Sex differences of THC-induced pharmacodynamic and pharmacokinetic effects.

1. Sex differences of THC effects in humans Linda Klumpers Clinical scientist

2. Background THC study 7 ♀ drop-outs (out of 11) vs 1 ♂ (out of 11): coincidence? Adipose tissue composition Metabolism Hormones

3. Gaps in knowledge Few human studies Observational studies Cannabis administration

4. Methods - Design Healthy ♀ (n=11) and ♂ (n=11) Mild cannabis users Mono-phasic contraceptive (♀) Randomised, double blind, 2-way cross-over design 2, 6, 6 mg THC or placebo inhalation (90-minute intervals)

5. Methods - Inhalation

6. Methods - Measurements Pharmacokinetics (PK) Plasma samples THC, 11-OH-THC, THC-COOH Pharmacodynamics (PD) Visual analogue scale (VAS) mood (mood, calmness, alertness) VAS psychedelic (‘feeling high’, external and internal perception) Neuro-endocrine (cortisol, prolactin, LH, FSH) Heart rate Safety Adverse events (AE), heart rate, blood pressure Analysis Linear mixed effect modelling for comparisons

7. Demographics *Mean ± SD **Median (IQR)

8. Results – Study Population

9. Adverse events

10. PK THC

11. PK 11-OH-THC

12. Feeling high

13. External perception

14. Anxiety

15. Results Sex differences VAS Internal perception VAS Alertness Treatment effect, no sex differences Heart rate Cortisol No treatment effect Prolactin FSH LH

16. Conclusion Females showed higher THC and 11-OH-THC concentrations Females showed larger PD effects

17. Discussion Sex differences in PD effects could be caused by differences in THC and 11-OH-THC PK Sex differences in PK could be caused by differences in Metabolism Adipose tissue composition Hormones THC use

18. Acknowledgements Centre for Human Drug Research AmitaSandhu Erik T. teBeek Joop M.A. van Gerven Marieke L. de Kam Leiden University Medical Center, Dpt Radiology RoelofP. Soeter Serge R.A.B. Rombouts Contact: www.chdr.nl – lklumpers@chdr.nl

19. Questions?