Stig Agurell

Quantitation of Δ1‐tetrahydrocannabinol in plasma from cannabis smokers

A method to identify and accurately measure non‐labelled Δ1‐tetrahydrocannabinol (Δ1‐THC) in blood of cannabis smokers has been developed. It consists of the following steps: To a 5 ml plasma sample is added deuterated Δ1‐THC (Δ1‐THC‐d2) as internal standard. After extraction with light petroleum and evaporation, the Δ1‐THC containing fraction is separated by chromatography on Sephadex LH‐20 (1 times 40 cm) using light petroleum‐chloroform‐ethanol (10:10:1) as eluant. A fraction containing Δ1‐THC is collected and subjected to mass fragmentography (LKB 9000; 3% OV‐17/Gas‐Chrom Q; 230°). The mass spectrometer was adjusted to record the intensities of m/e 299 and 314 of Δ1‐THC and m/e 301 and 316 of Δ1‐THC‐d2. The standard curve was made by plotting peak height m/e 299/m/e 301. Peak levels of 19–26 ng ml−1 were reached within 10 min after smoking a cigarette containing 10 mg Δ1‐THC.

Identification of monohydroxylated metabolites of cannabidiol formed by rat liver.

Cannabidiol (CBD) was metabolized in vitro by rat liver enzymes. Unchanged CBD and eight monohydroxylated metabolites were isolated and positively identified. As previously reported, 7‐hydroxy‐CBD was the major metabolite. The second most abundant metabolite was 6α‐hydroxy‐CBD; whereas only a trace amount of 6β‐hydroxy‐CBD was found. In addition hydroxylation occurred in all positions of the pentyl side chain, 4″‐hydroxy‐CBD being most abundant. 3″‐Hydroxy‐CBD was formed in half of the yield of 4″‐hydroxy‐CBD, while 1″‐, 2″‐, and 5″‐hydroxy‐CBD were each formed in approximately one fourth of the yield of 4″‐hydroxy‐CBD.

Biogenetic interrelationships of ergot alkaloids.

Abstract The biogenetic interconversions of clavine alkaloids have been studied by the use of clavine-C14 and clavine-H3 alkaloids labeled biosynthetically in saprophytic culture, and four different ergot strains in saprophytic cultures. Agroclavine was shown to be oxidized irreversibly to elymoclavine. The attack appears to be directly on the methyl group. Agroclavine, but not elymoclavine, was shown to be converted irreversibly to the following clavine alkaloids: festuclavine, pyroclavine, and setoclavine. Elymoclavine was shown to be the precursor of lysergol, isolysergol, penniclavine, and isopenniclavine. These conversion reactions are irreversible. Only three clavine alkaloids were found to be metabolized in ergot strain 47 A, viz., agroclavine, elymoclavine, and lysergene, all of which have a double bond in position 8. Chanoclavine was shown not to be a precursor of the clavine alkaloids. Evidences indicate that it was not a breakdown product of agroclavine or of any other clavine alkaloid derived from agroclavine. Lysergene was shown to be converted to lysergol, isolysergol, penniclavine, and isopenniclavine. No evidence was found suggesting that lysergene is a normal intermediate in the biosynthesis of these compounds from elymoclavine. Each stereoisomer was found to be biosynthesized as such and not to be the result of a chemical or biochemical isomerization process.

Biliary excretion of Δ1-tetrahydrocannabinol and its metabolites in the rat☆

Abstract Δ1-Tetrahydrocannabinol (Δ1-THC) administered i.v. (1 mg/kg) to anaesthetized rats with cannulated bile ducts is rapidly eliminated as metabolites in the bile. 60–70 per cent in 6 hr. In comparison with the slow excretion via faeces an extensive enterohepatic circulation, which may be of toxicological importance, is indicated. Unchanged Δ1-THC and cannabinol are eliminated in low amounts (0.05 0.1 percent) in the bile. A few per cent consists of two or more mono-oxygenated metabolites. neither of which is identical with 7-hydroxy-Δ1-THC or 6-β-hydroxy-Δ1-THC. The main part of the non-conjugated metabolites is present as compounds more polar than 7-hydroxy-Δ1-THC and as carboxylic acids. These acids were more polar than Δ1-THC-7-oic acid which could not be identified in a free or conjugated form. In the rat about 60 per cent of the metabolites are eliminated as water-soluble conjugates. Hydrolysis with glucuronidase liberated aglycones which were mainly neutral whereas hydrolysis with alkali released neutral but also some acidic compounds. 7-Hydroxy-Δ1-THC was identified as an aglycone of glucuronic acid and furthermore, three mono-oxygenated cannabinoids were isolated after hydrolysis and partially characterized.

Effects of Cannabinoids on Isolated Smooth Muscle Preparations

To investigate the mechanisms of action of the psychoactive cannabinoids, one can use isolated peripheral tissues as test preparations, provided that there is a close chemical relationship between the acute behavioral actions and the effects on the isolated organ. In addition, the cannabinoids should be active in concentrations that produce the behavioral effects. To find such a tissue, we have tested the effects of cannabinoids on a number of isolated preparations.