Background: Hormone replacement therapy (HRT) has been considered as the most effective method for the menopausal hot flashes.However, non-hormonal drugs are preferred by a majority of patients due to higher risks of cardiovascular events and breast cancer after HRT.Unfortunately, the therapeutic effects of non-hormonal drugs on the menopausal hot flashes are still not well defined.We therefore did a model based meta-analysis (MBMA) to quantitate and compare the efficacy of non-hormonal drugs on menopausal hot flashes.Methods: Literature research was carried out to the public database to collect the information of clinical trials on non-hormonal drugs including selective serotonin reuptake inhibitors (SSRI) or serotonin norepinephrine reuptake inhibitors (SNRI) (e.g.Paroxetine, Venlafaxine and Sertraline), phytoestrogen (e.g.Soy Isoflavones),Y-aminobutyric acid analogue (e.g.Gabapentin) and α-adrenergic agonist (e.g.Clonidine).Pharmacodynamic models were used for the quantitative analysis of each agent, and then compared to that of Estradiol, based on which to provide important information for the establishing of treatment regimen for menopausal hot flashes using non-hormonal drugs.Results: Thirty-nine studies (6955 subjects) were included in the analysis.The results revealed the Emax model could describe the time course of hot flashes reduction of non-hormonal drugs.After deducting the effects of placebo, the maximal effects (Emax) of SSRI/SNRI, Gabapentin, Clonidine and Soy Isoflavones were 13.9%, 14.8%, 18.5%, and 25.0% respectively, which were remarkably lower than that of Estradiol (44.9%).The time to achieve half of its maximal effects (ET50) of SSRI/SNRI, Gabapentin, Clonidine and Soy Isoflavones were 0.18 wk, 0 wk, 0 wk, and 11.6 wk, respectively.The ET50 of Estradiol was 3.09 wk.In addition, the effects of placebo showed large variances among the trials.The Emax of placebo in the SSRI/SNRI, Gabapentin, Clonidine and Soy Isoflavones trials were 43.4%, 42%, 34.4% and 34.7%,which were much lower than that of Estradiol (55.6%).Interpretation: The significant differences were existed among the non-hormonal drugs in the speed of onset.Regulators of central neurotransmitters, such as SSRI/ SNRI, Gabapentin and Clonidine had a rapid onset, which is mainly featured by the parameters ET50 of near 0.However, the onset of Soy Isoflavones was very slow, and a duration of ≥16 weeks was needed to surpassing the efficacy of Paroxetine (a type of SSRI , which is the only non-hormonal drug approved by the FDA for the treatment of menopausal hot flashes).The results indicated the potential application of drug combination of Paroxetine and Soy Isoflavones.To be exact, the Paroxetine also can be terminated after onset of Soy Isoflavones due to potential adverse events or drug interaction.Such treatment regimen may be effective with satisfactory clinical safety.In addition, the effects of placebo for the menopausal hot flashes were comparatively high, and the differences were remarkably among various drugs.As the type and the baseline levels of hot flashes in the subjects of all the included trials were similar, we speculated the variability of the placebo efficacy may be associated with the psychological hints.Therefore, for the patients only had to receive medication of non-hormonal drugs, the confidence of the drug efficacy is needed, which may get the additional efficacy due to the increased placebo efficacy.Conclusion: The pharmacodynamic features of the non-hormonal drugs with various mechanisms for the treatment of hot flashes are significantly different, and the appropriate clinical trial protocols and dosage regimens are needed to be developed.The information provided in this study can be used as an important supplementary for the treatment guidelines of non-hormonal drugs on menopausal hot flashes.