Journal of Analytical Toxicology 2013;37:386–389 doi:10.1093/jat/bkt040 Advance Access publication May 29, 2013 Case Report

Antemortem and Postmortem Methamphetamine Blood Concentrations: Three Case Reports

Iain M. McIntyre1*, Craig L. Nelson2, Bethann Schaber2 and Catherine E. Hamm1 1Forensic Toxicology Laboratory, County of San Diego Medical Examiner’s Office, 5570 Overland Ave., Suite 101, San Diego, CA 92123, USA, and 2Department of Forensic Pathology, County of San Diego Medical Examiner’s Office, 5570 Overland Ave., Suite 101, San Diego, CA 92123, USA

*Author to whom correspondence should be addressed. Email: [email protected]

We compare antemortem whole-blood to postmortem peripheral blood blood-to-peripheral blood (C/P) ratios were found to average concentrations of methamphetamine and its metabolite amphetamine 1.61 (+0.48), and liver to peripheral blood (L/P) ratios averaged in three medical examiner cases. Antemortem specimens, initially 5.68 (+2.32). Comparable data were found for amphetamine. Downloaded from https://academic.oup.com/jat/article-abstract/37/6/386/804808 by guest on 24 May 2019 screened positive for methamphetamine by ELISA, were subsequently These data showed a smaller average C/P ratio than that previ- confirmed, together with the postmortem specimens, by GC-MS ana- ously reported by Barnhart et al. (11), but established that meth- lysis following solid-phase extraction. Methamphetamine peripheral amphetamine and amphetamine were most likely prone to some blood to antemortem blood ratios averaged 1.51 (+++++0.049; n 5 3) and degree of postmortem redistribution (PMR). However, since amphetamine peripheral blood to antemortem blood ratios averaged there was no opportunity for analyses in both antemortem and 1.50 (n 5 2). These data show that postmortem redistribution occurs postmortem specimens from the same individuals, a direct as- for both methamphetamine and amphetamine, revealing that post- sessment of the degree of PMR could not be determined. mortem blood concentrations are ∼1.5 times greater than antemor- The study reported here examines three cases in which ante- tem concentrations. Furthermore, as both methamphetamine and mortem specimens were collected and postmortem peripheral amphetamine have previously been shown to have liver/peripheral blood specimens were also available. This study presents an in- blood (L/P) ratios of 5–8, it can be proposed that drugs displaying L/P vestigation of PMR, and provides better insight on the extent to ratios ranging from 5 to 10 may exhibit postmortem concentrations up which methamphetamine and amphetamine concentrations to twice those concentrations circulating in blood before death. may be expected to increase after death as a result of PMR.

Introduction Methods Methamphetamine is a highly addictive central nervous system stimulant that can be injected, snorted, smoked or ingested Cases orally. Although available by prescription for the treatment of attention-deficit disorder (1), the major use (abuse) of metham- Case 1 phetamine remains illicit—generally synthesized in clandestine This 44-year-old man had no reported medical history. On the laboratories. It is metabolized by N-demethylation to amphet- day of his death, he was with his girlfriend playing video games amine, which is also a pharmacologically active drug (2). when he suddenly grabbed his chest and became unresponsive. Single oral doses of methamphetamine have been reported to Bystander cardiopulmonary resuscitation (CPR) was initiated. He produce peak plasma concentrations up to 0.02 mg/L with a was transported by ground ambulance to a nearby hospital with 12.5 mg dose (3). A 30 mg oral dose resulted in an average peak an estimated down time of 35 min. He arrived in the emergency serum methamphetamine concentration of 0.094 mg/L (range room with CPR in progress with ventricular fibrillation. Despite 0.062–0.291 mg/L) (4). Single intravenous doses (0.50 mg/kg) administration of multiple cardiac medications, including epi- have resulted in an average peak plasma methamphetamine con- nephrine, lidocaine and amiodarone, and defibrillation attempts, centration of 0.132 mg/L, with amphetamine at 0.0092 mg/L he died in the emergency room. His girlfriend later admitted (5). Half-life of elimination is pH dependent, ranging from 6 to that they had been using methamphetamine. The autopsy docu- 15 h for methamphetamine and 7 to 34 h for amphetamine (2). mented findings of hypertensive and atherosclerotic cardiovas- Blood concentrations ranging from 0.15 to 0.56 mg/Lhave cular disease. The heart was enlarged (580 g) with concentric been reported in methamphetamine abusers showing violent and left ventricular hypertrophy. The coronary arteries demon- irrational behavior (6) and from 0.05 to 2.6 mg/Linindividuals strated focal, moderate to marked calcific atherosclerotic sten- arrested for erratic driving (7). Postmortem blood concentrations osis of the vessel lumens. Microscopic examination of the heart have been described to range from 1.4 to 13 mg/L in abusers muscle documented both acute cardiomyocyte necrosis and ex- who died of traumatic injury by violent means (8). Deaths tensive areas of older fibrosis. Toxicology testing confirmed only resulting from overdose have been shown with methampheta- methamphetamine. The cause of death was listed as hyperten- mine concentrations ranging from 0.09 to 18 mg/L, with an sive and atherosclerotic cardiovascular disease with acute meth- average of 1.0 mg/L(9). When attempting to compare blood and amphetamine intoxication contributing. Autopsy was performed clinical plasma/serum concentrations, it is important to be 30.5 h after death. Antemortem blood specimens were drawn aware that the blood/plasma ratio for methamphetamine is 22 min prior to pronouncement of death. 0.6–0.7 (2). The distribution of methamphetamine and amphetamine Case 2 in postmortem peripheral blood, central blood and liver has This 46-year-old man was the unrestrained rear seat passenger of been recently reported (10). Methamphetamine central a pickup truck traveling on an interstate when it veered off the

# The Author [2013]. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] CG 069_V1 Antemortem & Postmortem Methamphetamine Blood Concentrations Page 1 of 31 road and went down a center embankment, rolling over. He was Methamphetamine/amphetamine confirmation partially ejected. Witnesses found him initially responsive and yelling. He was transported by ground to a nearby location for Materials airlift, but lost his pulse while being loaded onto the helicopter. Solvents (dichloromethane, methanol, ethyl acetate, isopropanol He arrived at a regional trauma center with resuscitative efforts and acetone) were EMD Chemicals OmniSolvw grade, purchased still underway. Despite resuscitative efforts, death was pro- from VWR International (Radnor, PA). Pentafluoropropionic an- nounced almost 2 h following the initial report of the incident. hydride (PFPA) was obtained from Sigma-Aldrich (St. Louis, MO). The decedent’s medical history included fibromyalgia, chronic Ammonium hydroxide (ACS) and glacial acetic acid (ACS) were fatigue and methamphetamine use. Toxicology testing con- obtained from VWR International. Zinc sulfate heptahydrate firmed methamphetamine and cannabinoids (which were not (Certified ACS) was obtained from Fisher Scientific (Pittsburg, quantified). The autopsy documented multiple bone fractures PA), and anhydrous sodium acetate (GR ACS Mallinckrodt) was and visceral lacerations, and the cause of death was listed as mul- obtained from VWR, Inc. Methamphetamine, amphetamine, tiple blunt force injuries. Autopsy was performed 22.5 h after methamphetamine-D5 and amphetamine-D5 were obtained from death. Antemortem blood specimens were drawn 7 min prior to Cerilliant (Austin, TX). Solid-phase extraction (SPE) columns Downloaded from https://academic.oup.com/jat/article-abstract/37/6/386/804808 by guest on 24 May 2019 pronouncement of death. were Trace-Bw from SPEWare Corp. (Baldwin Park, CA). Aqueous working standards containing 1.0 mg/Leachof methamphetamine and amphetamine and internal standards Case 3 containing 1.0 mg/L each of methamphetamine-D5 and amphet- This 37-year-old male had a history of drug and alcohol abuse. amine-D5 were prepared. Linear calibration curves from 0.02 to On the day of his death, he developed erratic and bizarre behav- 2.0 mg/L produced using five calibrators (0.02, 0.05, 0.25, 1.0 and ior after consuming alcohol. While being taken to a regional hos- 2.0 mg/L) were made by diluting the working standard. All calibra- pital in a private passenger vehicle, he became unresponsive. On tors were prepared in deionized water. A commercial whole-blood arrival, he had agonal breathing, but no heartbeat. Death was pro- toxicology control containing 0.10 mg/L of methamphetamine nounced after resuscitative efforts in the emergency room. and amphetamine obtained from UTAK Laboratories, Inc. Toxicology testing confirmed alcohol (0.02%) and metham- (Valencia, CA) (Product #98818), and an in-house whole-blood phetamine; gastric contents contained 15 mg of methampheta- control containing 0.40 mg/L of methamphetamine and amphet- mine. The autopsy documented an empty, small, sealable plastic amine(preparedfromasecondsourceofdrugstock)wererun bag in the gastric contents, indicating ingestion of a “baggie” of with each batch of calibrators and cases. Additionally, both blank methamphetamine. He had no significant trauma or natural and negative control specimens were extracted with each batch disease. Pulmonary edema and congestion were evident (620 g, to confirm the lack of interference and/or contamination. right; 560 g, left). The cause of death was listed as acute metham- phetamine intoxication. Autopsy was performed 5.25 h after Extraction death. Antemortem blood specimens were drawn 9 min prior to Amphetamines were extracted using a solid-phase extraction pro- pronouncement of death. cedure. A 2.0 mL sample was extracted for all standards, controls and casework. A working internal standard (0.25 mL) was added to all tubes. 5.0 mL of 5% zinc sulfate/methanol solution (50/50) was added to each tube, and the tubes were vortexed and centri- fuged at 2,400 g for 10 min. The supernatant was buffered with Postmortem sample collection and storage 4 mL of 0.1 M sodium acetate buffer, pH 6. The SPE columns were Postmortem blood samples were collected by the pathologist conditioned by sequentially adding 2 mL each of ethyl acetate, during the autopsy and maintained at a refrigeration tempera- methanol and acetate buffer (pH 6). The buffered supernatant ture (48C) prior to, and after, the analysis. Peripheral blood was added to the SPE columns and allowed to flow through at specimens were drawn from the iliac arteries in the pelvis (suf- 2–5 mL/min. Columns were then washed by sequentially adding ficiently distant from the heart and other central organs) and 2 mL of deionized water and 1.0 mL each of 0.1 M acetic acid, stored in 10 mL BD Vacutainerw (Franklin Lakes, NJ) glass methanol and ethyl acetate. Columns were dried at maximum tubes containing sodium fluoride (100 mg) and potassium pressure (40 psi nitrogen) for 60–90 s. Amphetamines were oxalate (20 mg). eluted with 2.0 mL elution solvent (dichloromethane/isopropa- nol/ammonium hydroxide 78/20/2) and allowed to drip through. The extracts were evaporated at room temperature under a stream of nitrogen until just dry. Derivatization was accomplished Toxicology screening by adding 50 mL PFPA, capping tightly and vortexing, and allowed Toxicological screening was requested and performed on the to stand at room temperature for 20 min. The extracts were antemortem whole-blood specimens. The testing regimen con- reconstituted with 200 mL of ethyl acetate, mixed by vortexing sisted of alcohol (GC-FID headspace), and common drugs of and then transferred to autosampler vials. abuse by ELISA (cocaine metabolite, opiates, benzodiazepines, fentanyl cannabinoids and amphetamines–methamphetamine) (Immunalysis, Inc., CA). Positive results were confirmed and Instrumentation quantified by subsequent techniques in both the antemortem One microliter splitless injections were made onto an Agilent and postmortem peripheral blood specimens. Technologies 6890 Gas Chromatograph. The GC column was an

Antemortem and Postmortem Methamphetamine Blood Concentrations 387 CG 069_V1 Antemortem & Postmortem Methamphetamine Blood Concentrations Page 2 of 31 HP-1 capillary column (Agilent Technologies 15 m, 0.25 mm before autopsy (30.5 h). When antemortem bloods were collected diameter, 0.25 mm film thickness) with helium as the carrier gas. closer to the time of death and shorter autopsy delays were The GC oven was programmed to an initial temperature of 508C, recorded, the postmortem methamphetamine concentrations ramped 158C/min until it reached 2508C and held for 2 min. An showed smaller increases. Even with overdose (case 3), the post- Agilent 5973 MSD was used for the selective ion monitoring. mortem methamphetamine concentration showed a minimal in- The GCMS was controlled by Chemstation software. The total crease despite the possibility of incomplete drug distribution due chromatography time per injection was 12 min. to the acute ingestion of a substantial dose—a “baggie” of metham- The following ions were monitored and used for measuring phetamine in the stomach. the internal standard: m/z 208 for methamphetamine-D5 and It is now well documented that postmortem drug concentra- m/z 194 for amphetamine-D5. The ions monitored for quantita- tions in blood may not always reflect antemortem drug concen- tion were: m/z 204 for methamphetamine and m/z 190 for am- trations due to the movement of the drugs after death. The phetamine. The ions monitored as qualifiers were: m/z 118,160 mechanisms involved in PMR, however, are both complicated for methamphetamine and m/z 91,118 for amphetamine. Other and poorly understood. Nevertheless, postmortem drug concen- compounds routinely detected and quantified with this method trations in postmortem blood may follow some generally Downloaded from https://academic.oup.com/jat/article-abstract/37/6/386/804808 by guest on 24 May 2019 include ephedrine, pseudoephedrine, methylenedioxymetham- accepted trends that aid interpretation. Generally speaking, the phetamine, methylenedioxyamphetamine, phentermine and characteristics of the drug itself can be used to predict if a drug phenylephrine. The limits of detection and quantitation were is subject to PMR—large changes in blood drug concentrations 0.01 and 0.02 mg/L, respectively, for all compounds. are predicted for basic, lipophilic drugs with a high volume of distribution (.3L/kg). When PMR occurs, blood specimens drawn from the central body cavity and heart will generally have Accuracy and precision higher drug concentrations postmortem than specimens drawn The accuracy of the method for the quantitation of metham- from peripheral areas, most commonly the femoral region. The phetamine/amphetamine in blood was established over a 2-year diffusion of drugs from organ tissue into the blood may explain timeframe. It was 103%/100% at 0.10 mg/L and 109%/105% at the observed phenomenon (12). To compensate for PMR, it is 0.40 mg/L over 42 analyses. Precision was established over the frequently recommended that postmortem blood specimens are same period with methamphetamine/amphetamine having being collected from at least two areas of the body at autopsy; a coefficients of variation of 2.9%/3.0% and 3.7%/2.6% for peripheral area and a central area (often the heart), so that a concentrations of 0.10 and 0.40 mg/L, respectively, over 42 comparison can be made. determinations. Prouty and Anderson (13) first provided detailed information about blood drug concentrations attained from different sites for over 50 drugs. Then Dalpe-Scott et al. (14) presented a tabular Results and discussion list of the drug concentrations from both cardiac and peripheral blood samples expressed as a ratio of cardiac-to-peripheral blood The causes (manner) of death in cases 1 and 2 were determined (C/P) for over 100 drugs. The C/P ratio became the accepted to be hypertensive and atherosclerotic cardiovascular disease benchmark with the accepted guideline that “high ratios” were with acute methamphetamine intoxication (accident) and mul- associated with “potential for redistribution” (14). Based upon tiple blunt force injuries (accident), respectively. The third case previous work, the C/P ratio model suggests that both metham- was concluded to be acute methamphetamine intoxication (ac- phetamine and amphetamine have some propensity for PMR— cident), with a postmortem concentration within the range pre- ratios averaging 1.6 to 2.1 (10, 11). viously reported for such cases (9). Limitations of the C/P model, however, have been documen- Methamphetamine and amphetamine concentrations and ratios ted. While drug properties such as volume of distribution, for the antemortem and postmortem blood analyses are shown in protein binding and pKa are thought to contribute to PMR, a re- Table I. All cases showed higher postmortem concentrations—as lationship between C/P and drug properties has not been estab- indicated by ratios where methamphetamine and amphetamine lished (15). In addition, there has been little agreement as to concentrations were 1.5 times higher in postmortem peripheral what ratio actually defines that a compound is prone to PMR or blood. Interestingly, the greatest difference was found in case 1, not (16). Reports of a C/P ratio .1.0 have been published for sa- where the longest delay between antemortem blood collection and death was recorded (22 min) together with the greatest delay licylate (17), tramadol (18) and carisoprodol (16), which are not prone to redistribution. Arterio-venous differences, anatomic variability within individuals and statistical chance may result in aC/P ratio .1.0 in drugs that do not redistribute. In addition, re- Table I Methamphetamine and Amphetamine Concentrations and Ratios suscitation attempts may result in a C/P ratio ,1.0 (19). Inaccurate ratios may also be obtained as an artifact of sampling Case MeAMP, MeAMP, AMPH, AMPH, MeAMP, AMPH, when the cardiac blood volume is depleted by the collection of PB AM PB AM PB/AM ratio PB/AM ratio blood from connected blood vessels, from trauma, or in cases of 1 0.34 0.19 ND ND 1.79 N/A acute overdose where the drug has not undergone complete ab- 2 0.44 0.33 0.07 0.05 1.33 1.40 3 13.0 9.3 0.16 0.10 1.40 1.60 sorption and/or distribution. Additionally, although postmortem Mean 1.51 1.50 drug redistribution normally results from the diffusion of drugs S.D. 0.049 N/A from organ tissues into blood, and this process is most significant MeAMP, methamphetamine; AMPH, amphetamine; AM, antemortem blood; PB, peripheral blood; for blood collected from the central cavity, the possibility of ND, not detected; N/A, not available; Concentrations, mg/L. some degree of PMR occurring in the peripheral blood cannot

388 McIntyre et al. CG 069_V1 Antemortem & Postmortem Methamphetamine Blood Concentrations Page 3 of 31 be discounted (20). Consequently, the established C/P ratios dextromethamphetamine in man. Journal of Clinical can be inconclusive and even misleading with respect to the in- Pharmacology, 36, 1051–1063. terpretation of PMR. 5. Mendelson, J., Uemura, N., Harris, D., Nath, R., Fernandez, E., Jacob, P.I. et al. (2006) Human pharmacology of the methamphetamine The liver (L) to peripheral blood (P) ratio has recently been stereoisomers. Clinical Pharmacology and Therapeutics, 80, proposed as an alternative and more reliable marker for PMR, 403–420. with L/P ratios exceeding 20–30 indicative of a propensity for 6. Lebish, P., Finkle, B.S., Brackett, J.W., Jr. (1970) Determination of am- significant PMR, and ratios ,5 indicative of little to no propen- phetamine, methamphetamine, and related amines in blood and sity toward PMR (16, 21–23). The L/P ratios for methampheta- urine by gas chromatography with hydrogen-flame ionization detect- mine and amphetamine have been established to be 5–8 (10), or. Clinical Chemistry, 16, 195–200. suggesting a minimal potential for PMR. Since these compounds 7. Logan, B.K. (1996) Methamphetamine and driving impairment. Journal of Forensic Sciences, 41, 457–464. are basic and lipophilic, with volumes of distribution (Vd) of 8. Reynolds, P.C., Weingarten, H. (1983) Presented at the quarterly 3–7 L/kg (2), this is also consistent with reports that such meeting of the California Association of Toxicologists. Yosemite drugs—Vd . 3L/kg—may be prone to some PMR. National Park, CA. Information from these three new case reports is supportive 9. Logan, B.K., Fligner, C.L., Haddix, T. (1998) Cause and manner of Downloaded from https://academic.oup.com/jat/article-abstract/37/6/386/804808 by guest on 24 May 2019 of both C/P ratio and L/P ratio data, and shows that PMR occurs death in fatalities involving methamphetamine. Journal of Forensic for methamphetamine and amphetamine. Moreover, it purports Sciences, 43, 28–34.  10. McIntyre, I.M., Hamm, C., Bader, E. (2011) Postmortem metham- that the postmortem blood concentrations may be 1.5 times phetamine distribution. Journal of Forensic Research, 2, 122, doi: greater than blood levels circulating in the body at the time of 10.4172/2157-7145.1000122. death. These data also fit with the notion that L/P ratios ,5 11. Barnhart, F.E., Fogacci, J.R., Reed, D.W. (1999) Methamphetamine—a exhibit little to no PMR. With slightly higher ratios (5–8), the study of postmortem redistribution. Journal of Analytical expected PMR would be minimal or modest, consistent with Toxicology, 23, 69–70. postmortem blood methamphetamine and amphetamine 12. Pounder, D.J., Jones, G.R. (1990) Post-mortem drug redistribution—a toxicological nightmare. Forensic Science International, 45, increases of 1.5 times (or less) above antemortem concentra- 253–263. tions. Furthermore, it can be proposed that drugs with L/P ratios 13. Prouty, B.S., Anderson, W.H. (1990) The forensic science implica- ranging between 5 and 10 may exhibit postmortem concentra- tions of site and temporal influences on postmortem blood-drug tions up to twice those concentrations circulating in blood concentrations. Journal of Forensic Sciences, 35, 243–270. before death. Hence, larger L/P ratios (ranging between 10 and 14. Dalpe-Scott, M., Degouffe, M., Garbutt, D., Drost, M. (1995) A com- 20) will then be consistent with more substantial differences parison of drug concentrations in postmortem cardiac and periph- between postmortem and antemortem concentrations—con- eral blood in 320 cases. The Canadian Society of Forensic Science Journal, 28, 113–121. ceivably between 2 and 3 times—and even higher ratios produ- 15. Ferner, R.E. (2008) Post-mortem clinical pharmacology. British cing even greater PMR. It is hoped that further development of Journal of Clinical Pharmacology, 66, 430–443. this hypothesis will eventually lead to some predictive ability to 16. McIntyre, I.M., Sherrard, J., Lucas, J. (2012) Postmortem carisoprodol assess the degree of postmortem drug concentration increase and meprobamate concentrations in blood and liver: lack of (or degree of PMR) of many other drugs based on their charac- significant redistribution. Journal of Analytical Toxicology, 36, teristic L/P ratios. This capability will provide an obvious advan- 177–181. 17. Cook, J., Braithwaite, R.A., Hale, K.A. (2000) Estimating antemortem tage over the current description of many drugs, which simply drug concentrations from postmortem blood samples: the influence states that PMR “may occur.” of postmortem redistribution. Journal of Clinical Pathology, 53, 282–285. 18. Moore, K., Sina, S.J., Jones, R., Selby, D.M., Levine, B., Smith, M.L. (1999) Tissue distribution of tramadol and metabolites in an over- Acknowledgments dose fatality. American Journal of Forensic Medicine and The authors would like to thank the San Diego County Chief Pathology, 20, 98–100. Medical Examiner, Dr. Glenn Wagner, for making available case 19. Pe´lessier-Alicot, A.L., Gaulier, J.M., Champsaur, P., Marquet, P. (2003) Mechanisms underlying postmortem redistribution of drugs: a details described in this manuscript. review. Journal of Analytical Toxicology, 27, 533–544. 20. Gerostamoulos, D., Beyer, J., Staikos, V., Tayler, P., Woodford, N., Drummer, O.H. (2012) The effect of the postmortem interval on the redistribution of drugs: a comparison of mortuary admission and References autopsy blood specimens. Forensic Science, Medicine and 1. (2008) Physicians desk reference. 62nd edition. Thompson Pathology, 8, 373–379. Healthcare, Inc., Montvale, NJ. 21. McIntyre, I.M., Mallett, P. (2012) Sertraline concentrations and post- 2. Baselt, R.C. (ed). (2011) Disposition of toxic drugs and chemicals mortem redistribution. Forensic Science International, 223, in man. 9th edition. Biomedical Publications, Foster City. 349–352. 3. Driscoll, R.C., Barr, F.S., Gragg, B.J., Moore, G.W. (1971) 22. McIntyre, I.M., Meyer Escott, C. (2012) Postmortem drug redistribu- Determination of therapeutic blood levels of methamphetamine and tion. Journal of Forensic Research, 3, e108. doi:10.4172/ pentobarbital by GC. Journal of Pharmaceutical Sciences, 60, 2157-7145.1000e108. 1492–1495. 23. McIntyre, I.M., Anderson, D.T. (2012) Postmortem fentanyl concen- 4. Shappell, S.A., Kearns, G.L., Valentine, J.L., Neri, D.F., DeJohn, C.A. trations: a review. Journal of Forensic Research, 3, 157. doi:10.4172/ (1996) Chronopharmacokintics and chronopharmocodynamics of 2157-7145.1000157.

Antemortem and Postmortem Methamphetamine Blood Concentrations 389 CG 069_V1 Antemortem & Postmortem Methamphetamine Blood Concentrations Page 4 of 31 Barry K. Logan, 1 Ph.D., DABFT

Methamphetamine and Driving Impairment

REFERENCE: Logan, B. K., "Methamphetamine and Driving levels. The same study found that 17 doses of the drug were Impairment," Journal of Forensic Sciences, JFSCA, Vol. 41, No. necessary to obtain a qualitative urine positive amphetamine 3, May 1996, pp, 457-464. screen. Abuse of inhaler contents by extraction and concentration is not unknown, but is uncommon. 1-Methamphetarnine is also a ABSTRACT: Following a review of the effects of methamphet- amine on human performance, actual driving and behavior were metabolite of the anti-Parknisonian drug selegiline (Depranyl) (3). evaluated in 28 cases in which drivers arrested or killed in traffic Based on these considerations, the cases discussed in this paper accidents had tested positive for methamphetamine. The circum- are assumed to involve the d-isomer (methamphetamine), absent stances surrounding the arrest or accident were examined, together evidence to the contrary, since the analytical method used did not with any observations by the arresting officer regarding behavioral irregularities. The investigators also made a determination of culpa- distinguish between the isomers. Furthermore, none of the subjects bility. Most of the arrests resulted from accidents in which the interviewed in the cases reviewed in this study noted use of Vicks driver was determined to be culpable. Typical driving behaviors inhaler or selegiline, and many either had illicit methamphetamine included drifting out of the lane of travel, erratic driving, weaving, in their possession at the time of driving, or admitted to illicit speeding, drifting off the road, and high speed collisions. Behavioral methamphetamine use. manifestations of methampbetamine use in arrestees included rapid or confused speech, rapid pulse, agitation, paranoia, dilated pupils, Methamphetamine is used therapeutically for the treatment of violent or aggressive attitude. Combined alcohol and methamphet- attention deficit disorder, obesity and narcolepsy (1,4). Among the amine use was uncommon, however use of marijuana was evident effects reported at therapeutic concentrations in normal subjects in about one third of the cases. In addition to impairing judgment are mood elevation, increased alertness, decreased appetite and a and increasing risk taking, the effects of withdrawal from metham- phetamine use including fatigue, hypersonmolence, and depression feeling of well being (5). Methamphetamine is excreted unchanged are likely contributors to many of these accidents. A consideration and about 10% is metabolized to amphetamine (3,5), its elimination of the literature and the cases discussed here, leads to the conclusion half life ranges from 6 to 15 hours and is dependent on urinary that methamphetarrdne at any concentration is likely to produce pH (3). symptoms that are inconsistent with safe driving. Epidemiology KEYWORDS: forensic science, forensic toxicology, methamphet- amine, driving impairment, driving In two articles that deal specifically with methamphetamioe and driving, first in 1976 (6), and later in 1987 (7), Hurst reviewed epidemiological data then-available and concluded that there was In areas where there is significant methamphetamine abuse, little evidence to specifically implicate amphetamine use in traffic inevitably the effects of the drug on driving becomes an issue. In accidents. He cites as a deficiency the lack of control studies, order to examine the links between the effects of the drug, and where drug-use rates in the general population are compared with how these can impact skills required for safe driving, the epidemio- a specific population (for example, arrested or fatally injured driv- logical, clinical and toxicological literature was reviewed, together ers), but notes that such studies are notoriously difficult to perform, with 28 of our own impaired-driving cases involving metham- and that even a low refusal rate may invalidate the control sample phetamine. (6). Also limiting was the fact that many of the studies examining The amphetamines are commonly abused for their central stimu- drugs and driving reviewed in the noted articles, did not include lant properties, the most popular abused drug in the class being tests for amphetamines. The remaining epidemiological data that d-methamphetamine (hereafter methamphetamine), also known as do suggest rates of amphetamine use in specific populations can 'speed,' 'ice' or 'crank.' The drug can be smoked, ingested orally, be difficult to interpret however and tends to be of descriptive and or injected intravenously. The l-isomer (1-desoxyephedrine, Vicks comparative, rather than inferential value. Inhaler) is used as a decongestant, and has central nervous system Subsequent to these reviews by Hurst, several studies of driver potency of about 10% that of its enantiomer. The recommended populations have included tests for amphetamines, and show a dosage of 1-desoxyephedrine for treatment of decongestion is two significant incidence of their use. Lund et al. in 1988 (8) studied inhalations in each nostril every two hours for up to seven hours drug use in truck drivers on a major US transcontinental highway, (1). Each inhalation delivers an absorbable drug dose of 21 ng and found methamphetamine in 2% of those drivers voluntarily (2), so a seven hour treatment should deliver no more than 300 tested. Twelve percent of drivers contacted declined to participate ng, which would not result in measurable blood methamphetamine however. In 1993, Crouch et at. (9) reported on the prevalence of drug use in fatally injured truck drivers, and found amphetamine or methamphetamine in 7% of cases. Comparing Lund's data with tToxicologist, Washington State Toxicology Laboratory, Department of Crouch's suggests that methamphetamine use is over represented Laboratory Medicine, University of Washington, Seattle, WA. Received for publication 19 July 1995; revised manuscript received 18 in fatally injured truck drivers. This would support a causal rela- Sept. 1995; accepted for publication 20 Sept. 1995. tionship between methamphetamine use and increased risk of fatal

CG 069_V1 Antemortem & Postmortem Methamphetamine457 Blood ConcentrationsPage 5 of 31 458 JOURNALOF FORENSIC SCIENCES

accident involvement, however the refusal rate in Lund's study on judgment, with many studies showing an increase in optimism makes this comparison less than conclusive. and heightened self confidence. Hurst (14) examined the effects Kirby et al. (10) reported drug use in traffic accident victims of amphetamine on risk taking, based on subjects willingness to admitted to a level 1 trauma center in 1988, and found an incidence risk real money on a game of chance, and found a willingness to of amphetamine use of 2%. Robb et al. (11) in 1990 reported on take on increased risk following doses of 10-15 mg, corresponding drug use in drivers in New Mexico arrested under suspicion of to blood amphetamine concentrations of 0.05 mg/L. Other work driving under the influence of drugs (DUID), and found 1.7% by Hurst (15) examined the effects of amphetamine on judgment positive for non-cocaine phenethylamine stimulants. Logan and and decisions, and demonstrated both increased self-appraisal of Schwilke (12) in 1993 found 1.8% of fatally injured drivers in performance without improving actual performance, and demon- Washington state positive for methamphetamine. Unfortunately strated greater risk-taking behavior associated with that enhanced there is no corresponding control group in any of these studies to self perception. permit evaluation of the relative prevalence of amphetamine use A recent study of methamphetamine in the treatment of narco- in impaired drivers as opposed to the general driving population. lepsy (4) demonstrated improved performance by both narcoleptics In addition, since many of these studies tested only urine, blood- and control subjects in some psychomotor tests including a driving drug concentration data is not available. This is unfortunate since task. There was no evidence to suggest however that this improve- such information would be useful in establishing any link between ment in performance would be maintained at higher doses. the concentration of the drug and its role in the causation of the accident. Interpreting Blood Methamphetamine Concentrations In summary, there is some evidence from these studies that amphetamine use is prevalent in certain driver populations, but on As implied in the previous two sections, blood methamphet- this basis alone, it remains difficult to infer a causal link due to amine concentration is an important factor to consider, along with the absence of control data. Studies documenting rates of metham- behavior, in determining whether a given case involves metham- phetamine use in driving populations do, however, allow identifica- phetamine use or abuse, and consequently the degree and nature tion of trends, and comparisons of drug use patterns between of any likely impairment. Blood drug levels can help distinguish groups, and jurisdictions. those limited circumstances where methamphetamine may actually enhance performance, from those where it almost certainly causes Laboratory Studies deterioration in performance. Baselt (3) notes a normal therapeutic concentration for metham- The major limitation of clinical laboratory studies is that they phetamine of around 0.03 mg/L, and a volume of distribution of deal with methamphetamine use, not abuse. Methamphetamine 3 to 7 L/Kg. Garriot (19) and Winek (20) quote a therapeutic range (Dexedrine) is administered orally at doses of up to 15 mg/day of around 0.01 to 0.05 mg/L. Mitler et al. (4) achieved blood for the treatment of obesity, up to 25 rag/day in the treatment of methamphetamine concentrations in narcoleptics of 0.10 mg/L, attention deficit disorder in children, and up to 60 mg/day in and in controls of 0.02 mg/L, after doses of 60 and 10 mg, respec- the treatment of narcolepsy (1,4). Tolerance and dependency can tively. In an earlier study ~nggard et al. (21) administered 160 to develop to these drugs, so a course of treatment will usually only 200 mg of amphetamine sulphate to nonpsychotic amphetamine- last a few weeks, however even during that period the dose may dependent patients, and achieved blood amphetamine concentra- need to be increased to maintain therapeutic effect. Even so, doses tions in the range 0.31 to 0.51 mg/L. Symptoms associated with used therapeutically are significantly less than those used by meth- low dose (10-25 mg) methamphetamine use include euphoria, amphetamine abusers, which range from 30 to 300 mg or more wakefulness, and loss of appetite, together with less desirable side per dose, and can be used in sprees of several days or weeks, over effects such as irritability, nervousness, insomnia, headache and which period several grams may be administered. Since they deal motor restlessness (akathisia), increased libido, and increased, with low, single dose, oral administration, clinical studies are of often compulsive, activity (4). limited value in assessing the effects of intravenously administered Higher doses (25-60 rag) can cause confusion, apprehension, drug, high dose drug use, and extended runs or 'sprees' of drug volubility, hyperactive reflexes, excessive sweating, tremor, loqua- use. They are useful however in helping to distinguish between ciousness, fear, suspiciousness, awareness of being watched, hallu- therapeutic drug use and drug abuse. cinations in the peripheral vision, paranoia and excitement (22,23). Doses of methamphetamine in clinical studies generally do not Baselt (3) indicates a toxic range beginning at 0.15 mg/L, associ- exceed 60 mg, which would produce a blood methamphetamine ated with violent and irrational behavior after intravenous use, and concentration of no more than 0.2 mg/L (4,13-18). Hurst (6,7) notes fatalities at 1.5 mg/L from oral methamphetamine use and reviewed laboratory studies using methamphetamine, and notes 0.8 mg/L following intravenous use. Logan et al. (24) have reported that many of these where small doses of methamphetamine are survival of a subject who swallowed a package of methamphet- administered to subjects who then complete psychomotor perfor- amine and attained a blood drug concentration of 9.5 mg/L. mance testing, do show some enhancement of performance. The In a review of 310 patients reporting to a treatment center predominant benefit from the drug is in offsetting effects of fatigue. with acute high dose methamphetamine toxicity (25), the most In non-fatigued subjects the benefits were very small. In a review prominent complaints were acute anxiety (28%), amphetamine of performance enhancement by the amphetamines (13), Laties psychosis (18%), secondary illness (generally malnutrition) (12%), and Weiss confirm that the amphetamines are most effective in exhaustion syndrome (9%), and hepatitis (7%). Cellulitis, cubital restoring baseline performance in fatigued subjects. They note abscess, nausea and vomiting, muscle pain, headache, dizziness, positive effects of amphetamines on monitoring and vigilance, breathing difficulties and cardiac problems were also reported. motor coordination and control, and physical endurance and capac- Clearly the most prominent of these symptoms are central in nature, ity, when the drug is administered at low therapeutic doses. Even and would tend to have a negative effect on driving ability..g, nggard at those doses however there is the potential for a negative effect et al. (21) evaluated 18 subjects with amphetamine psychosis and CG 069_V1 Antemortem & Postmortem Methamphetamine Blood ConcentrationsPage 6 of 31 LOGAN 9METHAMPHETAMINE AND DRIVING IMPAIRMENT 459 found a marked incidence of lack of concentration, paranoid delu- means that these symptoms may be present when there is little or sions, hallucinatory behavior, and disorganization of thoughts. The no detectable methamphetamine in the blood. patients had amphetamine concentrations in the range 0.08 to 0.64 After considering the information summarized, the following mg/L. Interestingly, there was no correlation between the actual project was undertaken to evaluate the circumstances surrounding blood amphetamine concentration and the extent of the symptoms a series of traffic accidents, arrests, and fatalities in which metham- described above. phetamine use by the driver was indicated. Tolerance to the euphoric effects of methamphetamine are well known (26), but are difficult to quantify. The same tolerance does Me~o~ not appear to result in attenuation in suppression of fatigue. The Blood samples taken from drivers, living or deceased, were use of higher doses to obtain positive effects on mood, may simulta- collected in 10 mL tubes containing an anticoagulant and antibacte- neously trigger many of the negative effects on performance dis- rial (Vacutainer, Becton Dickinson, NJ). The samples were cussed above. For the same reasons, the withdrawal phase in a extracted and tested by gas chromatography for the presence of tolerant individual is likely to be more marked, and the symptoms weakly acidic/neutral drugs, and basic drugs using methods more pronounced as discussed later. described in detail elsewhere (31,32). All drug identifications were Also reported in the literature is a condition know as "over- confn-med by mass spectrometry. The limit of quantitation for this amping," in which very high doses of methamphetamine are used, assay was 0.05 mg/L. The limit of detection was 0.01 mg/L. This and there is a rapid increase in the blood methamphetamine concen- method does not distinguish between d- and l-methampbetamine. tration, generally after intravenous use (25,27,28). The effects Urine when available was tested for the above drugs and also for are in marked contrast to the normal excitatory effects of the marijuana metabolites using an enzyme immunoassay (EMIT II, amphetamines. The user typically maintains consciousness, but is Syva, CA). Investigative reports from each of arrests or fatalities catatonic, unable or unwilling to speak or move. The condition were reviewed, and the following information was tabulated: age, occasionally manifests itself in unconsciousness lasting minutes gender, blood methamphetamine level, blood amphetamine level, to hours, and the user may be aphasic or paralyzed for hours or days. blood alcohol level, other drug or medication use, driving behavior which resulted in the arrest or fatality, driver culpability, and the Withdrawal or "Crash" subject's observed behavior after apprehension or when in custody. All the available information is summarized in Table 1. In a discussion of stimulant-induced impairment, Ellinwood and Results and Discussion Nikaido (29) draw important distinctions between depressant and stimulant drug use. They propose a general form of a hysteresis The cases in Table 1 are arranged in order of increasing blood plot of psychomotor performance with changing blood stimulant methamphetamine concentration. Of 178 cases tested for drugs, concentration. This predicts improvement in performance at low methamphetamine was detected in 29 cases, cocaine or its metabo- concentrations, with deteriorating performance at higher concen- lites in 22, diazepam in 21, meprobamate in 17, morphine in 14, trations and during withdrawal. The authors do not however offer PCP in 1. Other drugs detected included propoxyphene, fluoxetine, appropriate blood concentration ranges for these different phases and cyclobenzaprine. Blood was not tested for marijuana metabo- of effect. They note the importance of considering duration of use rites. No methylenedioxy-substituted amphetamines were identi- in addition to dose, when assessing likely impairment. They also fied, and in no case was amphetamine found in the absence of introduce the concept of withdrawal-induced impairment, with methamphetamine. symptoms including hypersomnolence and fatigue. Abstinent The methampbetamine concentrations ranged from the limit of symptomatology (25,28,30) resulting from abuse of stimulants detection, 0.01 mg/L, up to 9.46 mg/L. The two cases with the includes exhaustion, depression, agitation, drug seeking behavior highest concentration are believed to have resulted from the sub- and, less frequently, suicidal or other self-destructive actions. These ject's ingestion of methamphetamine in an effort to destroy poten- conditions are more likely to prevail after extended or spree use, tially incriminating evidence. Of the remaining cases, the average after intravenous use, or after high dose use. The issue of with- blood methamphetamine concentration was 0.55 mg/L. In those drawal-induced impairment is an important consideration in cases where amphetamine was also detected, the concentration assessing possible impact on driving, since these symptoms may ranged from 5 to 38% of the methamphetamine concentration. be present even at low or negative blood methamphetamine concen- Several cases displayed high methamphetamine concentrations trations. The net result is that although concentrations below 0.1 with amphetamine levels below the limit of quantitation. Cook mg/L can be associated with performance enhancement as dis- et al. (5) examined the pharmacokinetics of orally administered cussed earlier, this is almost certainly not the case during with- methamphetamine, and found peak methamphetamine concentra- drawal, regardless of the blood drug concentration. tions occurring at 4-5 hours post ingestion, prior to which time The severity of withdrawal symptoms depends on the length of the amphetamine concentrations were less than 5% of the corre- the episode of use. Extended use or spree use can last for several sponding methamplietamine concentration. When methamphet- days or even weeks, stopping only when the supply of drug is amine was administered either by smoking or intravenous injection exhausted (26,27). During that period the user ingests the drug (33), the ratio of amphetamine to methamphetamine in the blood several times a day, may remain awake continuously for three to was even lower, and did not approach 5% until after ten hours six days, becoming gradually more tense, tremulous and paranoid. following administration. These findings suggest that high meth- The run or spree is followed by a "crash" during which the sleep amphetamine levels with low amphetamine levels most likely result debt accumulated during the run can result in bouts of profound either from an episode of intravenous drug use within the previous sleep lasting for a day or two. Clearly, the symptoms of metham- ten hours, or oral administration within the previous five hours. phetamine withdrawal are likely to have a negative impact on a On the other hand, elevated amphetamine to methamphetamine subject's driving performance. The nature of withdrawal however ratios do not exclude recent drug use, since the ratio could be CG 069_V1 Antemortem & Postmortem Methamphetamine Blood ConcentrationsPage 7 of 31 460 JOURNALOF FORENSIC SCIENCES

TABLE 1--Case information on drivers testing positive for methamphetamine use.

Subject Meth. Amp. Alcohol Circumstances resulting in # Age Sex (rag/L) (mg/L) (g/100 mL) Other drug use testing Drivers observed behavior

1 18 f <0.05 <0.05 neg --* Erratic driving White powder in nose starting stopping dilated pupils no turn signals no nystagmus methamphetamine in vehicle violent combatative admit to drug use 2 35 f 0.05 --q[ 0.03 --* Accident Slight odor of alcohol multivehicle causing driver pulled out into oncoming traffic 3 39 m 0.05 <0.05 0.06 marijuana Accident Watery bloodshot eyes multivehicle disoriented causing driver methamphetamine in possession pulled out into oncoming traffic uncooperative 4 22 m 0.1 <0.05 0.02 --* Accident Admits to methamphetamine use single vehicle watery bloodshot eyes causing driver shaking uncontrollably high speed nervous drifted off roadway 5 30 f 0.1 --9 neg --* Accident No information available multivehicle causing driver pulled out into oncoming traffic 6 30 f 0.17 --I neg --* Accident IV paraphenalia single vehicle rapid speech causing driver hysterical drifted off road 7 38 m 0.22 --~[ neg marijuana Weaving Falling asleep crossed center line bloodshot eyes 8 33 m 0.22 <0.05 neg --* Equipment stop Dilated pupils headlight out rapid speech repetative speech white powder in nose admit to drug use cooperative finger tapping 9 24 m 0.25 <0.05 neg cocaine Accident Dilated pupils single vehicle cooperative causing driver admitted a 3 day spree vehicle drifted off road hungry methamphetamine in vehicle 10 32 m 0.35 <0.05 neg marijuana Speeding Dilated pupils nervous agitated slurred speech watery bloodshot eyes methamphetamine in vehicle 11 27 f 0.36 --~[ neg marijuana Erratic speed Agitated pemoline poor cornering bloodshot eyes weaving nervous rapid speech methamphetamine in purse light sensitive poor coordination 12 32 f 0.38 0.14 neg marijuana Accident Slurred speech causing driver methamphetamine in vehicle multivehicle no braking rear ended braking vehicle red face swearing/screaming uncooperative drug paraphenalia 13 ? m 0.4 --q[ neg cocaine Accident Driver deceased single vehicle IV paraphenalia on body causing driver 14 24 f 0.47 <0.05 neg marijuana Failed to stop atstop sign Disorientated confused speech agitated and restless pupils dilated

CG 069_V1 Antemortem & Postmortem Methamphetamine Blood ConcentrationsPage 8 of 31 LOGAN 9METHAMPHETAMINE AND DRIVING IMPAIRMENT 461

TABLE l---Continued

Subject Meth. Amp. Alcohol Circumstances resulting in # Age Sex (mg/L) (mg/L) (g/100 mL) Other drug use testing Drivers observed behavior

15 26 m 0.55 <0.05 neg --* Accident Needle tracks single vehicle (unconscious) causing driver drifted off roadwaY 16 27 f 0.57 0.14 neg --* Accident Admits IV methamphetamine use single vehicle nervous eluding police anxious rammed by police very talkative rapid speech rapid pulse syringes repetative 17 24 m 0.57 0.15 neg --* Erratic driving Very talkative missing license plate rapid speech rapid pulse syringes 18 28 m 0.58 --el neg --* Speeding Slurred speech weaving methamphetamine in vehicle unsteady twitching short attention span red eyes IV paraphenalia spasm/jerking 19 26 f 0.7 <0.05 neg --* Accident IV paraphenalia single vehicle uncooperative causing driver trance-like state veered off road into tree 20 18 m 0.77 <0.05 neg --* Accident Dazed multivehicle admits to drug use causing driver snorting paraphernalia 21 22 m 0.8 0.3 neg cocaine Accident Deceased marijuana multivehicle methamphetamine in vehicle causing driver using for 2 days straight crossed center line 22 41 m 0.81 0.05 neg diazepam Accident Dilated pupils ibuprofen multiple vehicle rapid speech causing driver admission to drug use high speed collided while attempting to pass 23 30 m 0.088 <0.05 0.16 --* passed out Unconscious (physical control) white powder in nostrils methamphetamine in wallet confused 9 24 20 m 1.14 0.23 neg --* Accident Violent single vehicle argumentative causing driver incoherent speeding parmaoid failed to stop at stop sign 25 41 m 1.35 0.14 neg --* Accident Deceased single vehicle causing driver tractor trailer driver drifted off road 26 30 m 1.88 0. i 4 neg morphine Accident Unconscious multiple vehicle admits to heroin use causing driver admits to methamphetamine use crossed center line methamphetamine in vehicle 27 35 m 2.58 0.35 neg --* Accidentw Mood swings single vehicle irrational causing driver delusional agitated violent uncooperative WalTn

CG 069_V1 Antemortem & Postmortem Methamphetamine Blood ConcentrationsPage 9 of 31 462 JOURNALOF FORENSIC SCIENCES

TABLE 1--Continued Subject Meth. Amp. Alcohol Circumstances resulting in # Age Sex (mg/L) (mg/L) (g/100 mL) Other drug use testing Drivers observed behavior

28 20 m 9.46 0.05 neg --* Tail light violationw Panic agitated violent dilated pupils swallowed methamphetamine seizure *No other drug use detected or admitted to. w least some of the drug was ingested after stop or accident. ~lNo amphetamine detected. falsely elevated from residual amphetamine from prior episodes confused speech, dilated pupils, agitation, paranoia, rapid pulse, of use. and violent or aggressive demeanor. Sweating, and high tempera- Of the 28 cases evaluated, nine (32%) involved females and 19 ture were also noted, as were watery-bloodshot eyes. Since amphet- (68%) involved males. The average age was 29. Twenty three amines are not believed to irritate the eyes themselves, this may cases (82%) had blood methamphetamine levels above 0.10 mg/ be related to fatigue. The degree of the effects present generally L, the level normally considered to be the upper limit for therapeu- increased with the blood methamphetamine concentration, with tic use, and beyond the range for which improvements in some violent behavior being noticably more common at higher blood performance measures have been demonstrated. Seventeen drivers methamphetamine concentrations. Methamphetamine and other (61%) were tested as a result of being involved in an accident, drug paraphernalia were commonly found in the possession of the and the driver was the causing driver in all but one of these cases arrestee, and in two occassions there was drug residue reported (in that case the driver was fleeing police and was rammed by a on the subject's nose or face. Even at low concentrations, subjects police car). Of those drivers involved in accidents, the accident had fixed and dilated pupils, which would make them more sensi- frequently resulted from the driver allowing the vehicle to drift tive to glare in bright sunlight or from headlights of oncoming out of the lane of travel on to the shoulder, into fixed objects, or into vehicles at night. Other side effects cited above, nervousness, oncoming traffic. This apparent lack of attention is not normally insomnia, headache, tremor, and motor restlessness could also associated with stimulant use per se, and may be indicative of contribute to impairment even at therapeutic doses. The Physicians withdrawal-induced impairment as discussed later. Other accidents Desk Reference (1) notes that patients prescribed methamphet- resulted from an apparent error of judgment by the driver, inappro- amine clinically, should be cautioned about its effect on driving priately attempting to enter traffic flow, failing to stop at stop or operating heavy machinery. signs, high speed collisions, generally erratic driving, weaving, Many of the cases associated with lower blood methamphet- and speeding (Table 2). amine concentrations (<0.10 mg/L) also involved alcohol (Table In a large scale detailed study of drug use by fatally injured 1), which most likely contributed to impairment. There is some truck drivers the National Transportation Safety Board (NTSB) evidence that synergistic effects can amplify the impairment from (34) described 12 cases involving methamphetamine. Five of these methamphetamine or alcohol when both are present together (35). involved drivers drifting off the road, two involved drivers using Attempts to evaluate the combined effects of alcohol and amphet- methamphetamine rear ending other vehicles, and three involved amines however suggest that the interaction is complex (16-18,35). methamphetamine-related fatigue. This pattern of accident causa- Some workers have found an apparent abatement of alcohol tion is very similar to that found in the cases discussed in this study. induced narcotic effects, while in other cases, the opposite is true. Driving is a divided attention task, requiting fine motor skills, Any other factors however, including fatigue and other symptoms intelligent decision making, and rapid and appropriate responses of 'crash' or withdrawal would likely result in performance decre- to stimuli. The driver must simultaneously steer, brake, accelerate, ment, and would be manifested as 'nodding off,' or a lack of operate turn signals, observe and anticipate the behavior of other attention to driving conditions and other road users. Drivers falling road users, accurately judge time and distance, and observe and asleep at the wheel are known to be significant contributors to obey traffic signals and road signs. Impairment of any of these operations by drugs having an effect on the central nervous system, traffic accidents (36,37). The fatigue and sleep-pattern disruption will have a negative effect on overall driving performance. caused by methamphetamine use would thus be expected to Behavioral manifestations of methamphetamine use observed increase the risk of an accident in drug users. As a further confound- in arrestees were typical and distinctive. They included rapid or ing factor, general impairment from the drug may affect the drivers ability to recognize the extent of his or her fatigue (36). Alcohol or other central nervous system depressant consumption during TABLE 2--Typical driving behaviors in 28 methamphetamine: withdrawal would further exacerbate impairment. positive drivers. Seven of the 28 cases considered here had positive results for urinary cannabinoids, suggesting marijuana use within the previous Leaving lane of travel 13 Pulled out into oncoming traffic 4 hours or days. Due to its prolonged excretion time however, the Speeding 7 presence of marijuana metabolites in the urine does not necessarily Failed to stop at stop sign 2 imply that the subject is under the influence the drug. Effects from General erratic driving 5 combined methamphetamine and marijuana use have not been Rear ended another vehicle 1 studied. Marijuana and other antidepressants can be used during CG 069_V1 Antemortem & Postmortem Methamphetamine Blood ConcentrationsPage 10 of 31 LOGAN . METHAMPHETAMINEAND DRIVING IMPAIRMENT 463

improved reaction time light sensitivity relief from fatigue nervousness euph~ headache ~ ~ motor restlessness ~ao o "~- ] N tremor Blood methamphetamine concentration (mg/L) 0 I I f I II i I i.a ' ' ' ''''1 ' ' ' ' ''''1 i agitation 1 0.01 fatigue / O. l 10 100 o ..a exhaustion rehensiveness confusion nfusion ~. drueXtremefatigue piciousness g craving paranoia depression elusions hypersomnolence suicidal behavior al luici:dt~n~ behavior violence (b) "over-amping" ~ severe hypertension/chest pains ~ seizures

coma death

FIG. l--Hysteresis plot showing effects of methamphetamine that impact driving performance with respect to blood methamphetamine concentration (mglL). The figure shows examples of withdrawal effects from (a) low dose and (b) high dose drug use.

withdrawal to counteract the psychological effects of the crash. or into oncoming traffic. Similar patterns have been reported else- As with alcohol, combined stimulant and depressant use is unlikely where (34). to lead to a complete neutralization of psychomotor effects of Figure 1 is a hysteresis plot for impairment from methamphet- either, and is likely to exacerbate fatigue-related impairment. amine drawn after a general form proposed by Ellinwood and Toxic effects from methamphetamine use can begin at concentra- Nikaido (24). The concentration ranges and effects are based on tions greater than 0.1 mg/L, and are typically well established at the laboratory studies, clinical reports, and case reports in the levels of 0.2 mg/L, although their intensity may depend on the literature cited in the introduction, and on the cases discussed here. degree of tolerance developed by the user (11,22,23). Effects As with any drug, the concentrations required to produce these include paranoia, confusion, restlessness, irritability, hyperactive effects are not absolute, but will vary somewhat between individu- reflexes and tremor, pounding in the ears, and elevated pulse als based on patterns of use, tolerance, fatigue, other drug or and blood pressure. Severe intoxication can manifest as, delusion, alcohol use and any underlying psychoses. Two examples of the delirium, panic, and mania, with high temperature, flushing and withdrawal phase are included in Fig. 1 to illustrate the difference profuse sweating (18,20). Life threatening effects include violence in severity of withdrawal from methamphetamine at higher and to self or others, hallucinations, tachycardia, hypertension, severe lower doses. chest pain and circulatory collapse, occasionally followed by sei- The net conclusion of the material reviewed in this study was zure and death (17,18,20). Psychoses are possible at any level but that the circumstances under which any methamphetamine induced are more commonly associated with higher blood methamphet- performance increment is possible are extremely narrow, and is amine concentrations, and with intravenous use. Clearly a person not guaranteed because of typical side effects associated even with suffering with even minor elements from this constellation of low dose use. Furthermore, there is ample evidence from the symptoms will not be performing at a normal level, and would epidemiological, clinical, case report and toxicological data to therefore be at increased risk for accident involvement. conclude that the behavior displayed in the cases we reviewed is Withdrawal-induced impairment is a significant issue (24,25). consistent with impairment as a result of methamphetamine use, Withdrawal, 'crash,' or abstinence syndrome following extended drug withdrawal, or combined use of methamphetamine and methamphetamine use can manifest as severe depression, extreme other drugs. fatigue, lethargy, hypersomnolence, disturbed sleep, gastrointesti- nal pain, an intense craving for the drug, and drug-seeking behavior. References Self-destructive acts are often committed during this period. The symptoms can last for up to several days, and again are clearly (1) Physicians desk reference. 49th edition 1995. Medical Economics not consistent with safe driving. The accumulated sleep debt from Data, Montvale NJ. (2) Ando H, Shimizu H, Takahashi Y, Fukumoto M, Okonogi H, an extended use of methamphetamine, appears to be the likely Kadokura M. A basic study for estimating the level of exposure cause of the accident in many of the cases summarized in Table to a nasal inhalant containing a stimulant. Japan J Hygiene 1993; 1, where the driver drifted out of the lane of travel onto a shoulder 48(3):692-97. CG 069_V1 Antemortem & Postmortem Methamphetamine Blood ConcentrationsPage 11 of 31 464 JOURNALOF FORENSIC SCIENCES

(3) Baselt RC, Cravey RH. Disposition of toxic drugs and chemicals (22) Toxicology.The basic science of poisons. Casarett LJ, Doull I (eds.) in man. Fourth edn. 1995 Chemical Toxicology Institute, Foster first edition, 1975. Macmillan New York, NY. City, CA. (23) Drugs and drug abuse, a reference text. Second edition, Jacobs MR, (4) Mitler M, Hajdukovic R, Erman MK. Treatment of narcolepsy with Fehr KO (eds). Addiction Research Foundation, Toronto, 1987. methamphetamine. Sleep 1993;16(4):306-17. (24) Logan BK, Weiss EL, Harruff RC. Case report: tissue distribution (5) Cook CE, Jeffcoat AR, Sadler BM, Hill JM, Voyksner RD, Pugh of methamphetamine following a massive fatal ingestion. J Forensic DE, White WR, Perez-Reyes M. Pharmacokinetics of oral metham- Sci, March, 1996. phetamine and effects of repeated daily dosing in humans. Drug Met (25) Smith DE, Fischer CM. An analysis of 310 cases of acute high dose Disp 1992;20:856--62. methamphetamine toxicity in Haight-Ashbury. Clin Toxicol (6) Hurst PM. Amphetamines and driving behavior. Accid Anal Prev 1970;3( 1): 117-24. 1976;8:9-13. (26) Smith DE. The characteristics of dependence in high-dose metham- (7) Hurst PM. Amphetamines and driving. Alcohol drugs and driving phetamine abuse. Int J Addictions 1969;4(3):453-59. 1987;3(1):13--16. (27) Caldwell J, Sever PS. The biochemical pharmacology of abused (8) Lurid AK, Preusser DF, Blomberg RD, Williams AF. Drug use by drugs I. Amphetamines, cocaine and LSD. Clin Pharm Ther tractor trailer drivers. J Forensic Sci 1988;33(3):648-61. 1974; 16(4):625- -38. (9) Crouch DJ, Birky NLM, Gust SW, Rollins DE, Walsh JM, Mouldcn (28) Krarner JC. Introduction to amphetamine abuse. J Psychedelic JV, Quinlan KE, Beckel RW. The prevalence of drugs and alcohol drugs 1969;2:1-16. in fatally injured track drivers. J Forensic Sci 1993;38(6):1342-53. (29) Elinwood EH, Nikaido AM. Stimulant induced impairment: a per- (10) Kirby JM, Kimball IM, Fain W. Comparability of alcohol and drug spective across dose and duration of use. Alcohol Drugs and Driv- use in injured drivers. Southern Med J 1992;85(8):8(D-02. ing 1987;3(1):19-24. (11) Robb J, Wohlenberg N, Jasperson M, Lindsey T, Backer R. DUID (30) Gawin FH, Kleber HD. Abstinence symptomatology and psychiatric in New Mexico: Distribution of drug types and BAC. The DRE diagnosis in cocaine abusers. Clinical observations. Arch Gen Psych- 1992;4:1 !-13- iatr 1986;43:107-13. (12) Logan BK, Schwilke ES. Drug use in fatally injured drivers in (31) Logan BK, Fricl PN, Case GA. Analysis of sertraline (zoloft| and Washington State. J Forensic Sci, 1996. its major metabolite in postmortem specimens by gas and liquid (13) Laties VG, Weiss B. Performance enhancement by the amphet- chromatography. J Anal Tox 1994;18:139-42. amines: A new appraisal. Neuropsychopharmacology. Proceedings (32) Logan BK, Friei PN, Peterson KL, Predmore DB. Analysis ofketoro- of the fifth international congress of the Collegiium lnternationale lac in post mortem blood. J Anal Tox 1995;19~2):61-64. Neuro-psycho-pharmacologicum.Washington DC March 1966. Edi- (33) Cook CE, Jeffcoat AR, Hill JM, Pugh DE, Patetta PK, Sadler BM. tor H. Brill. International Congress Series no 129. Excrpta Medical White WR, Percz-Reyes M. Pharmacokinetics of methamphetamine Foundation, New York 1967. self administered by smoking s-(+)-methamphetamine hydrochlo- (14) Hurst PM. The effects of d-amphetamine on risk taking. Psychophar- ride. Drug Met Disp 1993;21:717-23. macologia 1962;3:283-90. (34) National Transportation Safety Board safety study: Fatigue, alcohol, (15) Hurst PM, Weidner MF, Radlow R. The effects of amphetamines other drugs, and medical factors in fatal-to-the-driver heavy truck upon judgement and decisions. Psychopharmacologia 1967;!1: crashes (vol I and II). Accession# PB90-917002, report# NTSB/SS- 397--404. 90/01/02, National Transportation Safety Board, Washington DC, (16) Wilson L, Taylor JD, Nash CW, Cameron DE The combined effects 1990. of alcohol and amphetamine sulphate on performance of human (35) YamamuraT, Hisida S, Hatake K. Alcohol addiction of methamphet- subjects. Can Med Association J 1966;94:478-84. amine abusers in Japan. J Forensic Sci 1991;36(3):754-64. (17) Rosenfeid G. Potentiation of the narcotic action and acute toxicity (36) Summala H, Mikkola T. Fatal accidents among car and truck drivers: of alcohol by primary aromatic monoamines. Q J Studies Alcohol effects of fatigue, age, and alcohol consumption. Hum Factors 1960;21:584-96. 1994;36(2):315 -26. (18) Newman HW, Newman EJ. Failure of dexedrine and caffeine as (37) Brown ID. Driver fatigue. Hum Factors 1994;36(2):298-314. practical antagonists of the depressant effect of ethyl alcohol in man. Q J Studies Alcohol 1956;17:406-10. (19) Garriott JC. Interpretive toxicology. Clin Lab Med 1983;3(2): Address requests for reprints or additional information to 367-84. Barry K. Logan, Ph.D. (20) Winek C. Drug and chemical blood level data 1994. Allegheny Washington State Toxicology Lab County Department of Laboratories, Pittsburgh PA, 1994. Dept. of Laboratory Medicine (21) ,~nggard E, Gunne LM, J6nsson LE, Niklasson E Pharmacokinetic University of Washington and clinical studies on amphetamine dependent subjects. Euro J Clin 2203 Airport Way South Pharmacol 1970;3:3-11. Seattle, WA 98134

CG 069_V1 Antemortem & Postmortem Methamphetamine Blood ConcentrationsPage 12 of 31 Methamphetamine — Effects on Human Performance and Behavior

B. K. Logan Forensic Laboratory Services Bureau Washington State Patrol Seattle, Washington United States of America

TABLE OF CONTENTS

INTRODUCTION ...... 134 I. CHEMISTRY ...... 134 A. Nomenclature ...... 134 B. Chemical Properties ...... 135 C. Stereochemistry ...... 135 D. Synthesis ...... 135 E. Analysis ...... 136 II. PHARMACOLOGY...... 136 A. CNS Effects...... 137 B. Peripheral Effects ...... 137 C. Route of Administration...... 137 D. Patterns of Use ...... 137 III. METABOLISM ...... 138 IV. PHARMACOKINETICS ...... 139 A. l-Methamphetamine and Use of Decongestant Inhalers ...... 139 B. d-Methamphetamine — Acute Dosing ...... 139 C. d-Methamphetamine — Chronic/High-Dose Dosing ...... 140 V. PHARMACODYNAMICS ...... 141 A. Acute Administration — Therapeutic Dose...... 141 B. Chronic Administration — Therapeutic Dose ...... 141 C. Abuse — High-Dose and Chronic Administration ...... 141 D. Summary ...... 142 VI. FORENSIC ISSUES...... 143 A. Methamphetamine and Violence ...... 143 B. Methamphetamine Combined with Alcohol and Other Drugs ...... 144 C. Military Use and Effects on Counteracting Fatigue...... 144 D. Methamphetamine and Driving ...... 145 REFERENCES ...... 148 ABOUT THE AUTHOR ...... 151

1042-7201/14-01/02-02/133Ð151/$9.50 ¥ Copyright © 2002 Central Police University Press

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Methamphetamine — Effects on Human Performance and Behavior

REFERENCE: Logan BK: Methamphetamine — Effects on human performance and behavior; Forensic Sci Rev 14:133; 2002.

ABSTRACT: Methamphetamine is a popular recreational drug that has also had some historical use as a therapeutic agent. Its effect profile is complex, with stimulant, alerting effects during acute low-dose administration, progressively more disorienting effects on cognition, reasoning, and psychomotor ability with increased dosing and duration of use, and a depressant-like profile during withdrawal, often compounded by delusions and psychotic episodes, especially after high-dose or chronic use. This manuscript reviews the synthetic, structural, and analytical chemistry of the drug; the pharmacology of its central and peripheral effects; its pharmacokinetics following various routes of administration and dosage regimens; and its pharmacodynamics in both acute and chronic administration and therapeutic and recreational doses, noting in particular its effects on judgment, decision making, risk-taking, cognition and psychomotor performance, and violence. Finally, the review considers the issue of how these various effects can impact driving ability and can contribute to impairment. From the material reviewed it is concluded that the use of methamphetamine in anything other than low-dose, therapeutic administration with medical oversight raises the likelihood of some impairment of performance in complex psychomotor tasks such as driving.

KEY WORDS: Driving, forensic toxicology, human performance, impairment, methamphetamine.

INTRODUCTION The technical nomenclature for methamphetamine is discussed below, but there are a variety of popular terms Methamphetamine is a central nervous system stimu- including meth, crystal meth, crystal, ice, speed, whiz, and lant with some legitimate therapeutic uses, but it has a crank. No term is specific for particular grade or chemical tremendous potential for abuse. It has a history as a product, although these terms are generally reserved for periodically popular drug of abuse, which at the time of illicit preparations, as opposed to diverted pharmaceuti- writing is undergoing a resurgence in popularity [6,15]. It cals. Frequently, drugs sold as methamphetamine may in is truly a mind-altering drug, and as such, its use by drivers fact contain no methamphetamine at all, and are actually constitutes a real public safety and traffic safety concern. substitutes such as caffeine, ephedrine, pseudoephedrine, This review attempts to summarize the chemistry, phar- or even cocaine, depending on local drug availability. macology, pharmacokinetics, pharmacodynamics, and

toxicology of the drug, and its specific effects on human CH CH CH 3 3 CH 3 performance and behavior. The review is designed to be a **3 NH NHCH NH summary and synopsis of major forensic issues arising 2 3 2 from use of this drug, and the reader is strongly encour- aged to seek out the primary literature cited for the detail necessarily omitted in any review. Amphetamine Methamphetamine Phentermine I. CHEMISTRY HO HO NH NH2 N 2 A. Nomenclature H

Methamphetamine (C10H15N) (Structure 1), is the OH OH OH common name for N,α-dimethylphenethylamine, also OH OH OH referred to as desoxyephedrine, methylamphetamine, Norepinephrine Epinephrine Dopamine phenylisopropylmethylamine, and a variety of other simi- lar systematic names. Methamphetamine is an amphet- Structure 1. Structures of the synthetic sympathomimetics amine derivative and belongs to the class of amphet- amphetamine, methamphetamine, and phentermine, together with those of the neurotransmitters whose release they are amines. The drug was first synthesized in Japan in 1919 by believed to promote. (* indicates asymmetric carbon atoms on Ogata [84], patented in 1920, and later licensed to amphetamine and methamphetamine.) Burroughs Wellcome, who marketed it as the anorectic Methedrine¨.

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B. Chemical Properties amphetamine, with yields of 54Ð82%. The red phospho- rus is obtained from matchbook striker plates or road As discussed below, methamphetamine exists in two flares, and although the sale of hydroiodic acid is now isomeric forms, dextro (d-), and levo (l-), and these may restricted, it can be synthesized with little difficulty from appear as prefixes to any of the terms discussed above to iodine. denote the particular isomer. The free base (pKa 9.9) has The second method also results in an enantiospecific a molecular weight of 149.24 a.m.u., and is a liquid at product, d-methamphetamine, and involves the reduction room temperature, so is invariably supplied and used as of the same l-ephedrine or d-pseudoephedrine precursors the hydrochloride salt (C10H16ClN, 185.74 a.m.u.), which using either sodium or lithium metal in condensed liquid o has a melting point of 170Ð175 C. Of note is the fact that ammonia. The lithium can be obtained from lithium this salt, unlike the hydrochloride salt of cocaine, volatil- batteries, sodium from electrolytic reduction of molten o izes without pyrolysis at 300Ð305 C, a temperature readily sodium hydroxide, and liquid ammonia from agricultural achieved in a butane lighter flame, meaning that it can be or specialty gas suppliers. The substitution of phenylpropa- smoked in the salt form without the tedious conversion to nolamine as the precursor in either synthesis yields am- the base required in order to smoke cocaine. phetamine. Obviously, fire and health risks from these reagents C. Stereochemistry are significant to investigators, firefighters, and others The configuration at the chiral center dictates the CNS finding the remains of a laboratory by accident. These activity of the product, with d-amphetamine (sometimes latter two syntheses are suitable for small-scale produc- denoted as S-(+)-amphetamine) having the greatest CNS tion. Recipes and directions for obtaining precursors are stimulant effects, 3-4 times that of the l-isomer [41]. The available on the Internet and have contributed to the terms d- and l- refer to the dextrorotatory or levorotatory growing popularity of the drug. properties with respect to plane-polarized light. Pure d- methamphetamine has an [α]D25 of +14 to +20o [73]. E. Analysis Determination of the enantiomeric ratio is helpful in determining whether the drug may have originated from Methamphetamine is a prototypical basic drug (pKa licit sources (l-desoxyephedrine is sold over the counter in 9.9), and is readily extracted from biological material into the U.S. as the nasal decongestant, Vicks¨ Inhaler), or organic solvents at alkaline pH. It is readily soluble in illicit or diverted sources. d-Methamphetamine is a legal chloroform, N-butyl chloride, ethyl acetate, and diethyl schedule II [1] prescription drug (Desoxyn¨) [88] and the ether, and is extracted in most common protocols de- predominant form in many current syntheses (discussed signed to isolate alkaloidal and basic drugs. It also readily below), while the racemic mixture arises from certain back-extracts into acid, and back into organic solvents specific illicit syntheses. without significant loss. Because of its volatility, how- ever, it can be lost during a dry-down or evaporation step D. Synthesis if that is part of the procedure. This loss can be avoided by the addition of a small amount of hydrochloric acid during Prior to 1980, the popular methamphetamine synthe- the evaporation step, or the addition of a less volatile sis was from phenyl-2-propanone (P2P, phenylacetone) “keeper” solvent such as dimethylformamide (DMF). by reductive amination with methylamine over an alumi- Methamphetamine is readily analyzed by gas chro- num amalgam catalyst. At that time, P2P was available matography (GC), and this is the most popular method in through commercial sources with no restrictions, but had use today for analysis of methamphetamine in biological significant neurotoxicity, making the labs dangerous to material. Its poor UV absorption properties make it an both investigators and the “meth cooks” that operated unsuitable candidate for high performance liquid chroma- them. The product of the reaction was a racemic mixture tography (HPLC) with ultraviolet (UV) detection, and it of d- and l-methamphetamine. Controls placed on P2P in has no native fluorescence, and no significant oxidative the early 1980s imposed the need for additional steps to electrochemical properties at low voltages. synthesize this precursor, and other syntheses involving When analyzed without derivatization, as is com- more readily obtainable starting materials became popu- monly done in GC drug screening, methamphetamine is lar. Two are briefly described here. readily eluted from most stationary phases at low tempera- The first is a reduction of l-ephedrine or d-pseudoephe- tures (~50 oC) due to its low molecular weight, but its drine over red phosphorus with hydroiodic acid. The basicity results in peak-tailing on some phases. Because of enantiospecific product with either precursor is d-meth- its early elution time, care should be taken in underivatized

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GC analysis where the detector is initially turned off to clear (Structure 1). Specifically, methamphetamine inter- allow elution of the solvent front because the drug may acts with presynaptic receptors by competitive antago- elute before the detector turns on. Standards for this drug nism, and has minimal, if any, effect as an agonist at and its major metabolite, amphetamine, should be run postsynaptic receptors. frequently, especially following column maintenance or changes in GC conditions. Its low molecular weight, the A. CNS Effects low intensity of its mass fragments in electron impact mode, and the structural similarity of many endogenous The amphetamines’ potent central nervous system and exogenous compounds mean that the mass spectrum (CNS) stimulating effects appear to result by promoting of methamphetamine is not as highly characteristic as the release of biogenic amines from their stores in the many others. For example, phentermine (Structure 1), a nerve terminals, and there is some association between structural isomer of methamphetamine, has a very similar specific aspects of the amphetamine experience, and neu- mass spectrum. Care should therefore be taken when rophysiological structure and chemistry [29,41]. performing analysis of methamphetamine to check both Enhanced release of norepinephrine from central no- the retention time of this drug and its analogs, and to radrenergic neurons appears to be responsible for the carefully review the mass spectra for consistency. alerting and anorectic effects of the amphetamines, and, There is evidence that at very high concentrations, together with dopamine release from dopaminergic nerve ephedrine or pseudoephedrine may be converted to meth- terminals, for the locomotor stimulating effects. The ste- amphetamine in the GC injection port [10,48]. A proce- reotyped repetitive behavior characterized by higher doses dure involving periodate pretreatment has been described of amphetamines is also a feature of dopamine release, which eliminates this interference [31]. Other researchers particularly in the neostriatum. At yet higher doses, dopam- have reported that methamphetamine can be demethylated ine release in the mesolimbic system and enhanced release to amphetamine during this periodate treatment, and rec- of 5-hydroxytryptamine (5-HT, serotonin) in tryptaminer- ommend the use of pH 6.2 to avoid this [85]. The Sub- gic neurons may be responsible for both disturbances of stance Abuse and Mental Health Services Administration perception and frank psychotic behavior [29]. (SAMHSA, formerly the National Institute on Drug Abuse, High-dose methamphetamine administration leads to NIDA) also requires that in regulated urine drug testing, at decreases in brain levels of the neurotransmitters dopam- least 0.200 mg/L of amphetamine be present before a ine and serotonin (5-HT), and a reduction in the activity of methamphetamine result can be reported [78]. In a non- the enzymes responsible for their synthesis (tyrosine regulated setting, where this criterion is not typically dehydroxylase and tryptophan hydroxylase, respectively). applied, but where ephedrine is shown to be present in Both acute and chronic administration of metham- great excess of methamphetamine, there should be a phetamine in an in vitro system caused a decrease in the careful review of the procedure and data. rate of dopamine and 5-HT uptake into the striatum as The issue of lack of specificity of the methamphet- soon as 30 minutes after exposure to the drug [36,60]. The amine mass spectrum can be resolved by derivatization effect was reversible and persisted less than 24 h, and [106]. Many methods have been published for the analysis could not be extinguished by washing the drug out of the of methamphetamine and related compounds [2,26,40,47, synaptosomes. The transporter activity returned to normal 71]; the reader is encouraged to review these further. after 24 h, but declined again after eight days, suggesting a second distinct effect, that of neurotoxicity and associ- II. PHARMACOLOGY ated terminal degeneration. There is evidence that other transporter systems such as norepinephrine are also af- The pharmacology of the amphetamines is complex, fected, but by a different mechanism, since washing and involves both central and peripheral actions. The residual methamphetamine out of the cell preparations did summary presented here is necessarily brief, and a review eliminate the effect [44]. of the pharmacology of neurohumoral transmission in a Tolerance to the CNS effects of amphetamines is comprehensive pharmacology textbook is encouraged. pronounced, and in therapeutic use, a course beyond six Methamphetamine is a sympathomimetic drug, mean- weeks is not recommended. Gygi et al. [42] demonstrated ing that it mimics endogenous transmitters in the sympa- that methamphetamine concentrations in the brains of rats thetic nervous system by interaction with their receptors. receiving a long-term methamphetamine pretreatment The prototypical sympathetic neurotransmitters are the were decreased compared to non-exposed animals when catecholamines, norepinephrine, dopamine, and epineph- exposed to a subsequent high-dose methamphetamine rine, and the structural similarity of methamphetamine is challenge. In the same animals, the plasma concentrations

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in the exposed animals were higher than in the non- associated with the use of this drug, gives it a popular exposed animals following the same challenge. This sug- reputation as a “sex drug”. However, at higher doses and gests that tolerance is not principally due to enhanced in more intense use patterns, users generally fail to achieve metabolism or increased renal clearance of methamphet- orgasm, and interest in sexual activity is consequently amine, but rather to changes in the structures responsible diminished. for uptake. Using a rat model, other workers [93] have also The stereoselective nature of the peripheral actions of shown that methamphetamine’s effects are not reliably the amphetamines means that the effects and side effects predicted from serum concentrations. In the first hour experienced by the user will be determined to a great following intravenous administration, brain concentra- extent by the enantiomeric content of the drug ingested. tions are eight times higher than in the serum. An exami- Tolerance to peripheral effects including mydriasis may nation of methamphetamine distribution in the brains of develop, although to what degree is extremely variable. decedents from methamphetamine-related deaths has The peripheral effects on the heart mean that the enantio- shown little difference in distribution between dopamine meric composition of the drug used may influence not rich and dopamine poor areas [57]. only the quality of the drug experience for the user, but Segal and Kuczenski [97] have reported a dopamine/ also the extent of the life-threatening pathophysiological behavioral response to low-dose amphetamine and meth- effects. Certainly, in a law enforcement environment, care amphetamine challenges in animals withdrawn from es- should be taken with restraints. “Hog tying”, sitting on the calating dose-binge treatment. They suggest that these subject’s chest, or actions that will obstruct breathing effects may be linked to the induction of stimulant psycho- should be avoided so as not to put additional strain on the sis in sensitized animals, and by extension in high-dose cardiorespiratory system [104]. amphetamine abusers. Other researchers [110] have more recently reported that sensitization to flashbacks can be- C. Route of Administration come induced in chronic users, lowering the threshold for reoccurrence of psychotic episodes. Flashbacks are then Methamphetamine can be ingested via a variety of triggered by stressors including social interaction, con- routes, and there is typically a progression following the flict, fear of imprisonment, discipline, family pressure, start of use, from oral ingestion (often in gelatin capsules and somatic discomfort. Those experiencing flashbacks or now commonly in small wads of toilet tissue), or nasal reported frightening auditory and visual hallucinations insufflation, to intravenous use. Smoking of the drug including dead bodies, ghosts, delusions of being at- achieved popularity in Asia and Hawaii in the 1980s, and tacked, and being followed or pursued. was associated with “Ice”, which was simply larger crys- tals of methamphetamine that were smoked in a pipe, B. Peripheral Effects much like crack cocaine. In spite of the media attention given this phenomenon, it never gained widespread popu- Peripheral effects of the amphetamines are more larity as a route of administration, and remains minor marked with the l-isomers, and come mainly through their compared to the others discussed above. In Seattle, the α and β1 and β2 adrenergic agonist properties. Character- routes of administration reported in the spring of 1998 istic “fight or flight” effects of methamphetamine medi- were smoking (19%), intranasal use (36%), and IV use ated through the α-receptors include mydriasis (pupillary (44%) [15]. dilation), bronchial muscle dilation, vasoconstriction, coronary dilatation, and bladder contraction. The heart D. Patterns of Use rate accelerates, blood pressure rises, and blood glucose levels increase. The peripheral vasculature is constricted, The motivation for abuse of methamphetamine is increasing venous blood pressure, and cardiac output may discussed later, but since the users’ drug experience is be slowed. These effects can result in arrhythmia, regard- determined largely by their pattern of use, and because of less of the dose or blood concentration, placing patients the limited degree to which the pharmacological literature with cardiovascular disease at high risk of heart attack. has studied patterns of use, some discussion is merited Other data suggests that cardiac effects may also be here. mediated indirectly by release of epinephrine into the Methamphetamine has legitimate therapeutic use in circulation [87], and may contribute to changes in heart the treatment of overeating disorders, where it can be used muscle following chronic use. Skin tremors may develop. to control appetite, in narcolepsy, and in the treatment of In the male, ejaculation is delayed and intensity of orgasm Attention Deficit Disorder (ADD) and Attention Deficit is enhanced, which, coupled with the increase in libido Hyperactivity Disorder (ADHD). Incentives for the mis-

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use of the drug vary widely, and include its use by shift In summary, the major negative effects of metham- workers to combat fatigue or postpone sleep, by teen-age phetamine abuse appear to be largely a result of higher- girls and others to suppress appetite during dieting (a dose, chronic, high-intensity, often intravenous, binge frequent route of entry to drug use), and by students to help use. Little about the drug’s most deleterious effects can with studying or meeting deadlines, in addition to straight- therefore be inferred from the oral administration of forward hedonistic, recreational use. Although the pur- clinical doses in a controlled environment over a period of pose for using will generally dictate the initial pattern of a day or less. The body of literature on this topic should use, habituation to the CNS effects develops rapidly, and, therefore be interpreted with caution when considering if use continues, will generally deteriorate into bingeing as recreational patterns of use. described below. Single therapeutic dose (5Ð10 mg) administration of III. METABOLISM methamphetamine has received by far the greatest degree of study both from a pharmacokinetic and behavioral Methamphetamine undergoes phase I metabolism by standpoint [13,14,20,45,46,86]. However, low-dose oral N-demethylation to amphetamine via the cytochrome administration is not a common pattern of abuse, and in P4502D6 isoenzyme system. Amphetamine itself is ex- fact these subjects will most likely experience relatively tensively metabolized to a variety of metabolites, includ- little in the way of excitatory or euphorigenic effects, or ing norephedrine and p-hydroxyamphetamine, both of other side effects that are likely to impair their perfor- which are pharmacologically active, and may be mance. glucuronidated prior to excretion. The treatment community sees in their population Several other drugs are metabolized to amphetamines. (many of whom are referred from the criminal justice Benzphetamine (Didrex¨), is metabolized to desmethyl- system), quite a different pattern — “binge” users, who benzphetamine, but also to d-methamphetamine and am- can be classified as either low-intensity or high-intensity phetamine, making enantiomeric resolution of limited bingers (Figure 1). Methamphetamine binges typically value in determining the origin of the amphetamines in take place over a period of two or more days, and will these cases [17,19]. Selegeline (Deprenyl¨), a drug given involve repeated administration of the drug at intervals of in the treatment of Parkinson’s disease, is unusual in that 1 to 5 h. The half-life of methamphetamine as discussed it is rapidly metabolized to l-amphetamine and l-metham- below is about 10 h, and highly elevated blood concentra- phetamine, generally in equivalent amounts [95]. tions can be achieved following this pattern of use. The Famprofazone (Gewodin¨), an analgesic with antipyretic user is often involved in partying, sexual activity, shift properties, is metabolized to d- and l- methamphetamine work, or repetitive tasks requiring simple but focused and amphetamine, as well as 3-hydroxymethyl-propy- attention, such as mechanical repair or tinkering, house phenazone. The latter metabolite is identified in urine only cleaning, or long-distance driving. Obsessive-compulsive after enzymatic hydrolysis with beta-glucuronidase/ “sorting” behaviors are often reported. Bingeing is most arylsulphatase. The average amount of (Ð)-methamphet- frequently associated with intravenous administration. amine isomer excreted in the urine was found to be three Once the drug supply is exhausted, or other imperatives times that of the (+)-isomer [80]. prevail, the use of the drug ends, and the user starts to come down. The subject will frequently experience a phase known as “tweaking”, (discussed below), which may last 6 to 18 h depending on the duration of the binge, followed by a crash characterized by lengthy non-restful sleep which may last a day or more, and then a return to apparent normalcy for a few days, during which a craving for the drug may appear, again depending on the degree of dependency developed in the subject. Binges that extend beyond two days can be character- ized as high-intensity binges. These may last for extended periods up to several weeks and may comprise shorter binges separated by brief periods (hours or days) of Figure 1. Schematic representation of a methamphetamine abstinence, but still contain all the phases discussed above, binge. The time axis is extremely variable and may represent with a gradually deteriorating state of mind, frequently from two days to several weeks. These phases are discussed in ending in a psychotic state. the text (after Stalcup [103]).

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Fenethylline (Catpagon¨), used in the treatment of Given the current availability of illicit d-methamphet- attention deficit disorder, is metabolized to d,l-amphet- amine and cocaine, the practice of inhaler abuse is now amine [83]. Clobenzorex (Dinintel¨), an anorectic, is uncommon. The relative rates of metabolism of d- versus metabolized to d-amphetamine, but use of the drug can be l-methamphetamine have been cursorily studied in some differentiated by measurement of the specific metabolite of the older literature. This literature, reviewed by Nagai 4-hydroxyclobenzorex [7,107]. Other drugs metabolized and Kamiyama [76], suggests that both enantiomers show to amphetamine include furfenorex [55], mefenorex [63], similar urinary excretion patterns; however, these au- fenproprex [64], and prenylamine [89]. thors’ studies in rats have suggested that the l-isomer is In summary, there are many drugs that metabolize to more extensively transformed to p-hydroxymethamphe- amphetamine or methamphetamine. Analysis of the spe- tamine and p-hydroxyamphetamine than the d-isomer. cific enantiomer present, together with tests for the spe- They also note that humans have no chiral isomerization cific metabolite of the ingested drug and a consideration of enzyme for d-methamphetamine. the concentration of methamphetamine or amphetamine present, will all provide clues as to the origin of the B. d-Methamphetamine — Acute Dosing measured drug. Nonetheless, irrespective of their origin, the effects associated with amphetamines in the blood, 1. Oral Dosing and consequently the brain, are significant and are dis- The most comprehensive pharmacokinetic study of cussed in detail later in this review. oral S(+)-methamphetamine (i.e., d-methamphetamine) was reported by Cook et al. [20]. The authors used deuter- IV. PHARMACOKINETICS ated drug for the first dose, followed by a sustained release preparation over 15 days, and concluded with a final A. l-Methamphetamine and Use of Decongestant In- deuterated dose. This allowed the evaluation of possible halers changes in metabolism or pharmacokinetics with chronic administration. With one exception (Cmax, discussed be- In the United States, l-methamphetamine (under the low) there were no differences between the kinetics of the label l-desoxyephedrine) is the active constituent of the first and last dose. The authors consider, but discount, Vicks Inhaler decongestant, an over-the-counter product concerns that there might be differences in the metabolism containing about 50 mg of drug. This isomer has about 25Ð of the isotopomers, and note that the elimination curves of 33% of the CNS activity of its d-enantiomer. While the the d0 and d3 isotopomers could be co-fit. only way to completely eliminate this as a cause of a Following oral administration of deuterated d-meth- methamphetamine positive drug test result is a stereospe- amphetamine hydrochloride doses of 0.125 or 0.250 mg/ cific test, the following considerations suggest that posi- Kg (equivalent to 8.75 mg, or 17.5 mg respectively, in a 70 tive drug test results from use of this product are unlikely. Kg (154 lb) subject), mean (n = 9) peak plasma metham- A single Vicks inhaler contains only 50 mg of l- phetamine concentrations of 0.020 mg/L and 0.039 mg/L, methamphetamine. The recommended dosage is two puffs respectively, were achieved. The absorption half-life was every 2 h for up to 7 h, with each puff dispensing about 21 0.67 h. The time to peak was between 2.6 and 3.6 h (mean, ng. A subject following these recommendations would 3.1 h), and the mean elimination half-life was 10.1 h, with therefore receive around 300 ng of the drug [4]. This is an a range of 6.4Ð15 h. insufficient quantity to produce significant CNS effects, The maximum plasma concentrations of the amphet- and would not result in a positive urine drug screen. amine metabolite were observed at approximately 12 h However, very heavy use has resulted in urine metham- after dosing, with mean concentrations of 0.0016 and phetamine concentrations of greater than 0.500 mg/L 0.004 mg/L (1.6 and 4 ng/mL) after the low and high [18,35]. Anecdotal data from workplace drug testing doses, respectively, i.e., approximately 15% of the con- programs suggests that the incidence of l-methamphet- centration of the parent drug concentration present at that amine positives in workplace specimens is virtually un- time. known [22,98]. Between 30% and 54% of the ingested dose was Abuse of l-desoxyephedrine products used to be quite excreted unchanged in the urine, with a greater percentage common [38], but this usually involved opening the in- being excreted unchanged at the lower dose. Between haler, extracting, and then injecting the drug. This practice 10% and 23% of the dose was excreted as amphetamine. is also followed for propylhexedrine [3], the active con- The pharmacokinetics were found to be essentially the stituent of the Benzedrex¨ inhaler. The resulting product same for the first dose (deuterated), as for the last dose is sometimes called “peanut butter methamphetamine”. (also deuterated) over a 15-day period, although follow-

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ing the end of the higher-dose regimen, peak concentra- 4. Summary tions were slightly (but statistically significantly) higher The smoked and intravenous routes of administration than they were at the beginning. There was no apparent resulted in quite similar kinetics, with a slightly later peak induction of metabolism or change in kinetics over the 15- following smoking. After oral ingestion, the peak was day dosing period. delayed by around 3 h. The mean elimination half-life Concentrations of the drug in the saliva were approxi- appears to be independent of route of administration and mately 7 times greater than in the plasma, but there was in these subjects was around 10 h (oral), 11 h (smoking), significant variability. The authors also note that metham- or 12 h (IV injection). However, the ranges for half-life are phetamine kinetics can be markedly affected by abnor- broad (extremes of 6.4 and 18.2 h were found in this small mally acidic or alkaline urinary pH. study population), and, as noted throughout, are a reflec- tion of variability in urinary pH. A volume of distribution 2. Smoking of 3.5 L/Kg was noted. Furthermore, the data from the The same authors reported on pharmacokinetic pro- report on smoking/intravenous administration also sug- files in subjects following smoked and intravenous ad- gested that methamphetamine kinetics might be dose- ministration of d-methamphetamine in a second study dependent with slower clearance at higher doses, due, at [21]. When smoked, approximately 73% of a 30-mg dose least in part, to a saturable excretion process in the kidney. was ingested as vapor, with the remainder of the drug This has important implications for the kinetics, and being left in the glass pipe. The average dose ingested by therefore the detection window, in high-dose, chronic, or the subjects was 22 mg of methamphetamine hydrochlo- binge use. ride. Following smoking, the peak plasma concentration Because of the late peaking of amphetamine, and the (mean, 0.047 mg/L) was achieved at around 2.5 h, but a low concentrations immediately following administra- plateau was sustained for an additional 2 h. The average tion, a high methamphetamine-to-amphetamine ratio could elimination half-life was 11.1 h, with a range of 8.3Ð18.2 be indicative of recent use, but as the authors note, mul- h. tiple doses would confound this interpretation. Peak plasma amphetamine concentrations after smok- ing were quite low (around 0.004 mg/L) and again were C. d-Methamphetamine — Chronic/High-Dose Dos- achieved at around 12±2.3 h after dosing. Approximately ing 37% of the ingested dose was excreted in the urine as the parent drug, while 7% was excreted as amphetamine. In a study of the efficacy of treating narcolepsy with The kinetics of smoked methamphetamine are quite methamphetamine, Mitler et al. [75] gave 5, 10, 20, different in character from those of smoked cocaine, 40, or 60 mg single daily oral doses each morning over which is absorbed very rapidly with kinetics similar to that four days, and found the following mean morning (~2 h of IV administration. The kinetics of smoked metham- post-dose) and afternoon (8 h post-dose) serum drug phetamine more closely resemble that of oral administra- concentrations (dose — mean a.m. conc. (mg/L), mean tion. Cook et al. [21] attribute this to subjects swallowing p.m. conc. (mg/L)): 5 mg — 0.011, 0.006; 10 mg — 0.023, some of the smoked dose, absorption of drug trapped or 0.020; 20 mg — 0.050, 0.046; 40–60 mg — 0.117, 0.093. adsorbed on the mucosa, or the drug being retained in and Perez Reyes et al. [86] administered a daily 10 mg slowly absorbed from the lungs. This is further com- dose of a sustained release preparation of methamphet- pounded by the long half-life of the drug. amine hydrochloride to six subjects for 15 days, with peak daily concentrations not exceeding 0.020 mg/L and drop- 3. Intravenous Injection ping to 0.005 mg/L. The pharmacokinetic parameters following intrave- Anggard et al. [5] administered 20, 40, 80 or 160 mg nous use were very similar to those seen following smok- of amphetamine intravenously to amphetamine-depen- ing, or oral use [21]. The peak methamphetamine concen- dent, psychotic and non-psychotic patients. The corre- tration was achieved almost instantaneously, as would be sponding serum amphetamine concentrations 1 h after expected, although there also appeared to be a rebound in administration were 0.056, 0.124, 0.260, and 0.595 mg/L. concentrations within the first hour. The mean peak plasma Other patients (n = 18) were administered 160 or 200 mg concentration after a mean 12-mg IV dose was 0.097 mg/ intravenously and achieved 1 h plasma concentrations of L. The mean elimination half-life was 12.2 h. Peak plasma 0.365Ð0.600 mg/L (mean 0.423 mg/L). amphetamine concentrations of around 0.004 mg/L were Useful information can be obtained from examining achieved after 17 h. Around 45% was excreted in the urine the concentrations of the drug in the blood of subjects as the parent drug with around 7% excreted as amphet- whose deaths were not a result of their drug use. This is amine.

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well illustrated as a “snapshot” of the concentrations in pressure (systolic and diasystolic) showed a marked in- these subjects’ blood at the time of their violent death. crease within the first 30 min, and a tendency toward Bailey and Shaw [8] reported median blood methamphet- increased levels throughout the subsequent 3 h. This is amine and amphetamine concentrations in homicide vic- correlated with an initial drop in total peripheral resis- tims (n = 25) of 0.490 mg/L (range: 0.030Ð7.100 mg/L) tance, which, particularly in the case of IV use, tended to and 0.085 mg/L (range: not detected to 1.200 mg/L) rebound to elevated levels over the ensuing 3 h. After respectively. Logan et al. [67] reported a median blood smoking 40 mg, subjects reported hypomanic symptoms methamphetamine concentration of 0.550 mg/L (range: for about 2 h, intense craving for further doses, difficulty 0.030Ð9.300 mg/L) in 39 homicide victims. In fatally in concentrating, memory lapses, and insomnia. These injured drivers, the same study reported mean blood changes in vital signs all have important consequences for methamphetamine concentrations of 0.350 mg/L (range: the Drug Evaluation and Classification Program (DECP, 0.050Ð2.600 mg/L). sometimes DRE) examination discussed later. It is clear that the typical concentrations in this abus- ing population represent rates of drug use far above those B. Chronic Administration — Therapeutic Dose encountered in the laboratory pharmacokinetic studies discussed earlier. This has important implications for the This type of dosing pattern is characteristic of thera- performance and behavioral effects likely to result, and peutic use in the treatment of narcolepsy, eating disorders, the reader is cautioned about inferring effects in the and attention deficit (ADD) and attention deficit hyperac- abusing population from those documented with low tivity disorders (ADHD). In these situations, the recom- doses in laboratory subjects. mended dose is 5- to 10-mg doses with occasionally as much as 60 mg being given. Mitler [75] reported improve- V. PHARMACODYNAMICS ments in mean sleep latency time, and also improvement in a driving simulator obstacle course, which is discussed A. Acute Administration — Therapeutic Dose later. Under these dosage conditions, he found no signifi- cant increase in blood pressure, pulse, or respiration rate, As noted in “Patterns of Use” above, the many nega- although these measurements were made each day some tive effects of methamphetamine are likely sequelae to hours after dosing. Side effects appeared in a dose-depen- chronic, high-dose, or binge use, so the acute effects of dent manner and included loss of appetite, insomnia, low-dose administration are of limited relevance. Further- headache, nervousness, and motor restlessness. There was more, there is no real therapeutic rationale for this type of no reported change in mood or libido. short-duration dosing given the conditions indicated for Perez Reyes’ study [86] did find some tolerance to the legitimate prescription of this drug. Be that as it may, these tachycardic effects of the drug over a 15-day period, but acute effects are the easiest to study and therefore the most not to the elimination half-life, subjective high, or blood widely reported. They are discussed here to provide a pressure. context for the chronic effects discussed later. At low doses, users report the following subjective C. Abuse — High-Dose and Chronic Administration effects: reduced appetite, increased alertness and energy, reduction of fatigue and drowsiness, general increase in For obvious reasons this is the most difficult kind of psychomotor activity, and a general sense of well-being. pattern to study in a laboratory setting due to ethical and They may also experience restlessness, dizziness, informed consent issues. A report by Bell [9] of work overstimulation, insomnia, mild confusion, and, in rare conducted between 1959 and 1967 describes a series of 14 instances, panic or psychotic states (generally in individu- psychotic patients with a history of methamphetamine use als predisposed to schizophrenia). who were administered high doses of methamphetamine In the smoking/intravenous study abstracted above in an effort to reproduce the psychosis. These subjects, [20], peak subjective effects were achieved 18 min after who reported maximum daily dosages as high as 1000 mg, the start of smoking, or 17 min after intravenous injection. received up to 640 mg of drug intravenously over about 1 When smoked, the peak subjective effects preceded the h, until symptoms of psychosis appeared. The psychosis peak plasma concentration by about 2Ð3 h, providing lasted 1Ð2 days in 9 patients, 5 days in 2, and intermittently evidence for the development of acute tolerance. in 1 patient for 26 days who, it later was discovered, was Effects from smoking or intravenous administration surreptitiously taking more of the drug! included an increase in mean heart rate (to 97 bpm (smok- Typical constellations of symptoms are described by ing) or 105 bpm (IV)), stroke volume, and cardiac output several authors [28,61,62,101] and are summarized here. for the first 30 min following administration [87]. Blood

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At higher doses, particularly following intravenous use, ety (28%), amphetamine psychosis (18%), malnutrition users typically report intense exhilaration and euphoria, (12%), and exhaustion syndrome (9%). More recently, extreme wakefulness, rapid flow of ideas, feelings of Derlet et al. [25] reported symptomatology in 127 cases of increased physical and mental capacity, garrulousness, amphetamine toxicity in Sacramento. The findings were talkativeness, and rapid speech. Elevated self-esteem and similar with 57% reporting altered mental status, includ- intense sexual arousal are also common. Thought patterns ing agitation, suicidal ideation, hallucinations, confusion, tend to be rapid and of a decisive nature. These effects are and despondent affect. Only 10% of the patients had been perceived as positive and generally encourage repeated found unresponsive. Richards et al. [90] have reported administration, producing a binge-type use pattern. As the blunt trauma as the most frequent cause of admission binge progresses, the drug is repeatedly administered (33%) to an emergency room in methamphetamine intoxi- every few hours over a period of hours or days. Often as cated patients, followed by an altered level of conscious- early as the second day, the subject enters a phase known ness (23%), including acute agitation, hallucinations, (e.g., as “tweaking”. During this phase, euphoria is gradually “skin bugs”), tonic-clonic seizures, and fainting. Similar replaced with mounting anxiety, inability to concentrate, patterns are reported by Chan et al. [16] in a group of eight and delusions. The user is anxious, irritable, short-tem- patients admitted to an emergency room in Taiwan. Three pered, and introspective. Pseudohallucinations can occur, patients were in a coma, and three of the remaining five and paranoia sets in. These unpleasant effects can be reported hallucinations, agitation, confusion, and muscu- temporarily eliminated by re-administration of the drug, lar twitching. again reinforcing use, but the highs become less intense In a review of symptomatology in a group of nine and the lows become lower as the binge proceeds. Even- patients reporting with amphetamine psychosis, Hall et al. tually the user becomes so tired and fatigued that they may [43] reported among the more frequent findings, ideas of “nod off” to sleep and then start awake, reporting dysphoria, reference, increased motor behavior, paranoid ideation, fatigue, anergia, anhedonia, and exhaustion. At this point paranoid delusions of influence, visual illusions in periph- drug administration will cease, and the user enters the eral field, lability of mood, and increased sex drive. Many “crash” phase. This period of restless, light sleep can last of the subjects were unable to separate their psychotic for a day or more, during which there is a compulsion to experiences from reality after the psychosis had resolved. sleep or an inability to maintain consciousness. The longer A similar description is provided for other drugs, in the duration of the binge, the greater the likelihood that a addition to amphetamine, by Hurlbut [49]. psychosis, characterized by true hallucinations and delu- The treatment of methamphetamine abusers with acute sions, will develop. This condition is often indistinguish- toxicity as described elsewhere has been addressed by able from a schizophreniform psychosis, and can only be Richards and co-workers [91,92]. They evaluated differentiated in that it will resolve over time as the drug droperidol and lorazepam for the chemical restraint of is cleared from the body and homeostasis restores the agitated, combative patients, most of whom had been neurochemical balance. As will be seen, the using methamphetamine. The subjects were typically symptomatology for acute high-dose use is very similar to very agitated, combative, violent, and out of control. that reported for chronic use, which is invariably high- Although both drugs effectively sedated the patients, the dose. Gawin and Kleber [39] have described and charac- authors recommend the use of droperidol because of its terized abstinence symptomatology in cocaine users, and longer half-life. that syndrome contains many features similar to those encountered in methamphetamine withdrawal. D. Summary Anggard et al. [5] measured amphetamine concentra- tions in serum of psychotic patients admitted to hospital Clearly the most important effects with respect to and found concentrations of 0.161Ð0.530 mg/L within the psychomotor impairment and behavioral effects are found first day of admission. Subjects were displaying lack of outside of the normal patterns of low-dose, therapeutic concentration, paranoid delusions, hallucinatory behav- use, and therefore the real value of most of these studies is ior, and disorganization of thoughts, but importantly there in helping us differentiate abuse from therapeutic use. It is was no correlation between the plasma amphetamine evident that normal therapeutic dosing is around 10 mg/ concentration and the degree of psychosis. day, and does not exceed 60 mg/day, generally by mouth, Smith and Fischer [102] reported symptomatology in usually in divided doses. Even this high dose will result in a group of 310 patients reporting to a treatment facility peak methamphetamine concentrations of 0.020 mg/L or with acute high-dose methamphetamine toxicity. Among less. If a sustained release preparation is used, concentra- the more prominent conditions reported were acute anxi- tions will typically be lower. More common are doses of

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5 mg or 10 mg, resulting in peak concentrations of 0.005 survival of a subject (following medical intervention) to 0.010 mg/L. Negative psychomotor effects at these with a blood methamphetamine concentration of 9.50 mg/ doses can occur, but are uncommon. Conversely, there is L, showing that extremely high methamphetamine con- excellent evidence that performance in some motor skills centrations are not always lethal. Similarly, in this series, is restored in fatigued subjects, and plentiful, if less in those cases with higher methamphetamine concentra- consistent, evidence that performance can be improved in tions, the cause of death was invariably gunshot wound. non-fatigued subjects. The presence of these high levels in ambulatory individu- The most profoundly impairing effects result from als illustrates one of the difficulties in designating a high-dose use, which in many cases may be distinguished presumptive “lethal” level or range for the drug, or deter- based on blood concentrations. As noted above, concen- mining cause of death solely from toxicology results. trations of methamphetamine exceeding 0.020 mg/L can Eighty-three percent of the homicide victims had blood reasonably be assumed to result from abuse, and effects of concentrations of methamphetamine less than 1.0 mg/L. the drug on self-perception, critical judgment, attention, These are likely representative of the levels routinely risk-taking, mood, and motor restlessness may all contrib- achieved in live methamphetamine abusers. ute toward a deterioration in safe driving. However, an Over the same period of time, for deaths in Washing- important exception to this ability to distinguish use from ton State in which the victim tested positive for morphine, abuse based on blood concentrations is in the impairment only 4% were homicide victims and 6% were suicides. By suffered during “tweaking” or withdrawal. During this comparison, in decedents testing positive for cocaine use, period, which can last for days following the time of last another stimulant, 18% were homicide victims and 9% use, the blood drug concentration will decline to sub- were suicides. This compares to 27% homicides and 14% therapeutic concentrations, while the potential for with- suicides testing positive for methamphetamine. Much drawal-induced impairment discussed above (irritability, anecdotal evidence has suggested an association between anxiety, paranoia, delusions, hallucinations, and most violence and stimulant use in general, and methamphet- importantly, fatigue) is at its height. Therefore, low (<0.020 amine use in particular. Logan [66] reported that violent mg/L) concentrations do not exclude the possibility of behavior in subjects arrested for driving under the influ- impairment. This is discussed in more detail when specific ence (DUI) who later tested positive for methamphet- effects on driving are considered below. amine was more consistently noted in individuals with blood concentrations greater than 1 mg/L. VI. FORENSIC ISSUES There is also a suggestion in both the sociological and criminological literature that users of illicit drugs, includ- A. Methamphetamine and Violence ing the amphetamines, are more prone to victimization than the general population. Kingery et al. [58] reported In a review of deaths associated with methamphet- that adolescent drug users fought more, took more risks amine use [67], one startling factor was the marked that predisposed them to assault, and were assaulted more incidence of homicidal or suicidal violence. Eighteen of often than non-drug users. Drug use by both the victim the deaths were suicides, and the causes of the other deaths (14%) and the victim’s dating partner (27%) was reported were gunshot wound (11 cases), CO poisoning (3 cases), in a study of violent dating incidents [12]. Drug use was hanging (2 cases), and falls (2 cases). In most cases it was also reported as being common in both victims and perpe- not possible to determine precisely the factors that led to trators of domestic violence [99]. Among the reasons cited the decision to commit suicide. However, methamphet- for this are a combination of the following: low self- amine use can contribute to suicidal behavior as a result of esteem, anxiety, and depression leading to drug use; economic, social, and psychological pressures, as well as involvement in a culture in which possession of weapons the impaired judgment and lack of critical thought associ- is common; and the development in co-users of paranoia, ated with both stimulant impairment and abstinence syn- violent tendencies, impaired judgment, and poor impulse drome. control. These factors can all engender an atmosphere in In this population [67] there were 40 homicides where which minor disagreements or misunderstandings can the subject tested positive for methamphetamine, with the quickly escalate to homicidal violence [27]. Although cause of death being gunshot wound (31 cases), stabbing there is much anecdotal evidence, there is no objective (7 cases), or strangulation (1 case). The blood metham- data clearly demonstrating the causal link between violent phetamine concentrations in homicide victims ranged behavior and methamphetamine use/blood concentration. from less than 0.03 mg/L to 9.30 mg/L (median 0.550 mg/ Stimulant-related violence is also discussed by many L). By way of comparison, Logan et al. [69] have reported other authors [49,61,74,99,101].

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B. Methamphetamine Combined with Alcohol and indicated that each drug modifies the effects of the other. Other Drugs Amphetamine produced no improvement of ethanol-im- paired performance in most tests, although in some simple Methamphetamine is frequently combined with other repetitive tasks (serial addition, coding, and trail-making), drugs, including alcohol [109], marijuana, narcotic anal- it did. The results indicated that when both drugs were gesics, other stimulants, and depressants [60] and it is present together, the effects could not be predicted on the often difficult to separate effects of one drug from another. basis of depressant versus stimulant competition. The combinations — “goofballs” (amphetamines and Mendelson et al. [72] reported that methamphetamine barbiturates), or “speedballs” and “bombitas” (amphet- (30 mg IV) did not change ethanol (BAC ~0.08g/100mL) amines or cocaine and heroin) — are taken to provide a intoxication self-ratings, although heart rate increase was “relaxed high” or to offset some of the agitation and greater and more sustained following administration of irritability experienced during high-dose amphetamine the combination. use. Depressants, including alcohol, are also used to help Newman and Newman [82] reported that neither during tweaking or withdrawal to assist with sleep. Mari- caffeine nor amphetamine (15 mg) were effective in juana may also be used in this phase, or simply to custom- restoring ethanol-induced performance impairment in tests ize the amphetamine experience. of balance, steadiness, and fusion. A concern in assessing potential effect of metham- In summary, there is no reason to believe that on a phetamine is whether the co-administration of stimulants neurophysiological level the stimulant effects of amphet- and depressants would tend to cancel out the effects of amine use would be negated by the ingestion of a depres- either drug. A few studies have examined the co-adminis- sant, or vice versa, and this is borne out by the studies tration of amphetamines with other drugs in man. reviewed. Combining drugs that individually have a com- In evaluating the combined effects of alcohol and plex effect on mood, sensorium, judgment, risk-taking, methamphetamine, Forney [37] reviewed work by and values inevitably complicates things even further, Rutenfrantz and Jansen [96], which suggested that low- making these executive operations less predictable and dose methamphetamine (9 mg, IV) partially reversed the more subject to error. These studies suggest that even at effects of low doses of alcohol in subjects in a driving the low doses of amphetamine used, the impairing effects simulator, yet their results were based on only two sub- are generally additive to those of the depressant, but, as in jects, have not been replicated, and in fact have been the case of fatigue, some performance decrement in simple contradicted by other researchers. In a study of alcohol repetitive tasks may be improved. (BAC ~0.05g/100mL) and amphetamine (dose: 0.2 mg/ Kg (14 mg/70 Kg)) effects on mood and volition measured C. Military Use and Effects on Counteracting Fatigue by betting in a card game [53], alcohol produced a greater degree of risk-taking. Amphetamine alone, or in combina- As early as 1966, it was recognized that the perfor- tion with alcohol at this dose, did not appear to affect risk- mance enhancement resulting from amphetamine use was taking. generally significant in restoring performance in fatigued In a blinded crossover design study [33] subjects were subjects, rather than producing performance above baseline administered placebo, amphetamine alone, marijuana in normal subjects [65]. The effects of fatigue are of great alone, or marijuana and amphetamine. However, the am- concern to the military, particularly in a combat setting. phetamine dose was oral, acute, and low (10 mg), and Newhouse et al. [81] reported on the efficacy of d- subjects could distinguish, with reliability, the amphet- amphetamine (10 or 20 mg) on restoring baseline perfor- amine from the placebo. Subjects still reported a more mance in subjects deprived of sleep for 48 h, and found a intense high from the drug combination than from either dose-related level of improvement. The use of amphet- drug alone. The effects appeared to be additive. Heart rate amines by the military is an issue that deserves attention, increased acutely with the smoking of marijuana, but the since superficially it may appear at odds with arguments increase was sustained longer when both drugs were co- expressed here that abuse of methamphetamine would ingested. Psychomotor changes (especially slowing of inevitably produce impairment. reaction time) appeared to be most readily attributable to Ever since its invention in 1919, the potential benefits the marijuana use, and there was no evidence that the from this drug in a military setting have been appreciated. amphetamine restored the performance lost. It was used by both the Allied and Axis powers during the Wilson et al. [108] co-administered a 15-mg dose of Second World War to allow prolonged forced marches, amphetamine with or without alcohol and had subjects and to keep troops awake and alert in protracted combat. perform a variety of psychophysical tests. The results Military use of the drug to counteract fatigue has contin-

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ued through to the present day. In Operations Desert proach is to examine case reports or epidemiology of Storm and Desert Shield during the Gulf War, pilots were drivers involved in traffic accidents or impaired driving issued “GO” pills (d-amphetamine, 5 mg) [32]. They were arrests. A third approach is to examine laboratory reports limited to the use of one pill every 4 h to combat fatigue of performance in driving simulators or laboratory tests of resulting from sustained flying operations (duty days of psychomotor performance following methamphetamine greater than 16 h and crew rest periods of less than 6 h), and administration. Considered together, this information time zone changes. As many as two thirds of the pilots should give a picture of the impact of methamphetamine flying there used the pills, and the rating of the effects was on driving, including information about any causative almost uniformly positive, many stating that they felt it link. made for safer flying operations. However, in contrast to typical recreational patterns of use, the drug was adminis- 1. Empirical Considerations tered orally, in small divided doses, under the direction of Starting with the first and most empirical approach, a flight surgeon. methamphetamine is a stimulant drug, which at low oral Caldwell et al. [14] demonstrated the ability of am- doses is effective in offsetting the consequences of fatigue phetamine (30 mg in divided 10-mg doses at 4-h intervals) on psychomotor performance. The effects reported at this to sustain helicopter pilot performance in a flight simula- level of dosing are improved alertness, improvement in tor during periods of sleep deprivation (over 48 h without reaction time, elevation of mood, reduction of sleepiness, sleep). There was reduced slow wave EEG activity, im- suppression of appetite, pupillary dilation, and some tran- proved alertness, and better self-ratings of fatigue and sient increase in heart rate and blood pressure. Occasion- vigor. These results were generally validated by Caldwell ally headaches, insomnia, light sensitivity, and irritability and Caldwell [13] in actual helicopter flight, although the are reported as side effects. Based on these considerations, drug’s effects were less significant, and did not become one would not expect widespread adverse effects on significant until after 24 h of sleep deprivation. driving from this pattern of use. Furthermore, it should be Fatigue is generally recognized as a major contributor recognized that in cases where a driver is fatigued from to driving impairment [11,105], so the notion that amphet- loss of sleep (24Ð36 h without any sleep), the drug might amines could be used to counteract this effect in fatigued restore some of the fatigue-induced impairment, and thus drivers is not so farfetched. Nevertheless, the doses of restore performance to baseline level. amphetamines typically used in a recreational situation Nevertheless, at elevated doses or after prolonged are well beyond what has been validated as being effective administration of the drug, and especially after intrave- in reversing these effects. Also, as discussed later, fatigue nous administration, the effects are quite different. During induced as a result of amphetamine abuse cannot be acute intoxication the CNS effects are intense, distracting, reversed by further administration of the drug. and overwhelming, including, as discussed earlier, exhila- In summary, when a subject is fatigued, performance ration and euphoria, rapid flow of ideas, feelings of great in simple psychomotor tests of short duration is barely physical strength and mental capacity, excitation, panic, effected, but performance impairment becomes marked and sexual arousal, often referred to as the “upside”. Less when sustained effort is required, or when the task is more frequently, hallucinations, delusions, perceptual distor- complex. The administration of 5- to 10-mg oral doses of tions, and assaultive behavior also occur. Most of these amphetamine at 4-h intervals has been shown to be effec- effects can reasonably be expected to contribute at a tive in restoring performance for periods up to 40 h. The minimum to a decline in concentration, inability to divide effects of more prolonged or frequent administration, attention, and errors in judgment and perception. Perhaps intravenous or smoked routes of administration, or the use more importantly, as the binge progresses, and the tweak- of higher doses has not been investigated. ing, and crash or withdrawal phases (often referred to as the “downside”) become established, the symptomatology D. Methamphetamine and Driving becomes quite different. The user becomes preoccupied with their thoughts and behavior, the euphoria is replaced There are at least three ways to evaluate the potential with agitation, concentration becomes difficult, and impact of methamphetamine on driving. The first is by “pseudohallucinations” appear (these are frightening vi- examining the physiological and psychological effects of sual images that the user knows to be unreal, or can be low-dose therapeutic administration through high-inten- persuaded are unreal). The subject often becomes con- sity binge abuse, and drawing conclusions about the fused, irritable, paranoid, and increasingly fatigued. Pro- potential impact of the typical signs and symptoms on a gressively, the presentation becomes one of CNS depres- complex psychomotor task like driving. The second ap- sion, progressing to periods of uncontrollable sleepiness

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and “microsleeps”, lasting a few seconds to minutes from between the concentration of the drug and its role in the which the user starts with disorientation and unease before cause of the accident. finally falling into a troubled, restless, sleep. The exten- In 1992, the National Highway Traffic Safety Admin- sive literature on driving impairment from CNS depres- istration (NHTSA) published a review of drug use in sants, particularly alcohol, demonstrates a clear link be- fatally injured drivers [77]. The most frequent type of tween their effects and driving impairment, suggesting accident among drivers testing positive for amphetamines that this phase of methamphetamine intoxication presents was a “non-collision” or drive-off-the-road-type accident real risks for psychomotor impairment and corresponding (50%, compared to 32% in the drug-free control group). A risks to driving performance. total of 83.3% of the amphetamine-positive drivers were deemed responsible for the accident, compared to 67.7% 2. Epidemiology in the drug-free control group, and 93.9% in the group The second approach is to consider epidemiological with blood alcohol greater than 0.09 g/100 mL. reports, such as rates of amphetamine use among fatally In summary, there is some evidence from these stud- injured drivers, or accident rates among drug users. ies that amphetamine use is prevalent in certain driver Smart et al. [100] reported on rates of accident in- populations, but it remains difficult on this basis alone to volvement among a variety of groups of drug abusers, and infer a causal link due to the absence of control data. found that the group of amphetamine users were the most Nevertheless, studies documenting rates of methamphet- likely to have an increased accident rate over the driving amine use in driving populations do allow identification of population in general. This study is unusual in that it trends and comparisons of drug-use patterns between contains a control group. groups and jurisdictions. The following literature review is taken in part from Logan [66]. Several studies of driver populations have 3. Laboratory Studies and Other Reports included tests for amphetamines and show a significant A third source of information is a review of the incidence of their use. Lund et al. [70] studied drug use in literature on amphetamines and driving performance. truck drivers on a major U.S. transcontinental highway Ferrara et al. [34] conducted an extensive review of and found methamphetamine in 2% of those drivers vol- literature on laboratory studies involving performance untarily tested. However, 12% of drivers contacted de- following administration of psychostimulants. Approxi- clined to participate. Crouch et al. [24] reported on the mately 5% reported impairment, 32% reported no effects, prevalence of drug use in fatally injured truck drivers and and 38% reported improvement, but Ferrara did not con- found amphetamine or methamphetamine in 7% of cases sider dose in this evaluation. (see [79]). Comparing Lund’s data to that of Crouch Evans et al. [33] had subjects rate whether their suggests that methamphetamine use is overrepresented in driving was impaired after a 10 mg/70Kg dose of d- fatally injured truck drivers. This would support a causal amphetamine. Of 11 subjects, one subject in the placebo relationship between methamphetamine use and increased group, versus three in the amphetamine group reported risk of fatal accident involvement, but the refusal rate in impairment (compared to 7 of 11 in the marijuana group, Lund’s study makes this comparison less than conclusive. and 8 of 11 in the combined amphetamine/marijuana Kirby et al. [59] reported drug use in traffic accident group). Mitler et al. [75], in studying the effects of meth- victims admitted to a level one trauma center in 1988 and amphetamine on narcoleptic patients and controls, in- found an incidence of amphetamine use of 2%. Robb et al. cluded 30-min sessions on a simple computer-based “driv- [94] reported on drug use in drivers in New Mexico ing simulator”. Methamphetamine displayed a dose-de- arrested under suspicion of driving under the influence of pendent improvement in performance in narcoleptics up drugs (DUID) and found 1.7% positive for non-cocaine to 60 mg, and in controls up to 10 mg. phenethylamine stimulants. Logan and Schwilke [68] Hurst [50] tentatively concluded that a 10-mg oral reported 1.8% of fatally injured drivers in Washington dose of amphetamine increased risk-taking. This finding State testing positive for methamphetamine. Unfortu- was supported by further work by Hurst et al. [54] evalu- nately, there is no corresponding control group in any of ating effects of amphetamine (14 mg/70 Kg) on judgment these studies to permit evaluation of the relative preva- and decision-making. These researchers found that both lence of amphetamine use in impaired drivers as opposed decisions to accept risk and self-appraisals of perfor- to the general driving population. In addition, since many mance were increased. In later work [52], he failed to of these studies tested only urine, blood drug concentra- measure any increased risk taking in another gambling tion data is not available. This is regrettable since such construct with the same dose. Although tentative, and information would be useful in establishing any link contradictory in places, and based on low-dose adminis-

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tration, these findings demonstrate at least the potential symptomatology from a series of 28 drug-impaired driv- for effects on decision-making and risk-taking that could ing cases, and used the data to produce a more detailed impact driving behavior. Subsequent to this work, Hurst model for methamphetamine-impaired driving based on had reviewed the issue of amphetamines and driving on Ellinwood and Nikaido’s general model (see Figure 2). two separate occasions [51,52]. He notes [51] that as That review concluded that while neither the degree of discussed above, there is little direct evidence that normal impairment nor the phase of intoxication could be pre- therapeutic doses affect driving, and downplays the risk- dicted from the blood methamphetamine concentration, taking aspects in his earlier studies due to their mild abuse could be distinguished from therapeutic use when effects. the concentration was greater than 0.200 mg/L. Con- Ritalin (methylphenidate) is another stimulant drug versely, however, lower concentrations do not exclude used to treat adults with attention deficit hyperactivity recreational use beyond the impairment threshold since disorder (ADHD), and the effects of this medication on the subject may be on the “downside”, or withdrawing. In their driving have been assessed [23]. These researchers the majority of cases reviewed, the pattern of driving found that ADHD adults had a higher accident rate, more (typically one-car, drive-off-the-road-type accidents) was moving violations, and poorer simulator driving perfor- highly suggestive of withdrawal-induced impairment, and mance than non-ADHD controls. Their performance un- several of the drivers reported “falling asleep”. Other der Ritalin treatment demonstrably improved their driv- driving patterns included high-speed and high-risk driv- ing over the unmedicated condition. Other researchers ing. The vast majority of subjects also demonstrated have shown similar findings [56]. behavioral signs suggestive of high-dose or binge use. Ellinwood and Nikaido [30] further explored the issue In support of this, Logan et al. [67] reviewed 146 of stimulant-induced impairment, looking in detail at the deaths involving methamphetamine, including 17 fatally issue of the effects of the downside of these drugs, includ- injured drivers. In this group, 14 of the 17 fatalities ing the amphetamines. They present a general dose- resulted from drive-off-the-road-type accidents, again dependent model for stimulant impairment, considering strongly suggesting withdrawal-induced impairment, and arousal, hyperarousal and withdrawal phases, which was consistent with the earlier report. developed further by Logan [66], who reported

Figure 2. Hysteresis plot showing examples of effects which can impact driving performance with respect to blood methamphetamine concentration (mg/L) in two illustrative cases. The figure shows examples of withdrawal effects from (a) low-dose, and (b) high-dose drug use. (Reproduced with permission from J Forensic Sci [66] — Copyright ASTM International, 100 Barr Harbor Drive, West Conshohocken, PA 19428.)

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4. Methamphetamine and the DRE Evaluation principally on the elevated pulse and blood pressure, and Methamphetamine falls into the stimulant category in dilated pupils, but absent the agitation and excitation the drug recognition expert (DRE) scheme. Physiological associated with stimulant use. Because of the limitations signs, which may help the DRE officer correctly identify on dose in this study, it cannot be reasonably used to assess stimulant use, include increased pulse and blood pressure, the efficacy of the DRE evaluation in amphetamine- dilated pupils, increased muscle tone, muscle tremors or impaired subjects. tics, restlessness, agitation, scratching, and repetitive, rapid speech. During the interview the subject may appear REFERENCES nervous, paranoid, may have delusions, may hallucinate, and may give confused responses to simple questions. 1. 21 CFR 1308.12. 2. Aalberg L, DeRuiter J, Noggle FT, Sippola E, Clark CR: They may also become violent, particularly if startled, or Chromatographic and mass spectral methods of identifica- frightened, such as may happen when taken into the dark tion for the side-chain and ring regioisomers of room for the pupil exam, so officers should be advised to methylenedioxymethamphetamine; J Chromatogr Sci take extreme caution. Pupillary dilation can make them 38:329; 2000. extremely sensitive to light, so care should be taken with 3. Anderson RJ, Reed WG, Hillis LD, Morgan CD, Garriott JC: History, epidemiology, and medical complications of the penlight or flashlight. nasal inhaler abuse; J Toxicol Clin Toxicol 19:95; 1982. A number of DRE officers have reported evaluating 4. Ando H, Shimizu H, Takahashi Y, Fukumoto M, Okonogi subjects on the “downside” of methamphetamine use, H, Kadokura M: A basic study for estimating the level of where the symptoms may be subtly different. As the exposure to a nasal inhalant containing a stimulant; Jpn J person moves from the “tweaking” phase to the “crash”, Hyg 43:692; 1993. their vital signs can become depressed, heart rate and 5. Anggard E, Gunne LM, Jonsson LE, Niklasson F: Pharma- cokinetic and clinical studies on amphetamine dependent blood pressure may be normal to low, pupil size has been subjects; Eur J Clin Pharmacol 3:3; 1970. reported to be in the low end of the normal range (~2Ð3 6. Anglin MD, Burke C, Perrochet B, Stamper E, Dawud- mm), and they become drowsy and sleepy, and may “nod Noursi S: History of the methamphetamine problem; J off”. This symptomatology includes many of the signs Psychoact Drugs; 32:37; 2000. associated with narcotic analgesics, or depressant use, 7. Baden KL, Valtier S, Cody JT: Metabolic production of amphetamine following multidose administration of such as depressed pulse and blood pressure, so care should clobenzorex: J Anal Toxicol 23:511; 1999. be taken with the evaluation. The major distinguishing 8. Bailey DN, Shaw RF: Cocaine and methamphetamine- features are the fact that the subject’s pupil, although related deaths in San Diego County (1987): Homicides and small, will still react to light, which the narcotic analgesic accidental overdoses; J Forensic Sci 34:407; 1989. user’s pupil will not. Even when they are nodding off, the 9. Bell DS: The experimental reproduction of amphetamine subject’s behavior and state of mind during the period psychosis; Arch Gen Psychiat 29:35; 1973. 10. Brooks KE, Smith NS: Lack of formation of methamphet- when they are awake are generally more alert than in the amine-like artifacts by the monoacetates of pseudoephedrine narcotic analgesics user, and some behavioral manifesta- and related compounds in the GC/MS analysis of urine tions of stimulant intoxication will generally be present. extracts; J Anal Toxicol 17:441; 1993. Heishmann et al. [45,46] presented data on subjects 11. Brown ID: Driver fatigue; Hum Factors 36:298; 1994. who had been administered oral doses of 0, 12.5, or 25 mg 12. Burcky W, Reuterman NA, Kopsky S: Dating violence among high school students; Sch Counsel 35:353; 1988. of amphetamine, and were then subjected to a DRE 13. Caldwell JA, Caldwell JL: An in-flight investigation of the evaluation 140 min later. These doses are extremely con- efficacy of dextroamphetamine for sustaining helicopter servative in terms of normal recreational doses, which pilot performance; Aviat Space Environ Med 68:1073; range into the 100s of mg to g, administered over many 1997. hours or days. The authors found that with the low dose 14. Caldwell JA, Caldwell JL, Crowley JS, Jones HD: Sustain- (12.5 mg) only 7 of the 18 subjects displayed any signs of ing helicopter pilot performance with dexedrine during periods of sleep deprivation; Aviat Space Environ Med intoxication, meaning that in a field or arrest setting, the 66:930; 1995. remaining 11 would not have been arrested or subjected to 15. CEWG (Community Epidemiology Work Group): the complete DRE exam. Furthermore, of the 7 deemed Epidemiologic Trends in Drug Abuse — Advance Report, impaired, only 2 were correctly identified as being under NIH Publication No. 01-4738; 2001. the influence of a stimulant. The high-dose subjects did 16. Chan P, Chen JH, Lee MH, Deng JF: Fatal and nonfatal methamphetamine intoxication in the intensive care unit; not test much better, with 8 of 18 being deemed impaired, Clin Toxicol 32:147; 1994. and only 3 of the 8 correctly identified as being under the 17. Cloyd ML: Diet pill metabolizes to d-methamphetamine; J influence of a stimulant. Most often these subjects were Occup Environ Med 39:1135; 1997 . thought to be under the influence of marijuana, based 18. Cody JT, Schwarzhoff R: Interpretation of methamphet-

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amine and amphetamine enantiomer data; J Anal Toxicol lowing use of nasal inhalers; J Anal Toxicol 12:255; 1988. 17:321; 1993. 36. Fleckenstein AE, Metzger RR, Wilkins DG, Gibb JW, 19. Cody JT, Valtier S: Detection of amphetamine and meth- Hanson GR: Rapid and reversible effects of methamphet- amphetamine following administration of benzphetamine; amine on dopamine transporters; J Pharmacol Exp Ther J Anal Toxicol 22:299; 1998. 282:834; 1997. 20. Cook CE, Jeffcoat AR, Sadler BM, Hill JM, Voyksner RD, 37. Forney R: Stimulants; In Willette RE (Ed): Drugs and Pugh DE, White WR, Perez-Reyes M: Pharmacokinetics of Driving, NIDA Research Monograph 11; National Bureau oral methamphetamine and effects of repeated daily dosing on Drug Abuse: Rockville, MD; p 73; 1977. in humans; Drug Metab Dispos 20:856; 1992. 38. Gal, J: Amphetamines in nasal inhalers; J Toxicol Clin 21. Cook CE, Jeffcoat AR, Hill JM, Pugh DE, Patetta PK, Toxicol 19:517; 1982. Sadler BM, White WR, Perez-Reyes M: Pharmacokinetics 39. Gawin FH, Kleber HD: Abstinence symptomatology and of methamphetamine self administered to human subjects psychiatric diagnosis in cocaine abusers. Clinical observa- by smoking s-(+)-methamphetamine hydrochloride; Drug tions; Arch Gen Psychiat 43:107; 1986. Metab Dispos 21:717; 1993. 40. Geiser L, Cherkaoui S, Veuthey JL: Simultaneous analysis 22. Cooke BJ: Chirality of methamphetamine and amphet- of some amphetamine derivatives in urine by nonaqueous amine from workplace urine samples; J Anal Toxicol 18:49; capillary electrophoresis coupled to electrospray ioniza- 1994. tion mass spectrometry; J Chromatogr A 895:111; 2000. 23. Cox DJ, Merkel RL, Kovatchev B, Seward R: Effect of 41. Hardman JG, Limbird LE (Ed): Goodman and Gilman’s stimulant medication on driving performance of young the Pharmacological Basis of Therapeutics, 9th ed; McGraw adults with attention-deficit hyperactivity disorder: a pre- Hill: New York, NY; 1996. liminary double-blind placebo controlled trial; J Nerv Ment 42. Gygi MP, Gygi SP, Johnson M, Wilkins DG, Gibb JW, Dis 188:230; 2000. Hanson GR: Mechanisms for tolerance to methamphet- 24. Crouch DJ, Birky MM, Gust SW, Rollins DE, Walsh JM, amine effects; Neuropharmacology 35:751; 1996. Moulden JV, Quinlan KE, Beckel RW: The prevalence of 43. Hall RCW, Popkin MK, Beresford TP, Hall AK: Amphet- drugs and alcohol in fatally injured truck drivers; J Foren- amine psychosis: Clinical presentations and differential sic Sci 38:1342; 1993. diagnosis; Psychiatr Med 6:73; 1988. 25. Derlet RW, Rice P, Horowitz BZ, Lord RV: Amphetamine 44. Haughey HM, Brown JM, Wilkins DG, Hanson GR, toxicity: experience with 127 cases; J Emerg Med 7:157; Fleckenstein AE: Differential effects of methamphetamine 1989. on Na(+)/Cl(Ð)-dependent transporters; Brain Res 863:59; 26. Di Pietra AM, Gotti R, Del Borrello E, Pomponio R, 2000. Cavrini V: Analysis of amphetamine and congeners in 45. Heishman SJ, Singleton EG, Crouch DJ: Laboratory vali- illicit samples by liquid chromatography and capillary dation study of drug evaluation and classification program: electrophoresis; J Anal Toxicol 25:99; 2001. ethanol, cocaine, and marijuana; J Anal Toxicol 20:468; 27. Ellinwood, EH: Assault and homicide associated with 1996. amphetamine abuse; Am J Psychi 127:90; 1971. 46. Heishman SJ, Singleton EG, Crouch DJ: Laboratory vali- 28. Ellinwood EH Jr: Amphetamine psychosis: I. description dation study of drug evaluation and classification program: of the individuals and process; J Nerv Ment Dis 144:273; alprazolam, d-amphetamine, codeine, and marijuana; J 1967. Anal Toxicol 22:503; 1998. 29. Ellinwood EH Jr., Kilbey MM: Fundamental mechanisms 47. Hensley D, Cody JT: Simultaneous determination of am- underlying altered behavior following chronic administra- phetamine, methamphetamine, methylenedioxyampheta- tion of psychomotor stimulants; Biol Psychi 15:749; 1980. mine (MDA), methylenedioxymethamphetamine 30. Ellinwood EH, Nikaido AM: Stimulant induced impair- (MDMA), and methylenedioxyethylamphetamine (MDEA) ment: a perspective across dose and duration of use; Alc enantiomers by GC-MS; J Anal Toxicol 23:518; 1999. Drug Driv 3:19; 1987. 48. Hornbeck CL, Carrig JE, Czarny RJ: Detection of a GC/MS 31. elSohly MA, Stanford DF, Sherman D, Shah H, Bernot D, artifact peak as methamphetamine; J Anal Toxicol 17:257; Turner CE: A procedure for eliminating interferences from 1993. ephedrine and related compounds in the GC/MS analysis of 49. Hurlbut KM: Drug-induced psychoses; Emer Med Clin amphetamine and methamphetamine; J Anal Toxicol 16:109; North Am 9:31; 1991. 1992. 50. Hurst PM: The effects of d-amphetamine on risk taking; 32. Emonson DL, Vanderbeek RD: The use of amphetamines Psychopharmacologia 3:283; 1962. in U.S. Air Force tactical operations during Desert Shield 51. Hurst PM: Amphetamines and driving behavior; Accid and Storm; Aviat Space Environ Med 66:260; 1995. Anal Prev 8:9; 1976. 33. Evans MA, Martz R, Rodda BE, Lemberger L, Forney RB: 52. Hurst PM: Amphetamines and driving; Alc Drug Driv 3:13; Effects of marihuana-dextroamphetamine combination; 1987. Clin Pharmacol Ther 30:350; 1977. 53. Hurst PM, Radlow R, Chubb NC, Bagley SK: Effects of 34. Ferrara, SD, Giorgetti R, Zancaner, S: Psychoactive sub- alcohol and d-amphetamine upon mood and volition; stances and driving: state of the art and methodology; Alc Psychol Rep 24:975; 1969. Drug Driv 10:1; 1994. 54. Hurst PM, Weidner MF, Radlow R: The effects of amphet- 35. Fitzgerald RL, Ramos JM Jr, Bogema SC, Poklis A: Reso- amines upon judgment and decisions; Psychopharmacolo- lution of methamphetamine stereoisomers in urine drug gia 11:397; 1967. testing: urinary excretion of R(Ð)-methamphetamine fol- 55. Inoue T, Suzuki S: The metabolism of 1-phenyl-2-(N-

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methyl-N-benzylamino)propane (benzphetamine) and 1- amine and ethanol interactions in humans; Clin Pharmacol phenyl-2-(N-methyl-N-furfurylamino)propane (furfenorex) Ther 57:559; 1995. in man; Xenobiotica1 6:691; 1986. 73. The Merck Index, 11th ed; Merck and Co.: Rahway, NJ; 56. Jerome L, Segal A: Benefit of long-term stimulants on 1996. driving in adults with ADHD; J Nerv Ment Dis 189:63; 74. Miller MM, Potter-Efron RT: Aggression and violence 2001. associated with substance abuse; J Chem Dep Treat 3:1; 57. Kalasinsky KS, Bosy TZ, Schmunk GA, Reiber G, An- 1989. thony RM, Furukawa Y, Guttman M, Kish SJ: Regional 75. Mitler M, Hajdukovic R, Erman MK: Treatment of distribution of methamphetamine in autopsied brain of narcolepsy with methamphetamine; Sleep 16:306; 1993. chronic human methamphetamine users; Forensic Sci Int 76. Nagai T, Kamiyama S: Simultaneous HPLC analysis of 116:163; 2001. optical isomers of methamphetamine and its metabolites, 58. Kingery PM, Pruitt BE, Hurley RS: Violence and illegal and stereoselective metabolism of racemic methamphet- drug use among adolescents: evidence from the U.S. na- amine in rat urine; J Anal Toxicol 15:299; 1991. tional adolescent student health survey; Int J Addict 27:1445; 77. National Highway Traffic Safety Administration: The Inci- 1992. dence and Role of Drugs in Fatally Injured Drivers, Report 59. Kirby JM, Kimball IM, Fain W: Comparability of alcohol No. DOT HS 808 065; 1992. and drug use in injured drivers; Southern Med J 85:800; 78. National Highway Traffic Safety Administration (Depart- 1992. ment of Transportation): Drug testing laboratories; what 60. Kokoshka JM, Metzger RR, Wilkins DG, Gibb JW, Hanson are the cutoff concentrations for initial and confirmation GR, Fleckenstein AE: Methamphetamine treatment rap- tests? Fed Reg 65:79539; 2000. idly inhibits serotonin, but not glutamate, transporters in rat 79. National Transportation Safety Board: Safety Study: Fa- brain; Brain Res 799:78; 1998. tigue, Alcohol, Other Drugs, and Medical Factors in Fatal- 61. Kramer JC: Introduction to amphetamine abuse; J Psychedel to-the-Driver Heavy Truck Crashes (Vol I and II), Acces- Drugs 2:1; 1969. sion No. PB90-917002, Report No. NTSB/SS-90/01/02; 62. Kramer JC, Fischman VS, Littlefield DC: Amphetamine National Transportation Safety Board: Washington DC, abuse; J Am Med Assoc 201:89; 1967. 1990. 63. Kraemer T, Vernaleken I, Maurer HH: Studies on the 80. Neugebauer M, Khedr A, el-Rabbat N, el-Kommos M, metabolism and toxicological detection of the amphet- Saleh G: Stereoselective metabolic study of famprofazone; amine-like anorectic mefenorex in human urine by gas Biomed Chromatogr 11:356; 1997. chromatography-mass spectrometry and fluorescence po- 81. Newhouse PA, Belenky G, Thomas M, Thorne D, Sing HC, larization immunoassay; J Chromatogr B 702:93; 1997. Fertig J: The effects of d-amphetamine on arousal, cogni- 64. Kraemer T, Theis GA, Weber AA, Maurer HH: Studies on tion, and mood after prolonged total sleep deprivation; the metabolism and toxicological detection of the amphet- Neuropsychopharmacology 2:153; 1989. amine-like anorectic fenproporex in human urine by gas 82. Newman HW, Newman EJ: Failure of dexedrine and chromatography-mass spectrometry and fluorescence po- caffeine as practical antagonists of the depressant effect of larization immunoassay; J Chromatogr B 738:107; 2000. ethyl alcohol in man; Q J Stud Alcohol 17:406; 1956. 65. Laties VG, Weiss B: Performance enhancement by the 83. Nickel B, Niebch G, Peter G, von Schlichtegroll A, Tibes amphetamines: a new appraisal; In Brill H (Ed): Neuro- U: Fenetylline: New results on pharmacology, metabolism psychopharmacology, Proceedings — Fifth International and kinetics; Drug Alcohol Depend 17:235; 1986. Congress of the Collegiium Internationale Neuro-psycho- 84. Ogata A: Constitution of ephedrine — Desoxyephedrine; J pharmacologicum; Washington, DC; March 1966; Inter- Pharm Soc Jpn 451:751; 1919. national Congress Series No. 129; Excerpta Medical Foun- 85. Paul BD, Past MR, McKinley RM, Foreman JD, McWhorter dation: New York, NY; p 800; 1967. LK, Snyder JJ: Amphetamine as an artifact of methamphet- 66. Logan BK: Methamphetamine and driving impairment; J amine during periodate degradation of interfering ephe- Forensic Sci 41:457; 1996. drine, pseudoephedrine, and phenylpropanolamine: an 67. Logan BK, Fligner CL, Haddix T: Cause and manner in improved procedure for accurate quantitation of amphet- death of fatalities involving methamphetamine; J Forensic amines in urine; J Anal Toxicol 18:331; 1994. Sci 43:26; 1998. 86. Perez-Reyes M, White WR, McDonald SA, Hicks RE, 68. Logan BK, Schwilke, EW: Drug and alcohol use in fatality Jeffcoat AR, Hill JM, Cook CE: Clinical effects of daily injured drivers in Washington state; J Forensic Sci 41:311; methamphetamine administration; Clin Neuropharm 1996. 14:352; 1991. 69. Logan BK, Weiss EL, Harruff RC: Tissue distribution of 87. Perez-Reyes M, White WR, McDonald SA, Hill JM, methamphetamine following a massive fatal ingestion; J Jeffcoat, AR, Cook CE: Clinical effects of methamphet- Forensic Sci 41:322; 1996. amine vapor inhalation; Life Sci 49:953; 1991. 70. Lund AK, Preusser DF, Blomberg RD, Williams AF: Drug 88. Physician’s Desk Reference, 55th ed; Medical Economics use by tractor trailer drivers; Forensic Sci 33:648; 1988. Co.: Montvale, NJ; 2001. 71. Maurer HH, Bickeboeller-Friedrich J, Kraemer T, Peters 89. 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emergency department utilization; West J Med 170:198; 100. Smart RG, Schmidt W, Bateman K: Psychoactive drugs 1999. and traffic accidents; J Safety Res 1:67; 1969. 91. Richards JR, Derlet RW, Duncan DR: Methamphetamine 101. Smith DE: The characteristics of dependence in high-dose toxicity: treatment with a benzodiazepine versus a ben- methamphetamine abuse; Int J Addict 4:453; 1969. zophenone; Eur J Emerg Med 4:130; 1997. 102. Smith DE, Fischer CM: An analysis of 310 cases of acute 92. Richards JR, Derlet RW, Duncan DR: Chemical restraint high dose methamphetamine toxicity in Haight-Ashbury; for the agitated patient in the emergency department: Clin Toxicol 3:117; 1970. lorazepam versus droperidol; J Emerg Med 16:567; 1998. 103. Stalcup A: Methamphetamine — Synthesis, pharmacol- 93. Riviere GJ, Gentry WB, Owens SM: Disposition of meth- ogy, analysis, and toxicology; Workshop — 50th Ameri- amphetamine and its metabolite amphetamine in brain and can Academy of Forensic Science annual meeting; San other tissues in rats after intravenous administration; J Francisco, CA; February 1998. Pharmacol Exp Ther 292:1042; 2000. 104. Stratton SJ, Rogers C, Brickett K, Gruzinski G: Factors 94. Robb J, Wohlenberg N, Jasperson M, Lindsey T, Backer R: associated with sudden death of individuals requiring DUID in New Mexico: distribution of drug types and BAC; restraint for excited delirium; Am J Emerg Med 19:187; The DRE 4:11; 1992. 2001. 95. Romberg RW, Needleman SB, Snyder JJ, Greedan A: 105. Summala H, Mikkola T: Fatal accidents among car and Methamphetamine and amphetamine derived from the truck drivers: Effects of fatigue, age, and alcohol con- metabolism of selegiline; J Forensic Sci 40:1100; 1995. sumption; Hum Factors 36:315; 1994. 96. Rutenfranz J, Jansen G: The compensation of the alcohol 106. Valtier S, Cody JT: Evaluation of internal standards for effect by caffeine and pervitin in a psychmotor perfor- the analysis of amphetamine and methamphetamine; J mance; Int Z Angew Physiol Einschl Arbeitsphysiol (Ber- Anal Toxicol 19:375; 1995. lin) 18:62; 1959. 107. Valtier S, Cody JT: Differentiation of clobenzorex use 97. Segal DS, Kuczenski R: Escalating dose-binge stimulant from amphetamine abuse using the metabolite 4- exposure — Relationship between emergent behavioral hydroxyclobenzorex; J Anal Toxicol 24:606; 2000. profile and differential caudate-putamen and nucleus 108. Wilson L, Taylor JD, Nash CW, Cameron DF: The com- accumbens dopamine responses; Psychopharmacology bined effects of ethanol and amphetamine sulphate on (Berlin) 142:182; 1999. performance of human subjects; Can Med Assoc J 94:478; 98. Shippee RL, Kippenberger DJ: Retrospective study of 1966. urinalysis for dl-amphetamine and dl-methamphetamine 109. Yamamura T, Hisida S, Hatake K: Alcohol addiction of analysis under current Department of Defense guidelines; methamphetamine abusers in Japan; J Forensic Sci 36:754; J Anal Toxicol 24:450; 2000. 1991. 99. Slade M, Daniel LJ, Heisler CJ: Application of forensic 110. Yui K, Goto K, Ikemoto S, Ishiguro T, Kamada Y: toxicology to the problem of domestic violence; J Forensic Increased sensitivity to stress and episode recurrence in Sci 36:708; 1991. spontaneous recurrence of methamphetamine psychosis; Psychopharmacology (Berlin) 145:267; 1999.

ABOUT THE AUTHOR B. K. Logan

Barry K. Logan was born in Bearsden, Scotland, and earned his bachelor’s degree (1982) in chemistry and Ph.D. (1986) in forensic toxicology from the University of Glasgow (Glasgow, U.K.). Dr. Logan is currently the director of the Washington State Patrol's Forensic Laboratory Services Bureau (Seattle, WA) overseeing the operations of the Crime Laboratory Division, and the Breath Test and Implied Consent sections. He also serves as the Washington State Toxicologist and as a clinical assistant professor at the University of Washington (Seattle, WA). In 1986, Dr. Logan accepted a research position in the Department of Toxicology and Chemical Pathology at the University of Tennessee in Memphis. In 1990, he joined the faculty of the University of Washington in the Department of Laboratory Medicine and was appointed Washington State Toxicologist. In 1999, the Washington State Toxicology Laboratory merged with the Washington State Patrol, and Dr. Logan was named director of the newly created Forensic Laboratory Services Bureau. Dr. Logan has over 60 publications in the field of forensic toxicology and drug analysis. His current research interests include stimulant use and driving impairment, drug interactions and postmortem toxicology, and drug-facilitated sexual assault. Dr. Logan is board certified (the American Board of Forensic Toxicology). He has been elected to the National Safety Council’s Committee on Alcohol and Other Drugs and to the International Council on Alcohol, Drugs, and Traffic Safety, and has served as a consultant to the National Institute of Justice, the United Nations Drug Control Program, and numerous state agencies. He is a fellow of the American Academy of Forensic Sciences, and an active member in the Society of Forensic Toxicologists. He also serves on the editorial boards of the Journal of Forensic Sciences and the Journal of Analytical Toxicology.

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