Figure 9. Pharmacokinetic-pharmacodynamic modeling.

Duloxetine lowered E_max in the MDMA concentration-effect curve (a) with little effect on EC₅₀, similar to the effect of MDMA on monoamine release in vitro. Diamonds and circles represent concentration-effect data pairs for ascending concentrations for placebo-MDMA and duloxetine-MDMA, respectively (a). The solid lines show the fit of a sigmoid E_max PD model to the observed PK data (a). Dashed lines indicate the 95% confidence interval (CI) of the estimation error (a). NE release predicted the observed subjective effect of MDMA in vivo (b). Predicted effects are shown as curves (mean ±95% CI) that represent the fit of the in vitro concentration-effect data to the 16 individual plasma concentration-time curves (b). Observed values are expressed as mean±SEM of 16 subjects (b). MDMA, 3,4-methylenedioxymethamphetamine; NE, norepinephrine; 5-HT, serotonin.