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Various cathinone-derived designer drugs (CATs) have recently appeared on the drug market. This study examined the mechanism for the generation of dehydrated ions for CATs during electrospray ionization collision-induced dissociation (ESI-CID). The generation mechanism of dehydrated ions is dependent on the amine classification in the cathinone skeleton, which is used in the identification of CATs. The two hydrogen atoms eliminated during the dehydration of cathinone (primary amine) and methcathinone (secondary amine) were determined, and the reaction mechanism was elucidated through the deuterium labeling experiments. The hydrogen atom bonded to the amine nitrogen was eliminated with the proton added during ESI, in both of the tested compounds. This provided evidence that CATs with tertiary amine structures (such as dimethylcathinone and α-pyrrolidinophenones [α-PPs]) do not undergo dehydration. However, it was shown that the two major tertiary amine metabolites (1-OH and 2″-oxo) of CATs generate dehydrated ions in ESI-CID. The dehydration mechanisms of the metabolites of α-pyrrolidinobutiophenone (α-PBP) belongs to α-PPs were also investigated. Stable-isotope labeling showed the dehydration of the 1-OH metabolite following a simple mechanism where the hydroxy group was eliminated together with the proton added during ESI. In contrast, the dehydration mechanism of the 2″-oxo metabolite involved hydrogen atoms in three or more locations along with the carbonyl group oxygen, indicating that dehydration occurred via multiple mechanisms likely including the rearrangement reaction of hydrogen atoms. These findings presented herein indicate that the dehydrated ions in ESI-CID can be used for the structural identification of CATs.