Artículos científicos Authors Article Title Source Title Language Document Type Author Keywords Keywords Plus Abstract Addresses Affiliations Reprint Addresses Email Addresses Publication Date Publication Year Volume Issue DOI DOI Link Tipo Área Categoría Research Areas Aardema, ML; DeSalle, R Can public online databases serve as a source of phenotypic information for Cannabis genetic association studies? PLOS ONE English Article The use of Cannabis is gaining greater social acceptance for its beneficial medicinal and recreational uses. With this acceptance has come new opportunities for crop management, selective breeding, and the potential for targeted genetic manipulation. However, as an agricultural product Cannabis lags far behind other domesticated plants in knowledge of the genes and genetic variation that influence plant traits of interest such as growth form and chemical composition. Despite this lack of information, there are substantial publicly available resources that document phenotypic traits believed to be associated with particular Cannabis varieties. Such databases could be a valuable resource for developing a greater understanding of genes underlying phenotypic variation if combined with appropriate genetic information. To test this potential, we collated phenotypic data from information available through multiple online databases. We then produced a Cannabis SNP database from 845 strains to examine genome wide associations in conjunction with our assembled phenotypic traits. Our goal was not to locate Cannabis-specific genetic variation that correlates with phenotypic variation as such, but rather to examine the potential utility of these databases more broadly for future, explicit genome wide association studies (GWAS), either in stand-alone analyses or to complement other types of data. For this reason, we examined a very broad array of phenotypic traits. In total, we performed 201 distinct association tests using web-derived phenotype data appended to 290 uniquely named Cannabis strains. Our results indicated that chemical phenotypes, such as tetrahydrocannabinol (THC) and cannabidiol (CBD) content, may have sufficiently high-quality information available through web-based sources to allow for genetic association inferences. In many cases, variation in chemical traits correlated with genetic variation in or near biologically reasonable candidate genes, including several not previously implicated in Cannabis chemical variation. As with chemical phenotypes, we found that publicly available data on growth traits such as height, area of growth, and floral yield may be precise enough for use in future association studies. In contrast, phenotypic information for subjective traits such as taste, physiological affect, neurological affect, and medicinal use appeared less reliable. These results are consistent with the high degree of subjectivity for such trait data found on internet databases, and suggest that future work on these important but less easily quantifiable characteristics of Cannabis may require dedicated, controlled phenotyping. [Aardema, Matthew L.] Montclair State Univ, Dept Biol, Montclair, NJ 07043 USA; [Aardema, Matthew L.; DeSalle, Rob] Amer Museum Nat Hist, Sackler Inst Comparat Genom, New York, NY 10024 USA Montclair State University; American Museum of Natural History (AMNH) Aardema, ML (corresponding author), Montclair State Univ, Dept Biol, Montclair, NJ 07043 USA.;Aardema, ML (corresponding author), Amer Museum Nat Hist, Sackler Inst Comparat Genom, New York, NY 10024 USA. aardemam@montclair.edu Feb-23 2021 16 2 10.1371/journal.pone.0247607 http://dx.doi.org/10.1371/journal.pone.0247607 Estudio Agrícola Producción Science & Technology - Other Topics Abame, MA; He, Y; Wu, S; Xie, ZF; Zhang, J; Gong, XD; Wu, CH; Shen, JS Chronic administration of synthetic cannabidiol induces antidepressant effects involving modulation of serotonin and noradrenaline levels in the hippocampus NEUROSCIENCE LETTERS English Article Synthetic cannabidiol; Depression; Serotonin; Noradrenaline; Nuclear factor kappa B INVOLVEMENT; DEPRESSION Cannabidiol (CBD) is a non-psychotomimetic compound derived from Cannabis sativa. Preclinical and clinical studies have shown therapeutic potential of CBD in a variety of disorders. Despite several research efforts on CBD, its antidepressant activity has been poorly investigated and the exact mechanism of action remains unclear. Thus, this study aimed to further explore the mechanism of CBD after chronic administration (7 days). First, the dose level of CBD that is enough to produce antidepressant effects after chronic administration was explored. Second, the changes in key proteins and neurotransmitters through such methods as real-time polymerase chain reaction (RT-PCR), western blotting, and high-performance liquid chromatography-electrochemical detection (HPLC-ECD) were critically studied. Furthermore, correlation between behavioral phenotypes with protein and neurotransmitters was established and the possible mechanism was herein postulated. The results showed that only the high dose CBD 100 mg/kg chronic administration induced antidepressant-like effects in mice subjected to forced swim test. Chronic CBD 100 mg/kg administration resulted in significant increases in serotonin (5-HT) and noradrenaline (NA) levels in the hippocampus (HPC). Similarly, the chronic administration of CBD 30 mg/kg and CBD 100 mg/kg significantly decreased nuclear factor kappa B (NF-kappa B) expression in the HPC. Moreover, none of the treatments were observed to induce locomotor effects. Thus, we concluded that chronic administration of CBD (100 mg/kg) induced antidepressant-like effects by increasing 5-HT and NA levels in the HPC. These results shed new light on further discovery of the antidepressant effect of CBD. [Abame, Melkamu Alemu; He, Yang; Shen, Jingshan] Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Medial, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; [Abame, Melkamu Alemu; Shen, Jingshan] Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China; [Wu, Song; Xie, Zhifei; Zhang, Jian; Gong, Xudong; Wu, Chunhui] Topharman Shanghai Co Ltd, Dept Druggabilty Evaluat, Shanghai 201203, Peoples R China Chinese Academy of Sciences; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS Wu, CH (corresponding author), Topharman Shanghai Co Ltd, Dept Druggabilty Evaluat, Shanghai 201203, Peoples R China.;Shen, JS (corresponding author), Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China. shenjingshan@simm.ac.cn JAN 23 2021 744 10.1016/j.neulet.2020.135594 http://dx.doi.org/10.1016/j.neulet.2020.135594 Estudio Médica Neurología Neurosciences & Neurology Abbotts, KSS; Ewell, TR; Butterklee, HM; Bomar, MC; Akagi, N; Dooley, GP; Bell, C Cannabidiol and Cannabidiol Metabolites: Pharmacokinetics, Interaction with Food, and Influence on Liver Function NUTRIENTS English Article cannabis; cannabinoid; metabolism; thermogenesis; energy expenditure; pharmacodynamics; insulin; triglyceride THERMOGENIC RESPONSIVENESS; ENDOCANNABINOID SYSTEM; ENERGY-EXPENDITURE; DOUBLE-BLIND; EXERCISE; SEIZURES; ADAPTATION; OBESITY; ACID; CB1 Cannabidiol (CBD) is widely available and marketed as having therapeutic properties. Over-the-counter CBD is unregulated, many of the therapeutic claims lack scientific support, and controversy exists as to the safety of CBD-liver interaction. The study aims were to compare the pharmacokinetics of commercial CBD and CBD metabolites following the ingestion of five different CBD formulations, determine the influence of CBD on food induced thermogenesis, determine the influence of food on CBD pharmacokinetics, and determine the influence of CBD on markers of liver function. Fourteen males (body mass index >= 25 kg/m(2)) were studied in a placebo-controlled, randomized, crossover design. On five occasions, different CBD formulations were ingested (one per visit). On two additional occasions, CBD or placebo was ingested following a meal. CBD servings were standardized to 30 mg. Considerable pharmacokinetic variability existed between formulations; this pharmacokinetic variability transferred to several of the metabolites. CBD did not influence food induced thermogenesis but did favorably modify early insulin and triglyceride responses. Food appreciably altered the pharmacokinetics of CBD. Finally, CBD did not evoke physiologically relevant changes in markers of liver function. Collectively, these data suggest that consumers should be aware of the appreciable pharmacokinetic differences between commercial CBD formulations, CBD is unlikely to influence the caloric cost of eating but may prove to be of some benefit to initial metabolic responses, consuming CBD with food alters the dynamics of CBD metabolism and increases systemic availability, and low-dose CBD probably does not represent a risk to normal liver function. [Abbotts, Kieran Shay Struebin; Ewell, Taylor Russell; Butterklee, Hannah Michelle; Bomar, Matthew Charles; Bell, Christopher] Colorado State Univ, Dept Hlth & Exercise Sci, Ft Collins, CO 80523 USA; [Akagi, Natalie; Dooley, Gregory P.] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA Colorado State University; Colorado State University Bell, C (corresponding author), Colorado State Univ, Dept Hlth & Exercise Sci, Ft Collins, CO 80523 USA. kieran.abbotts@colostate.edu; taylor.ewell@colostate.edu; hmbutter@rams.colostate.edu; matt.bomar@rams.colostate.edu; natalie.akagi@gmail.com; gregory.dooley@colostate.edu; christopher.bell@colostate.edu MAY 2022 14 10 10.3390/nu14102152 http://dx.doi.org/10.3390/nu14102152 Estudio Médica Nutrición Nutrition & Dietetics Abendroth, JA; Gondhalekar, AD; Scharf, ME; Couture, JJ Cannabidiol reduces fall armyworm (Spodoptera frugiperda) growth by reducing consumption and altering detoxification and nutritional enzyme activity in a dose-dependent manner ARTHROPOD-PLANT INTERACTIONS English Article Cannabidiol; Cannabis; CYP450; Plant-insect chemical ecology; Protease; Toxicology PROTEINASE-INHIBITORS; PLANT; MECHANISMS; RESISTANCE; PERFORMANCE; PHYTOCANNABINOIDS; DEFENSE Plant quality can shape plant-insect interactions and plant secondary metabolites are known to play an influential role in mediating these interactions. Cannabinoids are a group of terpenophenolic compounds in Cannabis that have demonstrated negative effects on insect herbivores, yet specific mechanisms are currently not well understood. Insects can modulate their rate of growth, food intake, or production of frass (i.e., insect feces) to mitigate consumption of a diet with poor nutritional quality. Detoxification and nutritional enzymes are essential in performing these functions. To test how cannabinoids impact insect performance and enzymatic activity, we performed no-choice feeding bioassays on fall armyworm (Spodoptera frugiperda) with artificial diet spiked with different concentrations of CBD and measured fall armyworm growth, consumption, and frass production and analyzed detoxification and nutritional enzyme activities. We found that as CBD concentration increased fall armyworm growth and consumption decreased, but found no impact on digestibility or conversion efficiencies. Results from the enzymatic assays varied, but CYP450 and protease activity decreased, while glucosidase activity increased, as CBD concentration increased. Relationships among enzyme activities suggest that a reduction in protease activity might limit a detoxification response, by limiting amino acid availability needed for detoxification enzyme production, even though energy collection activity, via increased glucosidase activity, occurred. These outcomes suggest specific mechanisms by which CBD has a negative influence on insect herbivore performance. [Abendroth, J. A.; Gondhalekar, A. D.; Scharf, M. E.; Couture, J. J.] Purdue Univ, Dept Entomol, W Lafayette, IN 47907 USA; [Abendroth, J. A.; Couture, J. J.] Purdue Univ, Ctr Plant Biol, W Lafayette, IN 47907 USA; [Couture, J. J.] Purdue Univ, Dept Forestry & Nat Resources, W Lafayette, IN 47907 USA; [Scharf, M. E.] Univ Florida, Entomol & Nematol Dept, Gainesville, FL 32611 USA; [Abendroth, J. A.] Penn State Univ, Dept Entomol, State Coll, PA 16801 USA Purdue University System; Purdue University; Purdue University West Lafayette Campus; Purdue University System; Purdue University; Purdue University West Lafayette Campus; Purdue University System; Purdue University; Purdue University West Lafayette Campus; State University System of Florida; University of Florida; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University Couture, JJ (corresponding author), Purdue Univ, Dept Entomol, W Lafayette, IN 47907 USA.;Couture, JJ (corresponding author), Purdue Univ, Ctr Plant Biol, W Lafayette, IN 47907 USA.;Couture, JJ (corresponding author), Purdue Univ, Dept Forestry & Nat Resources, W Lafayette, IN 47907 USA. couture@purdue.edu APR 2023 17 2 10.1007/s11829-023-09948-x http://dx.doi.org/10.1007/s11829-023-09948-x Estudio Biología Entomología Environmental Sciences & Ecology; Entomology Abichabki, N; Zacharias, LV; Moreira, NC; Bellissimo-Rodrigues, F; Moreira, FL; Benzi, JRL; Ogasawara, TMC; Ferreira, JC; Ribeiro, CM; Pavan, FR; Pereira, LRL; Brancini, GTP; Braga, GUL; Zuardi, AW; Hallak, JEC; Crippa, JAS; Lanchote, VL; Canton, R; Darini, ALC; Andrade, LN Potential cannabidiol (CBD) repurposing as antibacterial and promising therapy of CBD plus polymyxin B (PB) against PB-resistant gram-negative bacilli SCIENTIFIC REPORTS English Article ACINETOBACTER-BAUMANNII; DISSEMINATION; CANNABINOIDS; ANTIBIOTICS; MECHANISMS; COLISTIN; ASSAY This study aimed to assess the ultrapure cannabidiol (CBD) antibacterial activity and to investigate the antibacterial activity of the combination CBD + polymyxin B (PB) against Gram-negative (GN) bacteria, including PB-resistant Gram-negative bacilli (GNB). We used the standard broth microdilution method, checkerboard assay, and time-kill assay. CBD exhibited antibacterial activity against Gram-positive bacteria, lipooligosaccharide (LOS)-expressing GN diplococcus (GND) (Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella catarrhalis), and Mycobacterium tuberculosis, but not against GNB. For most of the GNB studied, our results showed that low concentrations of PB (<= 2 mu g/mL) allow CBD (<= 4 mu g/mL) to exert antibacterial activity against GNB (e.g., Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii), including PB-resistant GNB. CBD + PB also showed additive and/or synergistic effect against LOS-expressing GND. Time-kill assays results showed that the combination CBD + PB leads to a greater reduction in the number of colony forming units per milliliter compared to CBD and PB alone, at the same concentration used in combination, and the combination CBD + PB was synergistic for all four PB-resistant K. pneumoniae isolates evaluated. Our results show that CBD has translational potential and should be further explored as a repurposed antibacterial agent in clinical trials. The antibacterial efficacy of the combination CBD + PB against multidrug-resistant and extensively drug-resistant GNB, especially PB-resistant K. pneumoniae, is particularly promising. [Abichabki, Nathalia; Zacharias, Luisa, V; Moreira, Natalia C.; Moreira, Fernanda L.; Benzi, Jhohann R. L.; Ogasawara, Tania M. C.; Ferreira, Joseane C.; Pavan, Fernando R.; Brancini, Guilherme T. P.; Braga, Gilberto U. L.; Lanchote, Vera L.; Darini, Ana Lucia C.; Andrade, Leonardo N.] Univ Sao Paulo, Dept Clin Anal Toxicol & Food Sci DACTB, Sch Pharmaceut Sci Ribeirao Preto FCFRP, Av Cafe S-N,Campus Univ, BR-14040903 Ribeirao Preto, SP, Brazil; [Bellissimo-Rodrigues, Fernando] Univ Sao Paulo, Ribeirao Preto Med Sch FMRP, Dept Social Med, Ribeirao Preto, SP, Brazil; [Ribeiro, Camila M.] Sao Paulo State Univ UNESP, Sch Pharmaceut Sci FCF, Dept Biol Sci, Araraquara, SP, Brazil; [Pereira, Leonardo R. L.] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto FCFRP, Dept Pharmaceut Sci DCF, Ribeirao Preto, SP, Brazil; [Zuardi, Antonio W.; Hallak, Jaime E. C.; Crippa, Jose A. S.] Univ Sao Paulo, Ribeirao Preto Med Sch FMRP, Dept Neurosci & Behav Sci, Ribeirao Preto, SP, Brazil; [Zuardi, Antonio W.; Hallak, Jaime E. C.; Crippa, Jose A. S.] Conselho Nacl Desenvolvimento Cientif & Tecnol CN, Natl Inst Sci & Technol Translat Med INCT TM, Brasilia, DF, Brazil; [Canton, Rafael] Hosp Univ Ramon y Cajal, Madrid, Spain; [Canton, Rafael] Inst Ramon y Cajal Invest Sanitaria IRYCIS, Madrid, Spain Universidade de Sao Paulo; Universidade de Sao Paulo; Universidade Estadual Paulista; Universidade de Sao Paulo; Universidade de Sao Paulo; Hospital Universitario Ramon y Cajal Andrade, LN (corresponding author), Univ Sao Paulo, Dept Clin Anal Toxicol & Food Sci DACTB, Sch Pharmaceut Sci Ribeirao Preto FCFRP, Av Cafe S-N,Campus Univ, BR-14040903 Ribeirao Preto, SP, Brazil. leonardo@fcfrp.usp.br APR 19 2022 12 1 10.1038/s41598-022-10393-8 http://dx.doi.org/10.1038/s41598-022-10393-8 Estudio Biología Microbiología Science & Technology - Other Topics Abidi, AH; Abhyankar, V; Alghamdi, SS; Tipton, DA; Dabbous, M Phytocannabinoids regulate inflammation in IL-1 beta-stimulated human gingival fibroblasts JOURNAL OF PERIODONTAL RESEARCH English Article cannabinoids; CB1 receptor; CB2 receptor; cytokines; periodontal disease; periodontitis TUMOR-NECROSIS-FACTOR; ENDOCANNABINOID SYSTEM; CANNABINOID CONCENTRATIONS; INTERFERON-GAMMA; ORAL FLUID; RECEPTOR; INTERLEUKIN-2; PERIODONTITIS; PHARMACOLOGY; PREVALENCE Objectives Billions of individuals worldwide suffer from periodontal disease, an inflammatory disease that results in hard-tissue and soft-tissue destruction. A viable therapeutic option to treat periodontal disease may be via cannabinoids that exert immunomodulatory effects, and the endocannabinoid system (ECS) is readily present in periodontal tissues that exhibit cannabinoid type 1 and 2 receptors (CB1R and CB2R). Phytocannabinoids (pCBs), which are a part of a heterogeneous group of molecules acting on cannabinoid receptors (CBR) derived from the cannabis plants, have been attributed to a wide variety of effects including anti-inflammatory activity and some pro-inflammatory effects depending on the cell type. Thus, this study aims to examine the effects of pCBs on primary human gingival fibroblasts (HGFs) in IL-1 beta stimulated (simulated periodontal disease) HGFs. Materials and Methods Human gingival fibroblasts (HGFs) obtained from ATCC were cultured per the manufacturer's recommendation. The functional activity of cannabinoid receptors was measured using ACTOne (cAMP)-based CB1R and CB2R assay. The effects of three pCBs (0.1-10 mu g/ml or 10(-4.5)-10(-6.5) M) on cell viability were assessed using the CCK-8 cellular dehydrogenase assay. IL-1 beta (1 ng/ml) was added an hour before the treatment to stimulate inflammation in the HGFs before the addition of cannabinoid ligands. After 24-h incubation, the production of INF-gamma, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and TNF-alpha was measured using Mesoscale Discovery (MSD) Human Pro-Inflammatory kit. To measure prostaglandin E 2 levels (PGE2), Cisbio HTRF PGE2 assay kit was used per the manufacturer's recommendation to measure after 24-h incubation. The data were analyzed using GraphPad Prism 6.0. The analytes for each group were compared using a one-way ANOVA test with Bonferroni's correction. Results Cannabidivarin (CBVN or CBDV) (EC50 = 12 nM) and cannabigerol (CBG) (EC50 = 30 nM) exhibited agonist activity on CB2R with intermediate efficacy. Cannabidiol (CBD) did not exhibit activation of the CB2R, and the CB1R activation was not observed with any of the pCBs. Cytotoxicity results showed that concentrations of 2.50 mu g/ml or greater for the pCBs were toxic except for CBVN. Lower concentrations of CBD and CBG (0.1-0.75 mu g/ml), and CBVN at 2.50 mu g/ml exhibited significant effects on HGF proliferation. In IL-1 beta-stimulated HGFs, prostaglandin E2 (PGE2) production was significantly suppressed only by CBG and CBVN. CBD and CBG treatment alone did, however, elevate PGE2 production significantly compared to control. IL-1 beta stimulation resulted in a robust increase in the production of all cytokines tested. Treatment of IL-beta-stimulated HGF with the three pCBs (1 mu g/ml) significantly reduced INF-gamma, TNF-alpha, and IL-2. The significant suppression of IL-4 was seen with CBD and CBVN, while only CBVN exerted suppression of IL-13. The three pCBs significantly increased IL-6, IL-10, and IL-12 levels, while none of the pCBs reduced the expression of IL-8 in IL-1 beta-stimulated HGF. Conclusion The effective inhibition of IL-1 beta-stimulated production of PGE2 and cytokines by the pCB in HGFs suggests that targeting the endocannabinoid system may lead to the development of therapeutic strategies for periodontal therapy. However, each pCB has its unique anti-inflammatory profile, in which certain pro-inflammatory activities are also exhibited. The pCBs alone or in combination may benefit and aid in improving public oral health. [Abidi, Ammaar H.; Abhyankar, Vrushali; Tipton, David A.; Dabbous, Mustafa] Univ Tennessee, Coll Dent, Hlth Sci Ctr UTHSC, 711 Jefferson Ave,Suite 429, Memphis, TN 38163 USA; [Abidi, Ammaar H.; Abhyankar, Vrushali; Tipton, David A.; Dabbous, Mustafa] Univ Tennessee, Dept Biosci Res, Hlth Sci Ctr UTHSC, Memphis, TN 38163 USA; [Abhyankar, Vrushali] Univ Tennessee, Dept Periodontol, Hlth Sci Ctr UTHSC, Memphis, TN 38163 USA; [Alghamdi, Sahar S.] King Saud Bin Abdulaziz Univ Hlth Sci KSAU HS, Coll Pharm, Riyadh, Saudi Arabia; [Alghamdi, Sahar S.] Minist Natl Guard Hlth Affairs, King Abdullah Int Med Res Ctr KAIMRC, Riyadh, Saudi Arabia; [Dabbous, Mustafa] Univ Tennessee, Hlth Sci Ctr UTHSC, Dept Microbiol Immunol & Biochem, Memphis, TN 38163 USA University of Tennessee System; University of Tennessee Health Science Center; University of Tennessee System; University of Tennessee Health Science Center; University of Tennessee System; University of Tennessee Health Science Center; King Saud Bin Abdulaziz University for Health Sciences; King Saud Bin Abdulaziz University for Health Sciences; King Abdullah International Medical Research Center (KAIMRC); Ministry of National Guard - Health Affairs; University of Tennessee System; University of Tennessee Health Science Center Abidi, AH (corresponding author), Univ Tennessee, Coll Dent, Hlth Sci Ctr UTHSC, 711 Jefferson Ave,Suite 429, Memphis, TN 38163 USA. aabidi@uthsc.edu DEC 2022 57 6 10.1111/jre.13050 http://dx.doi.org/10.1111/jre.13050 Estudio Médica Odontología Dentistry, Oral Surgery & Medicine Abi-Jaoude, E; Bhikram, T; Parveen, F; Levenbach, J; Lafreniere-Roula, M; Sandor, P A Double-Blind, Randomized, Controlled Crossover Trial of Cannabis in Adults with Tourette Syndrome CANNABIS AND CANNABINOID RESEARCH English Article; Early Access Tourette syndrome; tics; cannabis; Delta(9)-tetrahydrocannabinol; cannabidiol; randomized controlled trial DELTA(9)-TETRAHYDROCANNABINOL THC; MEDICAL MARIJUANA; SCALE; TICS; DISORDERS Background: The number of effective evidence-based treatment options for patients with Tourette syndrome (TS) is limited. Emerging evidence shows cannabinoids as promising for the treatment of tics. Objectives: To compare the efficacy and tolerability of single doses of three vaporized medical cannabis products and placebo in reducing tics in adults with TS.Methods: In a randomized, double-blind, crossover design, each participant received a vaporized single 0.25 g dose of delta(9)-tetrahydrocannabinol (THC) 10%, THC/cannabidiol (CBD) 9%/9%, CBD 13%, and placebo at 2-week intervals. Our primary outcome was the Modified Rush Video-Based Tic Rating Scale (MRVTRS), taken at baseline and at 0.5, 1, 2, 3, and 5 h after dose administration. Secondary measures included the Premonitory Urge for Tics Scale (PUTS), Subjective Units of Distress Scale (SUDS), and Clinical Global Impression-Improvement (CGI-I). Correlations between outcomes and cannabinoid plasma levels were calculated. Tolerability measures included open-ended and specific questions about adverse events (AEs). Results: Twelve adult patients with TS were randomized, with nine completing the study. There was no statistically significant effect of product on the MRVTRS. However, there was a significant effect of THC 10%, and to a lesser extent THC/CBD 9%9%, versus placebo on the PUTS, SUDS, and CGI-I. As well, there were significant correlations between plasma levels of THC and its metabolites, but not CBD, with MRVTRS, PUTS, and SUDS measures. There were more AEs from all cannabis products relative to placebo, and more AEs from THC 10% versus other cannabis products, particularly cognitive and psychomotor effects. Most participants correctly identified whether they had received cannabis or placebo. Conclusions: In this pilot randomized controlled trial of cannabis for tics in TS, there was no statistically significant difference on the MRVTRS for any of the cannabis products, although the THC 10% product was significantly better than placebo on the secondary outcome measures. Also, THC and metabolite plasma levels correlated with improvement on all measures. The THC 10% product resulted in the most AEs. ClinicalTrials.gov ID: NCT03247244. [Abi-Jaoude, Elia] Univ Toronto, Hosp Sick Children, Dept Psychiat, Toronto, ON, Canada; [Abi-Jaoude, Elia; Bhikram, Tracy; Parveen, Ferdous; Levenbach, Jody; Lafreniere-Roula, Myriam; Sandor, Paul] Univ Toronto, Univ Hlth Network, Dept Psychiat, Toronto, ON, Canada; [Sandor, Paul] Youthdale Treatment Ctr, Toronto, ON, Canada; [Abi-Jaoude, Elia] Univ Toronto, Hosp Sick Children, Dept Psychiat, 555 Univ Ave, Toronto, ON M5G 1X8, Canada University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; University Health Network Toronto; University of Toronto; Hospital for Sick Children (SickKids) Abi-Jaoude, E (corresponding author), Univ Toronto, Hosp Sick Children, Dept Psychiat, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. elia.abi.jaoude@utoronto.ca 2022 AUG 30 2022 10.1089/can.2022.0091 http://dx.doi.org/10.1089/can.2022.0091 Estudio Médica Neurología Pharmacology & Pharmacy Abraham, AD; Leung, EJY; Wong, BA; Rivera, ZMG; Kruse, LC; Clark, JJ; Land, BB Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain NEUROPSYCHOPHARMACOLOGY English Article OPIOID SYSTEM; RATS; DEFICITS; CB2 Chronic pain affects a significant percentage of the United States population, and available pain medications like opioids have drawbacks that make long-term use untenable. Cannabinoids show promise in the management of pain, but long-term treatment of pain with cannabinoids has been challenging to implement in preclinical models. We developed a voluntary, gelatin oral self-administration paradigm that allowed male and female mice to consume increment (9)-tetrahydrocannabinol, cannabidiol, or morphine ad libitum. Mice stably consumed these gelatins over 3 weeks, with detectable serum levels. Using a real-time gelatin measurement system, we observed that mice consumed gelatin throughout the light and dark cycles, with animals consuming less THC-gelatin than the other gelatin groups. Consumption of all three gelatins reduced measures of allodynia in a chronic, neuropathic sciatic nerve injury model, but tolerance to morphine developed after 1 week while THC or CBD reduced allodynia over three weeks. Hyperalgesia gradually developed after sciatic nerve injury, and by the last day of testing, THC significantly reduced hyperalgesia, with a trend effect of CBD, and no effect of morphine. Mouse vocalizations were recorded throughout the experiment, and mice showed a large increase in ultrasonic, broadband clicks after sciatic nerve injury, which was reversed by THC, CBD, and morphine. This study demonstrates that mice voluntarily consume both cannabinoids and opioids via gelatin, and that cannabinoids provide long-term relief of chronic pain states. In addition, ultrasonic clicks may objectively represent mouse pain status and could be integrated into future pain models. [Abraham, Antony D.; Leung, Edward J. Y.; Wong, Brenden A.; Rivera, Zeena M. G.; Land, Benjamin B.] Univ Washington, Dept Pharmacol, 1959 NE Pacific St, Seattle, WA 98195 USA; [Kruse, Lauren C.; Clark, Jeremy J.] Univ Washington, Dept Psychiat & Behav Sci, 1959 NE Pacific St, Seattle, WA 98195 USA University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle Land, BB (corresponding author), Univ Washington, Dept Pharmacol, 1959 NE Pacific St, Seattle, WA 98195 USA. BBL2@uw.edu JUN 2020 45 7 10.1038/s41386-019-0585-3 http://dx.doi.org/10.1038/s41386-019-0585-3 Producto Médica Analgésico Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry Acquavia, MA; Tesoro, C; Pascale, R; Ostuni, A; Matera, I; Bianco, G; Scrano, L; Bufo, SA; Ciriello, R; Di Capua, A; Lelario, F Legal Cannabis sativa L. Dried Inflorescences: Cannabinoids Content and Cytotoxic Activity against Human HepG2 Cell Line APPLIED SCIENCES-BASEL English Article hemp; light cannabis; THC; CBD; THCA; CBDA; CBN; CBD ratio; liquid chromatography; mass spectrometry; collision-induced dissociation; UV detection; HepG2 EXTRACTS Cannabis sativa L. has health benefits, principally due to the levels and ratios of two important cannabinoids, Delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC:CBD ratio affects their pharmacological interaction for the treatment of different diseases as well as its modulation allows for a custom-made product that utilizes the distinguishing effects of CBD, THC, or both, for a peculiar patient or clinical effect. This study aims to investigate the total content of THC, CBD, and their ratio in 34 dried inflorescence legally sold in physical and online stores, by using a validated liquid chromatography-ultraviolet (HPLC-UV) method, after cannabinoids identification performed through MSn studies. Cannabinol (CBN) content was also monitored to evaluate hemp age or conservation status. CBN content always resulted lower than limit of quantification, thus confirming well-stored fresh hemp. All investigated samples showed a total THC amount below 0.59% w/w, thus responding to legal requirements.. The total CBD amount ranged from 2.62 to 20.27% w/w and it was not related to THC level. THC:CBD ranged among 1:3 and 1:26, thus ascertaining their suitability for different target pharmacological uses. In vitro studies using human hepatoblastoma cell line HepG2 suggested that hemp extracts with THC:CBD ratios of 1:9 exhibited higher toxicity than pure cannabinoids. [Acquavia, Maria Assunta; Tesoro, Carmen; Ostuni, Angela; Matera, Ilenia; Bianco, Giuliana; Bufo, Sabino A. A.; Ciriello, Rosanna; Di Capua, Angela; Lelario, Filomena] Univ Basilicata, Dipartimento Sci, Via Ateneo Lucano 10, I-85100 Potenza, Italy; [Pascale, Raffaella] Gnosis Lesaffre, I-75015 Pisticci, Matera, Italy; [Scrano, Laura] Univ Basilicata, Dipartimento Culture Europee & Mediterraneo DICEM, Via Lanera 20, I-75100 Matera, Italy; [Bufo, Sabino A. A.] Univ Johannesburg, Dept Geog Environm Management & Energy Studies, ZA-2092 Johannesburg, South Africa University of Basilicata; University of Basilicata; University of Johannesburg Di Capua, A; Lelario, F (corresponding author), Univ Basilicata, Dipartimento Sci, Via Ateneo Lucano 10, I-85100 Potenza, Italy. angela.dicapua@unibas.it; filomena.lelario@unibas.it APR 2023 13 8 10.3390/app13084960 http://dx.doi.org/10.3390/app13084960 Estudio Química Cuantificación Chemistry; Engineering; Materials Science; Physics Aebersold, AS; Kumar, A; Song, ZH LC-MS/MS quantitation of non-psychotropic cannabinoid cannabidiol in aqueous humor JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS English Article Cannabidiol; Aqueous humor; Liquid chromatography; Tandem mass spectrometry PRODRUG Cannabidiol (CBD) is the most abundant non-psychotropic phytocannabinoid isolated from Cannabis sativa. To support preclinical studies of ocular pharmacology of CBD, a bioanalytical method was developed and validated for quantification of CBD in aqueous humor using liquid chromatography-tandem mass spectrometry (LC-MS/ MS). Aqueous humor samples were subjected to protein precipitation by acetonitrile, followed by chromato-graphic separation using reversed phase LC on a Raptor ARC-18 column with mobile phase A: 0.1 % (v/v) formic acid in water (B) 0.1 % formic acid in acetonitrile (B) as eluents. Detection was carried out with a triple quadrupole mass spectrometer with electrospray ionization operated in positive ion mode. Stable-isotope labeled CBD (CBD-d3) was used as internal standard. The total run time was 8 min. Quantification was accomplished within the validated concentration range of 0.5-500 ng/mL for CBD using a 5 mu L sample. The lower limit of quantitation was 0.5 ng/mL. Inter-and intra-day precision is 4.737-7.620 % and 3.426-5.830 %, respectively. Inter-and intra-day accuracy ranged between 99.01 % and 100.2 % and 99.85-101.4 % respectively. The extraction recoveries were found to be 66.06 +/- 5.146 %. The established method was successfully applied to investigate ocular pharmacokinetics of CBD in mice. Following intraperitoneal (i.p.) administration of 50 mg/kg CBD, its concentration reaches a Cmax of 71.55 +/- 36.64 ng/mL in aqueous humor, with a Tmax of 2 h and a half-life of 1.046 h. The AUC was 183.4 +/- 49.17 ng * h/mL. The development and validation of this LC-MS/MS method is an important step toward the goal of assessing the aqueous humor concentrations of CBD and correlating the concentrations of this phytocannabinoid with its ocular pharmacologic effects. [Aebersold, Alyssa S.; Kumar, Akhilesh; Song, Zhao-Hui] Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA; [Aebersold, Alyssa S.] Pearl Med, Louisville, KY 40218 USA; [Kumar, Akhilesh] Phyto LabTech, Salt Lake City, UT 84414 USA University of Louisville Song, ZH (corresponding author), Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. zhsong@louisville.edu May-10 2023 228 10.1016/j.jpba.2023.115324 http://dx.doi.org/10.1016/j.jpba.2023.115324 Estudio Química Cuantificación Chemistry; Pharmacology & Pharmacy Aebersold, AS; Song, ZH The Effects of Cannabidiol on Aqueous Humor Outflow and Trabecular Meshwork Cell Signaling CELLS English Article cannabidiol; aqueous humor outflow; trabecular meshwork CB2 CANNABINOID RECEPTORS; DRUG; MODULATION; GLAUCOMA; CULTURE; LIGHT Intraocular pressure (IOP) is regulated primarily through aqueous humor production by ciliary body and drainage through uveoscleral and trabecular meshwork (TM) tissues. The goal of this study was to measure the effect of non-psychotropic cannabidiol (CBD) on aqueous humor outflow through TM and assess the effect of CBD on the TM cell signaling pathways that are important for regulating outflow. Perfused porcine eye anterior segment explants were used to investigate the effects of CBD on aqueous humor outflow. Cultured porcine TM cells were used to study the effects of CBD on TM cell contractility, myosin light chain (MLC) and myosin phosphatase targeting subunit 1 (MYPT1) phosphorylation, and RhoA activation. In the anterior segment perfusion experiments, aqueous humor outflow was increased significantly within 1 h after adding 1 mu M CBD and the effect was sustained over the 5 h of measurement. Treatment of TM cells with 1 mu M CBD significantly decreased TM cell-mediated collagen contraction, inhibited phosphorylation of MLC and MYPT1, and reduced RhoA activation. Our data demonstrate, for the first time, that as a potential therapeutic agent for lowering intraocular pressure, CBD can enhance aqueous humor outflow and modify TM cell signaling. [Aebersold, Alyssa S.; Song, Zhao-Hui] Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA University of Louisville Song, ZH (corresponding author), Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. zhsong@louisville.edu OCT 2022 11 19 10.3390/cells11193006 http://dx.doi.org/10.3390/cells11193006 Estudio Química Bioquímica Cell Biology Afshar, S; Khalili, S; Amin, G; Abbasinazari, M A Phase I Randomized, Double-blind, Placebo-controlled Study on Efficacy and Safety Profile of a Sublingually Administered Cannabidiol /Delta 9-tetrahydrocannabidiol (10:1) Regimen in Diabetes Type 2 Patients IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH English Article Cannabidiol; Delta 9-tetrahydrocannabi; Clinical Trial; Diabetes Melitus; HgA1C INSULIN-RESISTANCE; MARIJUANA; CANNABINOIDS; RIMONABANT; WEIGHT; LIVER; CB1 The current study aimed to evaluate the safety profile and efficacy of a cannabis-based sublingual spray, CBDEX10 & REG; (containing 100 & mu;g cannabidiol and 10 & mu;g & UDelta;9-tetrahydrocannabinol per puff; CBD/& UDelta;9-THC 10:1), in improving lipid profile and glycemic state of the diabetic patients. Fifty diabetic patients were randomly allocated to the treatment (n = 25; receiving two puffs of CBDEX10 & REG; twice daily) or the control groups (n = 25; receiving two puffs of placebo). The primary endpoint of the study was to evaluate the efficacy of the CBDEX10 & REG; adjunctive therapy in improving the lipid profile and glycemic state of diabetic patients; the secondary endpoint was to assess the safety profile and tolerability of the spray. A statistically significant decline in total cholesterol [estimated treatment difference (ETD) = -19.73 mg/dL; P < 0.05], triglyceride (ETD = -27.84 mg/dL; P < 0.01), LDL-C (ETD = -5.37 mg/dL; P < 0.01), FBS (ETD = -12 mg/dL; P < 0.01), Hb A1C (ETD =-0.21 mg/dL; P < 0.01) and insulin secretion (ETD =-5.21 mIU/L; P < 0.01) was observable in the patients treated with CBDEX10 & REG; at the end of the 8-week treatment period. Regarding safety, the mentioned adjunctive regimen was well, and there were no serious or severe adverse effects. Overall, CBDEX1 & REG; sublingual spray could be a new therapeutic agent for lipid and glycemic control in diabetic patients. [Afshar, Shima; Abbasinazari, Mohammad] Shahid Beheshti Univ Med Sci, Sch Pharm, Dept Clin Pharm, Tehran, Iran; [Khalili, Shayesteh] Shahid Beheshti Univ Med Sci, Imam Hossein Hosp, Dept Endocrione, Tehran, Iran; [Amin, Gholamreza] Univ Tehran Med Sci, Dept Pharmacognosy, Tehran, Iran Shahid Beheshti University Medical Sciences; Shahid Beheshti University Medical Sciences; Tehran University of Medical Sciences Abbasinazari, M (corresponding author), Shahid Beheshti Univ Med Sci, Sch Pharm, Dept Clin Pharm, Tehran, Iran. m_abbasi@sbmu.ac.ir DEC 2022 21 1 10.5812/ijpr-132647 http://dx.doi.org/10.5812/ijpr-132647 Producto Médica General Pharmacology & Pharmacy Aguiar, AFL; Campos, RMP; Isaac, AR; Paes-Colli, Y; Carvalho, VM; Sampaio, LS; Reis, RD Long-Term Treatment with Cannabidiol-Enriched Cannabis Extract Induces Synaptic Changes in the Adolescent Rat Hippocampus INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES English Article Cannabis; endocannabinoid system; synaptic changes ENDOCANNABINOID SYSTEM; OBJECT RECOGNITION; RESISTANT EPILEPSY; WORKING-MEMORY; KETOGENIC DIET; RECEPTORS; CB1; MICROGLIA; MICE; ACTIVATION The endocannabinoid system (eCS) is widely distributed in mammalian tissues and it is classically formed by cannabinoid receptors, endogenous bioactive lipids and its synthesis and degradation enzymes. Due to the modulatory role of eCS in synaptic activity in the Central Nervous System (CNS), phytocannabinoids have been increasingly used for the treatment of neurological disorders, even though little is known in terms of the long-term effect of these treatments on CNS development, mainly in the timeframe that comprises childhood and adolescence. Furthermore, an increased number of clinical trials using full-spectrum Cannabis extracts has been seen, rather than the isolated form of phytocannabinoids, when exploring the therapeutical benefits of the Cannabis plant. Thus, this study aims to evaluate the effect of cannabidiol (CBD)-enriched Cannabis extract on synaptic components in the hippocampus of rats from adolescence to early adulthood (postnatal day 45 to 60). Oral treatment of healthy male Wistar rats with a CBD-enriched Cannabis extract (3 mg/kg/day CBD) during 15 days did not affect food intake and water balance. There was also no negative impact on locomotor behaviour and cognitive performance. However, the hippocampal protein levels of GluA1 and GFAP were reduced in animals treated with the extract, whilst PSD95 levels were increased, which suggests rearrangement of glutamatergic synapses and modulation of astrocytic features. Microglial complexity was reduced in CA1 and CA3 regions, but no alterations in their phagocytic activity have been identified by Iba-1 and LAMP2 co-localization. Collectively, our data suggest that CBD-enriched Cannabis treatment may be safe and well-tolerated in healthy subjects, besides acting as a neuroprotective agent against hippocampal alterations related to the pathogenesis of excitatory and astrogliosis-mediated disorders in CNS. [Aguiar, Andrey F. L.; Campos, Raquel M. P.; Paes-Colli, Yolanda; Sampaio, Luzia S.; Reis, Ricardo de Melo A.] Univ Fed Rio de Janeiro, Inst Biophys Carlos Chagas Filho, BR-21941902 Rio De Janeiro, Brazil; [Isaac, Alinny R.] Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, Brazil; [Carvalho, Virginia M.] Univ Fed Rio de Janeiro, Fac Pharm, BR-21941902 Rio De Janeiro, Brazil Sampaio, LS (corresponding author), Univ Fed Rio de Janeiro, Inst Biophys Carlos Chagas Filho, BR-21941902 Rio De Janeiro, Brazil. andreyaguiar@biof.ufrj.br; camposrp@biof.ufrj.br; alinnyisaac@biof.ufrj.br; yolanda@biof.ufrj.br; virginiamc@pharma.ufrj.br; sampaio.lu@biof.ufrj.br; ramreis@biof.ufrj.br JUL 2023 24 14 10.3390/ijms241411775 http://dx.doi.org/10.3390/ijms241411775 Estudio Química Bioquímica Biochemistry & Molecular Biology; Chemistry Aguiar, DD; Oliveira, CD; Fonseca, FCS; de Almeida, DL; Pereira, WVC; Guimara, FS; Perez, AC; Duarte, IDG; Romero, TRL Peripherally injected canabidiol reduces neuropathic pain in mice: Role of the 5-HT1A and TRPV1 receptors BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS English Article Neuropathic pain; Cannabidiol; Peripheral antinociception; 5-HT 1A receptors; TRPV1 receptors VANILLOID RECEPTOR-1; PLANT CANNABINOIDS; RAT MODEL; CANNABIDIOL; EXPRESSION; ALLODYNIA; ANTINOCICEPTION; MODULATION; MECHANISMS Cannabidiol (CBD) is the most abundant non-psychoactive component found in plants of the genus Cannabis. Its analgesic effect for the treatment of neuropathy has been widely studied. However, little is known about its effects in the acute treatment when Cannabidiol is administered peripherally. Because of that, this research was aimed to evaluate the antinociceptive effects of the CBD when administered peripherally for the treatment of acute neuropathic pain and check the involvement of the 5-HT1A and the TRPV1 receptors in this event. Neuropathic pain was induced with the constriction of the sciatic nerve while the nociceptive threshold was measured using the pressure test of the mouse paw. The technique used proved to be efficient to induce neuropathy, and the CBD (5,10 and 30 mu g/paw) induced the antinociception in a dosage-dependent manner. The dosage used that induced a more potent effect (30 mu g/paw), did not induce a systemic response, as demonstrated by both the motor coordination assessment test (RotaRod) and the antinociceptive effect restricted to the paw treated with CBD. The administration of NAN-190 (10 mu g/paw), a selective 5-HT1A receptor antagonist, and SB-366791 (16 mu g/ paw), a selective TRPV1 antagonist, partially reversed the CBD-induced antinociception. The results of the research suggest that the CBD produces the peripheral antinociception during the acute treatment of the neuropathic pain and it partially involved the participation of the 5-HT1A and TRPV1 receptors.(c) 2023 Elsevier Inc. All rights reserved. [Aguiar, Danielle Diniz; Oliveira, Cristina da Costa; Fonseca, Flavia Cristina Sousa; de Almeida, Douglas Lamounier; Pereira, William Valadares Campos; Perez, Andrea Castro; Duarte, Igor Dimitri Gama; Romero, Thiago Roberto Lima] Univ Fed Minas Gerais, Inst Biol Sci, Dept Pharmacol, Belo Horizonte, MG, Brazil; [Guimara, Francisco Silveira] Univ Sao Paulo, Sch Med Ribeira Preto, Dept Pharmacol, Ribeira Preto, SP, Brazil; [Romero, Thiago Roberto Lima] Univ Fed Minas Gerais, Dept Pharmacol, ICB, Ave Antonio Carlos, 6627, BR-31270100 Belo Horizonte, MG, Brazil Universidade Federal de Minas Gerais; Universidade de Sao Paulo; Universidade Federal de Minas Gerais Romero, TRL (corresponding author), Univ Fed Minas Gerais, Dept Pharmacol, ICB, Ave Antonio Carlos, 6627, BR-31270100 Belo Horizonte, MG, Brazil. thiromero@ufmg.br Jun-11 2023 660 10.1016/j.bbrc.2023.04.022 http://dx.doi.org/10.1016/j.bbrc.2023.04.022 Estudio Médica Neurología Biochemistry & Molecular Biology; Biophysics Ahmed, AQ; Noshad, D; Li, PCH Quantification of Cannabinoids in Cultivars of Cannabis sp. by Gas Chromatography-Mass Spectrometry CHROMATOGRAPHIA English Article Cannabis; Chemical analysis; Cannabinoids; Medicinal plants; CBD; THC SOLID-PHASE MICROEXTRACTION; QUANTITATIVE-DETERMINATION; NEUTRAL CANNABINOIDS; SATIVA PLANTS; VALIDATION; EXTRACTS; HAIR; ACID; CBD In the chemical characterization of medically valued Cannabis, the present work has used a gas chromatography (GC) method coupled with mass spectrometry (MS) for identification and quantification of cannabinoids. We have modified a GC-MS method for chemical analysis of cannabinoids extracted from dried flowers of different Cannabis varieties. The method allows for quantification of major cannabinoids, i.e. cannabidiol (CBD), cannabichromene (CBC), tetrahydrocannabinol (THC), cannabigerol (CBG), and cannabinol (CBN) simultaneously. We found that the Cannabis cultivar called Cannabis 5-CW had the highest amount of CBD. We used a modified GC-MS method for chemical profiling of cannabinoids extracted from a variety of Cannabis samples, especially the high CBD, CBC, THC, CBG and CBN-producing ones. The method was successfully applied for identification and quantification of cannabinoids in a short time with better separation resolution among the reported methods. [Ahmed, Abdul Qudeer; Li, Paul C. H.] Simon Fraser Univ, Dept Chem, Dept Mol Biol & Biochem, 8888 Univ Dr, Burnaby, BC, Canada; [Noshad, David] Medleaf Biotechnol Inc, Vancouver, BC, Canada Simon Fraser University Li, PCH (corresponding author), Simon Fraser Univ, Dept Chem, Dept Mol Biol & Biochem, 8888 Univ Dr, Burnaby, BC, Canada. paulli@sfu.ca AUG 2021 84 8 10.1007/s10337-021-04060-9 http://dx.doi.org/10.1007/s10337-021-04060-9 Estudio Química Cuantificación Biochemistry & Molecular Biology; Chemistry Ahmed, B; Rizwanullah, M; Mir, SR; Akhtar, MS; Amin, S Development of cannabidiol nanoemulsion for direct nose to brain delivery: statistical optimization, in vitro and in vivo evaluation BIOMEDICAL MATERIALS English Article cannabidiol; nanoemulsion; Box-Behnken design; in vitro release; nasal permeation; intranasal delivery INTRANASAL DELIVERY; DESIGN; BIOAVAILABILITY; FORMULATIONS; RELEASE Cannabidiol (CBD) is a prescribed drug for epilepsy but has low oral bioavailability and gastric instability. Because of the direct link between the nasal cavity and the central nervous system, intranasal administration of CBD as nanoemulsions which are the small sized lipid carriers seem to improve the bioavailability. CBD-nanoemulsions (NEs) were made using Capryol 90, Tween 80, and Transcutol P as oil, surfactant, and co-surfactant, respectively, following aqueous titration approach. Then, using the Box-Behnken design, CBD-NE was statistically optimised for the selection of desirable excipient concentrations in order to create the optimal CBD-NE formulation. As independent variables in the statistical design, Capryol 90 (oil; coded as A), Tween 80 (surfactant; coded as B), and Transcutol P (co-surfactant; coded as C) were used. The dependent variables were droplet size (DS; coded as R (1)) and polydispersity index (PDI; coded as R (2)). The average DS, PDI, and the zeta potential of the optimized CBD-NEs were observed to be 88.73 +/- 2.67 nm, 0.311 +/- 0.015, and -2.71 +/- 0.52 mV respectively. Pure CBD and lyophilized CBD-NE Fourier-transform infrared spectra demonstrated no physicochemical interaction between excipients and the drug. Furthermore, differential scanning calorimetry and x-ray diffraction measurements revealed the amorphous CBD in the NE. As compared to pure CBD, the optimised CBD-NE showed considerably better in vitro drug release as well as ex vivo nasal permeability. The drug targeting efficiency and direct transport percentage of the optimised CBD-NEs were found to be 419.64% and 76.17%, respectively, in this research. Additionally, pharmacokinetic investigations after intranasal administration of CBD-NE revealed considerably higher drug concentrations in the brain with better brain targeting efficiency. As a result, the development of CBD-NE may be an excellent alternative for better intranasal delivery. [Ahmed, Bakr; Rizwanullah, Md; Amin, Saima] Jamia Hamdard, Sch Pharmaceut Educ & Res, Dept Pharmaceut, Formulat Res Lab, New Delhi 110062, India; [Mir, Showkat Rasool] Jamia Hamdard, Sch Pharmaceut Educ & Res, Dept Pharmacognosy & Phytochem, Phytopharmceut Lab, New Delhi 110062, India; [Akhtar, M. Shaheer] Jeonbuk Natl Univ, New & Renewable Energy Mat Dev Ctr NewREC, Jeonbuk, South Korea Jamia Hamdard University; Jamia Hamdard University; Jeonbuk National University Amin, S (corresponding author), Jamia Hamdard, Sch Pharmaceut Educ & Res, Dept Pharmaceut, Formulat Res Lab, New Delhi 110062, India.;Akhtar, MS (corresponding author), Jeonbuk Natl Univ, New & Renewable Energy Mat Dev Ctr NewREC, Jeonbuk, South Korea. shaheerakhtar@jbnu.ac.kr; samin@jamiahamdard.ac.in Nov-01 2022 17 6 10.1088/1748-605X/ac9267 http://dx.doi.org/10.1088/1748-605X/ac9267 Producto Ingeniería Materiales Engineering; Materials Science Ahmed, B; Rizwanullah, M; Usmani, Z; Mir, SR; Amin, S Box-Behnken Design Assisted Development and Optimization of RP-HPLC-PDA Technique for Determination of Cannabidiol in the Bulk and Nanoformulation EGYPTIAN JOURNAL OF CHEMISTRY English Article Cannabidiol; RP-HPLC; ICH guidelines; Box-Behnken design; Quality by Desig ANTICONVULSANT; EPILEPSY; SEIZURES; QUALITY; SLEEP The focus of this research was to implement a new RP-HPLC-PDA method for determining cannabidiol (CBD), which has been established with the help of Quality by Design (QbD). Design expert (version 12) software was used to conduct the factor screening studies. The mobile phase ratio, flow rate, and temperature conditions were used as independent variables, while retention time, peak area, and peak tailing were used as dependent variables in a Box-Behnken design. The best separation was obtained with acetonitrile and water as mobile phase in the ratio of 45:55 (%; v/v), a flow rate of 1.0 mL/ min, and an oven temperature of 30 degrees C with PDA detection at 210 nm. The newly optimized method showed the concentration linearity range in mu g/mL (1187.574 - 5997.835) of CBD with an excellent correlation coefficient R-2 = 0.9951. Whereas, the % recovery of the CBD was obtained between 97.84 to 99.34%, and the %RSD was not more than 2%, thus clearly confirming the high level of accuracy in the optimized form. The technique was assessed under the ICH guidelines, which revealed excellent linearity, precision, and robustness. Consequently, the approach was used to determine the retention time in CBD nanoemulsion formulations, which revealed no substantial change in retention time. [Ahmed, Bakr; Rizwanullah, Md; Amin, Saima] Jamia Hamdard, Sch Pharmaceut Educ & Res, Dept Pharmaceut, Formulat Res Lab, New Delhi 110062, India; [Usmani, Zakiya; Mir, Showkat Rasool] Jamia Hamdard, Sch Pharmaceut Educ & Res, Dept Pharmacognosy & Phytochem, Phytopharmceut Lab, New Delhi 110062, India Jamia Hamdard University; Jamia Hamdard University Amin, S (corresponding author), Jamia Hamdard, Sch Pharmaceut Educ & Res, Dept Pharmaceut, Formulat Res Lab, New Delhi 110062, India. samin@jamiahamdard.ac.in MAR 2022 65 3 10.21608/ejchem.2021.82528.4072 http://dx.doi.org/10.21608/ejchem.2021.82528.4072 Método Química Cuantificación Chemistry Ahmed, F; Torrens, A; Mahler, SV; Ferlenghi, F; Huestis, MA; Piomelli, D A Sensitive Ultrahigh-Performance Liquid Chromatography/Tandem Mass Spectrometry Method for the Simultaneous Analysis of Phytocannabinoids and Endocannabinoids in Plasma and Brain CANNABIS AND CANNABINOID RESEARCH English Article; Early Access ????????(9)-tetrahydrocannabinol; 2-arachidonoyl-sn-glycerol; anandamide; cannabidiol; endocannabinoid; shape selectivity; ultrahigh-performance liquid chromatography/tandem mass spectrometry SHAPE SELECTIVITY; UNITED-STATES; CANNABIS USE; PPAR-ALPHA; OLEOYLETHANOLAMIDE; RETENTION; DELTA(9)-TETRAHYDROCANNABINOL; PALMITOYLETHANOLAMIDE; QUANTIFICATION; ACTIVATION Introduction: delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) are major chemical constituents of cannabis, which may interact either directly or indirectly with the endocannabinoid and endocannabinoid-like ( paracannabinoid ) systems, two lipid-based signaling complexes that play important roles in physiology. Legislative changes emphasize the need to understand how THC and CBD might impact endocannabinoid and paracannabinoid signaling, and to develop analytical approaches to study such impact. In this study, we describe a sensitive and accurate method for the simultaneous quantification of THC, its main oxidative metabolites [11-hydroxy-delta(9)-THC (11-OH-THC) and 11-nor-9-carboxy-delta(9)-THC (11-COOH-THC)], CBD, and a representative set of endocannabinoid [anandamide and 2-arachidonoyl-sn-glycerol (2-AG)] and paracannabinoid [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)] compounds. Analyte separation relies on the temperature-dependent shape selectivity properties of polymerically bonded C18 stationary phases. Materials and Methods: Analytes are extracted from tissues using acetonitrile precipitation followed by phospholipid removal. The ultrahigh-performance liquid chromatography/tandem mass spectrometry protocol utilizes a commercially available C18 polymeric-bonded phase column and a simple gradient elution system. Results: Ten-point calibration curves show excellent linearity (R-2 > 0.99) over a wide range of analyte concentrations (0.02-500 ng/mL). Lowest limits of quantification are 0.05 ng/mL for anandamide, 0.1 ng/mL for 11-OH-THC and OEA, 0.2 ng/mL for THC and CBD, 0.5 ng/mL for 11-COOH-THC, 1.0 ng/mL for 2-AG, and 2.0 ng/mL for PEA. The lowest limits of detection are 0.02 ng/mL for anandamide, 0.05 ng/mL for 11-OH-THC and OEA, 0.1 ng/mL for THC and CBD, 0.2 ng/mL for 11-COOH-THC, 0.5 ng/mL for 2-AG, and 1.0 ng/mL for PEA. Conclusions: An application of the method is presented, which showed that phytocannabinoid administration elevates endocannabinoid levels in plasma and brain of adolescent male and female mice. [Ahmed, Faizy; Torrens, Alexa; Piomelli, Daniele] Univ Calif Irvine, Dept Anat & Neurobiol, 37 Hlth Sci Rd, Room 3107, Irvine, CA 92967 USA; [Mahler, Stephen V. V.] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA USA; [Ferlenghi, Francesca] Univ Parma, Dipartimento Sci Alimenti & Farmaco, Parma, Italy; [Huestis, Marilyn A. A.] Thomas Jefferson Univ, Inst Emerging Hlth Profess, Philadelphia, PA USA; [Piomelli, Daniele] Univ Calif Irvine, Dept Biol Chem, Irvine, CA USA; [Piomelli, Daniele] Univ Calif Irvine, Dept Pharmaceut Sci, Irvine, CA USA University of California System; University of California Irvine; University of California System; University of California Irvine; University of Parma; Jefferson University; University of California System; University of California Irvine; University of California System; University of California Irvine Ahmed, F (corresponding author), Univ Calif Irvine, Dept Anat & Neurobiol, 37 Hlth Sci Rd, Room 3107, Irvine, CA 92967 USA. fahmed@uci.edu 2022 NOV 11 2022 10.1089/can.2022.0216 http://dx.doi.org/10.1089/can.2022.0216 Método Médica Farmacéutica Pharmacology & Pharmacy Ahmed, S; Roth, RM; Stanciu, CN; Brunette, MF The Impact of THC and CBD in Schizophrenia: A Systematic Review FRONTIERS IN PSYCHIATRY English Review cannabis; marijuana; Schizophrenia; psychosis; CBD; THC; legalization; fMRI CANNABIS USE DISORDER; SUBSTANCE USE DISORDER; COLOR-WORD TEST; FUNCTIONAL CONNECTIVITY; PSYCHOTIC SYMPTOMS; ORAL CANNABIDIOL; PREVALENCE; ABUSE; DELTA-9-TETRAHYDROCANNABINOL; MARIJUANA Background: People with schizophrenia are more likely to develop cannabis use disorder (CUD) and experience worse outcomes with use. Yet as cannabis is legalized for medical and recreational use, there is interest in its therapeutic potential. Objectives: To conduct a systematic review summarizing the design and results of controlled trials using defined doses of THC and CBD in schizophrenia. Method: A keyword search of eight online literature databases identified 11 eligible reports. Results: One placebo controlled trial (13 stable patients without CUD) found that intravenous THC increased psychosis and worsened learning/recall. Two reports of a functional magnetic resonance (fMRI) study of smoked or oral THC in 12 abstinent patients with schizophrenia and CUD found no change in symptoms and cognition, and an amelioration of impaired resting state brain function in areas implicated in reward function and the default mode network. One 4 week trial in acutely psychotic inpatients without CUD (mean age 30 y) found 800 mg CBD to be similarly efficacious to amisupride in improving psychosis and cognition. Two 6 week studies of CBD augmentation of antipsychotics in stable outpatients reported mixed results: CBD 600 mg was not more effective than placebo; CBD 1,000 mg reduced symptoms in a sample that did not exclude cannabis use and CUD. A brain fMRI and proton magnetic resonance spectroscopy study of single dose CBD in a sample that did not exclude CUD and cannabis use found that CBD improved symptoms and brain function during a learning/recall task and was associated with increased hippocampal glutamate. Discussion: There is substantial heterogeneity across studies in dose, method of drug delivery, length of treatment, patient age, whether patients with cannabis use/CUD were included or excluded, and whether patients were using antipsychotic medication. Conclusion: There is insufficient evidence for an effect of THC or CBD on symptoms, cognition, and neuroimaging measures of brain function in schizophrenia. At this time, research does not support recommending medical cannabis (THC or CBD) for treating patients with schizophrenia. Further research should examine THC and CBD in schizophrenia with and without comorbid CUD and consider the role of CBD in mitigating symptom exacerbation from THC. [Ahmed, Saeed] Rutland Reg Med Ctr, Dept Psychiat, Rutland, VT USA; [Ahmed, Saeed] Rutland Reg Med Ctr, West Ridge Ctr, Vermont Hub & Spoke Syst Care, Rutland, VT USA; [Roth, Robert M.; Stanciu, Corneliu N.] New Hampshire Hosp, Concord, NH USA; [Roth, Robert M.; Stanciu, Corneliu N.; Brunette, Mary F.] Dartmouth Hitchcock Med Ctr, Dept Psychiat, Lebanon, NH 03766 USA; [Roth, Robert M.; Stanciu, Corneliu N.; Brunette, Mary F.] Dartmouth Coll, Geisel Sch Med, Hanover, NH 03755 USA; [Brunette, Mary F.] Bur Mental Hlth Serv, Concord, NH 03301 USA Dartmouth College; Dartmouth College Brunette, MF (corresponding author), Dartmouth Hitchcock Med Ctr, Dept Psychiat, Lebanon, NH 03766 USA.;Brunette, MF (corresponding author), Dartmouth Coll, Geisel Sch Med, Hanover, NH 03755 USA.;Brunette, MF (corresponding author), Bur Mental Hlth Serv, Concord, NH 03301 USA. mary.f.brunette@hitchcock.org Jul-23 2021 12 10.3389/fpsyt.2021.694394 http://dx.doi.org/10.3389/fpsyt.2021.694394 Estudio Psicología Psiquiatría Psychiatry Ahmed, SA; Ibrahim, AK; Radwan, MM; Slade, D; Chandra, S; Khan, IA; ElSohly, MA Microbial Biotransformation of Cannabidiol (CBD) from Cannabis sativa PLANTA MEDICA English Article cannabidiol; biotransformation; metabolites; antimicrobial; Cannabis sativa; Cannabaceae METABOLITES Microbial biotransformation of cannabidiol was assessed using 31 different microorganisms. Only Mucor ramannianus (ATCC 9628), Beauveria bassiana (ATCC 7195), and Absidia glauca (ATCC 22752) were able to metabolize cannabidiol. M. ramannianus (ATCC 9628) yielded five metabolites, namely, 7,4 '' beta -dihydroxycannabidiol ( 1 ), 6 beta ,4 '' beta -dihydroxycannabidiol ( 2 ), 6 beta ,2 '' beta -dihydroxycannabidiol ( 3 ), 6 beta ,3 '' alpha -dihydroxycannabidiol ( 4 ), and 6 beta ,7,4 '' beta -trihydroxycannabidiol ( 5 ). B. bassiana (ATCC 7195) metabolized cannabidiol to afford six metabolites identified as 7,3 '' -dihydroxycannabidivarin ( 6 ), 7-hydroxycannabidivarin-3 '' -carboxylic acid ( 7 ), 3 '' -hydroxycannabidivarin ( 8 ), 4 '' beta -hydroxycannabidiol ( 9 ), and cannabidivarin-3 '' -carboxylic acid ( 10 ) along with compound 1 . Incubation of cannabidiol with A. glauca (ATCC 22752) yielded three metabolites, 6 alpha ,3 '' -dihyroxycannabidivarin ( 11 ), 6 beta ,3 '' -dihyroxycannabidivarin ( 12 ), and compound 6 . All compounds were evaluated for their antimicrobial and antiprotozoal activity. [Ahmed, Safwat A.; Ibrahim, Amany K.] Suez Canal Univ, Dept Pharmacognosy, Fac Pharm, Ismailia, Egypt; [Radwan, Mohamed M.; Slade, Desmond; Chandra, Suman; Khan, Ikhlas A.; ElSohly, Mahmoud A.] Univ Mississippi, Res Inst Pharmaceut Sci, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA; [Radwan, Mohamed M.] Alexandria Univ, Dept Pharmacognosy, Fac Pharm, Alexandria, Egypt; [Khan, Ikhlas A.] Univ Mississippi, Sch Pharm, Dept Biomol Sci, University, MS 38677 USA; [ElSohly, Mahmoud A.] Univ Mississippi, Sch Pharm, Dept Pharmaceut & Drug Delivery, University, MS 38677 USA Egyptian Knowledge Bank (EKB); Suez Canal University; University of Mississippi; Egyptian Knowledge Bank (EKB); Alexandria University; University of Mississippi; University of Mississippi ElSohly, MA (corresponding author), Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, 806 Hathorn Rd,135 Coy Waller Complex, University, MS 38677 USA. melsohly@olemiss.edu APR 2022 88 5 10.1055/a-1468-3781 http://dx.doi.org/10.1055/a-1468-3781 Estudio Biología Botánica Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine Ajrawat, P; Yang, Y; Wasilewski, E; Leroux, T; Ladha, KS; Bhatia, A; Singh, M; Thaker, S; Kapoor, M; Furlan, AD; Kotra, LP; Clarke, H Medical Cannabis Use and Inflammatory Cytokines and Chemokines Among Adult Chronic Pain Patients CANNABIS AND CANNABINOID RESEARCH English Article; Early Access cannabis; Cannabidiol; chronic pain; inflammation; cytokines; chemokine NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CHRONIC NEUROPATHIC PAIN; SEX-DIFFERENCES; DELTA(9)-TETRAHYDROCANNABINOL; METABOLISM; MODULATION; VALIDITY; FEMALE; PLASMA; DELTA-9-TETRAHYDROCANNABINOL Background: Utilizing cannabis as a therapeutic option for chronic pain (CP) has increased significantly. However, data regarding the potential immunomodulatory effects of cannabis in CP patients remain scarce. We aimed at exploring the relationship between cannabis use and inflammatory cytokines and chemokines among a cohort of CP patients.Methods: Adult patients with a CP diagnosis and medical authorization of cannabis were enrolled. Patients completed validated clinical questionnaires and self-reported the effectiveness of cannabis for symptom management. Patients' blood and cannabis samples were analyzed for the presence of four major cannabinoids, two major cannabinoid metabolites, 29 different cytokines/chemokines, and cortisol. The multivariable linear regression model was used to identify cannabis and patient factors associated with immune markers.Results: Fifty-six patients (48 +/- 15 years; 64% females) were included, with dried cannabis (53%) being the most common type of cannabis consumed. Seventy percent of products were considered delta-9-tetrahydrocannabinol (Delta(9)-THC)-dominant. The majority of patients (96%) self-reported effective pain management, and 76% reported a significant decrease in analgesic medication usage (p <= 0.001). Compared with males, female patients had higher plasma levels of cannabidiol (CBD), cannabidiolic acid, Delta(9)-THC, and 11-hydroxy-Delta(9)-tetrahydrocannabinol but lower concentrations of delta-9-tetrahydrocannabinolic acid and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH). Females had significantly lower eotaxin levels (p=0.04) in comparison to male patients. The regression analysis indicated that high cannabis doses were related to increased levels of interleukin (IL)-12p40 (p=0.02) and IL-6 (p=0.01), whereas female sex was associated with decreased eotaxin (p <= 0.01) concentrations. Blood CBD levels were associated with lower vascular endothelial growth factor (p=0.04) concentrations, and THC-COOH was a factor related to decreased tumor necrosis factor alpha (p=0.02) and IL-12p70 (p=0.03).Conclusion: This study provides further support for the patient-perceived effectiveness of cannabis in managing CP symptoms and reducing analgesic medication consumption. The results suggest a potential sex difference in metabolizing cannabinoids, and the varying immune marker concentrations may support a possible immunomodulatory effect associated with patient sex and cannabis product type. These preliminary findings provide grounds for further validation using larger, well-designed studies with longer follow-up periods. [Ajrawat, Prabjit; Bhatia, Anuj; Singh, Mandeep; Clarke, Hance] Univ Toronto, Univ Hlth Network, Dept Anesthesiol & Pain Management, Toronto, ON, Canada; [Yang, Yi; Kotra, Lakshmi P.] Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON, Canada; [Wasilewski, Ewa; Kapoor, Mohit; Kotra, Lakshmi P.; Clarke, Hance] Univ Hlth Network, Krembil Res Inst, Toronto, ON, Canada; [Leroux, Timothy; Kapoor, Mohit] Univ Hlth Network, Schroeder Arthrit Inst, Osteoarthritis Res Program, Div Orthoped, Toronto, ON, Canada; [Ladha, Karim S.] St Michaels Hosp, Dept Anesthesia, Toronto, ON, Canada; [Thaker, Sonalben; Kotra, Lakshmi P.; Clarke, Hance] Toronto Gen Hosp, Pain Res Unit, Toronto, ON, Canada; [Kapoor, Mohit; Furlan, Andrea D.; Kotra, Lakshmi P.; Clarke, Hance] Ctr Cannabinoid Therapeut, Toronto, ON, Canada; [Furlan, Andrea D.] Univ Hlth Network, Toronto Rehabil Inst, KITE, Toronto, ON, Canada; [Furlan, Andrea D.] Univ Toronto, Fac Med, Dept Med, Toronto, ON, Canada; [Clarke, Hance] Toronto Gen Hosp, Dept Anesthesia & Pain Management, Pain Res Unit, 200 Elizabeth St 12PMB Rm 1200, Toronto, ON M5G 2C4, Canada University of Toronto; University Health Network Toronto; University of Toronto; Krembil Research Institute; University of Toronto; University Health Network Toronto; University of Toronto; University Health Network Toronto; University of Toronto; Saint Michaels Hospital Toronto; University of Toronto; University Health Network Toronto; Toronto General Hospital; University of Toronto; University Health Network Toronto; Toronto Rehabilitation Institute; University of Toronto; University of Toronto; University Health Network Toronto; Toronto General Hospital Clarke, H (corresponding author), Toronto Gen Hosp, Dept Anesthesia & Pain Management, Pain Res Unit, 200 Elizabeth St 12PMB Rm 1200, Toronto, ON M5G 2C4, Canada. hance.clarke@uhn.ca 2022 NOV 4 2022 10.1089/can.2022.0143 http://dx.doi.org/10.1089/can.2022.0143 Estudio Médica Analgésico Pharmacology & Pharmacy Alaia, MJ; Hurley, ET; Vasavada, K; Markus, DH; Britton, B; Gonzalez-Lomas, G; Rokito, AS; Jazrawi, LM; Kaplan, K Buccally Absorbed Cannabidiol Shows Significantly Superior Pain Control and Improved Satisfaction Immediately After Arthroscopic Rotator Cuff Repair: A Placebo-Controlled, Double-Blinded, Randomized Trial AMERICAN JOURNAL OF SPORTS MEDICINE English Article cannabidiol; CBD; shoulder arthroscopic surgery; rotator cuff repair; postoperative pain SHOULDER ARTHROSCOPY Background: Despite the widespread use and sales of cannabidiol (CBD) products in the United States, there is a paucity of literature to evaluate its effectiveness, safety, or ideal route of administration for postoperative pain. Purpose: To evaluate the potential analgesic effects of buccally absorbed CBD in patients who have undergone arthroscopic rotator cuff repair (ARCR). Study Design: Randomized controlled trial; Level of evidence, 1. Methods: This was a US Food and Drug Administration-sanctioned, multicenter, placebo-controlled, randomized, double-blinded trial conducted in patients undergoing ARCR. Patients aged from 18 to 75 years undergoing ARCR were prospectively enrolled and randomized to the control and experimental groups. The experimental group received an oral, buccally absorbed tablet containing 25 mg of CBD 3 times a day if <80 kg, or 50 mg of CBD 3 times a day if >80 kg, for 14 days postoperatively, while the control group received an identical placebo. Patients were followed up on days 1, 2, 7, and 14, and visual analog scale (VAS) for pain scores, opioid consumption, and satisfaction with pain control were recorded. Additionally, liver function tests were conducted on days 7 and 14 to assess safety, and nausea was monitored. P < .05 was considered to be statistically significant. Results: Overall, 100 patients were recruited, with 1 patient being excluded, for a total of 99 patients. There were no significant differences in patient demographics between the 2 groups. On day 1, the VAS pain score was significantly lower in the CBD group than in the control group (4.4 +/- 3.1 vs 5.7 +/- 3.2, respectively; P = .04), although this difference was no longer present on day 2 (4.7 +/- 2.8 vs 5.3 +/- 2.6, respectively; P = .32). On both days 1 and 2, patient satisfaction with pain control was significantly higher in the CBD group than in the control group (day 1: 7.0 +/- 3.0 vs 5.6 +/- 3.7, respectively [P = .04]; day 2: 7.3 +/- 2.5 vs 6.0 +/- 3.3, respectively [P = .03]). The quantity of opioids consumed was low in both groups, and there were no statistically significant differences in opioid consumption (P > .05). On days 7 and 14, there were no statistically significant differences in VAS scores, opioid consumption, or patient satisfaction with pain control between the CBD and control groups (P > .05 for all). There were no significant differences in liver function test results postoperatively (P > .05). Conclusion: Buccally absorbed CBD demonstrated an acceptable safety profile and showed significant promise in the reduction of pain in the immediate perioperative period after ARCR compared with the control. Further studies are currently ongoing to confirm dosing and effectiveness in other orthopaedic conditions. Registration: NCT04672252 (ClinicalTrials.gov identifier). [Alaia, Michael J.] NYU Langone Orthoped Ctr, 333 East 38th St,4th Floor, New York, NY 10016 USA; [Alaia, Michael J.; Hurley, Eoghan T.; Vasavada, Kinjal; Markus, Danielle H.; Gonzalez-Lomas, Guillem; Rokito, Andrew S.; Jazrawi, Laith M.] NYU Langone Hlth, New York, NY USA; [Britton, Briana; Kaplan, Kevin] Jacksonville Orthopaed Inst, Jacksonville, FL USA NYU Langone Medical Center Alaia, MJ (corresponding author), NYU Langone Orthoped Ctr, 333 East 38th St,4th Floor, New York, NY 10016 USA. michael.alaia@nyulangone.org SEP 2022 50 11 10.1177/03635465221109573 http://dx.doi.org/10.1177/03635465221109573 Estudio Médica Ortopedia Orthopedics; Sport Sciences Alalawi, A; Dodu, JC; Woolley-Roberts, M; Brodie, J; Di Marzo, V; Soderstrom, K Cannabidiol improves vocal learning-dependent recovery from, and reduces magnitude of deficits following, damage to a cortical-like brain region in a songbird pre-clinical animal model NEUROPHARMACOLOGY English Article Cannabinoid; Vocal learning; Animal model; CNS lesion MALE ZEBRA FINCHES; PHYTOCANNABINOID CANNABIDIOL; FUNCTIONAL RECOVERY; SEIZURES; MODULATION; WAY-100635; RESPONSES; EPILEPSY; SYSTEM; POTENT Cannabidiol (CBD), a non-euphorigenic compound derived from Cannabis, shows promise for improving recovery following cerebral ischemia and has recently been shown effective for the treatment of childhood seizures caused by Dravet and Lennox-Gastaut syndromes. Given evidence for activity to mitigate effects of CNS insult and dysfunction, we considered the possibility that CBD may also protect and improve functional recovery of a complex learned behavior. To test this hypothesis, we have applied a songbird, the adult male zebra finch, as a novel pre-clinical animal model. Their learned vocalizations were temporarily disrupted with bilateral microlesions of HVC (used as a proper name) a pre-vocal motor cortical-like brain region that drives song. These microlesions destroy about 10% of HVC, and temporarily impair song production, syntax and phonology for about seven days. Recovery requires sensorimotor learning as it depends upon auditory feedback. Four CBD doses (0, 1, 10 and 100 mg/kg) within three surgery conditions (microlesion, no-microlesion, sham-microlesion) were evaluated (n = 5-6). Birds were recorded over 20 days: three baseline; six pre-microlesion drug treatment days and; 11 post-microlesion treatment and recovery days. Results indicate 10 and 100 mg/kg CBD effectively reduced the time required to recover vocal phonology and syntax. In the case of phonology, the magnitude of microlesion-related disruptions were also reduced. These results suggest CBD holds promise to improve functional recovery of complex learned behaviors following brain injury, and represent establishment of an important new animal model to screen drugs for efficacy to improve vocal recovery. [Alalawi, Ali; Dodu, Julien C.; Soderstrom, Ken] ECU Brody Sch Med, Dept Pharmacol & Toxicol, Greenville, NC 27834 USA; [Alalawi, Ali] Taibah Univ, Dept Pharmacol & Toxicol, Pharm Coll, Medina, Saudi Arabia; [Woolley-Roberts, Marie; Brodie, James; Di Marzo, Vincenzo] GW Res Ltd, Sovereign House,Vis Pk, Cambridge CB24 9BZ, England; [Di Marzo, Vincenzo] CNR, Inst Biomol Chem, Endocannabinoid Res Grp, Via Campi Flegrei 34, I-80078 Pozzuoli, NA, Italy Taibah University; Consiglio Nazionale delle Ricerche (CNR) Soderstrom, K (corresponding author), ECU Brody Sch Med, Dept Pharmacol & Toxicol, Greenville, NC 27834 USA. soderstromk@ecu.edu Nov-01 2019 158 10.1016/j.neuropharm.2019.107716 http://dx.doi.org/10.1016/j.neuropharm.2019.107716 Estudio Médica Neurología Neurosciences & Neurology; Pharmacology & Pharmacy Alegre-Zurano, L; Lopez-Arnau, R; Lujan, MA; Camarasa, J; Valverde, O Cannabidiol Modulates the Motivational and Anxiety-Like Effects of 3,4-Methylenedioxypyrovalerone (MDPV) in Mice INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES English Article MDPV; cannabidiol; conditioned place preference; self-administration; anxiety; mice PHARMACOLOGICAL CHARACTERIZATION; ALPHA-PYRROLIDINOPENTIOPHENONE; TASTE AVOIDANCE; CONSTITUENT; CATHINONES; POTENCY 3,4-Methylenedioxypyrovalerone (MDPV) is a new psychoactive substance (NPS) and the most widespread and life-threatening synthetic cathinone of the bath salts. Preclinical research has proven the cocaine-like psychostimulant effects of MDPV and its potential for abuse. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that has emerged as a new potential treatment for drug addiction. Here, we tested the effects of CBD (20 mg/kg) on MDPV (2 mg/kg)-induced conditioned place preference and MDPV (0.05 and 0.075 mg/kg/infusion) self-administration paradigms. In addition, we assessed the effects of the co-administration of CBD and MDPV (3 and 4 mg/kg) on anxiety-like behaviour using the elevated plus maze (EPM). CBD mitigated the MDPV-induced conditioned place preference. On the contrary, CBD administration throughout the MDPV (0.075 mg/kg/infusion) self-administration increased drug-seeking and taking behaviours, but only in the high-responders group of mice. Furthermore, CBD exerted anxiolytic-like effects, exclusively in MDPV-treated mice. Taken together, our results indicate that CBD modulation of MDPV-induced motivational responses in mice varies depending on the requirements of the learning task, resulting in a complex response. Therefore, further research attempting to decipher the behavioural and molecular interactions between CBD and MDPV is needed. [Alegre-Zurano, Laia; Lujan, Miguel A.; Valverde, Olga] Univ Pompeu Fabra, Dept Expt & Hlth Sci, Neurobiol Behav Res Grp GReNeC NeuroBio, Barcelona 08003, Spain; [Lopez-Arnau, Raul; Camarasa, Jordi] Univ Barcelona, Pharmacol Sect, Fac Pharm & Food Sci, Dept Pharmacol Toxicol & Therapeut Chem, Barcelona 08028, Spain; [Lopez-Arnau, Raul; Camarasa, Jordi] Univ Barcelona, Inst Biomed IBUB, Barcelona 08028, Spain; [Valverde, Olga] IMIM Hosp Mar Res Inst, Neurosci Res Programme, Barcelona 08003, Spain Pompeu Fabra University; CHARMEU; University of Barcelona; CHARMEU; University of Barcelona; Institut Hospital del Mar d'Investigacions Mediques (IMIM) Valverde, O (corresponding author), Univ Pompeu Fabra, Dept Expt & Hlth Sci, Neurobiol Behav Res Grp GReNeC NeuroBio, Barcelona 08003, Spain.;Lopez-Arnau, R (corresponding author), Univ Barcelona, Pharmacol Sect, Fac Pharm & Food Sci, Dept Pharmacol Toxicol & Therapeut Chem, Barcelona 08028, Spain.;Lopez-Arnau, R (corresponding author), Univ Barcelona, Inst Biomed IBUB, Barcelona 08028, Spain.;Valverde, O (corresponding author), IMIM Hosp Mar Res Inst, Neurosci Res Programme, Barcelona 08003, Spain. laia.alegre@upf.edu; raullopezarnau@ub.edu; lujanperezma@gmail.com; jcamarasa@ub.edu; olga.valverde@upf.edu AUG 2021 22 15 10.3390/ijms22158304 http://dx.doi.org/10.3390/ijms22158304 Estudio Química Bioquímica Biochemistry & Molecular Biology; Chemistry Alessandria, G; Meli, R; Infante, MT; Vestito, L; Capello, E; Bandini, F Long-term assessment of the cognitive effects of nabiximols in patients with multiple sclerosis: A pilot study CLINICAL NEUROLOGY AND NEUROSURGERY English Article Multiple sclerosis; Spasticity; Cannabinoids; Nabiximols; Cognition DOUBLE-BLIND; SPASTICITY; VALIDITY; CANNABINOIDS; IMPAIRMENT; RELIABILITY; SERIAL; SPRAY Objective: Moderate to severe spasticity is commonly reported in Multiple Sclerosis (MS) and its management is still a challenge. Cannabinoids were recently suggested as add-on therapy for the treatment of spasticity and chronic pain in MS but there is no conclusive scientific evidence on their safety, especially on cognition and over long periods. The aim of this prospective pilot study was to assess the long-term effects of a tetra-hydrocannabinol-cannabidiol (THC/CBD) oromucosal spray (Sativex (R)) on cognition, mood and anxiety. Patients and Methods: An extensive and specific battery of neuropsychological tests (Symbol Digit Modalities Test-SDMT, California Verbal Learning Test-CVLT, Brief Visuospatial Memory Test-BVMT; PASAT-3 and 2; Free and Cued Selective Remind Test-FCSRT, Index of Sensitivity of Cueing-ISC) was applied to longitudinally in-vestigate different domains of cognition in 20 consecutive MS patients receiving Sativex for spasticity. The primary endpoint was to assess any variation in cognitive performance. Secondary outcomes regarding mood and anxiety were investigated by means of Beck Depression Inventory (BDI) and Hamilton Anxiety Rating Scale (HAM-A). Any change in patients' spasticity was evaluated using the 0-10 Numerical Rating Scale (NRS). Results: Twenty per protocol patients were followed up and evaluated at baseline, 6 and 12 months. Domains involving processing speed and auditory verbal memory significantly improved within the first 6 months of therapy (SDMT: p < 0.001; CVLT: p = 0.0001). Mood and anxiety did not show any significant variation. Additionally, the NRS score significantly improved since the beginning (p < 0.0001). Conclusions: These results are encouraging in supporting possible long-term benefits of Sativex on cognition and a wider role than symptom alleviator. Further studies on larger groups of patients would be necessary in order to test this intriguing possibility. [Alessandria, Giulia; Bandini, Fabio] S Paolo Hosp, Dept Neurol, Via Genova 30, I-17100 Savona, Italy; [Meli, Riccardo; Capello, Elisabetta] IRCCS Osped Policlin San Martino, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, Largo Daneo 3, I-16132 Genoa, Italy; [Infante, Maria Teresa] Sanremo Hosp, Dept Neurol, Via Borea 56, I-18039 San Remo, Italy; [Vestito, Lucilla] IRCCS Osped Policlin San Martino, Largo Rosanna Benzi 10, I-16132 Genoa, Italy Bandini, F (corresponding author), S Paolo Hosp, Dept Neurol, Via Genova 30, I-17100 Savona, Italy. f.bandini@asl2.liguria.it SEP 2020 196 10.1016/j.clineuro.2020.105990 http://dx.doi.org/10.1016/j.clineuro.2020.105990 Producto Médica Neurología Neurosciences & Neurology; Surgery Alexandri, F; Papadopoulou, L; Tsolaki, A; Papantoniou, G; Athanasiadis, L; Tsolaki, M The Effect of Cannabidiol 3% on Neuropsychiatric Symptoms in Dementia - Six-Month Follow-Up CLINICAL GERONTOLOGIST English Article; Early Access Behavioral and Psychological symptoms of Dementia (BPSD); cannabidiol; Cannabinoids; dementia; neuropsychiatric symptoms PSYCHOLOGICAL SYMPTOMS; METAANALYSIS; MANAGEMENT; INVENTORY ObjectivesTo investigate the beneficial outcomes of giving cannabidiol (CBD) 3% over a six-month period in the BPSD, the management of which is a crucial issue for everyday clinical praxis and to compare the progress in BPSD of patients who receive Cannabidiol 3% with those who follow usual medical treatment (UMT) in everyday clinical praxis.MethodsA total of 20 PwD with severe BPSD were recruited from the database of Alzheimer Hellas with NPI score >30. Ten of them were assigned to UMT, while ten were assigned to a six-month treatment with CBD drops. The follow-up assessment was performed with NPI, both clinically and by structured telephone interview.ResultsThe follow-up assessment with NPI showed significant improvement of the BPSD in all our patients who received CBD, and no or limited improvement in the second group, regardless of the underlying neuropathology of dementia.ConclusionsWe suggest that CBD may be a more effective and safe choice for managing BPSD than the typical intervention. Future large randomized clinical trials are needed to re-assure these findings.Clinical ImplicationsHealthcare professionals should consider incorporating CBD 3% into their practices to reduce BPSD in PwD. Regular assessments are necessary to ensure long-term effectiveness. [Alexandri, Foteini; Papadopoulou, Lydia; Tsolaki, Magda] Aristotle Univ Thessaloniki, Fac Hlth Sci, Med Sch, Neurosci & Neurodegenerat Dis,Postgrad Course, Macedonia, Greece; [Tsolaki, Anthoula; Tsolaki, Magda] Greek Assoc Alzheimers Dis & Related Disorders Al, Thessaloniki, Greece; [Tsolaki, Anthoula; Tsolaki, Magda] Aristotle Univ Thessaloniki, Fac Hlth Sci, Med Sch, 1st Dept Neurol, Macedonia, Greece; [Papantoniou, Georgia] Univ Ioannina, Fac Educ Sci, Dept Early Childhood Educ, Ioannina, Greece; [Athanasiadis, Loukas] Aristotle Univ Thessaloniki, Fac Hlth Sci, Med Sch, 1st Dept Psychiat, Macedonia, Greece Aristotle University of Thessaloniki; Aristotle University of Thessaloniki; University of Ioannina; Aristotle University of Thessaloniki Alexandri, F (corresponding author), Aristotle Univ Thessaloniki, Fac Hlth Sci, Med Sch, Neurosci & Neurodegenerat Dis,Postgrad Course, Macedonia, Greece. foteini.al@hotmail.com 2023 MAY 10 2023 10.1080/07317115.2023.2209563 http://dx.doi.org/10.1080/07317115.2023.2209563 Estudio Médica Geriatría Geriatrics & Gerontology; Psychiatry Alfonzetti, T; Moreau, M; Yasmin-Karim, S; Ngwa, W; Avery, S; Goia, D Phytoradiotherapy to enhance cancer treatment outcomes with cannabidiol, bitter melon juice, and plant hemoglobin FRONTIERS IN ONCOLOGY English Article phytoradiotherapy; radiotherapy; phytomedicines; cannabidiol (CBD); bitter melon juice (BMJ); pancreatic adenocarcinoma; plant hemoglobin; anemia Despite technological advances in radiation therapy for cancer treatment, many patient populations still experience mediocre survival percentages, local control, and quality of life. Additionally, much of the world lacks access to expensive, modern treatment options. The need for innovative, cost-effective solutions that can improve patient treatment outcomes is essential. Phytomedicines have been shown to induce apoptotic tumor cell death, diminish tumor progression, reduce cancer incidence, alleviate harmful hypoxic conditions, and more. While an ample amount of research is available that characterizes many phytomedicines as having anti-cancer properties that increase tumor cell killing/control and mitigate the harmful side effects of radiation damage, little work has been done to investigate the synergistic effect of phytoradiotherapy: combining radiation treatment with phytomedicines. In this study, a protocol for testing the radiosensitizing effects of phytomedicines was validated and used to investigate the well-known plant based medicine cannabidiol (CBD) and the lesser-known medicinal fruit Bitter Melon. Additionally, based on its high concentration of plant hemoglobin which has been shown to abate hypoxia, the African-indigenous Justicia plant was tested in pancreatic adenocarcinoma mouse models. The studies reveal that these phytomedicines can effectively enhance tumor cell killing, minimize tumor growth, and prolong mice survival. There is certainly the need for additional research in this regard, however, phytoradiotherapy: the use of phytomedicines to enhance radiation therapy treatment outcomes, continues to show potential as a promising, innovative way to improve cancer care. [Alfonzetti, Tyler; Avery, Stephen; Goia, Denisa] Univ Penn, Perelman Ctr Adv Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA; [Moreau, Michele; Ngwa, Wilfred] Johns Hopkins Univ, Dept Radiat Oncol & Mol Radiat Sci, Boston, MA USA; [Yasmin-Karim, Sayeda] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA USA; [Yasmin-Karim, Sayeda] Harvard Med Sch, Boston, MA USA; [Yasmin-Karim, Sayeda] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA USA University of Pennsylvania; Pennsylvania Medicine; Johns Hopkins University; Harvard University; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Dana-Farber Cancer Institute Avery, S (corresponding author), Univ Penn, Perelman Ctr Adv Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. stephen.avery@pennmedicine.upenn.edu JAN 26 2023 12 10.3389/fonc.2022.1085686 http://dx.doi.org/10.3389/fonc.2022.1085686 Estudio Médica Oncología Oncology Al-Ghezi, ZZ; Busbee, PB; Alghetaa, H; Nagarkatti, PS; Nagarkatti, M Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome BRAIN BEHAVIOR AND IMMUNITY English Article THC; CBD; EAE; Multiple sclerosis; Gut microbiome; Akkermansia muciniphila; SCFAs; LPS EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MULTIPLE-SCLEROSIS; T-CELLS; OROMUCOSAL SPRAY; FATTY-ACIDS; INDUCTION; DISEASE; PHYTOCANNABINOIDS; INFLAMMATION; ACTIVATION Currently, a combination of marijuana cannabinoids including delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is used as a drug to treat muscle spasticity in patients with Multiple Sclerosis (MS). Because these cannabinoids can also suppress inflammation, it is unclear whether such patients benefit from suppression of neuroinflammation and if so, what is the mechanism through which cannabinoids act. In the currently study, we used a murine model of MS, experimental autoimmune encephalomyelitis (EAE), to study the role of gut microbiota in the attenuation of clinical signs of paralysis and inflammation caused by cannabinoids. THC + CBD treatment attenuated EAE and caused significant decrease in inflammatory cytokines such as IL-17 and IFN-gamma while promoting the induction of anti-inflammatory cytokines such as IL-10 and TGF-beta. Use of 16S rRNA sequencing on bacterial DNA extracted from the gut revealed that EAE mice showed high abundance of mucin degrading bacterial species, such as Akkermansia muciniphila (A. muc), which was significantly reduced after THC + CBD treatment. Fecal Material Transfer (FMT) experiments confirmed that THC + CBD-mediated changes in the microbiome play a critical role in attenuating EAE. In silico computational metabolomics revealed that LPS biosynthesis, a key component in gram-negative bacteria such as A. muc, was found to be elevated in EAE mice which was confirmed by demonstrating higher levels of LPS in the brain, while treatment with THC + CBD reversed this trend. EAE mice treated with THC + CBD also had significantly higher levels of short chain fatty acids such as butyric, isovaleric, and valeric acids compared to naive or disease controls. Collectively, our data suggest that cannabinoids may attenuate EAE and suppress neuroinflammation by preventing microbial dysbiosis seen during EAE and promoting healthy gut microbiota. [Al-Ghezi, Zinah Zamil; Busbee, Philip Brandon; Alghetaa, Hasan; Nagarkatti, Prakash S.; Nagarkatti, Mitzi] Univ South Carolina, Sch Med, Dept Pathol Microbiol & Immunol, Columbia, SC 29208 USA University of South Carolina System; University of South Carolina Columbia Nagarkatti, PS (corresponding author), Univ South Carolina, 202 Osborne Adm Bldg, Columbia, SC 29208 USA. prakash@mailbox.sc.edu NOV 2019 82 10.1016/j.bbi.2019.07.028 http://dx.doi.org/10.1016/j.bbi.2019.07.028 Estudio Médica Neurología Immunology; Neurosciences & Neurology; Psychiatry Al-Ghezi, ZZ; Miranda, K; Nagarkatti, M; Nagarkatti, PS Combination of Cannabinoids, Delta 9-Tetrahydrocannabinol and Cannabidiol, Ameliorates Experimental Multiple Sclerosis by Suppressing Neuroinflammation Through Regulation of miRNA-Mediated Signaling Pathways FRONTIERS IN IMMUNOLOGY English Article multiple sclerosis; EAE; THC; CBD; CB1; CB2; miR-21a-5p EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; T-CELLS; TRANSCRIPTION FACTOR; IMMUNE-RESPONSE; GENE-EXPRESSION; VIRAL MODEL; ACTIVATION; INFLAMMATION; CB1 Multiple sclerosis (MS) is a chronic and disabling disorder of the central nervous system (CNS) characterized by neuroinflammation leading to demyelination. Recently a combination of Delta 9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) extracted from Cannabis has been approved in many parts of the world to treat MS-related spasticity. THC+CBD combination was also shown to suppresses neuroinflammation, although the mechanisms remain to be further elucidated. In the current study, we demonstrate that THC+CBD combination therapy (10 mg/kg each) but not THC or CBD alone, attenuates murine experimental autoimmune encephalomyelitis (EAE) by reducing neuroinflammation and suppression of Th17 and Th1 cells. These effects were mediated through CB1 and CB2 receptors inasmuch as, THC+CBD failed to ameliorate EAE in mice deficient in CB1 and CB2. THC+CBD treatment also caused a decrease in the levels of brain infiltrating CD4+ T cells and pro-inflammatory molecules (IL-17, INF-gamma, TNF-alpha, IL-1 beta, IL-6, and TBX21), while increasing anti-inflammatory phenotype such as FoxP3, STAT5b, IL-4, IL-10, and TGF beta Also, the brain-derived cells showed increased apoptosis along with decreased percentage in G0/G1 phase with increased percentage in G2/M phase of cell cycle. miRNA microarray analysis of brain-derived CD4+ T cells revealed that THC+CBD treatment significantly down-regulated miR-21a-5p, miR-31-5p, miR-122-5p, miR-146a-5p, miR-150-5p, miR-155-5p, and miR-27b-5p while upregulating miR-706-5p and miR-7116. Pathway analysis showed that majority of the down-regulated miRs targeted molecules involved in cycle arrest and apoptosis such as CDKN2A, BCL2L11, and CCNG1, as well as anti-inflammatory molecules such as SOCS1 and FoxP3. Additionally, transfection studies involving miR-21 and use of Mir21(-/- )mice suggested that while this miR plays a critical role in EAE, additional miRs may also be involved in THC+CBD-mediated attenuation of EAE. Collectively, this study suggests that combination of THC+CBD suppresses neuroinflammation and attenuates clinical EAE development and that this effect is associated with changes in miRNA profile in brain-infiltrating cells. [Al-Ghezi, Zinah Zamil; Miranda, Kathryn; Nagarkatti, Mitzi; Nagarkatti, Prakash S.] Univ South Carolina, Sch Med, Dept Pathol Microbiol & Immunol, Columbia, SC 29208 USA University of South Carolina System; University of South Carolina Columbia Nagarkatti, PS (corresponding author), Univ South Carolina, Sch Med, Dept Pathol Microbiol & Immunol, Columbia, SC 29208 USA. prakash@mailbox.sc.edu AUG 21 2019 10 10.3389/fimmu.2019.01921 http://dx.doi.org/10.3389/fimmu.2019.01921 Estudio Médica Neurología Immunology Alhadid, A; Luca, SV; Nasrallah, S; Minceva, M Experimental investigation and thermodynamic modeling of cannabidiol solubility in plant oils and hydrophobic eutectic systems JOURNAL OF MOLECULAR LIQUIDS English Article Cannabinoids; Green solvents; Deep eutectic solvents; COSMO-RS; Solubility SOLVENTS Cannabidiol (CBD) is one of the most important cannabinoids found in hemp plants, having numerous applications in the pharmaceutical and food industries. Due to its low solubility in water, CBD is usually supplied in hydrophobic solvents. The present work investigated the solubility of CBD in ten plant oils and various systematically designed hydrophobic eutectic systems (ESs). The CBD solubility was found to correlate with the molecular weight and structure of the oils and ES constituents. CBD was more sol-uble in medium-chain triglyceride oils than in oils containing long-chain unsaturated fatty acids. Moreover, the CBD solubility was found to be higher in ESs than in oils. The conductor-like screening model for realistic solvents (COSMO-RS) was then applied to estimate the CBD solubility in oils and ESs. COSMO-RS did not provide satisfactory predictions of the CBD solubility in oils, possibly because oils were regarded as simple mixtures of fatty acids. On the other hand, COSMO-RS predicted well the CBD solubility in ESs. This work showed that newly-designed hydrophobic ESs could be alternative green sol-vents for CBD formulation and extraction.(c) 2023 Elsevier B.V. All rights reserved. [Alhadid, Ahmad; Luca, Simon Vlad; Nasrallah, Sahar; Minceva, Mirjana] Tech Univ Munich, TUM Sch Life Sci, Biothermodynam, D-85354 Freising Weihenstephan, Germany Technical University of Munich Minceva, M (corresponding author), Tech Univ Munich, TUM Sch Life Sci, Biothermodynam, D-85354 Freising Weihenstephan, Germany. mirjana.minceva@tum.de Feb-15 2023 372 10.1016/j.molliq.2022.121172 http://dx.doi.org/10.1016/j.molliq.2022.121172 Estudio Química Fisicoquímica Chemistry; Physics Ali, S; Scheffer, IE; Sadleir, LG Efficacy of cannabinoids in paediatric epilepsy DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY English Review DOUBLE-BLIND; CANNABIDIOL; SEIZURES; ANTICONVULSANT; EXTRACTS; TRIAL; MOUSE There are hundreds of compounds found in the marijuana plant, each contributing differently to the antiepileptic and psychiatric effects. Cannabidiol (CBD) has the most evidence of antiepileptic efficacy and does not have the psychoactive effects of (9)-tetrahydrocannabinol. CBD does not act via cannabinoid receptors and its antiepileptic mechanism of action is unknown. Despite considerable community interest in the use of CBD for paediatric epilepsy, there has been little evidence for its use apart from anecdotal reports, until the last year. Three randomized, placebo-controlled, double-blind trials in Dravet syndrome and Lennox-Gastaut syndrome found that CBD produced a 38% to 41% median reduction in all seizures compared to 13% to 19% on placebo. Similarly, CBD resulted in a 39% to 46% responder rate (50% convulsive or drop-seizure reduction) compared to 14% to 27% on placebo. CBD was well tolerated; however, sedation, diarrhoea, and decreased appetite were frequent. CBD shows similar efficacy to established antiepileptic drugs. [Ali, Shayma; Sadleir, Lynette G.] Univ Otago, Dept Paediat & Child Hlth, Wellington, New Zealand; [Scheffer, Ingrid E.] Univ Melbourne, Dept Med, Melbourne, Vic, Australia; [Scheffer, Ingrid E.] Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia; [Scheffer, Ingrid E.] Austin Hlth & Royal Childrens Hosp, Heidelberg, Vic, Australia; [Scheffer, Ingrid E.] Florey & Murdoch Childrens Res Inst, Melbourne, Vic, Australia University of Otago; University of Melbourne; University of Melbourne Scheffer, IE (corresponding author), Melbourne Brain Ctr, 245 Burgundy St, Heidelberg, Vic 3084, Australia. i.scheffer@unimelb.edu.au JAN 2019 61 1 10.1111/dmcn.14087 http://dx.doi.org/10.1111/dmcn.14087 Estudio Médica Neurología Neurosciences & Neurology; Pediatrics Allendorfer, JB; Nenert, R; Bebin, EM; Gaston, TE; Grayson, LE; Hernando, KA; Houston, JT; Hansen, B; Szaflarski, JP fMRI study of cannabidiol-induced changes in attention control in treatment-resistant epilepsy EPILEPSY & BEHAVIOR English Article Epilepsy; Seizure; Attention control; Cannabidiol; Flanker task; fMRI QUALITY-OF-LIFE; PSYCHOPHYSIOLOGICAL INTERACTIONS; INTERFERENCE RESOLUTION; CANNABINOID MODULATION; FRONTAL-LOBE; NEURAL BASIS; SEIZURES; DELTA-9-TETRAHYDROCANNABINOL; NETWORKS; CHILDREN Patients with treatment-resistant epilepsy (TRE) frequently exhibit memory and attention deficits that contribute to their poor personal and societal outcomes. We studied the effects of adjunct treatment with pharmaceutical grade cannabidiol (CBD) oral solution (Epidiolex (R); Greenwich Biosciences. Inc.) on attention control processes related to stimulus conflict resolution in patients with TRE. Twenty-two patients with TRE underwent 3 T magnetic resonance imaging (MRI) before receiving (PRE) and after achieving a stable dose of CBD (ON). Functional MRI (fMRI) data were collected while patients performed 2 runs of a flanker task (FT). Patients were instructed to indicate via button press the congruent (CON) and incongruent (INC) conditions. We performed t-tests to examine with FT attention control processes at PRE and ON visits and to compare the 2 visits using derived general linear model (GLM) data (INC - CON). We performed generalized psychophysiological interaction (gPPI) analyses to assess changes in condition-based functional connectivity on FT. Median time between fMR1 visits was 10 weeks, and median CBD dose at follow-up was 25 mg/kg/d. From PRE to ON, participants experienced improvements in seizure frequency (SF) (p = 0.0009), seizure severity (Chalfont Seizure Severity Scale (CSSS); p < 0.0001), and mood (Total Mood Disturbance (TMD) score from Profile of Mood States (POMS); p = 0.0026). Repeated measures analysis of variance showed nonsignificant improvements in executive function from 34.6 (23.5)% to 41.9 (22.4)% CON accuracy and from 34.2 (25.7)% to 37.6 (24.4)% INC accuracy (p = 0.199). Change in CON accuracy was associated with change in INC accuracy (rs 0.81, p = 0.0005). Participants exhibited CBD-induced increases in IMRI activation in the right superior frontal gyrus (SFG) and right insula/middle frontal gyrus (MEG) and decrease in activation for both regions at ON rel