Aminoadamantane drugs are lipophilic amines that block the membrane-embedded influenza A M2 WT (wild type) ion channel protein. The comparative effects of amantadine (Amt) and its synthetic spiro[pyrrolidine-2,2'-adamantane] (AK13) analogue in dimyristoylphosphatidylcholine (DMPC) bilayers were studied using a combination of experimental biophysical methods, differential scanning calorimetry (DSC), X-ray diffraction, solid-state NMR (ssNMR) spectroscopy, and molecular dynamics (MD) simulations. All three experimental methods pointed out that the two analogues perturbed drastically the DMPC bilayers with AK13 to be more effective at high concentrations. AK13 was tolerated in lipid bilayers at very high concentrations, while Amt was crystallized. This is an important consideration in the formulations of drugs as it designates a limitation of Amt incorporation. MD simulations verify provided details about the strong interactions of the drugs in the interface region between phosphoglycerol backbone and lipophilic segments. The two drugs form hydrogen bonding with both water and sn-2 carbonyls in their amine form or water and phosphate oxygens in their ammonium form. Such localization of the drugs explains the DMPC bilayers reorientation and their strong perturbing effect evidenced by all biophysical methodologies applied.