Medical marijuana initiatives - Are they justified? How successful are they likely to be?

The principal constituent of cannabis, Delta(9)-tetrahydrocannabinol (THC), is moderately effective in treating nausea and vomiting, appetite loss, and acute and chronic pain. Oral THC (dronabinol) and the synthetic cannabinoid, nabilone, have been registered for medical use in the US and UK, but they have not been widely used because patients find it difficult to titrate doses of these drugs. Advocates for the medical use of cannabis argue that patients should be allowed to smoke cannabis to relieve these above-mentioned symptoms. Some US state governments have legislated to allow the medical prescription of cannabis, but the US federal government has tried to prevent patients from obtaining cannabis and threatened physicians who prescribe it with criminal prosecution or loss of their licence to practise. In the UK and Australia, committees of inquiry have recommended medical prescription (UK) and exemption from criminal prosecution (New South Wales, Australia), but governments have not accepted these recommendations. The Canadian government allows an exemption from criminal prosecution to patients with specified medical conditions. It has recently legislated to provide cannabis on medical prescription to registered patients, but this scheme so far has not been implemented. Some advocates argue that legalising cannabis is the only way to ensure that patients can use it for medical purposes. However, this would be contrary to international drug control treaties and is electorally unpopular. The best prospects for the medical use of cannabinoids lie in finding ways to deliver THC that do not involve smoking and in developing synthetic cannabinoids that produce therapeutic effects with a minimum of psychoactive effects. While awaiting these developments, patients with specified medical conditions could be given exemptions from criminal prosecution to grow cannabis for their own use, at their own risk.

Identification and total synthesis of novel fatty acids from the siphonarid limpet Siphonaria denticulata

The novel fatty acids 17-methyl-6(Z)-octadecenoic acid and 17-methyl-7(Z)-octadecenoic acid were identified for the first time in nature in the mollusk Siphonaria denticulata from Queensland, Australia. The principal fatty acids in the limpet were hexadecanoic acid, octadecanoic acid, and (Z)-9-octadecenoic acid, while the most interesting series of monounsaturated fatty acids was a family of five nonadecenoic acids with double bonds at either Delta (7), Delta (9), Delta (11), Delta (12), or Delta (13). The novel compounds were characterized using a combination of GC-MS and chemical transformations, such as dimethyl disulfide derivatization. The first total syntheses for the two novel methyl-branched nonadecenoic acids are also described, and these were accomplished in four to five steps and in high yields.

A suite of novel allenes from Australian melolonthine scarab beetles. Structure, synthesis, and stereochemistry

A suite of allenic hydrocarbons, previously unknown as a molecular class from insects, has been characterized from several Australian melolonthine scarab beetles. The allenes are represented by the formula CH3(CH2)nCH=.=CH(CH2)(7)CH3 with n being 11-15, 17 and 19, and thus, all have Delta(9,10)-unsaturation. These structures have been confirmed by syntheses and comparisons of spectral and chromatographic properties with those of the natural components. The enantiomers of (+/-)-Delta(9,10)-tricosadiene and Delta(9,10)-pentacosadiene were separable on a modified beta-cyclodextrin column (gas chromatography), and the natural Delta(9,10)-tricosadiene (n = 11) and Delta(9,10)-pentacosadiene (n = 13) were shown to be of >85% ee. Syntheses of nonracemic allenes of known predominating chirality were acquired using both organotin chemistry and sulfonylhydrazine intermediates, and comparisons then demonstrated that the natural allenes were predominantly (R)-configured.

Escalation of Drug Use in Early-Onset Cannabis Users vs Co-twin Controls

Context Previous studies have reported that early initiation of cannabis (marijuana) use is a significant risk factor for other drug use and drug-related problems. Objective To examine whether the association between early cannabis use and subsequent progression to use of other drugs and drug abuse/dependence persists after controlling for genetic and shared environmental influences. Design Cross-sectional survey conducted in 1996-2000 among an Australian national volunteer sample of 311 young adult (median age, 30 years) monozygotic and dizygotic same-sex twin pairs discordant for early cannabis use (before age 17 years). Main Outcome Measures Self-reported subsequent nonmedical use of prescription sedatives, hallucinogens, cocaine/other stimulants, and opioids; abuse or dependence on these drugs (including cannabis abuse/dependence); and alcohol dependence. Results Individuals who used cannabis by age 17 years had odds of other drug use, alcohol dependence, and drug abuse/dependence that were 2.1 to 5.2 times higher than those of their co-twin, who did not use cannabis before age 17 years. Controlling for known risk factors (early-onset alcohol or tobacco use, parental conflict/separation, childhood sexual abuse, conduct disorder, major depression, and social anxiety) had only negligible effects on these results. These associations did not differ significantly between monozygotic and dizygotic twins. Conclusions Associations between early cannabis use and later drug use and abuse/dependence cannot solely be explained by common predisposing genetic or shared environmental factors. The association may arise from the effects of the peer and social context within which cannabis is used and obtained. In particular, early access to and use of cannabis may reduce perceived barriers against the use of other illegal drugs and provide access to these drugs.

Being stoned: A review of self-reported cannabis effects

Although there has been considerable research into the adverse effects of cannabis, less attention has been directed toward subjective effects that may be associated with ongoing cannabis use. Examination of self-reported cannabis effects is an important issue in understanding the widespread use of cannabis. While reviews have identified euphoria as a primary factor in maintaining cannabis use, relaxation is the effect reported most commonly in naturalistic studies of cannabis users, irrespective of the method used. Self-reported effects in 12 naturalistic and 18 laboratory studies were compared. Regardless of methodology there was considerable variation in the effects experienced. Variation has been reported in terms of opposite effects being experienced by different individuals, variation of effects by individuals within a single occasion and between occasions of use. Factors that might explain this variation are outlined. Limitations of the available literature and suggested directions for future research are discussed.

Is cannabis a gateway drug? Testing hypotheses about the relationship between cannabis use and the use of other illicit drugs

We outline and evaluate competing explanations of three relationships that have consistently been found between cannabis use and the use of other illicit drugs, namely, ( 1) that cannabis use typically precedes the use of other illicit drugs; and that ( 2) the earlier cannabis is used, and ( 3) the more regularly it is used, the more likely a young person is to use other illicit drugs. We consider three major competing explanations of these patterns: ( 1) that the relationship is due to the fact that there is a shared illicit market for cannabis and other drugs which makes it more likely that other illicit drugs will be used if cannabis is used; ( 2) that they are explained by the characteristics of those who use cannabis; and ( 3) that they reflect a causal relationship in which the pharmacological effects of cannabis on brain function increase the likelihood of using other illicit drugs. These explanations are evaluated in the light of evidence from longitudinal epidemiological studies, simulation studies, discordant twin studies and animal studies. The available evidence indicates that the association reflects in part but is not wholly explained by: ( 1) the selective recruitment to heavy cannabis use of persons with pre-existing traits ( that may be in part genetic) that predispose to the use of a variety of different drugs; ( 2) the affiliation of cannabis users with drug using peers in settings that provide more opportunities to use other illicit drugs at an earlier age; ( 3) supported by socialisation into an illicit drug subculture with favourable attitudes towards the use of other illicit drugs. Animal studies have raised the possibility that regular cannabis use may have pharmacological effects on brain function that increase the likelihood of using other drugs. We conclude with suggestions for the type of research studies that will enable a decision to be made about the relative contributions that social context, individual characteristics, and drug effects make to the relationship between cannabis use and the use of other drugs.

Iron(III) and iron(II) complexes of 1-thia-4,7-diazacyclononane ([9]aneN(2)S) and 1,4-dithia-7-azacyclononane ([9]aneNS(2)). X-Ray structural analyses, magnetic susceptibility, Mossbauer, EPR and electronic spectroscopy

The complexes [Fe([9]aneN(2)S)(2)][ClO4](2), [Fe([9]aneN(2)S)(2)][ClO4](3) and [Fe([9]aneNS(2))(2)][ClO4](2) ([9]aneN(2)S = 1-thia-4. 7-diazacyclononane and [9]aneNS(2) = 1,4-dithia-7-azacyclononane) have been prepared and the latter two characterised by X-ray crystallography. The Mossbauer spectra (isomer shift/mm s(-1), quadrupole splitting/mm s(-1), 4.2 K) for [Fe([9]aneN(2)S)(2)][ClO4](2) (0.52, 0.57), [Fe([9]aneN(2)S)(2)][ClO4](3) (0.25, 2.72) and [Fe([9]aneNS(2))(2)][ClO4](2) (0.43, 0.28) are typical for iron(II) and iron(III) complexes. Variable-temperature susceptibility measurements for [Fe([9]aneN(2)S)(2)][ClO4](2) (2-300 K) revealed temperature-dependent behaviour in both the solid state [2.95 mu(B) (300 K)-0.5 mu(B) (4.2 K)] and solution (Delta H degrees 20-22 kJ mol(-1), Delta S degrees 53-60 J mol(-1) K-1). For [Fe([9]aneN(2)S)(2)][ClO4](3) in the solid state [2.3 mu(B) (300 K)-1.9 mu(B) (4.2 K)] the magnetic data were fit to a simple model (H = -lambda L . S + mu L-z) to give the spin-orbit coupling constant (lambda) of -260 +/- 10 cm(-1). The solid-state X-band EPR spectrum of [Fe([9]aneN(2)S)(2)][ClO4](3) revealed axial symmetry (g(perpendicular to) = 2.607, g(parallel to) = 1.599). Resolution of g(perpendicular to) into two components at Q-band frequencies indicated a rhombic distortion. The low-temperature single-crystal absorption spectra of [Fe([9]aneN(2)S)(2)][ClO4](2) and [Fe([9]aneNS(2))(2)][ClO4](2) exhibited additional bands which resembled pseudotetragonal low-symmetry splitting of the parent octahedral (1)A(1g) --> T-1(2g) and (1)A(1g) ---> T-1(1g) transitions. However, the magnitude of these splittings was too large, requiring 10Dq for the thioether donors to be significantly larger than for the amine donors. Instead, these bands were tentatively assigned to weak, low-energy S --> Fe-II charge-transfer transitions. Above 200 K, thermal occupation of the high-spin T-5(2g) ground state resulted in observation of the T-5(2g) --> E-5(g) transition in the crystal spectrum of [Fe([9]aneN(2)S)(2)][ClO4](2). From a temperature-dependence study, the separation of the low-spin (1)A(1g) and high-spin T-5(2g) ground states was approximately 1700 cm(-1). The spectrum of the iron(III) complex [Fe([9]aneN(2)S)(2)][ClO4](3) is consistent with a low-spin d(5) configuration.

Nutrient-induced perturbations to delta C-13 and delta N-15 in symbiotic dinoilagellates and their coral hosts

Inorganic nutrients play a critical role in determining benthic community structure in tropical seas. This study examined the impact of adding inorganic nutrients (ammonium and phosphate) on the isotopic composition of 2 reef-building corals, Pocillopora damicornis and Heliofungia actiniformis, on the southern Great Barrier Reef. The addition of elevated nutrients to patch reefs that pond at low tide did not perturb the C:N ratio of either species or their symbiotic dinoflagellates. The C:N ratios were significantly higher in material extracted from the skeleton (14.8 +/- 1.50 and 10.8 +/- 1.42) than either host (7.6 +/- 0.87 and 6.0 +/- 0.71) or symbiotic dinoflagellates (5.7 +/- 0.48 and 6.9 +/- 0.66) (P. damicornis and H. actiniformis respectively; 95 confidence intervals). The ratio of acquired N to background N suggests that the added dissolved inorganic nitrogen (DIN) accounted for 50 to 100% of total nitrogen within the tissues of P. damicornis and H. actiniformis at the end of the experiment. The addition of the isotopically depleted nutrients (delta(15) N = 0parts per thousand) to patch reefs significantly decreased delta(15)N from control values of between 3 and 4 to values to below 1 in the case of all compartments, while delta(13)C values were relatively unresponsive to nutrient treatments. These findings suggest that coral delta(15)N has the potential to provide a historical record of the delta(15)N of dissolved nitrogen surrounding reef-building corals and their symbiotic dinoflagellates.

Canopy carbon and oxygen isotope composition of 9-year-old hoop pine families in relation to seedling carbon isotope composition, growth, field growth performance, and canopy nitrogen concentration

Carbon isotope composition (delta C-13), oxygen isotope composition (delta O-18), and nitrogen concentration (N-mass) of branchlet tissue at two canopy positions were assessed for glasshouse seedlings and 9-year-old hoop pine (Araucaria cunninghamii Ait. ex D. Don) trees from 22 open-pollinated families grown in 5 blocks of a progeny test at a water-limited and nitrogen-deficient site in southeastern Queensland, Australia. Significant variations in canopy delta C-13, delta O-18, and N-mass existed among the 9-year-old hoop pine families, with a heritability estimate of 0.72 for branchlet delta C-13 from the upper inner canopy position. There was significant variation in canopy delta C-13 of glasshouse seedlings between canopy positions and among the families, with a heritability estimate of 0.66. The canopy delta C-13 was positively related to canopy N-mass only for the upper outer crown in the field (R = 0.62, p < 0.001). Phenotypic correlations existed between tree height and canopy delta C-13 (R = 0.37-0.41, p < 0.001). Strong correlations were found between family canopy delta C-13 at this site and those at a wetter site and between field canopy delta C-13 and glasshouse seedling delta C-13. The mechanisms of the variation in canopy delta C-13 are discussed in relation to canopy photosynthetic capacity as reflected in the N-mass and stomatal conductance as indexed by canopy delta O-18.

delta N-15 values of tropical savanna and monsoon forest species reflect root specialisations and soil nitrogen status

A large number of herbaceous and woody plants from tropical woodland, savanna, and monsoon forest were analysed to determine the impact of environmental factors (nutrient and water availability, fire) and biological factors (microbial associations, systematics) on plant delta(15)N values. Foliar delta(15)N values of herbaceous and woody species were not related to growth form or phenology, but a strong relationship existed between mycorrhizal status and plant delta(15)N. In woodland and savanna, woody species with ectomycorrhizal (ECM) associations and putative N-2-fixing species with ECM/arbuscular (AM) associations had lowest foliar delta(15)N values (1.0-0.6parts per thousand), AM species had mostly intermediate delta(15)N values (average +0.6parts per thousand), while non-mycorrhizal Proteaceae had highest delta(15)N values (+2.9 to +4.1parts per thousand). Similar differences in foliar delta(15)N were observed between AM (average 0.1 and 0.2parts per thousand) and non-mycorrhizal (average +0.8 and +0.3parts per thousand) herbaceous species in woodland and savanna. Leguminous savanna species had significantly higher leaf N contents (1.8-2.5% N) than non-fixing species (0.9-1.2% N) indicating substantial N acquisition via N-2 fixation. Monsoon forest species had similar leaf N contents (average 2.4% N) and positive delta(15)N values (+0.9 to +2.4parts per thousand). Soil nitrification and plant NO3- use was substantially higher in monsoon forest than in woodland or savanna. In the studied communities, higher soil N content and nitrification rates were associated with more positive soil delta(15)N and plant delta(15)N. In support of this notion, Ficus, a high NO3- using taxa associated with NO3- rich sites in the savanna, had the highest delta(15)N values of all AM species in the savanna. delta(15)N of xylem sap was examined as a tool for studying plant delta(15)N relations. delta(15)N of xylem sap varied seasonally and between differently aged Acacia and other savanna species. Plants from annually burnt savanna had significantly higher delta(15)N values compared to plants from less frequently burnt savanna, suggesting that foliar N-15 natural abundance could be used as marker for assessing historic fire regimes. Australian woodland and savanna species had low leaf delta(15)N and N content compared to species from equivalent African communities indicating that Australian biota are the more N depauperate. The largest differences in leaf delta(15)N occurred between the dominant ECM Australian and African savanna (miombo) species, which were depleted and enriched in N-15, respectively. While the depleted delta(15)N of Australian ECM species are similar to those of previous reports on ECM species in natural plant communities, the N-15-enriched delta(15)N of African ECM species represent an anomaly.

The synthesis and X-ray crystal structure of 9-carboxyhexahydro-7-methoxy-4a,7-ethano-benzopyran-5-en-1-one

9-Carboxyhexahydro-7-methoxy-4a,7-ethano-benzopyran-5-en-1-one (1) was prepared and examined by X-ray crystallography to probe its potential as a new peptide scaffold/template. The crystal structure of the anhydride precursor 7-(2-acetoxyethyl)-4-methoxy-3a,4,7,7a-tetrahydro-4,7-ethanoisobenzofuran-1,3-dione (6) is also reported.

CCR5-Delta 32 mutation is strongly associated with primary sclerosing cholangitis

CCR5 plays a key role in the distribution of CD45RO+ T cells and contributes to generation of a T helper 1 immune response. CCR5-Delta32 is a 32-bp deletion associated with significant reduction in cell surface expression of the receptor. We investigated the role of CCR5-Delta32 on susceptibility to ulcerative colitis (UC), Crohn's disease ( CD) and primary sclerosing cholangitis (PSC). Genotype and allelic association analyses were performed in 162 patients with UC, 131 with CD, 71 with PSC and 419 matched controls. There was a significant difference in CCR5 genotype (OR 2.27, P = 0.003) between patients with sclerosing cholangitis and controls. Similarly, CCR5-Delta32 allele frequency was significantly higher in sclerosing cholangitis (17.6%) compared to controls (9.9%, OR 2.47, P = 0.007) and inflammatory bowel disease patients without sclerosing cholangitis ( 11.3%, OR 1.9, P = 0.027). There were no significant differences in CCR5 genotype or allele frequency between those with either UC or CD and controls. Genotypes with the CCR5-Delta32 variant were increased in patients with severe liver disease defined by portal hypertension and/or transplantation (45%) compared to those with mild liver disease (21%, OR 3.17, P = 0.03). The CCR5-Delta32 mutation may influence disease susceptibility and severity in patients with PSC.

Palaeoclimatic implications of the growth history and stable isotope (delta O-18 and delta C-13) geochemistry of a Middle to Late Pleistocene stalagmite from central-western Italy

The age structure and, stable isotope composition of a stalagmite (CC I) from an upland cave in central-western Italy were studied to investigate regional response to global climatic changes. Four growth phases are constrained by 28 thermal ionization and multi-collector inductively coupled plasma mass spectrometry Th-U ages and reveal intermittent deposition through the period between Marine isotope Stage (MIS) 11 and 3 (similar to380 and similar to43 kyr). Most of the growth took place between similar to380 and similar to280 kyr, a period punctuated briefly by a hiatus in deposition through the glacial maximum of MIS 10. Growth was terminated abruptly at 280 kyr just prior to the MIS 8 glacial maximum. With a present-day chamber temperature of 7.5 degreesC, the timing of hiatuses close to these glacial maxima point to freezing conditions at the time. No deposition was recorded through the entirety of MIS 7 and most of MIS 6, whilst two minor growth phases occurred at similar to141-125 and similar to43 kyr. Growth at 141 kyr indicates temperatures >0 degreesC at a time when MIS 6 ice volumes were close to their maximum. High stable carbon isotope (delta(13)C) values (similar to2.8parts per thousand to +3.1parts per thousand) throughout the stalagmite's growth reflect a persistently low input of biogenic CO2, indicating that the steep, barren and alpine-like recharge area of today ha's been in existence for at least the last similar to380 kyr. During MIS 9, the lowest delta(13)C values occur well after maximum interglacial conditions, suggesting a lag in the development of post-glacial soils in this high-altitude karst. The stable oxygen isotope (delta(18)O) trends match the main structural features of the major climate proxy records (SPECMAP, Vostok and Devils Hole), suggesting that the delta(18)O of CC1 has responded to global-scale climate changes, whilst remarkable similarity exists between CC1 delta(18)O and regional sea-surface temperature reconstructions from North Atlantic core ODP980 and southwest Pacific marine core MD97-2120 through the most detailed part of the CC1 record, MIS 9-8. The results suggest that CC1 and other stalagmites from the cave have the potential to capture a long record of regional temperature trends, particularly in regards to the relative severity of Pleistocene glacial stages. (C) 2004 Elsevier B.V. All rights reserved.

delta O-18, Sr/Ca and Mg/Ca records of Porites lutea corals from Leizhou Peninsula, northern South China Sea, and their applicability as paleoclimatic indicators

Combined seasonal to monthly resolution coral skeletal delta(18)O, Sr/Ca, and Mg/Ca records are reported for one modem and two late Holocene Porites lutea corals from a fringing reef at Leizhou Peninsula, the northern coast of the South China Sea (SCS). All the profiles for the period 1989-2000 reveal annual cycles well correlated with instrumental sea surface temperatures (SST), and display broad peaks in summer and narrow troughs in winter, reflecting seasonal growth rate variations. Calibration against instrumental SST yields the following equations: delta(18)O=-0.174(+/- 0.010)xSST(degrees C)-1.02(+/- 0.27) (MSWD=5.8), Sr/Ca-(mmol/mol)=-0.0424(+/- 0.0031)xSST(degrees C)+9.836(+/- 0.082) (MSWD=8.6), and Mg/Ca-(mmol/mol)=0.110(+/- 0.009)XSST(degrees C)+ 1.32(+/- 0.23) (MSWD=55). The scatter in the Mg/Ca-SST relationship is much larger than analytical uncertainties can account for, suggesting the presence of SST-unrelated components in the Mg/Ca variation. Calculated Sr/Ca-SST values for two later Holocene Porites lutea samples (U-series ages similar to 541 BC and similar to 487 AD, respectively) from the same reef suggest that SST in the SCS at similar to 541 BC was nearly as warm as in the 1990s (the warmest decade of the last century), but at similar to 487 AD, it was significantly cooler. This observation is consistent with climatic data reported in Chinese historic documents, confirming that the Sr/Ca-SST relationship is a reliable thermometer. Removing the SST component in the delta(18)O variation based on calculated Sr/Ca-SST values, the residual delta(18)O reflects the deviation of the Holocene seawater delta(18)O from the modem value, which is also a measure of the Holocene sea surface salinity (SSS) or the summer monsoon moisture level in mainland China. Such residual delta(18)O was close to zero at similar to 541 BC and -0.3 parts per thousand at similar to 487 AD, suggesting that it was as wet as in the 1990s at similar to 541 BC but significantly drier at similar to 487 AD in mainland China, which are also consistent with independent historic records. Calculated Mg/Ca-SST values for the two late Holocene corals are significantly lower than the Sr/Ca-SST values and are also in conflict with Chinese historic records, suggesting that coral Mg/Ca is not reliable proxy for SST. At comparable Sr/Ca ranges, fossil corals always display negative Mg/Ca offsets if compared with the modem coral of the same site. We interpret this observation as due to preferential loss of Mg during meteoric dissolution of cryptic Mg-calcite-bearing microbialites in the exposed fossil corals. Microbialites (MgO up to 17%, Sr only 100-300 ppm) are ubiquitous during reef-building processes and their presence in only a trace amount will have a significant impact on coral Mg/Ca ratios without detectable influence on coral Sr/Ca ratios. (c) 2004 Elsevier B.V. All rights reserved.