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.

The disposition of deuterium-labelled cannabidiol, 2H2-CBD, was studied in five young men who were marihuana smokers. The pattern of use ranged from infrequent to frequent use of the drug. Plasma concentrations, determined by mass fragmentography, were followed for 72 h after both intravenous administration of 20 mg 2H2-CBD and smoking of an estimated amount of 18.8-19.4 mg 2H2-CBD. Systemic availability after smoking was determined by comparing the areas under the plasma concentration versus time curves for the two treatments and was found to be 31 +/- 13%. A four-fold difference in the availability of the compound was noted for the five subjects. Based on the area under the curve and the dose after intravenous administration, a plasma clearance of 960-1560 ml min-1 was calculated. A terminal elimination phase was not reached at 72 h, but the kinetic parameters were estimated from the 72 h beta-elimination. A half-life of 31 +/- 4 h after smoking and 24 +/- 6 h after injection was estimated as well as a distribution volume of 2520 +/- 470 l (32.7 +/- 8.61 kg-1).

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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.

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.

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Deuterium labelled delta 1-tetrahydrocannabinol was administered intravenously (5.0 mg) and by smoking (10.0 mg) to five heavy and four light marihuana users. All subjects smoked an estimated amount of 8.6-9.9 mg delta 1-tetrahydrocannabinol. The plasma levels of delta 1-tetrahydrocannabinol were followed for 48 hours and in two subjects fof 72 hours after administration. The systemic availability after inhalation calculated from the area under curve values was in the range of 27 +/- 10% for the heavy users and 14 +/- 1% for the light users. There was little difference between the groups with regard to the amount of smoked delta 1-tetrahydrocannabinol or plasma levels and area under curve values obtained after i.v. administration. Thus, it seems likely that the statistically significant difference in systemic availability of smoked delta 1-tetrahydrocannabinol was due to a more efficient smoking by the heavy users. It is also indicated that heavy users prefer slightly higher delta 1-tetrahydrocannabinol plasma levels than light users. Based on the area under curve values after i.v. administration, a plasma clearance of 760-1190 ml min-1 was calculated. The elimination half-life of delta 1-tetrahydrocannabinol is more than 20 hours. The present results do not suggest that tolerance or sensitivity to delta 1-tetrahydrocannabinol in heavy users is readily achieved.

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