This project seeks to demonstrate that persistent CNS sequelae of chronic cumulative marihuana (THC) exposure exist and can be identified and measured. This broad objective is expressed as a series of testable hypotheses derived from the positive results of two recently completed empirical pilot studies (plus anecdotal observations). Specifically, chronic THC exposure is predicted to be associated with a unique cluster of persistent quantitative topographic EEG changes, primarily involving frontal cortex, which consist of: (1) significant elevations of Absolute Power, Relative Power, and Interhemispheric Coherence of Alpha over bilateral frontal cortex (HYPERFRONTALITY OF ALPHA), (2) significant elevations of Theta and Delta Coherence over frontal cortex (3) significant decreases of Delta and Beta Relative Power over frontal cortex and (4) increased Absolute Power of all non-Alpha frequencies over all cortical regions without clear frontal accentuation (GENERALIZED POWER ENHANCEMENT). Chronic THC exposure will also associated with impairment of the eyes open Alpha Blocking response and distortions of specific evoked potential parameters. The project will also seek to identify those specific neuropsychological performance features which are associated with the above neurophysiological sequelae of chronic THC abuse. The project contains three interrelated components. The CHRONIC-EXPOSURE MAIN STUDY will obtain complete quantitative EEG, evoked potential, and neuropsychological evaluations, under blind measurement conditions, of 160 subjects screened to be free of significant medical illness or major psychiatric disturbance. Both a chemical definition of recent THC use pattern based on eight weeks of twice weekly urine testing as well as self report data will be used to place subjects into four defined age and sex equated THC use groups (CONTROL NON-USER, INFREQUENT-SPORADIC USER, LIGHT- MODERATE USER and CHRONIC-HEAVY USER GROUP). In the ACUTE EXPOSURE SUBSTUDY infrequent THC users without the above topographic EEG changes will receive neurophysiological testing before and after controlled exposure to either active THC or placebo in a double blind counterbalanced exposure order design. Acute THC exposure is predicted to produce transient topographic quantitative EEG change similar to the persistent effects induced by chronic use. A VERIFIED ABSTINENCE SUBSTUDY will obtain reward induced 16 week abstinence periods (verified by twice weekly urine tests) in selected chronic-heavy THC users in order to determine the degree to which neurophysiological sequelae of chronic use reverse following THC withdrawal. Positive project results will create an especially strong presumption that at some point neuronal response to continued THC challenge begins to involve lasting change in basic CNS electrical regulatory activity. This could provide a non-behavioral, direct biological measure of the degree of THC toxicity which could have substantial value in studies of behavioral change, dependency and withdrawal related to significant THC use.
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