The effect of methamphetamine and alcohol on cognition and driving performance.

Over the four-week experimental period, participation will receive all of the experimental doses. One dose combination will be taken at each session (i.e. active methamphetamine + active alcohol, active methamphetamine + placebo alcohol, placebo methamphetamine + active alcohol and placebo methamphetamine + placebo alcohol) and the order of dosing will be randomised. The active treatments are: 1. 0.42mg/kg d-methamphetamine in capsule, mixed with microcellulose crystalline in size #0 gelatine capsule. Administered using a combination of no more than three capsules to reach required dose, rounded to the nearest five (i.e. required dose of 33.1mg would be 35mg) (capsules will be 5mg, 10mg and 20mg). 2. Drink of weighted dose of vodka mixed with orange juice to obtain 0.04% blood alcohol content (BAC) The placebo treatments are: 1. Microcellulose crystalline only in size #0 capsule (identical in taste, texture, weight and smell) 2. Drink of orange juice only, with rim of glass wiped with 5ml vodka to ensure double- blind condition. Each dose is weight related. The doses of d-methamphetamine (and placebo) and the alcohol drink (and placebo) will be orally administered. The methamphetamine (and placebo) to be delivered in identical gelatine size #0 capsules. No more than three combined capsules will be provided at one time in order to reach the required dose. The dose of alcohol will be administered within a single 300mL cup of orange juice. The placebo drink will contain orange juice only. Adherence to the treatment protocol will be confirmed by assessing that the patient has consumed the treatment (both capsule and drink). The treatment combination administered (i.e. active methamphetamine + active alcohol, active methamphetamine + placebo alcohol, placebo methamphetamine + active alcohol and placebo methamphetamine + placebo alcohol) will be randomised and will be provided once to participants at baseline at each of the four testing sessions. A one-week washout period will occur between testing sessions. Prior to dosing at each testing visit (each at V1, V2, V3 and V4), participants will provide one saliva sample to screen for evidence of recent use of drugs [amphetamine/d-methamphetamine, 3,4- methylenedioxymethamphetamine (MDMA), cocaine, cannabis (del ta-9-tetrahydrocannabinol), opiates and ketamine] using the Securetec DrugWipe 6s device. This screening assessment requires an absorbent pad to be placed over the tongue for approximately 20 seconds. 1ml of saliva will be taken per sample, therefore approximately 4ml in total over each of the four experimental sessions. A sample volume of less than 10 micro litres is sufficient for analysis. The device is wiped on the tongue, when the colour has changed from pink to yellow there is the required amount of saliva to obtain the results. For the purpose of determining salivary d-methamphetamine concentrations, oral fluid samples will be collected at two time points during each testing session using the Quantisal™ Oral Fluid Collection Device (each at V1, V2, V3 and V4). Oral fluid samples will be collected by a registered nurse, and will occur: Prior to the first cognitive assessment (approximately 25 mins post-dosing), and prior to leaving the testing site (approximately 2 hours post-dosing). At each sample collection time-point, 1ml of oral fluid will be collected. A total of 8ml will be collected per participant over the four experimental sessions. Prior to dosing at each testing visit (each at V1, V2, V3 and V4), participants will also provide one baseline breathyser analysis to assess for the presence of alcohol. The breathalyser will then be used on four occasions over the course of the experimental session to ensure the desired BAC peak (0.04% BAC) is reached for testing, and record descending BAC post-peak. Specifically, breathalyser readings will be taken to ensure 0.0% BAC at the beginning of the testing session; confirm 0.04% BAC prior to cardiac and cognitive tasks; obtain BAC prior to the driving simulator task; obtain descending % BAC following the driving simulator task, prior to the second set of cognitive tasks; and obtain % BAC at the end of testing. All participants will be given a new, sterile mouth piece to use on each testing session. These will be deposited into biohazard bins after use. A registered research nurse trained in venepuncture or a qualified venepuncture technician will collect blood samples at three time-points at each testing session (each at V1, V2, V3 and V4): prior to cognitive and driving tests and at ~ 2 hours post-driving test. This will be done via cannulation. Heart rate, blood pressure readings will be measured using a blood pressure monitor. QT intervals will be assessed using the 12-lead Holter standard Electrocardiogram (ECG). Measurements will be taken to investigate participants’ cardiac effect of the treatments, individually and combined. Assessment will occur approximately 1 hour post ingestion of the treatment, and post driving-task (approximately 3 hours post dosing). The CogTrack™ System will be used to assess the cognitive effects of the intervention. Three tasks will be used in this study to assess visual processing, processing speed and reaction/decision speed, specifically: Digit vigilance, Spatial working memory, Numeric working memory. Participants will be assessed at 1 hour post-dosing and at 3 hours post dosing. Driving performance will be assessed using the Forum 8 driving simulator, and driving performance will be assessed once per study session, for a 1 hour duration. The simulator consists of a car unit with adjustable car seats and a dashboard and includes a steering wheel, turn sign indicators, gear lever, brake and accelerator pedals for vehicle control. The system generates realistic roadway scenery which is presented on three integrated TV screens 1.90 meters in front of the centre of the steering wheel. The speed and gear number are displayed on the dashboard and screen. Auditory feedback is provided by speakers and included the sound of the engine, braking, speeding in curves, and driving off-road. Driving assessment will take place at 2 hours post dosing.