This project will determine the relationships between the pharmacokinetics and pharmacodynamics of Delta9-tetrahydrocannabinol (THC) and its metabolites, 11-hydroxy-Delta9-tetrahydrocannabinol (OHTHC), 11-nor-9- carboxy-Delta9-tetrahydrocannabinol (COOHTHC), 8-alpha-11-dihydroxy-Delta9- tetrahydrocannabinol (8-alpha-diOHTHC) and 8-beta-11-dihydroxy-Delta9- tetrahydrocannabinol (8-beta-diOHTHC), to human mental and motor performance on a temporal basis after smoking. Establishing and understanding these relationships will permit the use of biologic fluid monitoring of cannabinoid concentrations as an effective tool to predict impaired performance after marihuana use. Young, healthy occasional marihuana users (male 18-40 y.o.) will be asked to smoke marihuana cigarettes (0,1,2,3% THC w/w) on a weekly basis in a randomized, double-blind, latin-square format. Subjects will be tested at 20 time intervals throughout two, eight-hour simulated work shifts over two calendar days (32 hour period) after smoking. Pursuit tracking performance, number recall, manual dexterity and body stability will be tested and correlated with blood and urine concentrations of the aforementioned cannabinoids. Pursuit tracking will be assessed using the Pursuit Meter II which is a task related perceptual motor skills testing device similar to those used in operating vehicles and other commonly encountered work and recreational equipment. Number recall and manual dexterity will be evaluated using a computer generated number test developed by this laboratory. Body stability will be tested using a motion sensitive platform called the Wobble Board. An integral part of the study will be establishment of pharmacokinetics and pharmacodynamic profiles of selected cannabinoids and correlation of the data with performance over a 32 hour period after graded doses of marihuana have been smoked. Of special interest will be those periods of time when the subject may no longer appear intoxicated but may still have measurable amounts of THC or its metabolites present in body fluids.
Specific aims of this proposal are: (1) to establish the subtle effects of smoking graded doses of marihuana on human simple and complex pursuit tracking (psychomotor performance) tasks and on number recall ability, manual dexterity and body's stability over a 32 hour period after an acute smoking exposure; (2) to correlate performance changes in specific aim (1) above with the pharmacokinetics and pharmacodynamic relationships of THC and its metabolites of OHTHC, COOHTHC, 8-alpha-diOHTHC and 8-diOHTHC, in blood and urine over the 32 hour period after smoking; and (3) to establish a model or algorithm using a chemical constituent in a biologic fluid of a marihuana user which results from smoking marihuana and which can be utilized as a predictive indicator associated with altered performance and psychomotor function similar to the model which is accepted for alcohol.
