Peyote alkaloids: identification in a prehistoric specimen of lophophora from coahuila, Mexico.

Mescaline, anhalonine, lophophorine, pellotine, and anhalonidine have been identified in alkaloid extracts of a prehistoric specimen of Lophophora from a burial cave in west central Coahuila, Mexico. The specimen is associated with radiocarbon dates of A.D. 810 to 1070 and is one of the oldest materials ever submitted to alkaloid analysis.

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.

Pressor response of oral tyramine in healthy men given amiflamine and placebo.

During two baseline challenge tests, oral tyramine (50 to 400 mg) was given to 12 healthy men to find each individual's cardiovascular pressor response. All 12 subjects "tolerated" 200 mg oral tyramine, but three of the 12 developed an increment in systolic blood pressure greater than 30 mm Hg when given a dose of 400 mg. Thereafter, amiflamine, 5 mg bid (n = 8), or placebo, 1 capsule twice a day (n = 4), were given in a double-blind fashion for 7 days, and oral tyramine challenge tests (12.5 to 400 mg) were given on days 5 to 7. During dosing with amiflamine or placebo, no subject tolerated 400 mg oral tyramine and no difference between the two regimens was found with regard to tyramine response. Plasma concentrations of amiflamine and two of its metabolites were measured on days 4 to 7. Steady-state concentrations were reached within 4 to 5 days. Plasma concentrations of tyramine after 400 mg tyramine showed a positive correlation with the increase in systolic blood pressure (P less than 0.001).

Tolerance and pilot pharmacokinetics of amiflamine after increasing single oral doses in healthy subjects.

Oral doses of 1 to 100 mg amiflamine, a new reversible monoamine oxidase type A-selective inhibitor, were given for the first time in humans to six healthy men. No apparent pharmacologic effects were recorded until the 80 mg dose. After 100 mg, one subject developed symptoms indicative of an overdose. Amiflamine is extensively metabolized by two consecutive N-demethylations. The biotransformation patterns in plasma and urine were found to correlate with the debrisoquin metabolic ratio.

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.

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.

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.

Cocaine in blood of coca chewers.

Coca leaves (Erythroxylum coca Lamarck) and powder (5 - 10 g) were taken orally by human subjects in the same way as South American natives do. The cocaine, as measured by mass fragmentography, was immediately detected in the blood, reached peak concentrations from 10 - 150 ng/ml plasma at 0.38 - 1.95 hours, and persisted in the plasma for more than 7 hours. Half-lives of the elimination of cocaine were calculated and ranged from 1.0 to 1.9 hours. The absorption half-lives ranged from 0.2 to 0.6 hours. The shape of the curves fits with the subjective effects reported. There is no reason to believe that the stimulating effect achieved by the use of either coca leaves or powder is not due to cocaine.