Certain 4-substituted analogs of 1-(2,5-dimethoxyphenyl)isopropylamine (2,5-DMA) are psychoactive classical hallucinogens or serotonergic psychedelic agents that function as human 5-HT_2A (h5-HT_2A) serotonin receptor agonists. Activation of a related receptor population, h5-HT_2B receptors, has been demonstrated to result in adverse effects including cardiac valvulopathy. We previously published on the binding of several such agents at the two receptor subtypes. We hypothesized that, due to their structural similarity, the 5-HT_2A and 5-HT_2B receptor affinities of these agents might be related, and that QSAR studies might aid future studies. For a series of 13 compounds, it is demonstrated here that i) their published rat brain 5-HT₂ receptor affinities are significantly correlated with their h5-HT_2A (r = 0.942) and h5-HT_2B (r = 0.916) affinities, ii) as with r5-HT₂ receptor affinity, h5-HT_2A affinity is correlated with the lipophilicity of the 4-position substituent (r = 0.798), iii) that eight of the ten compounds examined in functional (Ca⁺² mobilization in stable cell lines generated expressing the human 5-HT_2B receptor using the Flp-In T-REx system) assays acted as h5-HT_2B agonists (4-substituent = H, F, Br, I, OCH₂CH₃, NO₂, nC₃H₇, tC₄H₉) and two (n-hexyl and benzyl) as antagonists, iv) h5-HT_2B affinity but not action was correlated with the lipophilicity of the 4-position substituent (r = 0.750; n = 10). The findings suggest that h5-HT_2B receptor affinity, and its relationship to substituent lipophilicity, might be approximated by rat and h5-HT_2A affinity but cannot be used as a predictor of h5-HT_2B agonist action of 2,5-DMA analogs. Furthermore, given that certain 2,5-DMA analogs are on the clandestine market, their potential to produce cardiac side effects following persistent or chronic use via activation of h5-HT_2B receptors should be considered.