Six separate studies are being proposed, each bearing on some aspect of the action of delta-9-tetrahydrocannabinol (THC), the active component of marijuana, in man. 1) Interaction between tobacco smoking and clearance of delta-9-THC - Concurrent use of tobacco cigarettes and marijuana may increase disposition of THC and possibly increase marijuana users. Two groups of subjects will be studied: infrequent users of both marijuana and tobacco and frequent users of both. 2) Dose-titration by marijuana users - If frequent users of marijuana can not titrate doses to the desired state of intoxication, they might be vulnerable to excessive degrees of intoxication as they encounter the more potent forms of marijuana currently available. Experienced marijuana smokers will be tested in a blind fashion with a strong and a weak marijuana cigarette. The accuracy of their titrations to the same degree of intoxication will be confirmed by measurement of plasma concentrations of THC attained. 3) Pharmacokinetics of varying of delta-9-THC - Dose- dependent kinetics of THC has never been examined. This phenomenon might explain some prolonged intoxications from more potent materials. Three doses of THC, covering a four-fold range of dose, will be given to the same subjects under randomized, blind controls, to determine if the pharmacokinetics varies with dose. 4) Role of benzodiazepine receptor in action of delta-9-THC -The sedative properties of marijuana have been well documented. Conflicting evidence suggests a possible action on the benzodiazepine reports. Either a placebo or varying doses of flumazenil, a specific benzodiazepine antagonist covering a 40- fold range, would be given, measuring clinical manifestations of marijuana intoxication and plasma concentrations of THC. 5) Time-dependent sensitization of delta-9-THC - A newly described phenomenon with drugs, sensitization with the passage of time, would be tested with THC. This phenomenon, if present, might explain so-called """"""""reverse tolerance"""""""" for marijuana. 6) Effect of delta-9-THC on plasma melatonin concentrations - This newly described neuroendocrine action of marijuana may be pertinent to its sedative effects. Blood samples from studies previously described will be used initially to measure serum melatonin levels and to see if further inquiry is desirable.
