Published 2005 Wiley-Liss, Inc.w Birth Defects Research (Part B) 74:471–584 (2005) NTP-CERHR Expert Panel Report on the Reproductive and Developmental Toxicity Of Amphetamine and Methamphetamine Mari Golub,1 Lucio Costa,2 Kevin Crofton,3 Deborah Frank,4 Peter Fried,5 Beth Gladen6 Rogene Henderson,7 Erica Liebelt,8 Shari Lusskin,9 Sue Marty,10 Andrew Rowland11 John Scialli12 and Mary Vore13 1California Environment Protection Agency, Sacramento, California 2University of Washington, Seattle, Washington 3U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 4Boston Medical Center, Boston, Massachusetts 5Carleton University, Ottawa, Ontario 6National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 7Lovelace Respiratory Research Institute, Albuquerque, New Mexico 8University of Alabama at Birmingham School of Medicine, Birmingham, Alabama 9New York University School of Medicine, New York, New York 10The Dow Chemical Company, Midland, Michigan 11University of New Mexico, Albuquerque, New Mexico 12Phoenix, Arizona 13University of Kentucky, Lexington, Kentucky PREFACE studies indexed before December 31, 2004. References were also identified from databases such as REPRO- The National Toxicology Program (NTP) and the TOXs, HSDB, IRIS, and DART and from report National Institute of Environmental Health Sciences bibliographies. (NIEHS) established the NTP Center for the Evaluation This evaluation resulted from the efforts of a 13- of Risks to Human Reproduction (CERHR) in June 1998. member panel of government and non-government The purpose of the Center is to provide timely, unbiased, scientists that culminated in a public expert panel scientifically sound evaluations of human and experi- meeting held January 10–12, 2005. This report is a mental evidence for adverse effects on reproduction and product of the Expert Panel and is intended to (1) development caused by agents to which humans may be interpret the strength of scientific evidence that exposed. Amphetamines were selected for expert panel evalua- tion because of widespread usage in children, availability A report of the CERHR Expert Panel with the support of CERHR Staff: of studies on developmental effects in children and NTP/NIEHS, Michael Shelby, Ph.D. (Director, CERHR), Christopher Portier, Ph.D. (Associate Director, National Toxicology Program); Sciences experimental animals, and public concern about the International, Inc., Anthony Scialli, M.D. (Principal Scientist), Annette effects of these stimulants on child development. Iannucci, M.S. (Toxicologist), Gloria Jahnke, D.V.M. (Toxicologist), Jessie Amphetamines evaluated were d- and d,l-amphetamine Poulin, B.A. (Associate). and methamphetamine. d- and d,l-Amphetamine are This report is prepared according to the Guidelines for CERHR Panel Members established by NTP/NIEHS. The guidelines are available on the approved by the Food and Drug Administration (FDA) CERHR web site (http://cerhr.niehs.nih.gov/). The format for Expert Panel for the treatment of attention deficit hyperactivity Reports includes synopses of studies reviewed, followed by an evaluation disorder (ADHD) and narcolepsy. d-Methamphetamine of the Strengths/Weaknesses and Utility (Adequacy) of the study for CERHR evaluation. Statements and conclusions made under Strengths/ hydrochloride is used in pharmaceutical preparations in Weaknesses and Utility evaluations are those of the Expert Panel and are the United States and is approved for the treatment of prepared according to the NTP/NIEHS guidelines. In addition, the Panel ADHD and for short-term treatment of obesity. Metham- often makes comments or notes limitations in the synopses of the study. phetamine is also manufactured and used as an illicit Bold, square brackets are used to enclose such statements. As discussed in the guidelines, square brackets are used to enclose key items of drug. information not provided in a publication, limitations noted in the study, To obtain information about amphetamines for conclusions that differ from those of the authors, and conversions or the CERHR evaluation, the PubMed (Medline) and analyses of data conducted by the Panel. Toxline databases were searched with CAS RNs for Correspondence to: Michael D. Shelby, Ph.D., NIEHS EC-32, PO Box 12233, Research Triangle Park, NC 27709. 919-541-3455 d- and l-amphetamine (51-64-9; 156-34-3) and d-metham- E-mail: [email protected] phetamine (537-46-2) and its hydrochloride (51-57-0), Published online in Wiley InterScience (www.interscience.wiley.com) and relevant keywords. The search was limited to DOI: 10.1002/bdrb.20048 w This article is a U.S. Government work and, as such, is in the public domain in the United States of America. 472 GOLUB ET AL. amphetamines are reproductive or developmental tox- meant by the term ‘‘speed.’’ l-Methamphetamine can icants based on data from in vitro, animal, or human produce palpitations and gastrointestinal upset but does studies, (2) assess the extent of human exposures to not produce the psychological effects desired by recrea- include the general public, occupational groups, and tional users. There are no pharmaceuticals in the U.S. that other sub-populations, (3) provide objective and thor- contain the l-enantiomer. ough assessments of the scientific evidence that adverse Many of the Hazardous Substance Data Bank (HSDB) reproductive/developmental health effects may be asso- proprietary names in Table 1 were not found on the FDA ciated with such exposures, and (4) identify knowledge web site (http://www.accessdata.fda.gov/scripts/cder/ gaps to help establish research and testing priorities to drugsatfda/) and were presumed to be discontinued or reduce uncertainties and increase confidence in future foreign. Some proprietary names that were found on the assessments of risk. This report has been reviewed by FDA web site are for products listed as discontinued. The CERHR staff scientists, and by members of the Amphe- products that are currently marketed in the U.S. are listed tamines and Methylphenidate Expert Panel. Copies have in Table 2. been provided to the CERHR Core Committee, which is 1.1.2. Formula and molecular mass. The chemi- made up of representatives of NTP-participating cal formula for amphetamine is C9H13N and the agencies. molecular mass is 135.20. The chemical formula for This Expert Panel Report will be a central part of methamphetamine is C10H15N and the molecular mass is the subsequent NTP-CERHR Monograph on the 149.24. The structures are shown in Figure 1. Potential Human Reproductive and Developmental 1.1.3 Chemical and physical properties. Che- Effects of Amphetamines. This monograph will include mical and physical properties of amphetamine and the NTP-CERHR Brief, the Expert Panel Report, and all methamphetamine are listed in Table 3. public comments on the Expert Panel Report. The NTP- 1.1.4 Technical products and impurities. Table 2 CERHR Monograph will be made publicly available and summarizes active ingredient strength and lists the transmitted to appropriate health and regulatory inactive ingredients in each marketed amphetamine agencies. and methamphetamine product. The ophthalmic solu- The NTP-CERHR is headquartered at NIEHS, Re- tion (Paremyds) is marketed as a mydriatic and will not search Triangle Park, NC and is staffed and administered be further considered in this report. by scientists and support personnel at NIEHS and at Illicit amphetamines, chiefly methamphetamine hy- Sciences International, Inc., Alexandria, Virginia. drochloride, can be synthesized by different methods (Section 1.2.1) with the potential for different contami- nants. According to the U.S. Drug Enforcement Admin- 1.0 CHEMISTRY, USE AND istration (DEA) (2004), chemical supply houses HUMAN EXPOSURE internationally have restricted sales of the chemicals This exposure section is initially based on secondary used to produce methamphetamine of high purity, review sources. Primary study reports are addressed by resulting in substitution of other chemicals and a the Expert Panel if they contain information that is highly decrease in methamphetamine purity. In 1994, the relevant to a CERHR evaluation of developmental or average purity of methamphetamine seized by DEA reproductive toxicity or if the studies were released was 71.9%, whereas in 1999, the average purity was subsequent to the reviews. 30.7%. Purity of seized methamphetamine increased thereafter to 35.3% in 2000 and 40.1% in 2001. The nature of the impurities was not discussed. 1.1 Chemistry 1.1.1 Nomenclature. The term ‘‘amphetamines’’ is used to denote a class of chemicals with structural 1.2 Use and Human Exposure similarity to amphetamine. The amphetamines used in 1.2.1 Production information. The methods of clinical practice include two distinct bases, amphetamine production used in the pharmaceutical manufacture of and methamphetamine, available in pharmaceutical amphetamine and methamphetamine are not available; preparations as various mixtures of enantiomers and as however, there are Internet sites that give a number of various salts. The compounds relevant to this report are different methods for the synthesis of these compounds. identified in Table 1. Many of the trade names are no Amphetamine can be synthesized by the sequential longer in use, although they remain in current lists of alkylation of methyl acetoacetate with dimethyl sulfate drug names (ChemIDplus, 2004a; HSDB, 2004). The and benzyl chloride, followed by hydrolysis and deace- most commonly encountered