A comparative study was done in women and men of the effects of delta 9-tetrahydrocannabinol (delta 9-THC), intravenously or orally, on dynamic activity, metabolism, excretion, and kinetics. In general no differences between the two sexes were observed. delta 9-THC is converted by microsomal hydroxylation to 11-hydroxy-delta 9-THC (11-OH-delta 9-THC), which is both a key intermediate for further metabolism to 11-nor-delta 9-THC-9-carboxylic acid (11-nor-acid) by liver alcohol-dehydrogenase enzymes and a potent psychoactive metabolite. Major differences in the ratio of the concentration of 11-OH-delta 9-THC to that of delta 9-THC in plasma were found after intravenous dosing (ratio 1:10 to 20) compared with oral administration (ratio 0.5 to 1:1). The final metabolic products are the 11-nor-acids and the related, more polar acids. Urinary excretion of delta 9-THC is restricted to acidic nonconjugated and conjugated metabolites. After 72 hr mean cumulative urinary excretion, noted for both routes and for both sexes, ranged from 13% to 17% of the total dose. After 72 hr the cumulative fecal excretion for both sexes after intravenous administration ranged from 25% to 30%; after oral administration the range was 48% to 53%. Metabolites were found in the feces in large concentration in the nonconjugated form; concentrations of 11-OH-delta 9-THC were particularly noteworthy. Kinetics of delta 9-THC and metabolites were much the same for female and male subjects. For delta 9-THC, terminal-phase t1/2s for both sexes, irrespective of the route, ranged from 25 to 36 hr. A comparison of the results for AUC/dose (delta 9-THC) after oral dosing with comparable data from intravenous administration indicated bioavailability of the order of 10% to 20% for both sexes. After intravenous delta 9-THC, large apparent volumes of distribution were noted (about 10 l/kg for both sexes).

experiments concerned with the influence of the vagal and sympathetic innervations of the heart and of peripheral reflex mechanisms are reported on the deceleration of heart rate observed on test trials during classical conditioning in human Ss. An increase in vagal restraint was observed to be the basis of the deceleratory response, which in turn masks the manifestation of sympathetic acceleratory effects. The latter were only observed when the vagus was pharmacologically blocked and when a very intense UCS was used. When the conditioned pressor responses were blocked pharmacologically, as evaluated by direct recordings of arterial blood pressure, the deceleratory response was not changed, indicating that the peripheral homeostatic reflex mechanisms are not the basis for this response and that it is likely a conditioned response.

The metabolism of Δ9‐tetrahydrocannabinol (THC) and related cannabinoids in man has been studied in detail utilizing intravenous, oral, and smoking routes of administration. The general pattern of metabolism was the same in all studies involving THC and related cannabinoids. Microsomal hydroxylation allylic to the Δ9‐THC double bond occurs, the major product resulting in formation of an 11‐CH2OH moiety; minor hydroxylation occurs on the C‐8 carbon. Nonmicrosomal oxidation of the resultant 11‐OH‐Δ9‐THC to 11‐nor‐Δ9‐THC‐9‐carboxylic acid and to other more polar acids generates the major terminal metabolic products. After oral administration, approximately equal quantities of THC and its highly active 11‐hydroxy metabolite were formed, whereasthe latter metabolite is a minor constituent after administration by intravenous or smoking routes. Initial pharmacokinetic analyses of the data show that the mean terminal‐phase (β‐phase) plasma half‐life after intravenous administration of THC was about 30 hours; after oral administration, it was 23 hours. No significant statistical difference was noted between men and women as to metabolic routes or plasma terminal‐phase half‐lives.

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Marihuana cigarettes containing 1.32%, 1.97%, and 2.54% delta 9-tetrahydrocannabinol (THC) were smoked by six experienced marihuana users at weekly intervals in a double-blind cross-over design under laboratory conditions. Puff duration, number of puffs taken, duration of inhalation holding, interval between puffs, and duration of smoking were recorded for each cigarette smoked. The portion of each cigarette remaining after smoking was weighed and analyzed to determine THC content. Subjective ratings of the "high" achieved and the heart rate acceleration induced by smoking the marihuana were measured. The plasma concentrations of THC and of its principle metabolite, 11-nor-delta 9-THC-9-carboxylic acid (9-carboxy THC), were determined by radioimmunoassay of blood samples drawn at frequent intervals for 6 hr. The results indicate that, irrespective of the potency of the marihuana, the pattern of smoking was much the same. The magnitude of the subjective high, heart rate acceleration, THC, and 9-carboxy THC plasma concentrations were proportional to potency. This dose response was particularly clear between the 1.32% and the 2.54% cigarettes. Peak plasma concentrations of THC consistently occurred 7 to 8 min after initiation of smoking and declined thereafter despite continued smoking for another 6 to 10 min. Peak subjective high and peak heart rate acceleration occurred several minutes after the end of smoking and at a considerable interval after maximal THC plasma concentrations were reached.

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A microsuspension of Delta(9)-tetrahydrocannabinol and of its metabolic derivative 11-OH-Delta(9)-tetrahydrocannabinol has been prepared with 25 percent human serum albumin as the vehicle. Intravenous infusion of this preparation to humans indicates that both tetrahydrocannabinols are equally potent in producing the typical marihuana-like pschological and physiological effects.

This is a report of the results of a placebo-controlled study in which the effects of the interaction between ethanol and marihuana on drug plasma concentrations, subjective ratings of intoxication, heart rate acceleration, and psychomotor performance were investigated. Six healthy, male, paid volunteers, moderate users of ethanol and marihuana, participated in the study. Ethanol (0.42 g/kg, 0.85 g/kg, or placebo) was administered over a 30-min interval. Fifteen minutes later the subjects smoked, in their customary manner, NIDA cigarettes containing 2.4% or 0.0004% (placebo) delta-9-tetrahydrocannabinol (THC). Each subject was tested in a single-blind, latin-square crossover design with the following six conditions: placebo ethanol/placebo marihuana; low dose ethanol/placebo marihuana; high dose ethanol/placebo marihuana; placebo ethanol/marihuana; low dose ethanol/marihuana; and high dose ethanol/marihuana. The variables measured in the study were: (a) subjective rating of ethanol and/or marihuana intoxication; (b) heart rate; (c) accuracy and latency of response in the Simulator Evaluation of Drug Impairment (SEDI) task; (d) blood ethanol concentration by gas chromatography; and (e) plasma concentration of THC by radioimmunoassay. The results indicate that the decrements due to ethanol in performance of skills necessary to drive an automobile were significantly enhanced by marihuana in an additive and perhaps synergistic manner. The administration of ethanol prior to marihuana smoking did not produce significant effects on the subjective rating of "high," heart rate acceleration, or THC plasma concentration.