Eef L. Theunissen

High-Potency Marijuana Impairs Executive Function and Inhibitory Motor Control

Human performance studies have usually relied on low-potency marijuana (4% THC) for determining THC-induced impairment. The present study was designed to assess the effects of high-potency marijuana (13% THC) on human performance. In all, 20 recreational users of marijuana participated in a double-blind, placebo controlled, three way cross-over study. The treatments consisted of single doses of 0, 250, and 500 μg/kg THC. Performance tests were conducted at regular intervals between 15 min and 6 h postsmoking and included measures of motor control (Critical tracking task), executive function (Tower of London) motor impulsivity (Stop signal task), and risk taking (Iowa gambling task). THC significantly impaired performance in the Critical tracking task and decreased the number of correct decisions in the Tower of London task. In addition, THC significantly increased stop reaction time and the proportions of commission and omission errors in the Stop signal task. THC-induced impairments lasted up to 6 h postsmoking as indicated by the absence of a THC × Time after smoking interaction. Effect sizes for performance impairments produced by THC 250 μg/kg were relatively low but generally increased by a factor of two in case of THC 500 μg/kg. These data suggest that high potency marijuana consistently impairs executive function and motor control. Use of higher doses of THC in controlled studies may offer a reliable indication of THC induced impairment as compared to lower doses of THC that have traditionally been used in performance studies.

Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users

Abstract Performance impairment during Δ9-tetrahydrocannabinol (THC) intoxication has been well described in occasional cannabis users. It is less clear whether tolerance develops to the impairing effects of THC in heavy users of cannabis. The aim of the present study was to assess neurocognitive performance during acute THC intoxication in occasional and heavy users. Twenty-four subjects (12 occasional cannabis users and 12 heavy cannabis users) participated in a double-blind, placebo-controlled, two-way mixed model design. Both groups received single doses of THC placebo and 500 μg/kg THC by smoking. Performance tests were conducted at regular intervals between 0 and 8 h after smoking, and included measures of perceptual motor control (critical tracking task), dual task processing (divided attention task), motor inhibition (stop signal task) and cognition (Tower of London). THC significantly impaired performance of occasional cannabis users on critical tracking, divided attention and the stop signal task. THC did not affect the performance of heavy cannabis users except in the stop signal task, i.e. stop reaction time increased, particularly at high THC concentrations. Group comparisons of overall performance in occasional and heavy users did not reveal any persistent performance differences due to residual THC in heavy users. These data indicate that cannabis use history strongly determines the behavioural response to single doses of THC.

A dose‐ranging study of the effects of mequitazine on actual driving, memory and psychomotor performance as compared to dexchlorpheniramine, cetirizine and placebo

Background Mequitazine is a so‐called ‘non‐sedative’ second‐generation antihistamine even though it has never been firmly established that this drugs sedative potential actually differs from that of the ‘sedative’ first‐generation antihistamines.

A Randomized Trial on the Acute and Steady-State Effects of a New Antidepressant, Vortioxetine (Lu AA21004), on Actual Driving and Cognition

The aim of this study was to assess the effects of a novel antidepressant, vortioxetine 10 mg, on driving, cognitive, and psychomotor performance in 24 healthy subjects in a double‐blind, placebo‐controlled, three‐way crossover design. Mirtazapine 30 mg was included as an active comparator. Drugs were administered in the evening of 15 consecutive days. Performance was measured in the morning of days 2 and 16, using standardized tests measuring on‐the‐road driving, memory, tracking, divided attention, and vigilance. The statistical analysis on the primary measure of driving, i.e., SD of lateral position showed noninferiority of vortioxetine on days 2 and 16, and inferiority for mirtazapine on day 2. Vortioxetine did not cause cognitive or psychomotor impairment. Mirtazapine, however, impaired cognitive and psychomotor performance on day 2. Most of these effects disappeared after multiple doses of mirtazapine. To conclude, vortioxetine did not impair driving, cognitive, or psychomotor performance after single or multiple doses.

Effects of Acute MDMA Intoxication on Mood and Impulsivity: Role of the 5-HT2 and 5-HT1 Receptors

MDMA induces positive mood and increases impulse control during intoxication, but only a few studies on the neuropharmacological mechanisms underlying these processes have been conducted. It was hypothesized that pretreatment with 5-HT1 and 5-HT2 receptor blockers would prevent MDMA effects on mood and impulsivity. Subjects (N = 17) participated in a double-blind, placebo controlled, within-subject design involving 6 experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 minutes. T1–T2 combinations were: placebo-placebo, 20 mg pindolol-placebo, 50 mg ketanserin-placebo, placebo-75 mg MDMA, 20 mg pindolol-75 mg MDMA and 50 mg ketanserin-75 g MDMA. Subjects completed a Profile of Mood States (POMS) questionnaire and several impulsivity tasks (Stop signal task, Matching familiar figures task, Cue dependent reversal learning task) at 1.5 hrs post-treatment. MDMA alone increased both positive (vigor, arousal, friendliness, elation, positive mood) and negative affect (anxiety, confusion) as assessed by the POMS questionnaire. MDMA also increased stop reaction time in the Stop signal task and reaction time in the Matching familiar figures task. Pretreatment with ketanserin blocked MDMA effects on positive affect, but not negative affect. Ketanserin did not influence the effects of MDMA on impulsivity. Pindolol did not interact with MDMA on any of the measures. In conclusion, 5-HT2 receptors mediate positive moods induced by MDMA but not negative moods or impulsivity. 5-HT1 receptors do not appear to be involved in MDMA effects on mood and impulse control. Trial Registration Nederlands Trial Register NTR2352

Acute and subchronic effects of bilastine (20 and 40 mg) and hydroxyzine (50 mg) on actual driving performance in healthy volunteers

Bilastine is a new second-generation H1 antagonist. Although bilastine has been demonstrated to produce little or no performance impairment in laboratory tests, it cannot be excluded that it produces impairments in real-life performance such as driving. This study aims to assess the effects of two doses of bilastine (20 and 40 mg) on actual driving after single and repeated administration. Hydroxyzine 50 mg was included as an active control. Twenty-two particpants (11 females, 11 males) were tested in a placebo-controlled, randomized, double-blind, four-way cross-over design. Participants were treated with once-daily doses for eight consecutive days. On day 1 and 8 of each treatment period participants performed an actual highway driving test. The primary variable was standard deviation of lateral position (SDLP), a measure of weaving. Results demonstrated that hydroxyzine significantly increased SDLP on days 1 and 8 of treatment. Bilastine did not affect SDLP. It is concluded that hydroxyzine produces severe driving impairment after single doses and that this impairment only partly mitigates over time due to a lack of complete tolerance. Bilastine did not produce any driving impairment after single and repeated doses and can be safely used in traffic in doses up to 40 mg.

Psychomotor Function in Chronic Daily Cannabis Smokers during Sustained Abstinence

Background The present study assessed psychomotor function in chronic, daily cannabis smokers during 3 weeks continuously monitored abstinence on a secure research unit. We hypothesized that psychomotor performance would improve during abstinence of chronic, daily cannabis smokers. Methodology/Principal Findings Performance on the critical tracking (CTT) and divided attention (DAT) tasks was assessed in 19 male chronic, daily cannabis smokers at baseline and after 8, 14–16 and 21–23 days of continuously monitored abstinence. Psychomotor performance was compared to a control group of non-intoxicated occasional drug users. Critical frequency (λc) of the CTT and tracking error and control losses of the DAT were the primary outcome measures. Results showed that chronic cannabis smokers’ performance on the CTT (p<0.001) and the DAT (p<0.001) was impaired during baseline relative to the comparison group. Psychomotor performance in the chronic cannabis smokers improved over 3 weeks of abstinence, but did not recover to equivalent control group performance. Conclusions/Significance Sustained cannabis abstinence moderately improved critical tracking and divided attention performance in chronic, daily cannabis smokers, but impairment was still observable compared to controls after 3 weeks of abstinence. Between group differences, however, need to be interpreted with caution as chronic smokers and controls were not matched for education, social economic status, life style and race.

Medicinal Δ(9) -Tetrahydrocannabinol (Dronabinol) Impairs On-the-Road Driving Performance of Occasional and Heavy Cannabis Users but is not Detected in Standard Field Sobriety Tests

AIMS The acute and chronic effects of dronabinol [medicinal Δ(9) -tetrahydrocannabinol (THC)] on actual driving performance and the Standard Field Sobriety Test (SFST) were assessed. It was hypothesized that occasional users would be impaired on these tests and that heavy users would show less impairment due to tolerance. DESIGN, SETTING AND PARTICIPANTS Double-blind, placebo-controlled, randomized, three-way cross-over study. Twelve occasional and 12 heavy cannabis users (14 males/10 females) received single doses of placebo, 10 and 20 mg dronabinol. MEASUREMENTS Standard deviation of lateral position (SDLP; i.e. weaving) is the primary measure of road-tracking control. Time to speed adaptation (TSA) is the primary reaction-time measure in the car-following test. Percentage of impaired individuals on the SFST and subjective high on a visual analogue scale were secondary measures. FINDINGS Superiority tests showed that SDLP (P = 0.008) and TSA (P = 0.011) increased after dronabinol in occasional users. Equivalence tests demonstrated that dronabinol-induced increments in SDLP were bigger than impairment associated with BAC of 0.5 mg/ml in occasional and heavy users, although the magnitude of driving impairment was generally less in heavy users. The SFST did not discriminate between conditions. Levels of subjective high were comparable in occasional and heavy users. CONCLUSIONS Dronabinol (medicinal tetrahydrocannabinol) impairs driving performance in occasional and heavy users in a dose-dependent way, but to a lesser degree in heavy users due possibly to tolerance. The Standard Field Sobriety Test is not sensitive to clinically relevant driving impairment caused by oral tetrahydrocannabinol.

Blockade of 5-HT2 receptor selectively prevents MDMA-induced verbal memory impairment.

3,4-Methylenedioxymethamphetamine (MDMA) or ‘ecstasy’ has been associated with memory deficits during abstinence and intoxication. The human neuropharmacology of MDMA-induced memory impairment is unknown. This study investigated the role of 5-HT2A and 5-HT1A receptors in MDMA-induced memory impairment. Ketanserin is a 5-HT2A receptor blocker and pindolol a 5-HT1A receptor blocker. It was hypothesized that pretreatment with ketanserin and pindolol would protect against MDMA-induced memory impairment. Subjects (N=17) participated in a double-blind, placebo-controlled, within-subject design involving six experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 min. T1–T2 combinations were: placebo–placebo, pindolol 20 mg–placebo, ketanserin 50 mg–placebo, placebo–MDMA 75 mg, pindolol 20 mg–MDMA 75 mg, and ketanserin 50 mg–MDMA 75 mg. Memory function was assessed at Tmax of MDMA by means of a word-learning task (WLT), a spatial memory task and a prospective memory task. MDMA significantly impaired performance in all memory tasks. Pretreatment with a 5-HT2A receptor blocker selectively interacted with subsequent MDMA treatment and prevented MDMA-induced impairment in the WLT, but not in the spatial and prospective memory task. Pretreatment with a 5-HT1A blocker did not affect MDMA-induced memory impairment in any of the tasks. Together, the results demonstrate that MDMA-induced impairment of verbal memory as measured in the WLT is mediated by 5-HT2A receptor stimulation.

A combined neurophysiological and behavioural study into the stimulating effects of fexofenadine on performance

Antihistamines are known for their sedative effects. However, some studies suggested mild stimulant effects in the case of fexofenadine. The goals of this study are to examine whether fexofenadine possesses stimulating properties and to determine whether such stimulating effects are related to workload. Sixteen healthy volunteers received a single dose of 180 and 360 mg fexofenadine and placebo on separate test days. Drug effects were assessed using a divided attention task (DAT), continuous performance task (CPT) and motor choice reaction time test (MCRT). Sensitivity of the tasks was increased by manipulating the workload during task performance. Event Related brain Potentials (ERPs) were measured in the DAT and CPT to study the underlying neurophysiological processes. An interaction effect of Treatment and Workload was found on tracking performance in the DAT and on movement time in the MCRT. Performance on the DAT was less affected by increments in workload after fexofenadine as compared to placebo. P1 and P3 latency were affected by Treatment Workload and Treatment respectively and indicated faster attentional and information processing latencies following fexofenadine treatment. Treatment did not influence performance in the CPT task or in the ERPs measured during this task. The MCRT demonstrated faster movement times following fexofenadine treatment. These results suggest that although the neurophysiological data indicate central nervous system (CNS) activation after fexofenadine treatment, the magnitude of the centrally activating effects is too small to produce relevant performance improvement at the behavioural level.