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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Dopamine agonists used in Parkinson's disease patients are associated with excessive daytime sleepiness and sleep attacks occurring without prior warning. • Parkinson's disease accounts in itself for a variety of sleep disorders. It is therefore important to study the drug-induced sleepiness in healthy volunteers.• In healthy subjects, pramipexole has proved to decrease alertness and ropinirole to reduce sleep latency. WHAT THIS STUDY ADDS• Results from our study show that pramipexole reduces the mean sleep latency as measured by the Multiple Sleep Latency Test in healthy volunteers, hence providing an objective measure of increased sleepiness.• Furthermore, the reduction in sleep latency was not associated with a subjective impression of increased sleepiness.• Such dissociation may underlie the occurrence of sleep attacks without prior warning. AIMSTo assess the sleepiness induced by pramipexole, a D2/D3-dopamine receptor agonist commonly used in Parkinson's disease and restless legs syndrome, without the problem of the confounding factors related to the disease. METHODSPlacebo, bromocriptine (2.5 mg), L-dopa (100 mg) and pramipexole (0.5 mg) were administered in a single oral dose on four separate days, with at least a 2-week wash-out period in a randomized cross-over design. Induced somnolence was assessed using Multiple Sleep Latency Test (MSLT) and subjective scaling of vigilance. Twelve male subjects (26.3 Ϯ 5.5 years old) without anxiety, mood, sleep or sedation disorders were enrolled. RESULTSPramipexole significantly reduced mean sleep latency compared with placebo 3 h 30 min [-6.1 min (-9.8, -2.4), P = 0.002] and 5 h 30 min [-5.6 min (-7.7, -3.5), P = 0.003] after administration. In addition, the total duration of sleep during the tests was higher with pramipexole than with placebo [+6.0 min (2.3, 9.7), P < 0.001]. These differences were not observed with L-dopa and bromocriptine in comparison with placebo. The induced sleepiness was not associated with an increase in subjective somnolence scaling, indicating that this adverse event may occur without prior warning. CONCLUSIONSThese results show that a single oral dose of pramipexole induces sleepiness as assessed by MSLT in healthy young subjects, independent of disease-related sleep dysfunction.

-Purpose. A randomized cross-over, double blind placebo controlled study of smoked cannabis was carried out on occasional cannabis smokers. The objective of this research was to describe the pharmacokinetic parameters of THC and its metabolites in plasma, oral fluid and urine, from samples obtained simultaneously to provide estimations of THC and metabolites concentrations after smoking a cannabis cigarette. Methods. Blood, oral fluid and urine samples were collected until up to 72 h after smoking the cannabis cigarette (4% of delta-9-tetrathydrocannabinol (THC)). THC, 11-OH-THC and THC-COOH were analyzed by gas-chromatography-mass spectrometry. Pharmacokinetic parameters were estimated from these data. Results. Eighteen male healthy adults participated in the study. In total, 560 plasma, 288 oral fluid and 448 urine samples were quantified for cannabinoids. Plasma, oral fluid and urine pharmacokinetic parameters were calculated. A wide range of median THC Cmax (1.6-160.0 µg/L and 55.4-123120.0 µg/L in plasma and oral fluid, respectively), 11-OH-THC Cmax (0-11.1 µg/L in plasma) and THC-COOH Cmax (1.0-56.3 µg/L in plasma) was observed. When expressed as a percentage of the total available THC dose, and corrected for molar equivalents, mean percentage of total THC dose excreted was 1.9 +/-2.5 % with range of 0.2-7.5%. This high inter-individual variability was also observed on other calculated pharmacokinetic parameters. Conclusion. Prediction of plasma THC concentration from THC oral fluid concentration or from THC-COOH urinary concentrations is not feasible due to the large variations observed. The results from this study support the assumption that a positive oral fluid THC result or a positive urine fluid result are indicative of a recent cannabis exposure.

Resting-state connectivity has been widely studied in the healthy and pathological brain. Less well-characterized are the brain networks altered during pharmacological interventions and their possible interaction with vigilance. In the hopes of finding new biomarkers which can be used to identify cortical activity and cognitive processes linked to the effects of drugs to treat neurodegenerative diseases such as Alzheimer's disease, the analysis of networks altered by medication would be particularly interesting. Eleven healthy subjects were recruited in the context of the European Innovative Medicines Initiative 'PharmaCog'. Each underwent five sessions of simultaneous EEG-fMRI in order to investigate the effects of donepezil and memantine before and after sleep deprivation (SD). The SD approach has been previously proposed as a model for cognitive impairment in healthy subjects. By applying network based statistics (NBS), we observed altered brain networks significantly linked to donepezil intake and sleep deprivation. Taking into account the sleep stages extracted from the EEG data we revealed that a network linked to sleep is interacting with sleep deprivation but not with medication intake. We successfully extracted the functional resting-state networks modified by donepezil intake, sleep and SD. We observed donepezil induced whole brain connectivity alterations forming a network separated from the changes induced by sleep and SD, a result which shows the utility of this approach to check for the validity of pharmacological resting-state analysis of the tested medications without the need of taking into account the subject specific vigilance.