Phenethylamines are ingredients in many dietary supplements aimed at supporting weight loss or maintaining heightened energy levels for productive workouts. This class of compounds affects the central nervous and cardiac systems, but there is evidence that 2-phenethylamine itself or its derivatives can accumulate in the kidneys and induce nephrotoxicity. As such, we investigated the possible nephrotoxic effects of two naturally occurring compounds: 2-phenethylamine and N, N-dimethyl-β-phenethylamine, alone and in combination, because they are currently used in dietary supplements presently on the market. Our approach entailed testing these compounds using an established in vitro renal cell culture method. Human proximal tubule cells were directly exposed to increasing concentrations of these compounds for 24 hours and evaluated for evidence of cytotoxicity and mitochondrial dysfunction. We also specifically tested for nephrotoxic effects using biomarkers of proximal tubule cell injury. We found that whereas each compound alone produced little or no evidence of toxicity, their combination at high treatment concentrations consistently yielded evidence of potent proximal tubule cell injury. Our findings highlight the potential damage that two phenethylamines working together can cause, and justify further experimentation to better understand how one phenethylamine can potentiate the effects of another in the setting of a dietary supplement.