Tricyclic antidepressant drugs are commonly involved in drug overdose cases. This talk will focus on the binding of charged cationic drugs to the negatively charged surface of liposomes comprised of acidic phospholipids. Liposomes composed of 50:50 by mole of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dioleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (DOPG) were investigated as detoxifying agents for the weak bases imipramine, dosulepin, amitriptyline, nortriptyline, and the diprotic drug opipramol. Drug binding to serum proteins was also explored, as proteins will compete with liposomes for free drug molecules in vivo. Results show that liposomes bind a significant amount of drug primarily due to ionic interactions between the positively charged drug molecules and the negatively charged acidic phospholipids comprising the liposomes. The liposomes reduced the free drug concentration in protein mixtures and in human serum, but the drug uptake efficiency of liposomes was reduced in the presence of plasma proteins due to the adsorption of proteins on the liposomes. Accordingly, polymer shielded liposomes composed of 95:5 and 85:15 DOPG and 1,2-dipalmitoyl-snglycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DPPE-mPEG-2000), and 55:15:30 DMPC:DPPE-mPEG-2000:cholesterol were studied for their ability to sequester the drugs. The optimal amount of PEG-modified lipid incorporated into liposomes was found to 5%. 95:5 DOPG:DPPE-mPEG-2000 liposomes loaded at 1.44 mg lipid/mL were most effective at shielding protein interactions while still allowing the drugs to diffuse to the bilayer surface and bind. Absolute reductions of 99% in buffer and human serum samples were observed, while the free drug concentration reduction relative to binding in serum without liposomes was nearly 90% across a drug concentration range of 1 µM to 20 µM. With such reductions, serum drug concentrations could be rapidly reduced from toxic to therapeutic levels. Furthermore, storage tests revealed that such liposomes may be stored for at least one month without a change in drug binding ability. Comparisons between the reported drug affinity for acidic lipids in the body and the liposomes explored by us show that the partition coefficient for drug binding to the liposomes is an order of magnitude larger than that for drug binding to acidic phospholipids in the body. These results suggest that pegylated anionic liposomes are excellent candidates for drug overdose treatment.