Nicolas Simon, Bibiana Cardozo, Sarah Hartley, Islam Amine Larabi, Jean Claude Alvarez
Aix Marseille University
Objectives:
The World Drug Report 2023 by the United Nations Office on Drugs and Crime (UNODC) identifies cannabis as the most prevalent global drug, with around 4% of the global adult population using it. COVID-19 lockdowns have escalated cannabis consumption, with an estimated 41% of drug-related mental disorders now linked to its use, posing significant public health concerns, especially regarding its impact on driving behaviors. Indeed, Asbridge et al. (2012) found that acute cannabis consumption doubles the risk of motor vehicle collisions causing serious injury or death, emphasizing the need to address cannabis use’s implications for road safety. To address this concern, the Vigicann study was conducted aiming to explore the relationship between THC blood levels and driving performance using a York Driving simulator.
This work rethrieved the data from Vigicann study in order to develop a pharmacokinetic-pharmacodynamic (PKPD) model, examining the relationship between the THC levels at different doses across two consumer groups and the self-assessment of driving effects via two Visual Analog Scales: Mental sharpness & Driving Confidence. A linear model was also developed to explore the relationship between EVAs and the driving ability (SDLP).
Methods: Thirty healthy males aged 18–34, including 15 chronic users (1–2 joints/day) and 15 occasional users (1–2 joints/week), participated. Assessments covered self-rated driving confidence (visual analog scale), vigilance (Karolinska), reaction time (mRRT, psychomotor vigilance test), driving ability (SDLP on a York driving simulator), and blood THC concentrations. Measurements were taken before and at intervals after controlled inhalation of placebo, 10mg, or 30mg of THC mixed with tobacco in a cigarette.
Data Analysis: Population pharmacokinetic/pharmacodynamic analysis utilized nonlinear mixed-effects modeling in NONMEM version 7.4.1 with the Fortran 4.6.0 compiler. Wings for NONMEM version 743 served as the “front end” for the NONMEM program [Holford]. Graphical analysis employed R software version 3.4.2. The first-order conditional estimate (FOCE) method with the interaction option was employed for data analysis.
Results:
The PK of THC was described by 3 compartments and first-order absorption (adjusted from Alvarez et al, 2020). The PK was affected by the group (Chronic or Occasional consumer) and by the dose, both were retained in the PK mode as covariables. The PK model was fixed, and then different PD models were tested. The best PD model to describe the VAS self-assessments was a compartment effect.
Among the most relevant findings, It was found that cannabis consumption (10 and 30 mg) significantly reduced driving confidence within the first 2 hours, remaining below baseline at 8 hours. Driving confidence correlated with THC dose and concentrations in the effective compartment, with an EC50concentration of 0.11 ng/mL and a rapid onset of action (t1/2 37min). Cannabis consumption decreased driving confidence and skillfulness assessment times, which correlated with reduced driving ability and reaction times in both chronic and occasional consumers.
Regarding Driving Confidence no statistically significant covariates explaining between-subject variability were found among those explored (BMI, weight, age, VAS Baseline, group). Application of a proportional error model led to the most favorable description of residual variability.
Regarding Mental sharpness assessment age was found to be a significant covariate explaining between-subject variability and it was retained in the final model. A proportional error was selected.
The robustness of standard approximations for parameter uncertainty were verified by a bootstrap method using the lower 2.5% and the upper 97.5% value of each parameter percentile as the bootstrap confidence intervals.
Conclusions: Cannabis consumption rapidly diminishes driving confidence and mental sharpness assessment, correlating with reduced driving ability on a driving simulator.
References:
[1] World Drug Report 2023 United Nations Office on Drugs and Crime (UNODC), accessed 10 February 2024, www.unodc.org/unodc/en/data-and-analysis/wdr-2023-online-segment.html
[2] Asbridge, M., Hayden, J., and Cartwright, J. Acute Cannabis Consumption and Motor Vehicle Collision Risk: Systematic Review of Observational Studies and Meta-Analysis. BMJ, 2012, 344:e536. https://doi.org/10.1136/bmj.e536. [3] Asbridge, M., Hayden, J., and Cartwright, J. Acute Cannabis Consumption and Motor Vehicle Collision Risk: Systematic Review of Observational Studies and Meta-Analysis. BMJ, 2012, 344:e536. https://doi.org/10.1136/bmj.e536. [4] Hartley, S., Simon, N., Cardozo, B., Larabi, I. A., & Alvarez, J. C. Can inhaled cannabis users accurately evaluate impaired driving ability? A randomized controlled trial. Frontiers in Public Health, 2023, 11, 1234765. https://doi.org/10.3389/fpubh.2023.1234765
Reference: PAGE 32 (2024) Abstr 11241 [www.page-meeting.org/?abstract=11241]
Poster: Drug/Disease Modelling - Other Topics