Anthony Liguori - US grants

Marijuana is the most widely used illicit drug in the United States. It impairs equilibrium and is often found in the bloodstream of drivers involved in automobile accidents. While the effects of marijuana on equilibrium and driving have both been studied separately, a critical gap in the existing knowledge of marijuana effects on driving is the lack of a rigorous examination of these effects within the same group of subjects. The specific aim of the proposed study is to compare the effects of placebo and two potencies of marijuana on equilibrium and simulated automobile driving using a within-subject design. Twenty adult paid volunteer marijuana users with driving experience will undergo a battery of six tests at potencies of 0, 1.77, and 3.95% delta-9 THC via smoked cigarettes. The tests will include a) brake reaction time within a driving simulator, b) risk-taking maneuvers within the driving simulator, c) the EquiTest balance measurer, d) the critical flicker fusion test of CNS activity, e) a sensorimotor choice reaction time task, and f) subjective effects as measured by visual analog scales. Results will show whether marijuana doses that impair driving also affect motor equilibrium and vice versa. Marijuana doses that objectively appear to increase "cautious" driving may simultaneously worsen other essential aspects of driving, such as sense of balance. The varied tasks and within-subject design of the proposed research will clarify the various effects marijuana has simultaneously within a driver.

Excessive alcohol consumption contributes to tens of thousands of deaths each year. Animal studies have shown that internal stimuli produced by ethanol can function as discriminative stimuli enabling the animal in accordance with the presence or absence of alcohol, or even a particular alcohol dose. In this regard, humans who are trained to estimate their blood alcohol levels (BALs) accurately may be more likely to avoid excessive alcohol use by stopping drinking earlier within a drinking session. Prior efforts to train drinkers to discriminate their own BALs have compared the effectiveness of attending to "external" cues (e.g., knowledge of intake-time-metabolism interactions) versus "internal" cues (e.g., increased awareness of bodily sensations) of the stimulus effects of alcohol. The body will test the hypothesis that such feedback will enable adults to use impairment of their own equilibrium as a tool for accurate estimation of their own BALs. This study will use an A-B-A within-subjects design requiring three sessions for each of four groups. In the first and third sessions, subjects will estimate their BALs following each of six drinks of varying ethanol doses. Before making each BAL estimate during the second session, subjects attending to external cues will receive feedback from the results of a computerized dynamic posturography test, while subjects attending to internal cues will complete several self-report mood/symptom questionnaires and be informed of their heart rates and blood pressures. A third group will receive both cues, while a fourth group will receive no training. The main dependent variable is accuracy of BAL estimation following training. We hypothesize that self-monitoring of impaired balance is more generalizable than previously studied "external" cues for BAL estimation. Proper use of cue training by heavy drinkers could reduce their potential for alcohol-related problems.

DESCRIPTION: (Applicant's Abstract) Marijuana and alcohol are drugs that contribute to automobile accidents when used separately and in combination. A further danger to adults who drive after late-night drug use is sleep deprivation. While many post-accident blood analyses have implicated marijuana and alcohol, no controlled empirical studies have quantified the combined behavioral and subjective effects of sleep deprivation with either marijuana or marijuana-alcohol combinations. The novelty of this project is its use of controlled Sleep Laboratory measurements, a driving simulator, computerized body sway measurement, a test of divided attention, and self-report mood scales to assess the various ways sleep deprivation and alcohol impair a driver who uses marijuana. The project has three specific aims. The first aim is to quantify how alcohol alters the effects of marijuana on mood, equilibrium, attention, and simulated automobile driving. The second aim is to quantify how partial sleep deprivation alters the effects of marijuana on these measures. The third aim is to quantify the effects of sleep deprivation on marijuana-alcohol combinations. Three studies using randomized placebo controlled designs are proposed. In each study, subjects will smoke a marijuana cigarette (0, 1.77, or 3.95% delta 9 THC) in two or three separate conditions. Study 1 will manipulate a concurrent dose of alcohol (0.0, 0.5, or 0.8 g/kg). Study 2 will manipulate pre-session sleep hours (8 vs. 3). Study 3 will add the expectation and experience of alcohol to the conditions of Study 2, with each subject drinking a dose of alcohol (0.0, 0.5, or 0.8 g/kg) before testing. The dependent variables to be studied include 1) body sway as measured by computerized dynamic posturography, 2) subjective effects scales (Profile of Mood States and Visual Analog Scales), 3) the Stroop Color Test of divided attention, and 4) brake latency within the driving simulator. By clarifying the separate and combined effects of marijuana, alcohol, and sleep deprivation on these ecologically valid measures, the results will contribute to the prevention of drug-related highway fatalities.

DESCRIPTION (provided by applicant): Marijuana use impairs memory, attention, and executive functioning. These impairments increase with long-term use. While several studies have reported residual cognitive impairments within days of abstinence from long-term use, the extent to which marijuana-induced cognitive performance deficits extend further into the abstinence period has received little study. These cognitive deficits may be further confounded by residual impairing effects of marijuana on motivation. That is, cognitive performance deficits during abstinence from heavy marijuana use may be due to impairment of processing ability, diminished motivation to perform well, or both. The goal of this research proposal is to fill these two critical knowledge gaps by quantifying marijuana withdrawal effects on memory and attention. We will repeatedly test memory and attention in marijuana-dependent adults with a heavy use history both before and during withdrawal from chronic marijuana use. A group of former light users will serve as a control group. We will also isolate the role of motivational drive in marijuana-related and withdrawal-related impairments. Monetary incentive for accurate performance will be provided to separate groups of marijuana abstinent adults and control subjects. The key dependent variable will be improvement of performance over repeated testing. Testing during abstinence will coincide with the ascent (day 1), peak (day 3), and descent (days 7 and 21) of the typical withdrawal syndrome. By quantifying cognitive impairment, then dissociating processing deficit from effort expended, the proposed studies will further our understanding of the effects of THC on cognitive performance before and after abstinence.

[unreadable] DESCRIPTION (provided by applicant): Trazodone, the most widely used sleep aid in the U.S., is indicated for depression, and is not indicated for insomnia. The factors shaping the use of trazodone as a sleep aid are unknown, but have been speculated to include physician wariness over the regulatory limitations governing standard hypnotics, coupled with providers' unsubstantiated belief that trazodone is safe and effective. Standard hypnotics have been implicated in increased risk of falls, motor vehicle accidents, delayed reaction time, daytime sleepiness, and memory problems. The preferential prescription by physicians of trazodone over approved hypnotics suggests that physicians may believe trazodone is a safer substitute for hypnotic medication. This is an important and unanswered question as the risk of bedtime dosing of trazodone has not been systematically investigated in insomniacs. The primary goal of this grant is to examine surrogates of accident risk with trazodone in chronic insomniacs. The usual initial hypnotic dose of trazodone, 50 mg, will be compared with placebo in a within-subject design. All dosing will be conducted at bedtime. This Developmental and Exploratory Proposal will estimate the effect size of various adverse effects seen the morning after bedtime dosing and at steady state of trazodone. The outcome measures are proximal strength, postural equilibrium, simulated driving performance, next-day physiologic sleep tendency, anterograde verbal memory, and acute subjective and polysomnographic hypnotic efficacy. Completion of these aims will contribute to improved public health by clarifying the presence or absence of possible risks associated with this frequently prescribed sleep aid. Ultimately, the results may alter the perception and prescription of this putatively safe compound. PUBLIC HEALTH RELEVANCE: Completion of these project aims will contribute to improved public health by clarifying the presence or absence of possible risks associated with this frequently prescribed sleep aid. Ultimately, the results may alter the perception and prescription of this generally well-accepted compound. [unreadable] [unreadable] [unreadable]

Breath alcohol estimation (BrACE) training, which emphasizes biofeedback and education about the effects of alcohol, is an intervention that may be valuable in the context of prevention programs. Preliminary data in our laboratory have identified enduring post-training changes in approaches to drinking and driving. The overarching goal of this Project is to extend quantification of the feasibility and benefits of BrACE training to adults who report early life stress (ELS). ELS, defined as experience of abuse or neglect through age 18, is a risk factor for alcoholism and has been associated with memory deficits in adulthood. Individuals with ELS are particularly prone to anxiety, an additional risk factor for alcohol use disorders. Thus, identification of an intervention that can minimize the potential for excess alcohol use among these individuals is of paramount importance. This Project will recruit three groups of nondependent alcohol drinkers: individuals with no ELS, individuals with ELS, and individuals with ELS plus high trait anxiety. The Project will differentiate baseline BrACE accuracy (Aim 1), efficacy of BrACE training (Aim 2), the influence of BrACE training on alcohol use and related behaviors (Aim 3), and sensitivity to the impairing effects of alcohol on memory, balance, and simulated driving (Aim 4) among these groups. Adults in these three groups will be randomized to Intervention and Control groups that will attend pretraining, training, and testing sessions. During these sessions, subjects will receive the equivalent of four standard drinks in a two-hour period. A cognitive/behavioral test battery will be completed before and after alcohol drinking, and subjects will estimate breath alcohol concentration at multiple time points. During the training session, the Intervention group, but not the Control group, will receive BrACE training. One and three months after the testing session, all subjects will return to the laboratory and complete self-report questionnaires regarding alcohol intake and alcohol-related risk-taking behaviors, including driving under the influence of alcohol. We hypothesize that BrACE errors and alcohol-related memory impairments will be highest in the ELS+Anxiety group, followed by the ELS group, then the no ELS group. We also hypothesize that BrACE training will be efficacious in all three groups. RELEVANCE (See instructions): Relevance of this Research to Public Health: The Project will identify feasibility of an educational intervention in two populations at significant risk for alcohol abuse and dependence: individuals with ELS with and without concurrent trait anxiety. The Project will also measure the effectiveness of this training in altering alcohol use and driving while intoxicated in these populations. Successful completion of this proposal's Specific Aims will clarify the utility of breath alcohol estimation training as a viable intervention for binge drinkers.