We have shown recently that concurrent harmaline,a monoamine oxidase-A inhibitor(MAOI),potentiates serotonin(5-HT) receptor agonist 5-methoxy-N,N-dimethyltryptamine(5-Me O-DMT)-induced hyperthermia.The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic(PK/PD) model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice.Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control.Harmaline-induced hypothermia and 5-Me O-DMT–elicited hyperthermia were attributable to the loss of heat through the activation of 5-HT1 Areceptor and thermogenesis via the stimulation of 5-HT2 Areceptor,respectively.Thus serotonergic 5-Me O-DMT–induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic effects.This PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on5-Me O-DMT and harmaline PK properties,and drug- and stress-induced simple hypo/hyperthermic and complex biphasic effects.Furthermore,the modeling results revealed a 4-fold decrease of apparent SC_(50) value(1.88–0.496 mmol/L) for 5-Me O-DMT when harmaline was co-administered,providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-Me ODMT–induced hyperthermia.In addition,the hyperpyrexia caused by toxic dose combinations of harmaline and 5-Me O-DMT were linked to the increased systemic exposure to harmaline rather than5-Me O-DMT,although the body temperature profiles were mispredicted by the model.The results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation. We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI), potentiates serotonin (5-HT) receptor agonist 5-methoxy-N, N-dimethyltryptamine (5-Me O-DMT) -induced hyperthermia. of this study was to develop an integrated pharmacokinetic / pharmacodynamic (PK / PD) model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control. Harmaline -induced hypothermia and 5-Me O-DMT-elicited hyperthermia were attributable to the loss of heat through the activation of 5-HT1 Areceptor and thermogenesis via the stimulation of 5-HT2 Areceptor, respectively. Thus serotonergic 5-Me O-DMT- induced hyperthermia was readily distinguished from handling / injection stress-provoked hyperthermic effects. This PK / PD model was able to now describe all experimental data including the impact of drug-metabolizing enzyme statu s on5-Me O-DMT and harmaline PK properties, and drug- and stress-induced simple hypo / hyperthermic and complex biphasic effects. Future Thermo, the modeling results revealed a 4-fold decrease of the apparent SC 50 (1.88-0.496 mmol / L for 5-Me O-DMT when harmaline was co-administered, providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-Me ODMT-induced hyperthermia. In addition, the hyperpyrexia caused by toxic dose combinations of harmaline and 5-Me O-DMT were linked to the increased systemic exposure to harmaline rather than 5-Me O-DMT, although the body temperature profiles were mispredicted by the model. The results that current PK / PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.