The purpose of this study was to examine the effects of acute and chronic treatment with l-alpha-acetylmethadol (LAAM), a long-acting mu opioid agonist that is used to treat opioid dependence. In pigeons responding under an FR20 schedule of food presentation, LAAM decreased responding in a dose- and time-dependent manner, with the largest decrease occurring 4 hr after the administration of 5.6 mg/kg. Acute (1.0-5.6 mg/kg) or chronic (1.0-5.6 mg/kg/day) treatment with LAAM decreased sensitivity to morphine and increased sensitivity to naltrexone, although for both drugs changes in sensitivity were 3- to 10-fold greater during chronic treatment. Chronic LAAM treatment (5.6 mg/kg/day) also decreased sensitivity to fentanyl and etonitazene by 3-fold and increased sensitivity to nalorphine and nalbuphine by 30- and 6-fold, respectively; sensitivity to enadoline and ketamine increased only 2- to 3-fold. When LAAM treatment was temporarily suspended for 1 day, response rates decreased to 33% of control; this disruption was reversed by acute administration of morphine or etonitazene. Increased sensitivity to naltrexone and disruptions in responding when LAAM treatment was temporarily suspended indicate that dependence developed to LAAM. Tolerance and cross-tolerance to agonists as well as increased sensitivity to antagonists can be similar during chronic treatment with morphine or LAAM; however, increased sensitivity to nalbuphine during LAAM treatment is not typically observed during morphine treatment, suggesting that dependence on LAAM might not be identical to dependence on morphine. Finally, changes in sensitivity to other drugs might predict altered sensitivities to opioids and nonopioids in humans receiving LAAM.