Hallucinogenic phenethylamines such as 2,5-dimethoxyphenethylamines (2C–X) and their N-(2-methoxybenzyl) derivatives (25X–NBOMe) have seen an increase in novel analogues in recent years. These rapidly changing analogues make it difficult for laboratories to rely on traditional targeted screening methods to detect unknown new psychoactive substances (NPS). In this study, twelve 2C–X, six 2,5-dimethoxyamphetamines (DOX), and fourteen 25X–NBOMe derivatives, including two deuterated derivatives (2C–B-d₆ and 25I–NBOMe-d₉), were analyzed using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Collision-induced dissociation (CID) experiments were performed using collision energies set at 10, 20, and 40 eV. For 2C–X and DOX derivatives, common losses were observed including neutral and radical losses such as NH₃ (17.0265 Da), •CH₆N (32.0500 Da), C₂H₇N (45.0578 Da) and C₂H₉N (47.0735 Da). 2C–X derivatives displayed common product ions at m/z 164.0837 ([C₁₀H₁₂O₂]^+•), 149.0603 ([C₉H₉O₂]⁺), and 134.0732 ([C₉H₁₀O]^+•) while DOX derivatives had common product ions at m/z 178.0994 ([C₁₁H₁₄O₂]^+•), 163.0754 ([C₁₀H₁₁O₂]⁺), 147.0804 ([C₁₀H₁₁O]⁺), and 135.0810 ([C₉H₁₁O]⁺). 25X–NBOMe had characteristic product ions at m/z 121.0654 ([C₈H₉O]⁺) and 91.0548 ([C₇H₇]⁺) with minor common losses corresponding to 2-methylanisole (C₈H₁₀O, 122.0732 Da), 2-methoxybenzylamine (C₈H₁₁NO, 137.0847 Da), and •C₉H₁₄NO (152.1074 Da). Novel analogues of the selected classes can be detected by applying neutral loss filters (NLFs) and extracting the common product ions.