in foods containing hemp components. This review systematizes the latest discoveries relating to the characteristics of cannabinoids from Cannabis sativa L. var. sativa, it also presents a characterization of the mentioned plant. In this review, we present data on the opportunities and limitations of cannabinoids in food production. This article systematizes the data on the legal aspects, mainly the limits of Δ9-THC in food, the most popular analytical techniques (LC-MS and GC-MS) applied to assay cannabinoids in finished products, and the available data on the stability of cannabinoids during heating, storage, and access to light and oxygen. This may constitute a major challenge to their common use in food processing, as well as the potential formation of undesirable degradation products. Hemp-containing foods have great potential to become commercially popular among functional foods, provided that our understanding of cannabinoid stability in different food matrices and cannabinoid interactions with particular food ingredients are expanded. There remains a need for more data on the effects of technological processes and storage on cannabinoid degradation.     

Assessing environmental chemical uptake in fetal brain in utero: A preliminary PET/CT study

Summary Exposure to several environmental chemicals in utero is associated with subtle deleterious effects in cognitive, motor and behavioral functions. In order to assess in utero exposure to possible neurotoxins, fetal brain uptake of an exogenous compound given to a pregnant rhesus macaque was investigated using PET/CT imaging. CT clearly delineated the fetus which allowed the time course of the PET tracer in the fetal brain and other organs to be monitored. This study demonstrates the feasibility of quantifying the absolute fetal uptake of chemicals given systemically to the mother.     

Traumatic Stress,Chronic Ethanol Exposure,or the Combination,Alter Cannabinoid System Components in Reward and Limbic Regions of the Mouse Brain

The cannabinoid system is independently affected by stress and chronic ethanol exposure. However, the extent to which co-occurrence of traumatic stress and chronic ethanol exposure modulates the cannabinoid system remains unclear. We examined levels of cannabinoid system components, anandamide, 2-arachidonoylglycerol, fatty acid amide hydrolase, and monoacylglycerol lipase after mouse single-prolonged stress (mSPS) or non-mSPS (Control) exposure, with chronic intermittent ethanol (CIE) vapor or without CIE vapor (Air) across several brain regions using ultra-high-performance liquid chromatography tandem mass spectrometry or immunoblotting. Compared to mSPS-Air mice, anandamide and 2-arachidonoylglycerol levels in the anterior striatum were increased in mSPS-CIE mice. In the dorsal hippocampus, anandamide content was increased in Control-CIE mice compared to Control-Air, mSPS-Air, or mSPS-CIE mice. Finally, amygdalar anandamide content was increased in Control-CIE mice compared to Control-Air, or mSPS-CIE mice, but the anandamide content was decreased in mSPS-CIE compared to mSPS-Air mice. Based on these data we conclude that the effects of combined traumatic stress and chronic ethanol exposure on the cannabinoid system in reward pathway regions are driven by CIE exposure and that traumatic stress affects the cannabinoid components in limbic regions, warranting future investigation of neurotherapeutic treatment to attenuate these effects.     

Cannabidiol Discovery and Synthesis—a Target-Oriented Analysis in Drug Production Processes

The current state of evidence and recommendations for cannabidiol (CBD) and its health effects change the legal landscape and aim to destigmatize its phytotherapeutic research. Recently, some countries have included CBD as an antiepileptic product for compassionate use in children with refractory epilepsy. The growing demand for CBD has led to the need for high-purity cannabinoids on the emerging market. The discovery and development of approaches toward CBD synthesis have arisen from the successful extraction of Cannabis plants for cannabinoid fermentation in brewer's yeast. To understand different contributions to the design and enhancement of the synthesis of CBD and its key intermediates, a detailed analysis of the history behind cannabinoid compounds and their optimization is provided herein.     

Combined high-pressure liquid chromatography and radioimmunoassay method for the quantitation of delta 9-tetrahydrocannabinol and some of its metabolites in human plasma

A high-pressure liquid chromatography-radioimmunoassay (HPLC-RIA) method for the measurement of cannabinoid levels in plasma is described. The method is capable of quantifying 0.1 ng of a cannabinoid in 1 ml of plasma. The experimental procedure consists of an initial separation of cannabinoids in a plasma extract by HPLC followed by collection of the HPLC eluate and RIA. A chromatogram consisting of the cross-reacting cannabinoids in plasma may then be constructed. The plasma concentrations of cannabinoids with retention volumes equivalent to those of delta 9-tetrahydrocannabinol, cannabinol and mono-hydroxylated metabolites have been measured by this technique.     

Real-time effects of nicotine exposure and withdrawal on neurotransmitter metabolism of hippocampal neuronal cells by microfluidic chip-coupled LC-MS

Nicotine ingested from smoking exerts neuroprotection and developmental neurotoxicity in central nervous system. It can produce several changes of cognitive behaviors through regulating the release of different neurotransmitters in the brain. However, the effects of nicotine exposure or withdrawal on neurotransmitter metabolism of hippocampus are still unclear. In this study, we real-time evaluated the dynamic alterations in neurotransmitter metabolism of hippocampal neuronal(HT22) cells induced...     

A search for properties which produce discrimination between cannabinoid psychoactivity and analgesic activity

One long-range goal of our work has been the design of cannabinoid analgesics with reduced psychopharmacological liability. We review here the progress we have made toward this goal. When we began our work on the cannabinoids, no cannabinoid analgesic had been reported that did not also possess significant psychoactivity. We approached the cannabinoid problem by calculating molecular reactivity characteristics (MRCS ) of template molecules for each activity: (?)-trans-delta-9-tetrahydrocannabinol (Δ⁹-THC) for psychoactivity, and (?)-9-nor-9-betahydroxyhexahydrocannabinol (9-nor-9β-OH? HHC) for analgesic activity. We then compared the MRC s of each template with the MRCS of a carefully chosen set of other cannabinoids (both active and inactive). Our focus in the calculation of MRCS was on accessible conformations of each subject molecule and on the molecular electrostatic potential generated in key planes by each accessible conformer. Our working hypothesis concerning the molecular basis of psychopharmacological activity in the cannabinoids was that activity is conferred by the set of molecular properties generated (1) by the orientation of the lone pairs of electrons of the phenyl group hydroxyl oxygen and (2) by the orientation of the carbocyclic ring and its C–9 substituent relative to this oxygen. Our working hypothesis concerning the molecular basis of cannabinoid analgesic activity was that activity is conferred by the set of molecular properties generated by the presence and relative location of two negative potential regions in the top half of the cannabinoid analgesic molecule. Our work thus far has revealed important steric and electronic features of the cannabinoids that may be used to enhance discrimination. We have shown that a simple structural feature, a C–9 substituent protruding into the α face of the molecule, can abolish or significantly diminish psychoactivity. We have also demonstrated that a free phenol group is not an absolute requirement for activity. Instead, we have found that compounds that do not possess free phenolic hydrogens, but that do maintain the orientation of the lone pairs of electrons of the “phenolic” oxygen toward the carbocyclic ring, exhibit selectivity toward analgesia.     

UV-B RADIATION EFFECTS ON PHOTOSYNTHESIS, GROWTH and CANNABINOID PRODUCTION OF TWO Cannabis sativa CHEMOTYPES

The effects of UV-B radiation on photosynthesis, growth and cannabinoid production of two greenhouse-grown C. sativa chemotypes (drug and fiber) were assessed. Terminal meristems of vegetative and reproductive tissues were irradiated for 40 days at a daily dose of 0, 6.7 or 13.4 kJ m^-2 biologically effective UV-B radiation. Infrared gas analysis was used to measure the physiological response of mature leaves, whereas gas-liquid chromatography was used to determine the concentration of cannabinoids in leaf and floral tissue.
There were no significant physiological or morphological differences among UV-B treatments in either drug- or fiber-type plants. The concentration of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), but not of other cannabinoids, in both leaf and floral tissues increased with UV-B dose in drug-type plants. None of the cannabinoids in fiber-type plants were affected by UV-B radiation.
The increased levels of Δ⁹-THC in leaves after irradiation may account for the physiological and morphological tolerance to UV-B radiation in the drug-type plants. However, fiber plants showed no comparable change in the level of cannabidiol (a cannabinoid with UV-B absorptive characteristics similar to Δ⁹ THC). Thus the contribution of cannabinoids as selective UV-B filters in C. sativa is equivocal.     

High-Throughput Quantitation of Cannabinoids by Liquid Chromatography Triple-Quadrupole Mass Spectrometry

The high-throughput quantitation of cannabinoids is important for the cannabis industry. As medicinal products increase, and research into compounds that have pharmacological benefits increase, and the need to quantitate more than just the main cannabinoids becomes more important. This study aims to provide a rapid, high-throughput method for cannabinoid quantitation using a liquid chromatography triple-quadrupole mass spectrometer (LC-QQQ-MS) with an ultraviolet diode array detector (UV-DAD) for 16 cannabinoids: CBDVA, CBDV, CBDA, CBGA, CBG, CBD, THCV, THCVA, CBN, CBNA, THC, Δ8-THC, CBL, CBC, THCA-A and CBCA. Linearity, limit of detection (LOD), limit of quantitation (LOQ), accuracy, precision, recovery and matrix effect were all evaluated. The validated method was used to determine the cannabinoid concentration of four different Cannabis sativa strains and a low THC strain, all of which have different cannabinoid profiles. All cannabinoids eluted within five minutes with a total analysis time of eight minutes, including column re-equilibration. This was twice as fast as published LC-QQQ-MS methods mentioned in the literature, whilst also covering a wide range of cannabinoid compounds.     

Elucidation of the Chemical Structure of a Gas Chromatographic Artifact of Synthetic Cannabinoid <Emphasis Type="Italic">N</Emphasis>-(1-Carbamoyl-2-Methylpropyl)-1-(Cyclohexylmethyl)-1<Emphasis Type="Italic">H</Emphasis>-Indazol-3Ccarboxamide by High-Resolution Mass Spectrometry

Synthetic cannabinoids are the most popular psychoactive compounds on the illegal market. In the gas chromatographic determination, some synthetic cannabinoids undergo chemical transformations because of their thermal interaction with the chromatographic system. This paper is devoted to the elucidation of the structure of a gas chromatographic artifact formed from synthetic cannabinoid N-(1-carbamoyl-2-methylpropyl)-1-(cyclohexylmethyl)-1H-indazol-3-carboxamide as a result of dehydration of its terminal carbamoyl moiety. The chemical structure of the artifact is determined by high-resolution mass spectrometry.     

Cannabidiol Attenuates MK-801-Induced Cognitive Symptoms of Schizophrenia in the Passive Avoidance Test in Mice

Schizophrenia is a chronic mental disorder that disturbs feelings and behavior. The symptoms of schizophrenia fall into three categories: positive, negative, and cognitive. Cognitive symptoms are characterized by memory loss or attentional deficits, and are especially difficult to treat. Thus, there is intense research into the development of new treatments for schizophrenia-related responses. One of the possible strategies is connected with cannabidiol (CBD), a cannabinoid compound. This research focuses on the role of CBD in different stages of memory (acquisition, consolidation, retrieval) connected with fear conditioning in the passive avoidance (PA) learning task in mice, as well as in the memory impairment typical of cognitive symptoms of schizophrenia. Memory impairment was provoked by an acute injection of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (animal model of schizophrenia). Our results revealed that an acute injection of CBD (30 mg/kg; intraperitoneally (i.p.) improved all phases of long-term fear memory in the PA test in mice. Moreover, the acute injection of non-effective doses of CBD (1 or 5 mg/kg; i.p.) attenuated the memory impairment provoked by MK-801 (0.6 mg/kg; i.p.) in the consolidation and retrieval stages of fear memory, but not in the acquisition of memory. The present findings confirm that CBD has a positive influence on memory and learning processes in mice, and reveals that this cannabinoid compound is able to attenuate memory impairment connected with hypofunction of glutamate transmission in a murine model of schizophrenia.     

Thioamide derivatives of cannabinoids. A study of the influence of the thioamide function on regiochemistry in the synthesis of thioamide cannabinoids from 2,4-dihydroxybenzothioamides

Several thiocarbamoyl derivatives of cannabinoids were obtained in the collidine-catalysed condensation of 2,4-dihydroxybenzothioamides with citral and citronellal. The thioamide function was found to change the regioselective preferences of the reaction as compared with the known cannabinoid syntheses from hydroxyacetophenones. The experimental results and theoretical (FMO theory) considerations made it possible to advance the reaction mechanism. Convenient methods were developed for the synthesis of the starting 2,4-dihydroxybenzothioamides from resorcinol and isothiocyanates in the presence of the boron trifluoride/acetic acid 1:2 complex or aluminum chloride in nitromethane.     

LC/ESI-MS/MS method for quantification of 28 synthetic cannabinoids in neat oral fluid and its application to preliminary studies on their detection windows

Serum and urine samples are commonly used for the analysis of synthetic cannabinoids in biofluids; however, their utilization as analytical matrices for drug abstinence control features some substantial drawbacks. While for blood collection invasive sampling is inevitable, the urinary analysis of synthetic cannabinoids is limited by the lack of available reference standards of the respective major metabolites. Moreover, the long detectability of synthetic cannabinoids in both matrices hampers the identification of a recent synthetic cannabinoid use. This article describes the development, validation and application of an LC/ESI-MS/MS method for the quantification of 28 synthetic cannabinoids in neat oral fluid (OF) samples. OF samples were prepared by protein precipitation using ice-cold acetonitrile. Chromatographic separation was achieved by gradient elution on a Luna Phenyl Hexyl column (50?×?2 mm, 5 μm), while detection was carried out on a QTrap 4000 instrument in positive ionization mode. The limits of detection ranged from 0.02 to 0.40 ng/mL, whereas the lower limits of quantification ranged from 0.2 to 4.0 ng/mL. The method was applied to authentic samples collected during two preliminary studies in order to obtain insights into the general detectability and detection windows of synthetic cannabinoids in this matrix. The results indicate that synthetic cannabinoids are transferred from the blood stream into OF and vice versa only at a very low rate. Therefore, positive OF samples are due to contamination of the oral cavity during smoking. As these drug-contaminations could be detected up to approximately 2 days, neat oral fluid appears to be well suited for detection of a recent synthetic cannabinoid use.

Genistein: A Potential Natural Lead Molecule for New Drug Design and Development for Treating Memory Impairment

Genistein is a naturally occurring polyphenolic molecule in the isoflavones group which is well known for its neuroprotection. In this review, we summarize the efficacy of genistein in attenuating the effects of memory impairment (MI) in animals. Scopus, PubMed, and Web of Science databases were used to find the relevant articles and discuss the effects of genistein in the brain, including its pharmacokinetics, bioavailability, behavioral effects, and some of the potential mechanisms of action on memory in several animal models. The results of the preclinical studies highly suggested that genistein is highly effective in enhancing the cognitive performance of the MI animal models, specifically in the memory domain, including spatial, recognition, retention, and reference memories, through its ability to reduce oxidative stress and attenuate neuroinflammation. This review also highlighted challenges and opportunities to improve the drug delivery of genistein for treating MI. Along with that, the possible structural modifications and derivatives of genistein to improve its physicochemical and drug-likeness properties are also discussed. The outcomes of the review proved that genistein can enhance the cognitive performance and ameliorate MI in different preclinical studies, thus indicating its potential as a natural lead for the design and development of a novel neuroprotective drug.     

Constituents of cannabis sativa L. XII—mass spectral fragmentation patterns for some. Cannabinoid acid as their TMS derivatives

Fragmentation schemes for a number of TMS derivatized cannabinoid acids are described. Specific fragmentation pathways and rearrangement mechanisms were determined based on the ion composition of deuterium labeled derivatives. Significant differences in the mode of fragmentation of the two isomeric Δ⁹-tetrahydrocannabinolic acids are described. These results are based on information obtained from deuterium labeling and high resolution data or by the extension of previously reported mechanisms for neutral cannabinoids. Comparisons of the fragmentation schemes between the neutral and acidic cannabinoids are used to confirm many of the fragmentation mechanisms.     

The Therapeutic Potential of Cannabis in Counteracting Oxidative Stress and Inflammation

Significant growth of interest in cannabis (Cannabis sativa L.), especially its natural anti-inflammatory and antioxidative properties, has been observed recently. This narrative review aimed to present the state of the art of research concerning the anti-inflammatory activity of all classes of cannabinoids published in the last five years. Multimodal properties of cannabinoids include their involvement in immunological processes, anti-inflammatory, and antioxidative effects. Cannabinoids and non-cannabinoid compounds of cannabis proved their anti-inflammatory effects in numerous animal models. The research in humans is missing, and the results are unconvincing. Although preclinical evidence suggests cannabinoids are of value in treating chronic inflammatory diseases, the clinical evidence is scarce, and further well-designed clinical trials are essential to determine the prospects for using cannabinoids in inflammatory conditions.     

Comparative proteomic and phosphoproteomic profiling of pancreatic adenocarcinoma cells treated with CB1 or CB2 agonists

The pancreatic adenocarcinoma cell line Panc1 was treated with cannabinoid receptor ligands (arachidonylcyclopropylamide or GW405833) in order to elucidate the molecular mechanism of their anticancer effect. A proteomic approach was used to analyze the protein and phosphoprotein profiles. Western blot and functional data mining were also employed in order to validate results, classify proteins, and explore their potential relationships. We demonstrated that the two cannabinoids act through a widely common mechanism involving up‐ and down‐regulation of proteins related to energetic metabolism and cell growth regulation. Overall, the results reported might contribute to the development of a therapy based on cannabinoids for pancreatic adenocarcinoma.     

Quantitative analysis of cannabinoids from Cannabis sativa using 1H-NMR

A (1)H-NMR method has been developed for the quantitative analysis of pure cannabinoids and for cannabinoids present in Cannabis sativa plant material without any chromatographic purification. The experiment was performed by the analysis of singlets in the range of delta 4.0-7.0 in the (1)H-NMR spectrum, in which distinguishable signals of each cannabinoid are shown. Quantitation was performed by calculating the relative ratio of the peak area of selected proton signals of the target compounds to the known amount of the internal standard, anthracene. For this method no reference compounds are needed. It allows rapid and simple quantitation of cannabinoids with a final analysis time of only 5 min without the need for a pre-purification step.     

Development of Gas-Chromatographic Method for Simultaneous Determination of Cannabinoids and Terpenes in Hemp

An original gas chromatographic method has been developed for simultaneous determination of major terpenes and cannabinoids in plant samples and their extracts. The main issues to be addressed were the large differences in polarity and volatility between both groups of analytes, but also the need for an exhaustive decarboxylation of cannabinoid acidic forms. Sample preparation was minimised, also by avoiding any analyte derivatisation. Acetone was found to be the most appropriate extraction solvent. Successful chromatographic separation was achieved by using a medium polarity column. Limits of detection ranged from 120 to 260 ng/mL for terpenes and from 660 to 860 ng/mL for cannabinoids. Parallel testing proved the results for cannabinoids are comparable to those obtained from established HPLC methods. Despite very large differences in concentrations between both analyte groups, a linear range between 1 and 100 µg/mL for terpenes and between 10 and 1500 µg/mL for cannabinoids was determined.