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This review examines the concentration of seven major cannabinoids, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), in illicit herbal cannabis products seized by the Drug Enforcement Administration (DEA) over the last 10 years in the United States. Cannabis samples received from DEA regional laboratories were analyzed by a validated gas chromatography with flame ionization detection method, and the results are given in the report. A total of 14,234 samples of herbal cannabis have been analyzed over the last 10 years (between January 1, 2009, and December 31, 2019). The number of samples received over the last 5 to 6 years has decreased dramatically owing to the legalization of marijuana for either medical or recreational purposes in many U.S. states. The results showed that the mean Δ9-THC concentration has increased over the last 10 years, from 9.75% in 2009 to 14.88% in 2018 and 13.88% in 2019. The mean Δ9-THC:CBD ratio rose substantially from 24.81 in 2009 to 103.48 in 2017. A decrease in THC:CBD ratio was recorded in the last 2 years, 54.39 in 2018 and 24.58 in 2019, indicating the trend in the production of more high-CBD-containing products. Our results showed an overall increase in potency of illicit cannabis, from approximately 10% in 2009 to approximately 14% in 2019. These results are in agreement with other potency monitoring programs in several European countries. There appears to be a recent trend of the inclusion of higher CBD levels containing chemovars in illicit cannabis.

Primaquine (PQ) is a racemic drug used in treatment of malaria for six decades. Recent studies suggest that the two enantiomers of PQ are differentially metabolized in animals, and this results in different pharmacological and toxicological profiles. The current study characterizes the pharmacokinetic (PK) properties, metabolism and tolerability of the individual enantiomers of PQ in healthy human volunteers with normal glucose-6-phosphate dehydrogenase (G6PD) activity. Two cohorts (at two dose levels), each with 18 subjects, participated in three study arms in a crossover fashion: a single dose of the (-)-R enantiomer (RPQ), a single dose of the (+)-S enantiomer (SPQ), and a single dose of racemic PQ (RSPQ). PQ and its key metabolites carboxyprimaquine (cPQ) and PQ-N-carbamoyl glucuronide (PQ-N-CG) were analyzed. Clear differences were observed in PK and metabolism of the two enantiomers. Relative PQ exposure was higher with SPQ as compared to RPQ. PQ maximum plasma concentration (C

Purpose: To isolate new antimicrobial agents from the leaves of Markhamia platycalyx (Baker) Sprague and assess their phytochemical characteristics and antimicrobial activity. Methods: Different chromatographic and spectroscopic techniques (NMR and ESI-MS) were applied for the identification of antimicrobial compounds. Agar-well diffusion technique was used for determination of antimicrobial activity. Anti-HCV effects were investigated using VITROS Anti-HCV assay. Results: Eighteen compounds were isolated for the first time from this genus. These were phytol, noctacosanoic acid (OCTA), tormentic acid and β-sitosterol-3-O-(6'-O-heptadecanoyl)-β-Dglucopyranoside. The other compounds were β-sitosterol, ursolic acid (URSA), oleanolic acids, pomolic acid (POMA), 2-epi-tormentic and β-sitosterol-3-O-β-D-glucopyranoside. However, stigmasterol and acteoside, which were seen in previous studies, were also present. Total ethanol extract (TEE) was the most effective against Escherichia coli, with the lowest minimum inhibitory concentration (MIC) of 1.0 μg/mL. Acteoside, URSA and 2-epi-tormentic acid showed the highest antibacterial effect on Pseudomonas aeruginosa while 2-epi-tormentic acid and acteoside produced the least MIC on Candida glabrata. These effects were superior to those produced by standard antibiotics. However, 2-epitormentic acid and β-sitosterol-3-O-β-D-glucopyranoside had no anti-HCV effects. Conclusion: Due to the good antimicrobial properties of Markhamia platycalyx, it is a potential source of new antimicrobial drugs.

New series of [1,2,4]triazolo [4,3-a]quinoxaline and bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives have been designed, synthesized and biologically evaluated for their cytotoxic activities against three tumor cell lines (HePG-2, Hep-2 and Caco-2). Compounds 16e, 21, 25a and 25b exhibited the highest activities against the examined cell lines with IC50 values ranging from 0.29 to 0.90 μM comparable to that of doxorubicin (IC50 ranging from 0.51 to 0.73 μM). The most active members were further evaluated for their topoisomerase II (Topo II) inhibitory activities and DNA intercalating affinities as potential mechanisms for their anti-proliferative activities. Interestingly, the results of Topo II inhibition and DNA binding assays were consistent with that of the cytotoxicity data, where the most potent anti-proliferative derivatives exhibited good Topo II inhibitory activities and DNA binding affinities, comparable to that of doxorubicin. Moreover, the most active compound 25a caused cell cycle arrest at G2/M phase and induced apoptosis in Caco-2 cells. In addition, Furthermore, molecular docking studies were performed for the novel compounds against DNA-Topo II complex to investigate their binding patterns. Based on these studies, it was concluded that DNA binding and/or Topo II inhibition may contribute to the observed cytotoxicity of the synthesized compounds.

Four new ceramides (1–4) were isolated from the sponge Monanchora clathrata, along with four epidioxysterols (5–8), two sterols (9, 10), uracil (11), and three triglycerides (12–14). All compounds were isolated for the first time from the genus Monanchora, also this is the first time for isolation and identification of compounds 5–8, and the ceramide moieties from the family Crambeidae. Acetylation of compounds (5–8) yielded two new chemically modified compounds (15, 16), in addition to the known 17, 18. Their chemical structures were elucidated using a combination of spectroscopic methods, including extensive 1D and 2D NMR, IR, HRESIMS, and GC/MS. The configuration of compounds 1–4 were assigned as 2S,3S,4R,2′R based on the modified Mosher’s reaction, optical rotation measurements and spectroscopic data comparison. The compounds were evaluated for their, cytotoxic, antiprotozoal, antimicrobial, and antimalarial potentials. Compound 1 showed remarkable cytotoxicity against MES-SA, MCF-7, and HK-2 cell lines with IC50 values of 3.29, 17.95 and 4.45 μM, respectively.

Photooxygenation of Δ8 tetrahydrocannabinol (Δ8-THC), Δ9 tetrahydrocannabinol (Δ9-THC), Δ9 tetrahydrocannabinolic acid (Δ9-THCA) and some derivatives (acetate, tosylate and methyl ether) yielded 24 oxygenated derivatives, 18 of which were new and 6 were previously reported, including allyl alcohols, ethers, quinones, hydroperoxides, and epoxides. Testing these compounds for their modulatory effect on cannabinoid receptors CB1 and CB2 led to the identification of 7 and 21 as CB1 partial agonists with Ki values of 0.043 μM and 0.048 μM, respectively and 23 as a cannabinoid with high binding affinity for CB2 with Ki value of 0.0095 μM, but much less affinity towards CB1 (Ki 0.467 μM). The synthesized compounds showed cytotoxic activity against cancer cell lines (SK-MEL, KB, BT-549, and SK-OV-3) with IC50 values ranging from 4.2 to 8.5 μg/mL. Several of those compounds showed antimicrobial, antimalarial and antileishmanial activities, with compound 14 being the most potent against various pathogens.

VEGF/VEGFR2 pathway is the crucial therapeutic target in the treatment of cancer. So that, a new series of quinoxaline-2(1H)-one derivatives were designed and synthesized. The synthesized compounds were tested against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) aiming to evaluate its anti-proliferative activities. Doxorubicin as a universal anticancer drug and sorafenib as a potent VEGFR-2 inhibitor were used as positive controls. The data obtained from biological activity were found highly correlated with that obtained from molecular modeling studies. The most sensitive cell line to the influence of our new derivatives was HCT-116. Compounds 13b, 15, 16e and 17b exert the highest cytotoxic activities against the tested cell lines. Overall, compound 15 was the most active member with IC50 values of 5.30, 2.20, 5.50 µM against HepG-2, MCF-7 and HCT-116, respectively. Compounds 15 and 17b showed better anti-proliferative activities than doxorubicin and sorafenib against the three cancer cell lines. Additionally, compound 16e showed better anti-proliferative activities than doxorubicin and sorafenib against HepG-2 and HCT-116 but exhibited lower activity against MCF-7 cell line. In addition, the most promising members were further evaluated for their inhibitory activities against VEGFR-2. Compounds 15 and 17b potently inhibited VEGFR-2 at lower IC50 values of 1.09 and 1.19 µM, respectively, compared to sorafenib (IC50 = 1.27 µM). Moreover, docking studies were conducted to investigate the binding pattern of the synthesized compounds against the prospective molecular target VEGFR-2.

Peroxisome proliferator-activated receptor gamma (PPARγ) and sulfonylurea receptor (SUR) play crucial roles in management of type-2 diabetes mellitus. In this study, a series of novel quinazoline-4(3H)-one-sulfonylurea hybrids were designed and synthesized as dual PPARγ and SUR agonists. The synthesized compounds were evaluated for their in vivo anti-hyperglycemic activities against STZ-induced hyperglycemic rats. Four compounds (19a, 19d, 19f and 25g) demonstrated potent activities with reduction in blood glucose levels of 40.43, 46.42, 41.23 and 42.50 %, respectively. The most active ten compounds were further evaluated in vitro for their PPARγ binding affinities and insulin-secreting abilities. Compounds 19b, 19d, 19f, 25f and 25g exhibited the highest affinities against PPARγ with IC50 values of 0.371, 0.350, 0.369, 0.408 and 0.353µM, respectively. In addition, compounds 19d, 19f, and 25d showed the highest insulin-secreting activities with EC50 values of 0.97, 1.01 and 1.15µM, respectively. Furthermore, molecular docking and pharmacophore generation techniques were carried out to investigate binding patterns and fit values of the designed compounds with PPARγ and SUR, respectively. Also, two QSAR models were generated to explore the structural requirements controlling the different biological activities of the synthesized compounds against PPARγ and SUR.

The ethanol extract of Cynara cornigera L. was fractionated and the fractions were subjected to hepatoprotective assays using Wistar albino rats at a dose of 500 and 250 mg/kg. The liver injury was induced in rats using carbon tetrachloride. Biochemical parameters such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin were estimated as reflections of the liver condition, with silymarin as a positive control. Phytochemical investigation and chromatographic separation of the hepatoprotective fractions led to the isolation of a new sesqui-lignan namely cornigerin ( 1 ), along with eight known compounds: apigenin ( 2 ), luteolin ( 3 ), β-sitosterol glycoside ( 4 ), apigenin 7-O-β-D-glucopyranoside ( 5 ), luteolin-7-O-β-D-glucopyranoside ( 6 ), apigenin-7-O-rutinoside ( 7 ), cynarin 1,5-di-O-caffeoylquinic acid ( 8 ), and apigenin-7-O-β-D-glucuronide ( 9 ). This is the first report for the isolation of 8 and 9 from this plant.

A series of new VEGFR-2 inhibitors were designed, synthesized and evaluated for their anti-proliferative activities against hepatocellular carcinoma (HepG-2 cell line). Compound 29b (IC50 = 4.33 ± 0.2 µg/ml) was found to be the most potent derivative as it has showed to be more active than doxorubicin (IC50 = 4.50 ± 0.2 µg/ml) and 78% of sorafenib activity (IC50 = 3.40 ± 0.25 µg/ml). The inhibitory profiles against VEGFR-2 were also assessed for the most promising candidates (16b, 20c, 22b, 24a, 24b, 28c, 28e, 29a, 29b and 29c). Compounds 29b, 29c and 29a exhibited potent inhibitory activities towards VEGFR-2 at IC50 values of 3.1 ± 0.04, 3.4 ± 0.05 and 3.7 ± 0.06 µM, respectively, comparing sorafenib (IC50 = 2.4 ± 0.05 µM). Furthermorer, compound 29b induced apoptosis and arrested the cell cycle growth at G2/M phase. Additionally, in vivo antitumor experiments revealed that compounds 29b and 29c have significant tumor growth inhibition. The test of immuno-histochemical expression of activated caspase-3 revealed that there is a time-dependent increase in cleaved caspase-3 protein expression upon exposure of HepG-2 cells to compound 29b. Moreover, the fibroblastic proliferative index test revealed that compound 29b could attenuate liver fibrosis. Docking studies also supported the results concluded from the biological screening via prediction of the possible binding interactions of the target compounds with VEGFR-2 active sites using the crystal structure of VEGFR-2 downloaded from the Protein Data Bank, (PDB ID: 2OH4) using Discovery Studio 2.5 software. Further structural optimization of the most active candidates may serve as a useful strategy for getting new lead compounds in search for powerful and selective antineoplastic agents.

Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Thus, nineteen new quinazoline-4(3H)-one derivatives were designed and synthesized. Preliminary cytotoxicity studies of the synthesized compounds were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Five compounds were found to have promising cytotoxic activities against all cell lines. Compound 16f, containing a 2-chloro-5-nitrophenyl group, has emerged as the most active member. It was approximately 4.39-, 5.73- and 1.96-fold more active than doxorubicin and 3.88-, 5.59- and 1.84-fold more active than sorafenib against HepG2, HCT-116 and MCF-7 cells, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities. The results of in vitro VEGFR-2 inhibition were consistent with that of the cytotoxicity data. Molecular docking of these compounds into the kinase domain, moreover, supported the results.

Sixteen novel quinazoline-based derivatives were designed and synthesized via modification of the VEGFR-2 reported inhibitor 7 in order to increase the binding affinity of the designed compounds to the receptor active site. The designed compounds were evaluated for their VEGFR-2 inhibitory effects. Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. The bioactivity of the new compounds was performed against HepG-2, MCF-7 and HCT-116 cell lines. Doxorubicin and sorafenib were used as positive controls. Compound 18d was observed to have promising cytotoxic activity (IC50 = 3.74 ± 0.14, 5.00 ± 0.20 and 6.77 ± 0.27 µM) in comparison to the reference drug doxorubicin (IC50 = 8.28, 9.63 and 7.67 µM) and sorafenib (IC50 = 7.31, 9.40 and 7.21 µM). The most active compounds were tested for their in vitro VEGFR-2 inhibitory activities. Results of VEGFR-2 inhibition were consistent with that of the cytotoxicity data. Thus, compound 18d showed VEGFR-2 inhibitory activity (IC50 = 0.340 ± 0.04 µM) superior to that of the reference drug, sorafenib (IC50 = 0.588 ± 0.06 µM). Furthermore, docking study was performed in order to understand the binding pattern of the new compounds into VEGFR-2 active site. Docking results attributed the potent VEGFR-2 inhibitory effect of the new compounds as they bound to the key amino acids in the active site, Glu883 and Asp1044, as well as their hydrophobic interaction with the receptor hydrophobic pocket. Results of cytotoxic activities, in vitro VEGFR-2 inhibition together with docking study argument the advantages of the synthesized analogues as promising anti-angiogenic agents.

Background Marijuana is the most widely used illicit drug in the United States and all over the world. Reports indicate that the potency of cannabis preparation has been increasing. This report examines the concentration of cannabinoids in illicit cannabis products seized by the U.S. Drug Enforcement Administration over the last 2 decades, with particular emphasis on Δ 9 -tetrahydrocannabinol and cannabidiol. Methods Samples in this report were received over time from materials confiscated by the Drug Enforcement Administration and processed for analysis using a validated gas chromatography with flame ionization detector method. Results Between January 1, 1995, and December 31, 2014, 38,681 samples of cannabis preparations were received and analyzed. The data showed that although the number of marijuana samples seized over the last 4 years has declined, the number of sinsemilla samples has increased. Overall, the potency of illicit cannabis plant material has consistently increased over time since 1995 from ~4% in 1995 to ~12% in 2014. The cannabidiol content has decreased on average from ~.28% in 2001 to 9 -tetrahydrocannabinol to cannabidiol from 14 times in 1995 to ~80 times in 2014. Conclusions There is a shift in the production of illicit cannabis plant material from regular marijuana to sinsemilla. This increase in potency poses higher risk of cannabis use, particularly among adolescents.

The present study describes a simple, efficient and one step regeneration system for rapid shoot proliferation and in vitro rooting of Cannabis sativa nodal explants using meta-topolin (mT), an aromatic natural cytokinin. The best response in terms of explants producing maximum number of shoots with maximum shoot length and percent explants producing shoots was recorded on Murashige and Skoog (MS) medium supplemented with 2 μM mT. Shoots multiplied on the same medium for two sub-cultures were able to induce healthy roots within 4–6 weeks. A separate medium containing auxin was not required for root induction. Regenerated plantlets were successfully acclimatized and hardened off in the climatic controlled grow room with 100% survival rate. Genetic fidelity of in vitro propagated plants was tested using inter simple sequence repeat (ISSR) markers. Our results show that all the ISSR profiles from in vitro propagated plants were monomorphic and comparable to that of the mother plant, thereby confirming the genetic fidelity. Qualitatively and quantitatively, cannabinoid profiles and the content, using gas chromatography-flame ionization detector (GC–FID), in mother plant and in vitro propagated plants were found to be similar to each other. Furthermore, regenerated plants were eco-physiologically and functionally comparable to that of the mother plant. The maximized regeneration protocol using mT is thus effective and safe for large scale production of true to type C. sativa plants.

Chemical investigation of the Red Sea soft coral Sarcophyton auritum led to the isolation and structure elucidation of a new ceramide N-((2S,3R,4E,6E)-1,3-dihydroxyhenicosa-4,6-dien-2-yl)tridecanamide (1). Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The anticonvulsant activity of the isolated ceramide was measured in vivo using the pentylenetetrazole (PTZ)-induced seizure model, where it successfully antagonized the lethality of pentylenetetrazole in mice. In addition, the isolated ceramide showed good anxiolytic activity when used in the light–dark transition box and the elevated plus maze compared to diazepam. The molecular modeling studies for the antiepileptic and antianxiety mechanism of the isolated ceramide suggested a CNS depressing activity possibly through GABA and serotonin receptors modulation. The pharmacological activity of the ceramide involved agonistic activity on GABA-A receptors but not 5HT3 receptors.

OBJECTIVES: Cannabidiol (CBD) is the major non-psychotropic phytocannabinoid present in Cannabis sativa. In 2018, Congress designated select C. sativa cultivars as “hemp” removing them from the DEA's list of controlled substances. As a result, CBD-containing hemp extracts and other CBD products are now widely available and heavily marketed, yet their FDA regulatory status is still hotly debated. Further complicating the debate is CBD's vastly under-researched safety profile. Safety concerns yet to be adequately addressed include CBD's drug interaction potential and its effect on the gut microbiome. METHODS: Using acetaminophen (APAP), the most commonly ingested over-the-counter pain medication, we demonstrated that CBD-rich cannabis extract (CRCE) poses a significant drug interaction risk. RESULTS: Mice exposed to both CRCE and APAP developed severe liver injury. This hepatotoxicity, however, was not observed when either CRCE or APAP were administered separately. Importantly, this injury was observed in two different strains of mice with susceptibilities seemingly linked to sex (female) and age (older animals). Furthermore, both beneficial and adverse effects of CRCE on the gut microbiome were observed. Specifically, CRCE exposure increased the relative abundance of the beneficial gut microbe, Akkermansia muciniphila, however, an overall decrease in the relative abundance of all gut bacterial species was noted. This decrease was paralleled by numerous pro-inflammatory responses in the proximal jejunum and colon. CONCLUSIONS: Taken together, these findings raise significant concerns about the safety of widespread CBD usage and underlines the need for additional well-designed studies into its safety and efficacy. FUNDING SOURCES: NIGMS 1P20 GM109005.

Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Accordingly, new quinazoline-based derivatives having the structural features of VEGFR-2 inhibitors were designed and synthesized. Anti-proliferative activities were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Compounds 26b, 29a, 29b and 30 showed excellent anti-cancer activities against all cell lines. Moreover, compound 31 was the most active with IC 50 values of 3.97 ± 0.2, 4.83 ± 0.2 and 4.58 ± 0.3 µM, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities, compound 31 showed a high activity against VEGFR-2 with an IC50 value of 2.5 ± 0.04 µM, almost equal to that of sorafenib (IC50 = 2.4 ± 0.05 µM). Further studies revealed the ability of this promising quinazoline derivative 31 to induce apoptosis and arrest cell cycle growth at G2/M phase. In vivo antitumor activities of the synthesized compounds revealed that compounds 30 and 31 possessed significant tumor growth inhibition effect. Molecular docking studies were also performed and finally we can say that VEGFR-2 inhibition confers the reported cytotoxic activities.

The effect of different levels of photon flux densities (000, 400, 800, 1200, 1600 and 2000 μmol m −2 s −1 ) on gas and water vapor characteristics of four high Δ 9 -tetrahydrocannabinol (Δ 9 -THC) yielding drug type varieties (HPM, K2, MX and W1) of Cannabis sativa was studied. Plants of each variety were grown from seeds. On flowering, male plants were removed and vegetatively propagated clones of selected female plants were used for gas and water vapor studies at different photosynthetic photon flux densities (PPFDs). Our data show an increasing trend in photosynthesis ( P N ), transpiration ( E ) and stomatal conductance ( g CO 2 ) with increase in PPFD up to 2000 μmol m −2 s −1 in all varieties at optimum growth temperature (25 ± 3 °C). However, the magnitude of increase and maximum rate of P N ( P N max ) varied considerably with the varieties. Highest P N was observed in W1 followed by MX, K2 and HPM. Water use efficiency (WUE) in W1, MX and HPM increased with PPFDs up to the highest level tested, whereas, in K2 the highest WUE was observed at 1600 μmol m −2 s −1 . Our results suggest that this species is able to use high level of PPFDs for its P N and therefore, may be cultivated in sun exposed areas in the field or under high PPFDs using indoor grow lights for the optimum growth. Strict control of other environmental factors, however, needs to be maintained while growing the plants indoor.

Chemical investigation of the Red Sea soft coral Sarcophyton auritum led to the isolation and structure elucidation of two new diterpene cembranoids; 2- epi -sarcophine ( 2 ) and (1 R ,2 E ,4 S ,6 E ,8 R ,11 R ,12 R )-2,6-cembradiene-4,8,11,12-tetrol ( 4 ), as well as two known diterpene cembranoids, reported for the first time from this species, namely sarcophine ( 1 ) and (+)-7α,8β-dihydroxydeepoxysarcophine ( 3 ). Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The isolated cembranoids were found to display high cytotoxicity against HepG2 (liver cancer cell line) and MCF-7 (breast cancer cell line).

Microbial metabolism of cannflavin A (1) and B (2), two biologically active flavonoids isolated from Cannabis sativa L., produced five metabolites (3-7). Incubation of 1 and 2 with Mucor ramannianus (ATCC 9628) and Beauveria bassiana (ATCC 13144), respectively, yielded 6''S,7''-dihydroxycannflavin A (3), 6''S,7''-dihydroxycannflavin A 7-sulfate (4) and 6''S,7''-dihydroxycannflavin A 4'-O-alpha-L-rhamnopyranoside (5), and cannflavin B 7-O-beta-D-4'''-O-methylglucopyranoside (6) and cannflavin B 7-sulfate (7), respectively. All compounds were evaluated for antimicrobial and antiprotozoal activity.

The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. This study was conducted to assess the antidepressant-like activity of Delta(9)-THC and other cannabinoids. Cannabinoids were initially evaluated in the mouse tetrad assay to determine doses that do not induce hypothermia or catalepsy. The automated mouse forced swim (FST) and tail suspension (TST) tests were used to determine antidepressant action. At doses lacking hypothermic and cataleptic effects (1.25, 2.5, and 5 mg/kg, i.p.), both Delta(9)-THC and Delta(8)-THC showed a U-shaped dose response with only Delta(9)-THC showing significant antidepressant-like effects at 2.5 mg/kg (p0.05) in the FST. The cannabinoids cannabigerol (CBG) and cannabinol (CBN) did not produce antidepressant-like actions up to 80 mg/kg in the mouse FST, while cannabichromene (CBC) and cannabidiol (CBD) exhibited significant effect at 20 and 200mg/kg, respectively (p0.01). The antidepressant-like action of Delta(9)-THC and CBC was further confirmed in the TST. Delta(9)-THC exhibited the same U-shaped dose response with significant antidepressant-like action at 2.5 mg/kg (p0.05) while CBC resulted in a significant dose-dependent decrease in immobility at 40 and 80 mg/kg doses (p0.01). Results of this study show that Delta(9)-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.

Nine dihydroartemisinin acetal dimers (6-14) with diversely functionalized linker units were synthesized and tested for in vitro antiprotozoal, anticancer and antimicrobial activity. Compounds 6, 7 and 11 [IC(50): 3.0-6.7 nM (D6) and 4.2-5.9 nM (W2)] were appreciably more active than artemisinin (1) [IC(50): 32.9 nM (D6) and 42.5 nM (W2)] against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of the malaria parasite, Plasmodium falciparum. Compounds 10, 13 and 14 displayed enhanced anticancer activity in a number of cell lines compared to the control drug, doxorubicin. The antifungal activity of 7 and 12 against Cryptococcus neoformans (IC(50): 0.16 and 0.55 microM, respectively) was also higher compared to the control drug, amphotericin B. The antileishmanial and antibacterial activities were marginal. A number of dihydroartemisinin acetal monomers (15-17) and a trimer (18) were isolated as byproducts from the dimer synthesis and were also tested for biological activity.

Nutmeg, the seeds of Myritica fragrans (family Myristicaceae), is a well known kitchen spice with a long-standing reputation as a psychoactive herb. Nutmeg at high doses is considered a cheap substitute to several drugs of abuse. Earlier reports have attributed amphetamine-like activities to nutmeg.To characterize the neuropharmacological effects of different nutmeg extracts, administered orally and intraperitoneally, in comparison to Delta(9)-terahydrocannabinol, amphetamine, and morphine.Methanolic (ME), dichloromethane (DE), and hexane (HE) extracts were obtained from a chromatographically fingerprinted batch of nutmeg. Biological evaluation was conducted in sets of 6-8 mice in the tetrad assay at doses ranging from 100 to 500 and 500 to 1000 mg/kg for i.p. and oral administration, respectively.While oral administration of all the nutmeg extracts at 500 mg/kg caused a significant increase in locomotor activity, the i.p. administration of DE showed significant reduction in rectal temperature along with a significant increase in tail flick latency at 300 mg/kg. A significant decrease in core body temperature was observed with HE at 100 mg/kg, while higher doses caused significant increases in hot plate latency.Different behavioral effects were observed that varied by the type of extract as well as by the route of administration.

Three new cannabichromanone derivatives were isolated from high potency cannabis, along with the known cannabichromanone. Full spectroscopic data, including the use of electronic circular dichroism and Mosher ester analysis to determine the absolute configuration of these compounds, are reported. All isolates were tested for antimicrobial, antimalarial, antileishmanial, and anti-oxidant activities.

The objective of this research was to stabilize a heat-labile novel prodrug of Delta(9)-tetrahydrocannabinol (THC), THC-hemiglutarate (THC-HG), in polyethylene oxide (PEO) [PolyOx WSR N-80 (PEO N-80), MW 200,000 Daltons] polymeric matrix systems produced by hot-melt fabrication for systemic delivery of THC through the oral transmucosal route. For this purpose, the effects of processing conditions (processing temperature and heating duration), plasticizer type and concentration and storage conditions on the stability of the prodrug were investigated. The selected plasticizers studied included vitamin E succinate (VES), acetyltributyl citrate (ATBC), triethyl citrate (TEC), triacetin and polyethylene glycol 8000 (PEG 8000). Furthermore, the influence of plasticizer concentration on drug release was also studied. The stability of THC-HG in PEO matrices was influenced by all the aforementioned variables. Films processed at 110 degrees C for 7min were found to be favorable for hot-melt processing with a post-processing drug content of 95%, while significant degradation of THC-HG ( approximately 42%) was observed in those processed at 200 degrees C for 15min. The degradation of the prodrug during hot-melt fabrication and also upon storage was considerably reduced in the presence of the plasticizers investigated, VES being the most effective. Modulation of the microenvironmental pH to an acidic range via incorporation of citric acid in PEO-plasticizer matrices significantly improved the stability of the prodrug, with almost 90% of the theoretical drug remaining as opposed to only 15% remaining in PEO-only matrices when stored at 40 degrees C for up to 3 months. The release of drug from PEO matrices was influenced both by the plasticizer type and concentration. A faster release resulted from water-soluble plasticizers, PEG 8000 and triacetin, and with increasing concentration. However, a slower release was observed with an increase in concentration of water-insoluble plasticizers, VES and ATBC.

The objectives of the present research investigations were to (i) elucidate the mechanism for the oxidative degradation of Delta(9)-tetrahydrocannabinol (THC) in polymer matrix systems prepared by a hot-melt fabrication procedure, and (ii) study the potential for controlling these mechanisms to reduce the degradation of THC in solid dosage formulations. Various factors considered and applied included drug-excipient compatibility, use of antioxidants, cross-linking in polymeric matrices, microenvironment pH, and moisture effect. Instability of THC in polyethylene oxide (PEO)-vitamin E succinate (VES) patches was determined to be due to chemical interaction between the drug and the vitamin as well as with the atmospheric oxygen. Of the different classes and mechanisms of antioxidants studied, quenching of oxygen by reducing agents, namely, ascorbic acid was the most effective in stabilizing THC in PEO-VES matrices. Only 5.8% of the drug degraded in the ascorbic acid-containing patch as compared to the control (31.6%) after 2 months of storage at 40 degrees C. This coupled with the cross-linking extent and adjustment of the pH microenvironment, which seemed to have an impact on the THC degradation, might be effectively utilized towards stabilization of the drug in these polymeric matrices and other pharmaceutical dosage forms. These studies are relevant to the development of a stable transmucosal matrix system for the therapeutic delivery of amorphous THC.

The objective of the present research was to investigate the stability of an amorphous drug, Delta(9)-tetrahydrocannabinol (THC) in polymer-based transmucosal systems. THC was incorporated in polyethylene oxide and hydroxypropylcellulose matrices by a hot-melt fabrication procedure, utilizing various processing aids. The chemical stability of the drug in the polymeric matrices was investigated with respect to processing temperature, processing time, formulation additives, and storage conditions. HPLC analysis of the THC-loaded systems indicated that the extent of drug degradation was influenced by all of the above mentioned variables. THC was particularly unstable in the vitamin E succinate-processed films, indicating a potential incompatibility. Thermal stability of the drug, polymers, and other ingredients at the elevated processing temperatures during the fabrication procedure, was evaluated using the isothermal mode of thermo-gravimetric analysis. When held at 160 and 200 degrees C, the weight percentage of THC decreased linearly as a function of time. Weight loss was controlled by blending the drug with polymers, PEO and HPC, of which PEO was determined to be more effective. Although higher temperatures lowered the polymer melt viscosity, THC and other materials were chemically and thermally unstable at such high temperatures. Due to this, matrix fabrication was found to be favorable at relatively lower temperatures, such as 120 degrees C.

A procedure was developed for the determination of low levels of the anthraquinones aloe-emodin and aloin A (barbalin) in aloe products based on gas chromatography/mass spectrometry (GC/MS) of the trimethyl silyl (TMS) derivatives of these analytes in the presence of Chrysophanol used as internal standard. The method was used to analyze several aloe based commercial products (liquids, gels and solids). Wide variation in the level of these anthraquinones was observed among the different products. The method had a sensitivity of 0.005 ppm of aloe-emodin and 0.05 ppm of aloin.

Cannabisol (1), a unique dimer of Δ9-tetrahydrocannabinol (Δ9-THC) with a methylene bridge, was isolated from Cannabis sativa. This is the first example of a C-bridged dimeric cannabinoid. The structure of 1 was unambiguously deduced by HRESIMS, GCMS, and NMR spectroscopy. A plausible biogenesis of 1 is described.

The biflavanone (2S,2"S)-7,7"-di-O-methyltetrahydroamentoflavone and five known flavonoids, 7-O-methylnaringenin, 7,3'-O-dimethylquercetin, 7-O-methylapigenin, 7-O-methylluteolin, and eriodictyol were isolated from the leaves of Rhus retinorrhoea Steud, Ex Olive. The biflavanone exhibited moderate antimalarial activity with IC50 0.98 microg/ml against Plasmodium falciparum (W2 Clone) and weak activity against P. falciparum (D6 Clone) with IC50 2.8 microg/ml. Nevertheless, it did not display any cytotoxicity. 7-O-Methylnaringenin showed weak antimicrobial activity against Candida albicans, C. krusei, Staphylococcus aureus, Mycobacterium smegmatis, M. intracellulare, and M. xenopi with MIC approximately 100 microg/ml. Characterization of each compound was based on spectral analysis and comparison with reported data.

m-Hydroxybenzoylecgonine (m-OH-BE) and d3-m-hydroxybenzoylecgonine (d3-m-OH-BE) have been synthesized, and a GC/MS procedure with d3-m-OH-BE as internal standard has been developed. Among 24 human urine specimens that were positive for BE, all of them have shown detectable levels of m-OH-BE with 75% of the specimens exceeding the LoQ (5 ng/mL), compared with only 50% of the specimens containing detectable levels of EME. The presence of m-OH-BE in urine suggested that this metabolite may serve as a valuable marker of cocaine use in addition to BE and EME.

Appetite stimulation by cannabinoids is highly variable. Four within-subject design studies explored the effects of age, gender, satiety status, route of drug administration, and dose on intake. One study involved a single oral administration of active drug (15 mg males, 10 mg females) or placebo to an age and gender stratified sample of 57 healthy, adult light marijuana users. Eleven subjects received single doses by oral, sublingual, and inhaled routes in a second study. In the third study, 10 subjects ingested a single oral dose in fasted and fed states. A 2.5 mg dose was administered b.i.d. for 3 days by oral and rectal suppository routes in the fourth study. Mean daily energy intake was significantly elevated following chronic dosing by rectal suppository, but not oral capsule, relative to all acute dosing regimens except inhalation. Total daily energy intake was comparable on fed and fasted days, suggesting satiety mechanisms were not impaired by the drug. Subject age, gender, reported "high," and plasma drug level were not significantly associated with drug effects on food intake.

An oral formulation of Δ-9=tetrahydrocannabinol (THC) in sesame oil (Marinol®) is at present used for the management of chemotherapy-related nausea and emesis. However, due partly to poor bioavailability, its efficacy is variable. To circumvent possible metabolism in the gut and a first-pass effect by the liver, a suppository formulation of THC hemisuccinate ester was prepared. Administration of the suppository containing 11.8 mg of the hemisuccinate ester (equivalent to 9 mg THC) to three adult females (two of whom had previously exhibited low plasma drug levels following a 10-mg dose of the oral formulation) led to a marked and sustained elevation of plasma drug levels. Areas under the curves for plasma THC were more than 30-fold higher than after oral dosing. The suppository was well tolerated. The higher and more sustained plasma drug level achieved with this new formulation should enhance its antiemetic efficacy.

Background Allergic sensitization to Cannabis sativa is rarely reported, but the increasing consumption of marijuana has resulted in an increase in the number of individuals who become sensitized. To date, little is known about the causal allergens associated with C sativa . Objective To characterize marijuana allergens in different components of the C sativa plant using serum IgE from marijuana sensitized patients. Methods Serum samples from 23 patients with a positive skin prick test result to a crude C sativa extract were evaluated. IgE reactivity was variable between patients and C sativa extracts. IgE reactivity to C sativa proteins in Western blots was heterogeneous and ranged from 10 to 70 kDa. Putative allergens derived from 2-dimensional gels were identified. Results Prominent IgE reactive bands included a 23-kDa oxygen-evolving enhancer protein 2 and a 50-kDa protein identified to be the photosynthetic enzyme ribulose-1,5-bisphosphate carboxylase/oxygenase. Additional proteins were identified in the proteomic analysis, including those from adenosine triphosphate synthase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and luminal binding protein (heat shock protein 70), suggesting these proteins are potential allergens. Deglycosylation studies helped refine protein allergen identification and demonstrated significant IgE antibodies against plant oligosaccharides that could help explain cross-reactivity. Conclusion Identification and characterization of allergens from C sativa may be helpful in further understanding allergic sensitization to this plant species.

A high-performance liquid chromatographic procedure for the separation of urushiol congeners isolated from poison ivy and poison oak was developed. Each of the congeners was characterized by a retention index and the ratio of UV detector responses at 254 nm and 280 nm. The retention index of each congener was determined experimentally from a scale established by the relative retention of a series of 2-keto alkane standards (C 3 C 23 ). A simple semi-empirical equation using Hansch substituent constants (π values) was also used to estimate the retention index of each congener.

The development of contact sensitivity to poison ivy urushiol in Hartley guinea pigs was inhibited by i.v. injection of the diacetate esters of poison ivy and oak urushiols into guinea pigs 2 weeks prior to attempted sensitization with homologous antigen. Immune tolerance to urushiols of poison ivy and oak developed in 80% or more of the treated animals and persisted for the duration of the study, 8 weeks. The tolerance was immunologically specific for urushiols since the tolerant animals were sensitizable to the unrelated sensitizer 2, 4-dinitrochlorobenzene. Guinea pigs already sensitive to urushiol were also desensitized or hyposensitizied by i.v. injection of urushiol acetates in successively increasing doses. After receiving the equivalent of 16 mg of poison ivy and oak urushiols in the acetate form over a period of 12 weeks, 54% of a group of guinea pigs were desensitized to poison ivy. all of the remaining 46% of the guinea pigs still sensitive to poison ivy were substantially hyposensitized (no longer responded to 1.5 or 0.80 microgram test doses of PDC). A control group of guinea pigs was not hyposensitized by injection of vehicle, and remained highly sensitive throughout the 15 week study. The majority of treated animals (less than 80%) were also hyposensitized to poison sumac and cashew nut shell liquid allergens.

It was not known if Cannabichromene (CBC), which is a major constituent of drug types of Cannabis , has anti-inflammatory properties as do other cannabinoids. CBC was tested in vivo using the rat paw edema test and in vitro using the erythrocyte membrane stabilization assay. CBC was as effective as phenylbutazone (PBZ) at equivalent doses. Since CBC is less toxic than PBZ, larger doses may be given to produce a greater therapeutic effect.

The effects of cannabichromene (CBC), Δ 9 -tetrahydrocannabinol ( Δ 9 -THC) and their combination (all doses 50 mg/kg orally) were determined after being administered to female mice for 7 days beginning on the 20th day of gestation. The THC treatment reduced postnatal viability, impaired male reproductive behavior at maturity and significantly reduced seminal vesicle weights. No changes from control values occurred after CBC or CBC + THC. Thus, CBC alone at this dosage did not act like THC; moreover, it antagonized the effects of THC when the two were given in combination.

Full details are provided on the isolation, spectral data and X-ray crystallographic analysis of cannabispiran ( 1 ) [7' - hydroxy - 5' - methoxyspiro(cyclohexane - 1,1' - indan) - 4 - one] and its correlation to Δ 2 -cannabispiran (dehydrocannabispiran) ( 2 ); both of which are novel spiro-compounds isolated from the leaves of Cannabis sativa L. Cannabispiran ( 1 ) crystallizes in the space group Pbca , cell dimensions: a = 10.388(5) A, b = 14.754(7)A, c = 16.950(8)A, with eight molecules in the unit cell. The structure model was refined, using 852 observed reflections collected by counter methods, to an R -factor of 0.074 and a weighted R w of 0.054.

The structure of ruscodibenzofuran, a new naturally occurring dibenzofuran from the roots of Ruscus aculeatus L. (Farn. Liliaceae), was determined by spectral means, the synthesis of model compounds and was confirmed by X-ray diffraction analysis.

The effects of cocaine, its metabolites, and other alkaloids from Erythroxylon coca on the primary immune responses of ICR mice to sheep red blood cells (sRBC) and dinitrofluorobenzene (DNFB) were studied. The Jerne hemolytic plaque assay (PFC) was used to evaluate the humoral immune response to sheep red blood cells, and the delayed type hypersensitivity (DTH) response to DNFB was used to study cellular immune responsiveness. Drugs were given in single daily po doses for 5 consecutive days beginning on the day of immunization or 3 days prior to and on Days 3 and 4 after immunization. Inhibition of both PFC and DTH responses occurred at doses of 15 to 60 mg/kg of cocaine and was greatest when fed during immunization. Five other alkaloids also suppressed the PFC and/or DTH response. Cocaine was more suppressive than the six other alkaloids tested. Ethanol (5 g/kg) did not suppress the DTH response and only marginally suppressed the PFC response. delta 9-THC inhibited the PFC response at doses of 10 mg/kg and marginally suppressed the DTH response at doses of 30 mg/kg, but not at other doses ranging from 10 to 90 mg/kg. Coadministration of 5 g/kg ethanol and 15 mg/kg cocaine resulted in 50% antagonism of effects of cocaine on the PFC response and complete antagonism of the suppression of the DTH response, but only if these substances were given during the period of immunization. Like ethanol, delta 9-THC also abolished the inhibitory effects of cocaine on the PFC and DTH response but only if coadministered during the period of immunization. Coadministration of ethanol and delta 9-THC resulted in synergistic inhibition of both DTH and PFC responses.

The effects of cocaine and two extracts of the coca leaf were compared using locomotor activity and limited access food consumption paradigms. The three treatments were tested using both IP and PO routes of administration. The extracts were prepared by first extracting the powdered leaves with 95% ethanol, evaporating the ethanol and then partitioning the residue between water and chloroform. The doses of the extracts studied were 60, 120, 240, and 480 mg/kg. The doses of cocaine studied were 3.45, 6.9, 13.8, and 27.6 mg/kg. These doses corresponded to the amount of cocaine contained in the four doses of the chloroform layer. Cocaine and the chloroform layer (via both routes) produced dose related increases in locomotor activity and dose related decreases in food consumption. The water layer (containing only trace amounts of cocaine) produced no changes in locomotor activity; however, the highest IP dose did significantly reduce food consumption. Furthermore two of the doses (one IP, one PO) of the chloroform layer produced significantly greater effects than an equivalent amount of cocaine. These data suggest that plant constitutents other than cocaine may contribute to the overall effect achieved by chewing the leaf.

1. 1. LD50's in mice after single intraperitoneal (i.p.) doses of cannabichromene (CBC) and Δ9-tetrahydrocannabinol (Δ9-THC) were 113.4 and 276.3 mg/kg, respectively. A small dose (25 mg/kg) of CBC given concurrently with Δ9-THC lowered the LD50 of Δ9-THC to 152.0 mg/kg. 2. 2. CBC, like Δ9-THC, caused hypothermia in mice; it reduced the effect of Δ9-THC at early times and increased it at later times after the two were injected simultaneously i.p. 3. 3. CBC and Δ9-THC, in 25 mg/kg i.p. doses, each prolonged hexobarbital hypnosis equally in mice, but had no additive effect in combination.

A procedure is described for the analysis of urushiol content of pharmaceutical preparations containing extracts of poison ivy (Toxicodendron radicans) and poison oak (T. diversilobum) in vegetable oils. The procedure involves extraction of the urushiols from the oily solutions using 90% methanol in water followed by GLC analysis of the extracts. Recoveries of both poison ivy and poison oak urushiols from solutions in corn oil, olive oil, sesame seed oil, and cottonseed oil were calculated. Correlation coefficients (r2) ranged from 0.97 to 1.00, and the coefficients of variations ranged from 3.08 to 7.90%.

An investigation of the alkaloidal fraction of Erythroxylon coca leaves, collected in Peru, has resulted in the isolation and characterization of c

GC analysis of the ethanolic extract of poison sumac ( Toxicodendron vernix ) showed five urushiol components four of which were identical with those