The effects of drugs are not only determined by their pharmacological action, but also by user characteristics. This analysis explored the influence of personality on the differences in subjective effects in response to a standardized pharmacological challenge with the cannabinoid CB1/CB2 partial agonist Δ9-tetrahydrocannabinol (THC). To express the sensitivity to THC, pharmacokinetic–pharmacodynamic (PK–PD) non-linear mixed effects modelling was applied to the subjective response of 184 healthy subjects to a pharmacological challenge with inhalation of THC. The subjective effects were measured using visual analogue scales and described by three clusters: ‘perception’, ‘relaxation’ and ‘dysphoria’. The sensitivity for THC (described as EC50) was related to scores on Cloninger׳s temperament and character inventory (TCI) using multiple linear regression. Effect compartment models were used to describe the PK–PD relations of THC. Within the multivariate model, ‘harm avoidance’ was significantly correlated with changes in ‘perception’, and ‘self-transcendence’ with changes in ‘dysphoria’. Within the psychobiological model of personality, ‘harm avoidance’ is related to serotonergic systems. Subjects with either very low (easy-going) or very high (cautious) scores were less sensitive to THC-induced changes in ‘perception’. ‘Self-transcendence’ relates to schizotypy. Subjects with more schizotypy were more sensitive to the dysphoric subjective effects of THC.