Psychopharmacology (2005) 182: 426–435 DOI 10.1007/s00213-005-0102-8 ORIGINAL INVESTIGATION Thomas F. Newton . John D. Roache . Richard De La Garza II . Tim Fong . Christopher L. Wallace . Shou-Hua Li . Ahmed Elkashef . Nora Chiang . Roberta Kahn Safety of intravenous methamphetamine administration during treatment with bupropion Received: 18 April 2005 / Accepted: 14 June 2005 / Published online: 15 September 2005 # Springer-Verlag 2005 Abstract Rationale: Methamphetamine dependence is a growing problem for which no medication treatments have proven effective. Objectives: We evaluated bupropion, an antidepressant with beneficial effects for the treatment of nicotine dependence, in patients with methamphetamine dependence, to assess the safety and tolerability of meth- amphetamine administration during bupropion treatment. Methods: Twenty-six participants entered the study and 20 completed the protocol. Participants received intrave- nous methamphetamine (0, 15, and 30 mg) before and after randomization to twice-daily bupropion (150 mg SR) or matched placebo. Dependent measures included car- diovascular effects of methamphetamine, methamphet- amine and amphetamine pharmacokinetics, and peak and trough plasma concentrations of bupropion and its me- tabolites. Results: Bupropion treatment was well tolerated, with bupropion- and placebo-treated groups reporting sim- ilar rates of adverse events. Methamphetamine administra- tion was associated with expected stimulant cardiovascular effects, and these were not accentuated by bupropion treat- ment. Instead, there was a trend for bupropion to reduce methamphetamine-associated increases in blood pressure and a statistically significant reduction in methamphetamine- associated increases in heart rate. Pharmacokinetic anal- ysis revealed that bupropion treatment reduced the plasma clearance of methamphetamine and also reduced the ap- pearance of amphetamine in the plasma. Methamphet- amine administration did not alter the peak and trough plasma concentrations of bupropion or its metabolites. Conclusions: Methamphetamine administration was well tolerated during bupropion treatment. There was no evidence of additive cardiovascular effects when the drugs were co- administered. This study provides initial evidence for the safety of prescribing bupropion for the treatment of meth- amphetamine abuse and dependence. The impact of bup- ropion treatment in patients who abuse larger doses of methamphetamine remains undetermined. Keywords Methamphetamine . Bupropion . Drug abuse . Safety evaluation . Pharmacokinetics Introduction Methamphetamine dependence is rapidly increasing in the United States (SAMHSA 2004) and in many other regions globally. Current treatments emphasize psychosocial inter- vention (Huber et al. 1997; Rawson et al. 1999; Shoptaw et al. 1994), and, although effective for some patients, im- proved treatment approaches are urgently needed. To date, only a few medications for the treatment of methamphet- amine dependence have been studied in randomized clin- ical trials (Galloway et al. 1994, 1996; Huber et al. 2000), and these have been without notable evidence for efficacy. Bupropion is an antidepressant with stimulant properties (Stahl et al. 2004) that is effective for the treatment of nicotine dependence (Richmond and Zwar 2003). Bupro- pion is an attractive candidate medication for the treatment of methamphetamine dependence for several reasons. Pre- clinical data indicate that bupropion treatment may reduce methamphetamine-induced neurotoxicity (Marek et al. 1990) and may reduce amphetamine self-administration at doses not associated with significant behavioral toxicity (Rauhut et al. 2003). Methamphetamine dependence is associated T. F. Newton (*) . R. De La Garza II . T. Fong Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA e-mail: tnewton@mednet.ucla.edu Tel.: +1-310-2670159 Fax: +1-310-7949951 J. D. Roache . C. L. Wallace Department of Psychiatry, University Clinical Psychopharmacology Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA S.-H. Li . A. Elkashef . N. Chiang . R. Kahn Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, Bethesda, MD, USA