Delta-1-tetrahydrocannabinol: structure of a major metabolite.

triangle up(1)-Tetrahydrocannabinol, the major psychotomimetically active compound of Cannabis, was metabolized in vitro by the 10, OOOg supernatant from rabbit liver. By mass and nuclear magnetic resonance spectrometry, the major metabolite was identified as 7-hydroxy-triangle up(1)-tetrahydrocannabinol. The latter compound of Cannabis, was metabolized in vitro by the 10,OOOg supernatant from

Kinetics of chlormethiazole in patients with alcohol withdrawal manifestations.

Chlormethiazole administered orally to patients in mild degrees of alcohol withdrawal was generally rapidly absorbed, showed a rapid distributive phase, and had an elimination phase 1 1/2 of 2.6 to 4.7 hr. The plasma concentrations of drug attained following higher oral doses were greater than is usually the case with augmentation of dose. Intravenously infused chlormethiazole in similar patients produced relatively high plasma concentrations of the drug, with distributive and eliminative 1 1/2 similar to those of oral doses. These pharmacokinetic patterns in alcoholic patients more closely resemble those previously reported for normal young subjects than they do for normal aged subjects.

Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking.

Delta-9-tetrahydrocannabinol (THC) was given intravenously, by smoking, and by mouth to 11 healthy subjects. Plasma profiles of THC after smoking and intravenous injection were similar whereas plasma levels after oral doses were low and irregular, indicating slow and erratic absorption. Based on AUC0-360 min systemic availability of THC after smoking was estimated to be 18 +/- 6%. Oral THC in a chocolate cookie provided systemic availability of 6 +/- 3%. Of the two major clinical signs of cannabis intoxication, reddened conjunctivae persisted for as long as THC levels were above 5 ng/ml, and tachycardia was a less reliable measurement of prevailing THC levels or "high." The time courses of plasma concentrations and clinical "high" were of the same order for intravenous injection and smoking, with prompt onset and steady decline over a 4-hr period. The appearance of "high" lagged behind the increase in plasma concentrations, suggesting that brain concentrations were increasing as plasma concentrations decreased. After oral THC, the onset of clinical effects was much slower and lasted longer, but effects occurred at much lower plasma concentrations than after the other two methods of administration.

Clinical effects and plasma levels of delta 9-tetrahydrocannabinol (delta 9-THC) in heavy and light users of cannabis.

delta 9-Tetrahydrocannabinol (delta 9-THC) was administered in a crossover design by smoking and IV injection to groups of heavy and light users of marihuana. Plasma concentrations of delta 9-THC were similar for the groups after IV injection of 5.0 mg delta 9-THC, but the AUC0-240 min showed a trend towards lower values for the heavy user group. To achieve a maximum desired "high", both groups smoked similar amounts (about 13 mg) of delta 9-THC. Heavy users tended to have higher plasma levels than light users. The systemic availability of smoked delta 9-THC was significantly higher for the heavy users (heavy users 23 +/- 16% vs 10 +/- 7% for light users). These results also indicate that heavy cannabis users smoke more efficiently than casual smokers. Both light and heavy users showed more clinical effect following IV administration than after smoking. The response of the heavy users, both with respect to effect on heart and "high", was quite comparable to that of light users. The present study does not suggest that tolerance readily develops in heavy users.

Do plasma concentrations of delta 9-tetrahydrocannabinol reflect the degree of intoxication?

Plasma concentrations of THC were measured by gas-liquid chromatography and mass spectrometry following three routes of administration and correlated with clinical effects. Plasma concentrations peaked at 3 minutes after intravenous injection and then sharply declined. The peak "high" occurred at 30 minutes while plasma concentrations were declining. This lag between plasma concentration and "high" continued during most of the span of the drug's effects. The situation was quite similar following smoking, except that peak plasma concentrations were lower. After oral administration of THC, absorption was slow, with peak concentration occurring at 1 to 2 hours. Plasma concentrations were much lower. Correlations between plasma concentrations of drug and "high" were significant but not impressive. The degree of "high" was quite variable in relation to the prevailing plasma concentration. Conjunctival injection was found so long as plasma concentration of THC could be measured. Pulse rate increases occurred at lower concentration after oral administration than after the other two routes. It is unlikely that a range of plasma concentrations can be reliably equated with impaired performance. The mode of administration will become important should THC or some homolog become a therapeutic agent.

delta 1-Tetrahydrocannabinol and 1 alpha, 2 alpha-epoxyhexahydrocannabinol: mutagenicity investigation in the Ames test.

1,2-Epoxyhexahydrocannabinol is a metabolite of delta 1-tetrahydrocannabinol. Because many epoxides are mutagens, we investigated 1,2-epoxyhexahydrocannabinol as well as delta 1-tetrahydrocannabinol for mutagenicity with Salmonella typhimurium TA1535, TA1537, TA98 and TA100 in the presence and in the absence of S9 mix from liver homogenate of rats treated with Aroclor 1254. Additionally, an epoxide hydratase inhibitor was used in some experiments. Whereas several other epoxides and further positive controls, not requiring activation or activated under the same conditions, respectively, showed strong mutagenicity, no indications of a mutagenic hazard by 1,2-epoxyhexahydrocannabinol or by delta 1-tetrahydrocannabinol were found.

Acidic metabolites of delta1-tetrahydrocannabinol isolated from rabbit urine.

The in vivo metabolism of delta1-tetrahydrocannabinol (delta1-THC) was investigated in the rabbit after i.v. administration. Thirteen acidic metabolites were isolated from rabbit urine and identified by gas chromatography-mass spectrometry and by proton magnetic resonance spectroscopy. One additional metabolite was tentatively identified. All but three were new metabolites and all but one were oxidized in the pentyl side chain. The metabolites included dicarboxylic acids, monocarboxylic acids and mono- or dihydroxylated derivatives thereof. However, the dicarboxylic acid metabolites were the most prominent.

Acidic in vivo metabolites of cannabinol isolated from rat faeces.

Six acidic metabolites were isolated from rat faeces and identified by gas chromatographymass spectrometry and proton magnetic resonance. Cannabinol-7-oic acid was the most abundant acidic metabolite isolated. Others present in decreasing order of prominence were 1"-hydroxy-, 4"-hydroxy-, 3"-hydroxycannabinol-7-oic acid, cannabinol-3"-one-7-oic acid and 2"-hydroxycannabinol-7-oic acid.

More acidic metabolites of delta1-tetrahydrocannabinol isolated from rabbit urine.

The in vivo metabolism of delta1-tetrahydrocannabinol (delta1-THC) was further investigated in the rabbit after i.v. administration. Nine acidic metabolites were isolated from a previously not investigated fraction of the urine and identified by gas chromatography-mass spectrometry and by proton magnetic resonance spectroscopy. The major metabolites were side-chain hydroxylated monocarboxylic acids. Three side-chains monocarboxylic acids hydroxylated in allylic positions in the isoprene moiety were also characterized. The metabolites 4''-hydroxy-delta1-THC-7-oic acid and 7-hydroxy-4'',5''-bisnor-delta1-THC-3''-oic acid were hitherto not identified. An earlier described dicarboxylic metabolite was present in high concentration. Further, the identity of an O-glucuronide as an in vivo urinary metabolite of delta1-THC was here for the first time unambiguously established by m.s. and p.m.r.

Prolonged apparent half-life of delta 1-tetrahydrocannabinol in plasma of chronic marijuana users.

The aim of this study was to characterize the elimination half-life of delta 1-tetrahydrocannabinol in blood plasma in chronic marijuana users. The subjects smoked four cigarettes during a two day period, each cigarette containing 15 mg deuterium-labelled delta 1-tetrahydrocannabinol. The plasma concentrations of deuterium-labelled tetrahydrocannabinol were measured for 13 days using gas chromatography-mass spectrometry equipped with selected ion monitoring. The elimination half-life for delta 1-tetrahydrocannabinol in blood plasma was calculated to be 4.1 +/- 1.1 days (range 2.9-5.0 days) from the two week plasma level curves. Albeit the present results are based upon a small sample, an elimination half-life of delta 1-tetrahydrocannabinol in blood plasma of about 4 days is more in line with apparent half-life excretion of delta 1-tetrahydrocannabinol metabolites in the urine of chronic marijuana smokers.

Neutral in vivo metabolites of cannabinol isolated from rat faeces.

The in vivo transformation of cannabinol (CBN) in the rat has been studied. Unchanged CBN and nine neutral mono-oxygenated and dioxygenated CBN metabolites have been identified. In the mono-oxygenated series the metabolites occurred in decreasing order of prominence as follows: 7-hydroxy-CBN, 4''-hydroxy-CBN, 1''-hydroxy-CBN, 2''-hydroxy-CBN, 3''-hydroxy-CBN, 5''-hydroxy-CBN and CBN-7-al. In the dihydroxylated metabolite series only 1'',7-dihydroxy-CBN and 4'',7-dihydroxy-CBN were found with the former as the more prominent metabolite.

Dioxygenated metabolites of cannabidiol formed by rat liver.

The metabolism of cannabidiol (CBD) was studied in vitro using a 10 000 g supernatant from rat liver. After removal of unchanged CBD and its monohydroxylated metabolites, a polar fraction remained from which ten dioxygenated metabolites were isolated. Mass spectrometry and nuclear magnetic resonance spectroscopy were used to identify the following metabolites: 6,7-dihydroxy-CBD, 1 inch,7-dihydroxy-CBD, 3 inch,7-dihydroxy-CBD, 4 inch,7-dihydroxy-CBD, 5 inch,7-dihydroxy-CBD, 2 inch,6-dihydroxy-CBD, 3 inch,6beta-dihydroxy-CBD, 4 inch, 6beta-dihydroxy-CBD (tentative), 3 inch-hydroxy-6-oxo-CBD, and 4 inch-hydroxy-6-oxo-CBD. The abundance of isolated dihydroxy metabolites reflected the quantity of monohydroxy metabolites that was previously found. In both series, 7-hydroxylation occurred to the greatest extent. Side chain hydroxylation occurred predominantly at C-4 inch and to a lesser degree at C-3 inch. Trace amounts of metabolites were hydroxylated at C-1 inch,-2 inch, or 5 inch.

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 6alpha-hydroxy-CBD; whereas only a trace amount of 6beta-hydroxy-CBD was found. In addition hydroxylation occurred in all positions of the pentyl side chain, 4 inches-hydroxy-CBD being most abundant. 3 inches-Hydroxy-CBD was formed in half of the yield of 4 inches-hydroxy-CBD, while 1 inches-, 2 inches-, 5 inches-hydroxy-CBD were each formed in approximately one fourth of the yield of 4 inches-hydroxy-CBD.