Semiquantitative activity-based detection of JWH-018, a synthetic cannabinoid receptor agonist, in oral fluid after vaping

The rapid proliferation of new synthetic cannabinoid receptor agonists (SCRAs) has initiated considerable interest in the development of so-called “untargeted” screening strategies. One of these new screening technologies involves the activity-based detection of SCRAs. In this study, we evaluated whether (synthetic) cannabinoid activity can be detected in oral fluid (OF) and, if so, whether it correlates with SCRA concentrations. OF was collected at several time points in a placebo-controlled JWH-018 administration study. The outcome of the cell-based cannabinoid reporter system, which monitored the cannabinoid receptor activation, was compared to the quantitative data for JWH-018, obtained via a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. A total of 175 OF samples were collected and analyzed via both methods. The cannabinoid reporter assay correctly classified the vast majority of the samples as either negative (<0.25 ng/mL; 74/75 = 99%) or having low (0.25−1.5 ng/mL; 16/16 = 100% and 1.5−10 ng/mL; 37/41 = 90%), mid (10−100 ng/mL; 23/25 = 92%) or high (>100 ng/mL; 16/18 = 89%) JWH-018 concentrations. Passing−Bablok regression analysis yielded a good linear correlation, with no proportional difference between both methods (slope 0.97; 95% confidence interval 0.86−1.14) and only a small systematic difference. This is the first study to demonstrate the applicability of an untargeted, activity-based approach for SCRA detection in OF. Additionally, the outcome of the cannabinoid reporter assay was compared to the gold standard (LC-MS/MS), showing a good correlation between both methods, indicating that the cannabinoid reporter assay can be used for an estimation of drug concentrations

A phase 1/2 trial to assess safety and efficacy of a vaporized 5-methoxy-N,N-dimethyltryptamine formulation (GH001) in patients with treatment-resistant depression

BackgroundTreatment-resistant depression (TRD) is a substantial public health burden, but current treatments have limited effectiveness. The aim was to investigate the safety and potential antidepressant effects of the serotonergic psychedelic drug 5-MeO-DMT in a vaporized formulation (GH001) in adult patients with TRD.MethodsThe Phase 1 part (n = 8) of the trial investigated two single dose levels of GH001 (12 mg, 18 mg) with a primary endpoint of safety, and the Phase 2 part (n = 8) investigated an individualized dosing regimen (IDR) with up to three increasing doses of GH001 (6 mg, 12 mg, and 18 mg) within a single day, with a primary endpoint of efficacy, as assessed by the proportion of patients in remission (MADRS ≤ 10) on day 7.ResultsAdministration of GH001 via inhalation was well tolerated. The proportion of patients in remission (MADRS ≤ 10) at day 7 was 2/4 (50%) and 1/4 (25%) in the 12 mg and 18 mg groups of Phase 1, respectively, and 7/8 (87.5%) in the IDR group of Phase 2, meeting its primary endpoint (p &lt; 0.0001). All remissions were observed from day 1, with 6/10 remissions observed from 2 h. The mean MADRS change from baseline to day 7 was −21.0 (−65%) and − 12.5 (−40%) for the 12 and 18 mg groups, respectively, and − 24.4 (−76%) for the IDR.ConclusionAdministration of GH001 to a cohort of 16 patients with TRD was well tolerated and provided potent and ultra-rapid antidepressant effects. Individualized dosing with up to three doses of GH001 on a single day was superior to single dose administration.Clinical Trial registration: Clinicaltrials.gov Identifier NCT04698603

Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype

INTRODUCTION: Esmirtazapine is evaluated as a novel drug for treatment of insomnia. PURPOSE: The present study was designed to assess residual effects of single and repeated doses of esmirtazapine 1.5 and 4.5 mg on actual driving in 32 healthy volunteers in a double-blind, placebo-controlled study. Treatment with single doses of zopiclone 7.5 mg was included as active control. METHODS: Treatments were administered in the evening. Driving performance was assessed in the morning, 11 h after drug intake, in a standardized on-the-road highway driving test. The primary study parameter was standard deviation of lateral position (SDLP), a measure of "weaving". All subjects were subjected to CYP2D6 phenotyping in order to distinguish poor metabolizers from extensive metabolizers of esmirtazapine. RESULTS: Overall, esmirtazapine 1.5 mg did not produce any clinically relevant change in SDLP after single and repeated dosing. Driving impairment, i.e., a rise in SDLP, did occur after a single-dose administration of esmirtazapine 4.5 mg but was resolved after repeated doses. Acute driving impairment was more pronounced after both doses of esmirtazapine in a select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected. CONCLUSION: It is concluded that single and repeated doses of 1.5 mg esmirtazapine are generally not associated with residual impairment. Single-dose administration of 4.5 mg esmirtazapine was associated with residual impairment that generally resolved after repeated administration. Exploratory analysis in a small group of poor CYP 2D6 metabolizers suggested that these subjects are more sensitive to the impairing effects of esmirtazapine on car driving

Tolerance and cross-tolerance to neurocognitive effects of THC and alcohol in heavy cannabis users

and cross-tolerance to neurocognitive effects of THC and alcohol in heavy cannabis user

Driving Aptitude and Fitness to Drive

The number of annual road traffic deaths is steadily increasing. This chapter provides a general overview of the techniques for identifying risk factors for road traffic accidents and the assessment of driving performance and related functioning, as well as their strengths and weaknesses. Traffic medicine and forensic medicine are closely related disciplines that overlap a great deal. Whereas traffic medicine is mainly concerned with driving capability, forensic medicine is concerned with driver culpability. The most widely adopted study design for investigating contributing factors to road traffic accidents and at-risk drivers is the case–control study. On-road driving tests are often considered as the most ecologically valid assessments of driving performance. Epidemiological and experimental research attempts to uncover risk factors for road traffic accidents. After a driver has been judged to be unfit to drive, an assessment of driving aptitude may be necessary

Cannabis Use and Neuroadaptation:A Call for Δ 9 -Tetrahydrocannabinol Challenge Studies

Currently, the assessment of the neurobehavioral consequences of repeated cannabis use is restricted to studies in which brain function of chronic cannabis users is compared to that of non-cannabis using controls. The assumption of such studies is that changes in brain function of chronic users are caused by repeated and prolonged exposure to acute cannabis intoxication. However, differences in brain function between chronic cannabis users and non-users might also arise from confounding factors such as polydrug use, alcohol use, withdrawal, economic status, or lifestyle conditions. We propose a methodology that highlights the relevance of acute Δ9-tetrahydrocannabinol (THC) dosing studies for a direct assessment of neuroadaptations in chronic cannabis users. The approach includes quantification of neurochemical, receptor, and functional brain network changes in response to an acute cannabis challenge, as well as stratification of cannabis using groups ranging from occasional to cannabis-dependent individuals. The methodology allows for an evaluation of THC induced neuroadaptive and neurocognitive changes across cannabis use history, that can inform neurobiological models on reward driven, compulsive cannabis use