Methamphetamine abuse is a significant public health concern. The search for a medication to help treat methamphetamine abuse and dependence has begun and the importance of not only discovering an effective pharmacotherapy but also validating existing paradigms utilized in the development of pharmacotherapies is great. The drug discrimination paradigm has been used for these purposes based on the idea that the interoceptive effects of drugs contribute to their abuse. Two approaches, antagonist and agonist, have traditionally been taken in pharmacotherapy development for stimulant abuse with agonist-replacement therapy being the most promising thus far. An ideal agonist replacement medication for methamphetamine dependence would produce some methamphetamine-like behavioral effects while having lower abuse liability. d-Amphetamine, for example, is effective in reducing illicit amphetamine use in outpatient settings. Evidence from animal models suggests that, using drug discrimination methods, an effective agonist-replacement medication given chronically would attenuate the discriminative effects of methamphetamine. Administered acutely, however, this medication would have an additive or synergistic influence on the discriminative effects of methamphetamine.

To the best of my knowledge, these were the first studies to explore this notion using the drug discrimination paradigm in human volunteers. Two separate laboratory studies were conducted that examined the effects of sustained-release d-amphetamine and extended-release bupropion, two potential agonist-replacement medications for stimulant dependence, on the discriminative, subject-rated, cardiovascular and performance effects of methamphetamine in recreational stimulant users. Procedures used in both studies were identical. Participants learned to discriminate methamphetamine (10 mg) from placebo. Following acquisition of the discrimination (i.e ≥ 80% correct responding on 4 consecutive days) a range of doses of methamphetamine (0, 1.25, 2.5, 5 and 10 mg) was tested alone and in combination with sustained-release d-amphetamine (0 or 15 mg) or extended-release bupropion (0 or 150 mg). Pretreatment with sustained-release d-amphetamine shifted the methamphetamine dose response curve leftward.

Pretreatment with bupropion did not significantly alter the discriminative-stimulus effects of methamphetamine. The results of these studies translate findings from the animal laboratory to the human laboratory and help to establish the predictive-validity of drug discrimination methods in the discovery of agonist-replacement medications.

KEYWORDS: Methamphetamine, Drug Discrimination, Human, Amphetamine, Bupropion