Recurrent episodes of mild to severe opiate-like toxic effects were observed in 3 of 18 monkeys maintained on 2 mg/kg p.o. dose of LAAM on alternate days 3 times a week for up to one year. Despite antagonist administration and artificial respiration, the final toxic reaction in 3 LAAM sensitive monkeys progressed rapidly to cardio-respiratory arrest and death 3, 6, and 12 months after LAAM treatment. The blood chemistry and hematology were not significantly altered during chronic LAAM administration. Necropsy did not reveal any aberrant gross, histological or neuropathological features other than pulmonary edema. Differential rates of formation and elimination of active metabolites of LAAM may play a significant role in this potentially lethal toxicity. These findings may have important clinical implications for LAAM maintenance treatment programs.