AbstractConfusion and misunderstanding exist regarding the lack of cardiovascular and other adverse health effects of p‐synephrine and p‐octopamine relative to ephedrine and m‐synephrine (phenylephrine) which are known for their effects on the cardiovascular system. These four molecules have some structural similarities. However, the structural and stereochemical differences of p‐synephrine and p‐octopamine as related to ephedrine and m‐synephrine result in markedly different adrenergic receptor binding characteristics as well as other mechanistic differences which are reviewed. p‐Synephrine and p‐octopamine exhibit little binding to α‐1, α‐2, β‐1 and β‐2 adrenergic receptors, nor are they known to exhibit indirect actions leading to an increase in available levels of endogenous norepinephrine and epinephrine at commonly used doses. The relative absence of these mechanistic actions provides an explanation for their lack of production of cardiovascular effects at commonly used oral doses as compared to ephedrine and m‐synephrine. As a consequence, the effects of ephedrine and m‐synephrine cannot be directly extrapolated to p‐synephrine and p‐octopamine which exhibit significantly different pharmacokinetic, and physiological/pharmacological properties. These conclusions are supported by human, animal and in vitro studies that are discussed.