DFT/B3LYP/6-311G＋(d,p) basis set including solvent effect was first used to calculate a set of molecular descriptors of 55 phenylalkylamine and 20 tryptamine compounds with hallucinogenic activity. Four quantitative structure-activity relationship (QSAR) models of the hallucinogenic activity for phenylalkylamines and tryptamines were obtained by employing multiple linear regression (MLR) method. The QSAR analysis indicated that electron-related descriptors were major contributors to the hallucinogenic activities of phenylalkylamines and tryptamines. In addition, electron-unrelated descriptors have some impact on the hallucinogenic activities of phenylalkylamines. Based on the results of QSAR study, a novel Conformation Complementary Judgement, Transformation and Induction (CCJTI) model had been proposed to explain different action mechanisms of phenylalkylamines and tryptamines with their target receptors. It was concluded that phenylalkylamines might combine with receptor by electronic effect, but steric factor could affect it also, whereas tryptamines could act only through the electronic effect.