After cannabis, the most commonly used illicit substance worldwide is amphetamine and its derivatives, such as methamphetamine, with an ever-increasing number of synthetic modifications. Thus, fast and reliable methods are needed to identify them according to their spectral patterns and structures. Here, we have investigated the use of molecular spectroscopy methods to describe the 3D structures of these substances in a solution that models the physiological environment. The substances were analyzed by Raman and infrared (IR) absorption spectroscopy and by chiroptical methods, vibrational circular dichroism (VCD) and Raman optical activity (ROA). The obtained experimental data were supported by three different computational approaches based on density functional theory (DFT) and molecular dynamics (MD). Successful interpretation relies on good agreement between experimental and predicted spectra. The determination of the conformer populations of the studied molecules was based on maximizing the similarity overlap of weighted conformer spectra by a global minimization algorithm. Very good agreement was obtained between the experimental spectra and optimized-population weighted spectra from MD, providing a detailed insight into the structure of the molecules and their interaction with the solvent. The relative population of three amphetamine and six methamphetamine conformers was determined and is consistent with a previous NMR study. However, this work shows that only a few isolated conformers are not sufficient for the successful interpretation of the spectra, but the entire conformational space needs to be sampled appropriately and explicit interaction with the solvent needs to be included.