3,4-Methylenedioxymethamphetamine - Effects on Human ...

3,4-Methylenedioxymethamphetamine -Effects on Human Performance and Behavior

B. K. LoganForensic Laboratory Services Bureau

Washington State PatrolSeattle, Washington

United States of America

F. J. CouperOffice of the Chief Medical Examiner

Washington, District of ColumbiaUnited States of America

TABLE OF CONTENTS

INTRODUCTION .. 12I. CHEMISTRy................................................................................................ 12

A. Nomenclature 12B. Chemical Properties 13C. Synthesis 13D. Chemical Analysis 13

II. PHARMACOLOGY ,....................................................................... 16A. Route of Administration , 16B. Metabolism 16C. Pharmacokinetics.................................................... 17D. Neurotransmitter and Receptor Effects 18E. Pharmacodynamics......... 18

III. FORENSIC ISSUES.. 20A. Toxicity and Death 20B. MDMA and Driving 20CONCLUSIONS 24REFERENCES 24ABOUT THE AUTHORS 28

3,4.Methylenedioxymethamphetamine -Effects on Human Performance and Behavior

REFERENCE: Logan BK, Couper FJ: 3,4-Methyl.enedioxymethamphetamine - Effects on human performanceand behavior; Forensic Sci Rev 15: 11; 2003.

ABSTRACT: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a unique drug, sharing properties ofhallucinogens and stimulants. The acute effects of empathy, euphoria, and excitement for which it is usedrecreationally can make it overwhelmingly distracting for the user in the context of driving. This review considersthe chemistry, synthesis, analysis, pharmacology, pharmacokinetics, and documented effects of MDMA oncognitive and psychomotor skills important to driving, Laboratory studies show that users do experience cognitiveimpairments, and may also act more impulsively while under the influence of the drug's sympathomimetic effects.Psychomotor impairment may occur with elevated doses or after repeated administration, and residual psychomotorimpairment during the "coming-down" phase may be compounded by fatigue, dehydration, combined drug use, orother confounding factors. There is growing anecdotal information providing evidence ofMDMA-impaired driving,and it is evident that many users recognize and attempt to mitigate the effects by delaying driving until the acuteaffects have dissipated. The drug inevitably may affect a subject's judgment and ability to properly assess theirfitness to drive also. Blood concentrations in MDMA-impaired drivers suggest that this impairment can be causedby normal patterns of recreational use, and MDMA use should be considered inconsistent with safe drivingimmediately following ingestion, and for up to a day or longer following use.

KEY WORDS: Drugs and driving, ecstasy, MDMA, 3,4-methylenedioxymethamphetamine.

INTRODUCTION

3,4-Methylenedioxymethamphetamine (MDMA) isthe most prominent member of the methylenedioxy-sub-stituted amphetamines to gain popularity for illicit recre-ational use. The incidence of reported use in the DrugAbuse Warning Network (DAWN) data set has increasedfrom 253 emergency department mentions in 1994, to2,850 in 1999, and 5,542in 200 1 (http://www.samhsa.gov/oas/dawn.htm). At normal doses, the drug has an appeal-ing combination of mild to moderate central nervoussystem (eNS) stimulating effects, and profoundly en-hances feelings of empathy, closeness, and response tointimate touch. As such it is often referred to as anempathogen, or entactogen. It currently has no legitimateapproved therapeutic use, although has been evaluatedhistorically in psychotherapy. and is being studied forpossible use in the treatment of posttraumatic stress [41].

Widespread recreational use of the drug began in the1980s following the publication of Alexander Shulginsbook, PiHKAL [100]. The ready availability of precursorsand the synthetic schemes on the Intemet have all contrib-uted to subsequent growth in its popularity. The drug is inwidespread use in Europe as part of the "rave" or danceclub scene, and is now enjoying increasing levels of use inNorth America.

There is a growing body of anecdotal evidence show-ing an association between recreational use of this drugand effects on cognition and psychomotor performance aswell as evidence of neurotoxicity from high-dose or long-

term use. All of these may under different circumstancescontribute to deterioration in the skills necessary for safedriving. This review considers the chemistry, pharmacol-ogy, pharmacokinetics, and pharmacodynamics of thedrug, and considers its specific effects on human perfor-mance and behavior. The manuscript is designed to be asummary of the major forensic issues surrounding thedrug, and the reader is encouraged to seek out the primaryliterature cited for the detail necessarily omitted in anyreview.

I. CHEMISTRY

A. Nomenclature

3,4-Methylenedioxymethamphetamine (ell H lsN02)(Structure 1), is the methylenedioxy substituted analogof methamphetamine, and as such is known by a variety ofsystematic names related to that drug, such as N-methyl-3,4-methylenedioxyphenylisopropylamine, andN-methyl-3,4-methylenedioxyamphetamine [84]. Itis often referredto as a "designer drug", borrowing a popular term from the1980s intended to reflect its outre status, and glamorize itsuse [9,47].

It appears thatMDMA' s analog, 3,4-methylenedioxy-amphetamine (MDA), was first synthesized in 1910 [63],and that MDMA itself was patented by Merck in 1914.Various structural analogs (Structure 1) have subsequentlybeen synthesized, including 3,4-methylenedioxyethylam-phetamine (MDEA) andp-methoxyamphetamine (PMA).

Forensic Science Review • Volume Fifteen Number One > January 2003

---- .-- -- ----~ /

Methamphetamine 3,4-Methylenedioxymethamphetamine (MDMA)

/H

~~H

HFO~ CH3

p-Methoxyamphetamine (PMA)

/H

O~~H

3,4-Methylenedioxyamphetamine (MDA)

3,4· Meth y lencdiox yethy lamphetam ine (MD EA)

Structure 1. MDMA and related compounds.

MDMA, its salts, isomers, and salts of isomers to-gether with many of its analogs, are controlled substances(hallucinogens) listed in the U.S. Code of Federal Regu-lations [107], MDMA is known popularly as "ecstasy"and it goes by a variety of other slang terms that vary bylocation (for example; e, eckies, essence, euphoria, fanta-sia, adarn, beans, booty juice, decadence, candy flips,disco biscuits, domex, doctor, dove, hug drug, ice, lovedoctor, love drug, love potion #9, love trip, luck flip,MDM, roll, vitamin e, whiz bombs, X, XTC, and many,many others),

Invariably taken orally, the drug is typically suppliedas small round pills, usually white, but also available in avariety of colors, usually with an embossed logo. Thelogos are very varied and regional, and tend to be some-what short-lived on the market. The logos have generateda number of other pseudonyms for the drug, which changewith availability. Frequently, drugs sold as ecstasy con-tain no MDMA, but rather other illicit, usually stimulant,drugs including methamphetamine, amphetamine,methylphenidate, ketamine, MDEA, and PMA[45,98,103], Sometimes the pills contain nothing morethan caffeine. This observation has been validated by thewide range of compounds found in the urine of attendeesat rave parties [117].

B. Chemical Properties

MDMA is a tertiary amine with a molecular weight of193.25 a.m.u. It is an oil at room temperature with aboiling point of 100-110 "C. It is invariably supplied andused as the hydrochloride salt (CIIHJ6NCI02), a whitecrystalline material with a melting point of 148-149 °C[83], It has a chiral center zivinz rise to two enantiomers_ b . ,

each with different degrees of CNS activity, and differentaffinities for the enzyme systems responsible for its break-

Solid dosage samples ofMDMA and its many analogshave been analyzed by thin layer chromatography [2],capillary electrophoresis [34], infrared spectroscopy [103],gas chromatography-mass spectrometry (GC-MS) [3],and tandem GC-MS (GC-MS-MS) [7,8].

Some authors have reported the use of solid phaseextraction (SPE) of tablets prior to GC- MS analysis [91],

Logan and Couper· MDMA

13

down. All currently popular syntheses produce a racemicmixture.

C. Synthesis

The popular synthesis of MDMA begins with anessential oil containing saffrole, usually sassafras oil,which can contain 95% saffrole. The saffrole is convertedby heating with base to isosaffrole, which is then con-verted to methylenedioxyphenyl-2-propanone (MDP2P)by oxidation with peroxide. This is followed by reductiveamination with methylamine over an aluminum/mercurycatalyst to MDMA. This latter step is similar to the oldersynthesis of methamphetamine from phenyl- 2-propanone(P2P), a process that lost favor due to the alleged neurotox-icity of P2P. The neurotoxicity of MDP2P has not beenstudied, but the use of the mercury amalgam catalyst raisesconcerns about environmental toxicity in dump sites usedby individuals illicitly manufacturing this drug. The re-ductive amination reaction produces a distinct and un-pleasant chemical odor, which can aid in the identificationof clandestine labs manufacturing this drug. Various othersyntheses exist [99]. Anecdotally, some users report an"aniseed" odor can allegedly help detect whether a pillcontains MDMA. MDMA itself, however, has no odor,and this odor (associated with the saffrole itself) is un-likely to persist in a purified preparation., .The hydrochloride salt of MDMA is generally pre-

cipitated from a solution of the base with a hydrogenchloride gas generator to produce a white crystallinematerial generally compressed into pills. The yield is high.Depending on the synthetic route, a variety of by' productshave been identified that can assist in determininz the. b

likely synthesis used [6,92]. Some of these markers mayalso show up in biological samples.

It should be evident from the above description thatthe reagents for illicit synthesis of MDMA are at least asreadily available as those for methamphetamine, anddetailed recipes are widespread on the Internet. At the timeof writing, a pound of sassafras oil retails for 130, andwould generate about 500 g of MDMA. Divided intotypical doses of SO mg, selling for $10 each would netabout $1 million U.S.

D. Chemical Analysis

For drug testing in biological fluids and tissues, the initialdetection is usually accomplished with an immunoassayscreening test, followed by a chromatographic confirma-tory analysis.

1. Toxicological Screening TechniquesImmunoassay is by far the most commonly used

technique to screen for MDMA in urine, and with enzymelinked immunosorbent assay (ELISA) assays increas-ingly in other specimens also, such as blood, tissuehomogenates, and digests of hair or nails. Mandatoryguidelines for the Federal Workplace Drug Testing re-quire the identification of amphetamine and methamphet-amine, but currently not the identification of their respec-tive derivatives, MDA and MDMA.

Many commercial immunoassays, including enzymeimmunoassay (EIA), ELISA, kinetic interaction ofmicroparticles in solution (KIMS), and fluorescence po-larization immunoassay (FPIA) tests, use antibodies spe-cific for either d-amphetamine and/or d-methamphet-amine in urine, at a cutoff of 1000 ng/mL. The degree ofcross-reactivity of these antibodies with methylenedioxy-substituted amphetamines varies, with antibodies raisedto immunogens protein-linked to the amphetamine mol-ecule through the phenyl ring having better cross reactiv-ity than those linked through the side chain. Althoughsome information on cross reactivity is available throughthe literature and from manufacturers (see Table 1), eachlaboratory should consider independent validati on of theirimmunoassay methods if they are interested in using themto detect this class of compounds, since this can changeover time, and from lot to lot. Most manufacturers reportonly a single cross-reactivity value, usually at their cut-off; however, as noted by Cody and Schwarzhoff [18],cross reactivity can vary as a function of concentration.

A recent assessment of the ability of several immu-noassays to detect MDMA use in urine from participantsat a rave, found that the Abbott TDX Amphetamine/Methamphetamine II and the new Roche HS Amphet-amineIMDMA assays demonstrated greater detection sen-sitivity for MDMA than the other tested immunoassays,including Abuscreen Online Hitachi AMPS, AbuscreenOnline Integra AMPS, Abuscreen Online In tegra AMPSX,CEDIA AMPS and EMIT il AMPS [117]. Other authorshave also reported favorably on the ability of TDX am-phetamine reagents to detect MDMA and MDEA[30,57,90,94]. Cross reactivities of a variety of otheramphetamine analogs using both the TDX methamphet-amine/amphetamine IT, and Triage portable test have alsobeen evaluated [33].

Radioimmunoassays are less commonly used today,but have also been evaluated showing a similar pattern ofgood cross reactivity for MDMA with methamphetamine

14

reagents, and poor cross reactivity with amphetaminereagents [16,17,94,114].

2. Toxicological Confirmation TechniquesIn a forensic context, confirmation of positive immu-

noassay screening results is essential. MDMA and itsprincipal metabolite MDA can be readily isolated fromurine in the basic fraction; however, studies of drugdisposition need to account for the significant hydroxyl a-tion and glucuronidation of both MDMA and MDA, andwill precede the extraction with a hydrolysis step. Themajority of published methods for analysis of members ofthe amphetamine class in urine, plasma, and blood useeither liquid-liquid extraction (LLE) or SPE, followed byderivatization and GC, GC-MS, or liquid chromatography(LC).

a. Sample PreparationUrinary hydrolysis is used to improve the detection of

hydroxy-metabolites ofMDMA and MDA since they areprimarily excreted as conjugates. Both acidic and enzy-matic hydrolysis techniques have been used. For acidhydrolysis, 3 mL of 30% HCl is added to 10 mL urine for15 min, then the sample is alkalinized and extracted [30].

~-Glucuronidase is often used for enzymatic hydroly-sis; however, this can involve lengthy incubation. Ortunoet a1. [85] added 1 mL of 1.1 M acetate buffer (pH 5.2) to1 mL urine, and incubated the mixture with ~-glucu-ronidase (HP2) at 37 °C, overnight. Maurer [66] andHelmlin et a1. [46] evaluated both acidic and enzymatichydrolysis and determined that acidic hydrolysis wasfaster (1 h), more efficient, and less expensive than enzy-matic hydrolysis.

It is evident that more complete information regard-ing duration and extent of MDMA use, evaluation oftoxicity, and clues to metabolic insufficiency with respectto glucuronidation can only be evaluated by hydrolysis ofthese metabolites. Analysis of polar conjugated metabo-lites may also permit a longer detection window [30,55].These authors note that for MDEA, the parent compoundcan be detected for only 2-3 days, while its hydroxymethoxy metabolite can be detected for 7-8 days. Forroutine urine drug of abuse screening, however, or for thepurposes of demonstrating drug use, most urine assays areconducted without hydrolysis [4,13,35,54,57,71,105,108].

Liquid-liquid extraction remains the most commonsample preparation procedure, and MDMA, MDA, andMDEA are readily recovered in the basic faction of mostcomprehensive drug-extraction protocols. A wide varietyof solvents have been used, including Toxi-A tubes[105, I06], butyl chloride [57], dichloromethane:isopropan-ol:ethyl acetate (1:1:3) [30], diethyl ether [4,64],hexane:ethyl acetate (1 :3) [13]; ethyl acetate:hexane: 1-


--- ---- --.-- --

15

Table 1. Immunoassay cross reactivity data

Manufacturer Assay name and date or ref.Cross reactivity with analyte (%)

Principle d-Methamph d-Amph MDMA MDA

OraSure Methamphetamine ELISA 100 1.30 1513 2.80Bethlehem, PA March 22,2002OraSure Amphetamine ELISA <1.0 54.6 <1.0 >100Bethlehem, PA March 22,2002Neogen Methamphetamine ELISA 100 0.60 733 4.0Lexington, KY 2000Neogen Amphetamine ELISA 1000 100 2.20 OAOLexington, KY 2000Irnmunalysis MethamphetaminelMDMA ELISA 100 2.0 135 <1.0San Dimas, CA August 1,2001Immunalysis AmphetaminelMDA ELISA 6.50 100 <1.0 250

August 1,2001Syva (Dade Behring) EMIT II plus Monoclonal EMIT 100 93 11 47Cupertino, CA AmphlMethamph

November 2000Abbott TDx II Amph/l\1ethamph II FPIA >10 100 91.5- 136-Abbott Park, IL [18] 104 170Abbott TDx Amphetamine Class FPIA 100 46.5- 26-

[18) 7.4 4.8Abbott AXSYM AmphlMethamph II FPIA >10 100 >3.3 >3.3

November 1997Beckman Synchron LX Amphetamine EMIT 100 100 >40 >40Brea, CA May 2000Microgenics DRI Ecstasy EIA EMIT 0.1 0.1 100 67Fremont, CA September 2001Microgenics CEDIA Amphetamines/Ecstasy EMIT 100 68n 196 lIS

September 2001DPC Methamphetamine RIA 100 570- 0.7-Los Angeles, CA [17) 312 1.8DPC Amphetamine RIA 100 0- 173-Los Angeles, CA [17) 0.87 108Roche Abuscreen Amphetamine RIA 1.38- 100 0.6- 107-Indianapolis, IN [16] 1.9 0.41 158

d,l-Amphetamine.

butanol (10:10:1) [72], and hexane [95]. The more polarsolvents are more effective at recovering the polar hydro-lyzed metabolites. Extraction is performed under basicconditions using such buffers as borate, sodium hydrox-ide, and sodium hydroxide/ammonium sulfate buffers.

Solid phase extraction (SPE) is becoming increas-ingly popular to isolate MDMA from simple biologicalmatrices such as urine and plasma [35,46,75]. A typicalSPE procedure has been described by Ortuno et al. [85].To extract MDMA from plasma or hydrolyzed urine, thesample is first mixed with a pH 6.0 buffer. The biologicalsamples are then added to Bond Elut Certify® cartridgesconditioned with methanol and pH 6.0 buffer. The car-

tridges are then rinsed with acetic acid and methanol. Forplasma, MD MA and NillA are eluted using chloroform: 2%NH40H, while for urine, MDMA and its polar metabolitesare eluted with ethyl acetate:2% NH40H. The more polarsolvent, ethyl acetate, extracts the polar metabolites moreefficiently than chloroform.

Solid phase microextraction (SPME) is a technique inwhich the drugs are adsorbed onto a fused silica fibercoated with an appropriate stationary phase. For MDMA,this has been reported both directly from matrices such asurine [108] and from the headspace above the sample [54].While these latter techniques hold promise, they are notyet in widespread use.

Logan and Couper> MDMA

-----_._-- - .

17

/H /HO~N......CH3 __ -... O~N......H

~ CH3 ~ CH3

3,4-MethYlenediOXymelh-"'- / 3,4-Melhylenedioxy-amphetamine (MDMA) . ~ amphetamine (MDA)

~ / H Excretion ~

34~~:~I 3:~~~;"(DHMA) (DHA)

Conjugation and

~ I H /excretiOl, ~ I H

H3C~N......CH3 -, H3C~~N......H

HO~ CH3 HO~ CH3

4-Hydroxy-3-melhoxymelh-amphetamine (HMMA)

Figure 1. Principal pathways of MDMA metabolism.

4-Hydroxy-3-melhoxy-amphetamine (HMA)

C. Pharmacokinetics

Following oral administration, effects begin after 25-30min and may last 1h or longer, depending on dose. Peakplasma or blood concentrations lag the peak effect, and areobserved at 1.5-4 h, suggesting tachyphylaxis. MDMA'shalf-life is approximately 7 h, although nonlinear pharma-cokinetics have been observed. For the purposes of thefollowing discussion, it should be noted that pharmacoki-netic studies typically report plasma concentrations, whileforensic reports are of blood concentrations. The likelyrange for whole-blood-to-plasma concentration ratio hasnot been reliably established; however, DeLetter et al.[24] have reported whole-blood-to-serumratios in a singlepostmortem case of 0.83 (subclavian), and 0.54 (aorta) forMDMA and 0.90 (subclavian) and 0.85 (aorta) for MDA.The CV for their assay was only reported as better than±20%, however, allowing for quite a broad potential rangefor serum-to-whole-blood ratios. A report by Clauwert etal. of whole-blood-and-serum analysis is consistent al-though actual ratios are not specifically reported [13]. Thestudy by DeLetter et al. showed that MDMA concentra-tions in postmortem cardiac blood, and some tissues maybe elevated, suggesting caution in comparing these toantemortem whole blood or serum concentrations [24].Reported ratios ranged from 1.13 for subclavian/femoraland iliac/femoral, to 2.45 for the left atrial/femoral. Theauthors recommend femoral blood as the ideal postmor-tem specimen.

Recreational MDMA users indicate a preferred doseof 1.76-4.18 mg/Kg (mean 2.51 rng/Kg, or about 175 mgin a 70-Kg subject) [28]. Other users surveyed report a

range of doses between 50-700 mg in a session, with anaverage of 120 mg [101], and the Addiction ResearchFoundation reports a normal dose range of 50-200 mg[52J.

Following oral ingestion of 1.5 mg/Kg (105 mg/70Kg) doses, average peak serum concentrations of 0.33 mg/L were obtained in two subjects at 120min [46]. TheMDAconcentration peaked at 380 min and 150 min, and wasconsistently less than 5% of the parent drug concentration.Verebey et al. [110] report a peak serum MDMA concen-tration of 0.106 mg/L in a 74-Kg adult male, 2 h followingthe ingestion of 50 mg. The MDA concentration peaked at0.028 mg/L after 4 h. De la Tone et al. [23] reports peakplasma concentrations at 1.5-4 h following ingestion of50-150 mg of MDMA. The mean plasma concentrations(or ranges) associated with each dose were as follows(dose/mean concentration or range (S.D)): 50 mg/O.02-0.08 rng/L; 75 mg/0.13 mg/L (0.04); 100 mg/0.21-0.19mg/L; 125mg/0.24mg/L(0.06); 150 mg/0.44-0.49 rng/L.The authors report that the plasma MDA (metabolite)concentrations peaked later (4-6 h) and never exceeded5% of the parent compound concentration.

The apparent half-lives of the MDMA enantiomersare reported as 5.8±2.2 and 3.6±0.9 h for the (-)-R- and(+)-S-enantiomers, respectively [32]. This differentialmetabolism results in nonlinear kinetics, however. Sincethe (+)-S-enantiomer has greater pharmacological activ-ity than the (-)-R form, but is metabolized more slowly,the blood drug concentration-effect profile of the drugbecomes more difficult to interpret when a nonstereospe-cific analysis is performed. The authors report a combinedmean peak plasma concentration (both enantiomers) of

Logan and Couper' MDMA

0.06 mg/L at 2-4 h following the administration of 40 mgof MDMA, which is consistent with earlier references.

D. Neurotransmitter and Receptor Effects

MDMA can be categorized as a stimulant as a resultof its sympathomimetic effects, including peripheral vaso-constriction, bronchodilation, cardiorespiratory stimula-tion, pupillary dilation, and appetite suppression. It canalso be categorized as an empathogen, entactogen, andhallucinogen since it can produce these effects to varyingdegrees depending on dose. The hallucinations are gener-ally mild, and frequently tactile in nature. While the drugis a sympathomimetic, it has significantly less eNS stimu-lant properties than methamphetamine.

There are several neurotransmitter systems appar-ently affected by MDMA, including serotonin (5-hydrox-ytryptamine, 5-HT), norepinephrine, dopamine, and theneurotransmitter y- amino butyric acid (GABA). In ani-mals, MDMA promotes release of serotonin, causing anincrease in synaptic concentrations and a depletion ofpresynaptic stores. This is believed to result from MDMA' seffect in reversing the 5-HT uptake transporter. Indeed, inrats, the administration of the selective serotonin reuptakeinhibitor fluoxetine has been shown to block the MDMA-induced release of both 5-HT and dopamine, and todiminish its associated effects [42,96,1 12]

While much of this data comes from animal modelsand has not been validated in humans, there are functionalcorrelates, both reported by users and observed in con-trolled studies, which are consistent with the knowneffects of disruptions in these systems. For example, usersreport the "Tuesday Blues" - a sudden feeling of depres-sion and isolation two or three days following a weekend'suse of ecstasy. This is consistent with the observations thatabstinent regular ecstasy users often display reduced lev-els of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), tryp-tophan hydroxylase, and serotonin transporter density[87).

In addition to its effects on serotonin release, MDMAitself has a direct affinity for the post-synaptic 5-HT2receptors, whose activation is associated with hallucina-tions and visual disturbances, which can be a feature ofMDMA use, particularly at higher doses [89).

The role of dopamine in MDMA intoxication is lessclear, but probably accounts for some of the euphoriaexperienced after taking MD MA. Dopamine release in theserotonergic neurons has also been invoked as a possiblemediator of long-term neurotoxicity in MDMA users.Monamine oxidase B, which predominates in these neu-rons, produces highly reactive free radical species fromdopamine, which may cause cell damage and death, caus-

18

ing or contributing to the documented decrease in seroton-ergic neural activity in long-term MDMA users [31].

E. Pharmacodynamics

Having an understanding of the neurotransmitter sys-tems impacted by MDMA can help in explaining thecommon effects associated with its use, which has impli-cations for its effects on skills related to driving.

1. Acute Recreational DosingTypical doses and patterns of dosing are discussed

under "Pharmacokinetics" above. Individual pills havebeen found to contain between 50 and 150 mg ofMDMA[40). The term "rolling" is used throughout the ecstasy/rave community and can be used to mean the act of takingthe drug, or the period of time during which the effects aremost intense. Users also talk about "coming down", mean-ing that the effects of the drug are wearing off.

Doses of 1.7 mg/Kg (~120 mg in a 70-Kg subject)[112] have been used in clinical studies and have producedin MDMA-naive subjects feelings of enhanced mood,well-being, and increased emotional sensitiveness, someanxiety, but no hallucinations or panic reactions. Milddepersonalization and derealization phenomena, moder-ate thought disorder, signs of loss of body control, andalterations in the meaning of percepts also occurred.Interestingly all effects, particularly hallucinogen-likeperceptual alterations, appear to be greater in women thanin men for a given weight-adjusted dose [59]. Bothgenders, however, displayed changes in sense of spaceand time, and showed heightened sensory awareness andincreased psychomotor drive.

MDMA did not impair selective attention. The mostfrequently cited acute adverse somatic complaints werejaw clenching, lack of appetite, impaired gait, and restlesslegs. Adverse effects during the following 24 h includedlack of energy and appetite, feelings of restlessness, in-somnia, occasional difficulty concentrating, and brood-ing.

Used recreationally, the drug has specific propertiesthat have made it popular as a recreational, party, rave, ordance drug. Users report as positive effects: changes infeelings and emotions; enhanced communication, empa-thy, or understanding; changes in cognitive or mentalassociations; euphoria or elation; and changes in percep-tion, including hallucinations [101). Other reported ef-fects include a great sense of pleasure, dissociation, sexualstimulation, relaxation, increased responsiveness to inti-mate touch, increased self-esteem, and high energy (19,52).These effects have led to the drug being classed as anempathogen or entactogen [80).

Forensic Science Review • Volume Fifteen Number One' January 2003

-- -- ..__ ._-------

One study [60] reports the short-term effects in agroup of 20 psychiatrists who had taken MDMA as:altered time perception (90%), increased ability to interactwith or be open with others (85%), decreased defensive-ness (80%), decreased fear (65%), decreased sense ofseparation or alienation (60%), changes in visual percep-tion (55%), increased awareness of emotions (50%), de-creased aggression (50%), speech changes (45 %), aware-ness of unconscious memories (40%), decreased obses-siveness (40%), and cognitive changes (40%). Subjectsalso reported medium-term effects of decreased sleep(40%), decreased appetite (30%), increased sensitivity toemotions (25%), decreased ability or desire to performmental or physicaJ tasks (20%), increased ability to inter-act with or be open with others (20%), and decreaseddefensiveness (20%).

A range of negative effects invariably accompaniesthe perceived positive effects of recreational MDMA use.These include vomiting immediately following ingestion,tachycardia, dry mouth, bruxism, muscle tension or jawclenching leading to muscle pain, increased sweating,blurred vision, ataxia, nausea, and anxiety [101], pupillarydilation, nystagmus, a nervous desire to be in motion,panic attacks, urinary urgency, double vision, and insom-nia [14], hyperthermia, hyponatremia, convulsions,catatonic stupor, vomiting, and motor tics [86,88]. Alsoreported were panic, paranoia, and unfulfilled expecta-tions, mostly resulting from other factors such as com-bined drug use and set and setting.

Following cessation of use, during the "coming down"or withdrawal phase, users frequently report muscle aches,fatigability, irritability, depression, difficulty concentrat-ing, and exhaustion, [69,89]. Work by Verheyden et al.indicates that women are more affected by midweekwithdrawal than men, although both genders show in-creased aggression attributed to attenuation of 5HT func-tion following use [111].

In terms of impairment, MDMA in low to moderatedoses (50-200 mg) produces mild to moderate intoxica-tion, euphoria, an increase in physical and emotionalenergy, a great sense of pleasure, increased sociability andcloseness, mild visual disturbances, nystagmus, pupillarydilation and blurred vision, all of which can be distractingand could contribute to impairment. Muscular effects arealso prominent, including instability and incoordinationin gait, in finger-to-nose testing, and deep tendon reflexes,which could impact both fine and coarse motor control.Although these effects generally dissipate within 24 hafter use, users reported prolonged physical and psycho-logical problems, most frequent among which were muscletension in the jaw, fatigue, depression, anxiety, and in-somnia. Insomnia, fatigue, mandibular muscle pain, loss

19

of balance, and headache may persist into the next day.Some users report confusion, depression, and anxiety thatcan last for several weeks following a single dose [112, 113].

Siegel [101] reported a survey of 44 experiencedMDMA users. Typical initial doses were around 100 mg(range 50-390 mg), with the total dose in a given sessionbeing 120 mg (50-700 mg). The intoxication effects notedincluded the following: changes in feelings and emotions(80%); enhanced communication, empathy, or under-standing (68%); changes in cognitive or mental associa-tions (68%); euphoria or elation (63%), and changes inperception (44%). Undesirable effects included muscletension (100%), increased sweating (91 %), blurred vision(77%), and ataxia (77%). Several subjects reported illu-sory or hallucinatory experiences, although these aretypically associated with higher doses. Many subjects hadattentional dysfunction, manifested as difficulty in main-taining attention during complicated tasks, focusing in-stead on inner personal experience, and preoccupationwith personal problems. Those subjects who reportedchanges in perception noted increased light sensitivity,blurred vision, and difficulty in focusing, which is also ofconcern with respect to driving.

2. High Intensity or Chronic UseGiven that even normal recreational use might pro-

duce symptoms that result in impairment of psychomotorand cognitive functions, at higher doses the risks arecorrespondingly greater and likely to persist for a longerperiod of time. Along with the distracting and overwhelm-ing emotional and empathic effects experienced, the usermay experience distortion of perception, thinking, ormemory [14,19,28,59,73,101]. Illusory or hallucinatoryexperiences are more likely to occur with higher doses.Drug "stacking" refers to the ingestion of single MDMAdoses consecutively as effects begin to wane, similar tococaine or methamphetamine binges. This often occursduring the weekend and can produce down-side effects ofexhaustion, depression, insomnia, and muscle tensionduring withdrawal, i.e., experiencing "terrible Tuesdays"or "Tuesday blues" following extensive weekend use.There is evidence for prolonged cognitive deficits inregular users for at least several weeks after use hasstopped [39,68] and some evidence that this may beirreversible [76], although this is a contentious topic.There is mounting evidence of persistent neurologicaldeficits in MDMA users, even when the subject has beendrug-free for a period of time. This is believed to beassociated with damage to serotonergic neurons, resultingin lowered endogenous brain serotonin production. Thesechanges result in poor memory recall [88], flashbacks,depersonalization, panic attacks, and psychosis [70]. Per-


sistent performance decrements in a number of measuresof complex task performance such as selective attention,divided attention [39], sustained attention, and complexattention tasks [67] have been reported in long-term ec-stasy users. These changes are associated with lowercerebrospinal fluid levels of the serotonin metabolite 5-HIAA, providing further evidence that MDMA is neuro-toxic to brain serotonergic neurons, resulting in long-termcognitive deficits [102]. Morgan [76], subjected a cadre oflong-term ecstasy users to a battery of psychological tests,and found that the users were more psychologically dis-turbed and impulsive than nondrug controls, and thatthose who had taken the most ecstasy had the mostelevated trait impulsiveness scores. The authors note thatincreased impulsivity is consistent with reduced levels ofserotonergic function. In a follow-up study, the sameauthors found that selective impairments ofneuropsychological performance associated with regularecstasy use were not reversed by prolonged abstinence[77]. Finally, Zakzanis and Young [116] report impair-ment of executive function correlated to extent of ecstasyuse, including problems with memory formation/recall,and integration.

III. Forensic Issues

A. Toxicity and Death

It must be said that given the extent of its use, there arerelatively few reported deaths associated with MDMAuse. The DAWN medical examiner data set reported only27 deaths between 1994 and 1998 involving MDMA.Similarly low rates are reported elsewhere [38]. Nonethe-less, these deaths do occur, and there is little doubt thatMDMA above a certain threshold for that individual,often compounded by the presence of other drugs, poorhydration, or overexertion, can and does lead to death[20,21,27]. When taken in a setting involving strenuousactivity such as all night dancing, fatigue, exhaustion,dehydration, sympathetic hyperactivity, increased pulseand blood pressure, and tachyarrythmias can contribute tothe risk ofmortality. At elevated doses, MDMA will causeexcessive hyperthermia (> 105 OF) with muscular rigidity,disseminated intravascular coagulopathy, rhabdomyolysis,hyponatremia, hyperkalemia, acute renal failure, coma,and death [44,53,81]. In rare circumstances, high-dose orhigh-intensity MDMA use can be accompanied by theonset of new and potentially very dangerous effects re-lated to toxic neuronal serotonin levels. Most notably,these include loss of thermoregulatory control, accompa-nied by profuse sweating and hyperthermia, which, ifsustained, will lead to disseminated intravascularcoagulopathy, and rhabdomyolysis. Coma and death will

20

follow. Hyponatremia, and dehydration resulting fromstrenuous dance activity, or overhydration from increasedfluid intake may exacerbate the above effects [43]. Thehyperthermic effects of MDMA result from disruption ofcentral neurotransmitter-mediated thermoregulatory con-trol. Serotonergic hyperstimulation (serotonin syndrome)has been implicated in some ecstasy deaths [25,79], and ischaracterized by the presence of at least three of thefollowing: behavioral changes (confusion, agitation,hypomania, or coma), alteration of muscle tone (incoordi-nation, shivering, tremor, hyperreflexia, myoclonus, ri-gidity), autonomic instability (diaphoresis, tachycardia,hypertension, hypotension), hyperthermia, and diarrhea[72,104].

Gill et al. reviewed MDMA-positive deaths fromNew York City between 1997 and 2000 [36]. Of22 deathsduring that period, 13 were due to acute drug intoxica-tions, 7 due to mechanical injury, and 2 due to a combina-tion of natural disease and acute drug intoxication. Co-caine or opiates were also present in 7 of the 13acute drugintoxications. The decedents were predominantly whitemales between 17 and 41 years old.

B. MDMA and Driving

This issue has been reviewed by us in a prior publica-tion [62], and we revisit that review here with someupdates.

L Empirical ConsiderationsBy some estimates, upward of 35% of subjects using

drugs, predominantly ecstasy, at raves or dance partieswill chive home afterward [93]. MDMA can enhanceimpulsivity and make it difficult to maintain attentionduring complex tasks (selective attention, divided andsustained attention, and complex attention tasks). It shouldbe no surprise, therefore, that MDMA has the capacity toimpair driving. Changes in cognition, perception, andmental associations, instability and incoordination in gait,and poor memory recall are well documented. Distortionof perception, thinking, and memory, disorientation totime and place, and altered reaction times are also knownperformance effects, all of which can contribute to re-duced driving ability. When considering the followingreports, note the discussion in the pharmacokinetics sec-tion above regarding whole blood/serum ratios, and thepotential for redistribution of MDMA when interpretingpostmortem toxicology results.

2. Laboratory Studies and Other ReportsAcute changes in cognitive performance in users

before, during, and after a Saturday night dance where the


drug was self-administered, were evaluated by Parrott andLasky [88]. These authors note that MDMA markedlyimpaired information-processing ability, and they empha-size the dangers of undertaking skilled activities like cardriving when under its influence. Downing et a1. [28]concluded, based on impairment in cognitive perfor-mance, that tasks requiring significant coordination andconcentration should not be performed while under theinfluence of MDMA, especially operating a motor ve-hicle.

Laboratory studies of psychomotor and cognitiveskills show mixed results in terms of effects on thecomponent tasks that make up driving. Lamers et a1.administered MDMA (75 mg) to subjects (n = 12), andassessed driving-related task performance through a criti-cal tracking task, a divided attention task, a motor choicereaction time task, a time-to-contact perception task, anda visual search [58]. They found evidence of improvementin tracking, and divided attention after MDMA comparedto the placebo, and no effect on visual search. Only thetime-to-contact task showed impairment from MDMAunder this design. This behavior is representative of leav-ing reduced gaps between vehicles, which the authorsbelieve may be associated with greater risk taking. Sub-jects did show objective physiological changes in pulse,body temperature, and blood pressure associated with theuse ofMDMA. The authors believe that impairmen t in theperception and correct estimation of object movement aresignificant in predicting the likely effect on driving.

DeWaard et a1. [26] tested subjects using an advanceddriving simulator after the subjects had self-administeredMDMA (average dose 56 mg). This is arguably a modestdose compared to normal reported use patterns of 50-700mg, with 120 mg being more typical [39,40,10]]. Underthese conditions there were only moderate effects onvehicle control compared to the same subjects prior toself-administering the drug. They report that while theincidence of crashes during simulated driving was low (4of 20 rides), it was twice as high as in the control group.Taking this together with reduced gap between vehicles,the authors suggest that subjects acutely under the influ-ence of MDMA were prepared to accept higher levels ofrisk than when in the control condition. This is an issuethat has been raised with respect to methamphetamine[50,51,61], and Morgan [74] has also noted that recre-ational use ofMDMA is associated with increased impul-sivity, which raises concerns about judgment and appro-priate decision-making while under the influence of thedrug. In a related study using the same methodology,Brookhuis [10] looked at a set of subjects using otherdrugs or alcohol in addition to MDMA, and found similarbut more pronounced effects.

21

The conclusions, collectively, of these authors werethat the greatest potential acute affects at the doses studiedwere on the cogniti ve component of driving with minimaleffect on visual search, and perhaps even improvement insome of the psychomotor components such as tracking insome subjects. These improvements can presumably beattributed to the eNS-stimulating effects of the drug.

Turning to case reports, Giraud et al. [37] report threecases of drivers under the influence of MDMA withwhole-blood MDMA and MDA concentrations of 0, 121and 0.008 mg/L, 0.078 and 0.005 mg/L, and 0.141 mg/Land undetectable, respectively. The authors cite the psy-chotropic properties of the drug as being incompatiblewith the safe operation of an automobile. They also notethat in the case of a positive urine drug test alone, even inthe absence of MDMA in the blood, the ability to drivemay be heavily compromised until the driver has recov-ered after an evening of partying, and from the secondaryeffects of the drug.

Schifano [97] reports a series of case reports of fivedri vel'Sreferred for neuropsychiatric assessment. Betweenthem they were responsible for 11 serious accidents whileunder the influence ofMDMA. Specific behavioral changesthat led to the crashes included speeding (numerous men-tions), jumping red lights, hallucinations/delusions, and asense of detachment or distance from the real world.Patterns of use most frequently mentioned involved dailydoses of200 mg, although the upper limit ranged from 600to 1500 mg/day. 0 blood drug concentrations werereported.

Bost [9] reported two cases of intoxicated dri vers withMDMA in their blood, and five cases ofMDEA, althoughconcentrations were not reported for the former. Onedriver had alcohol present also (0.06 gllOO mL). In theother case where MDMA was the only substance reported,the driver had abruptly changed lanes, resulting in anaccident. He admitted to using what he thought wasMDEA 2.5 h earlier. The author drew no specific conclu-sions about the nature of the impairment produced by thedrug.

Moeller and Hartung [74] have reported serum con-centration ofMDMA in 18 impaired drivers. They reporta median MDMA concentration of 0.076 mg/L (range0.001-0.514 mg/L) , and a median MDAconcentration of0.013 mg/L (range 0.001-0.067 mg/L) in 23 cases as ametabolite of either MDMA or MDEA. They also note avery high incidence (83%) of combined use ofMDMA orMDEA and marijuana in Germany. However, other thannoting that 12 of the 18 MDMA drivers were involved inaccidents, they give no details of the specifics of thedriving involved.


._--- --------- --------

Omtzigt et al. [82] list blood drug-concentration dataina series of nine impaired driving cases involving MDMA.The mean (SD), range, and medium MDMA concentra-tion were O.1S (0.14), 0.04-0.3S, and 0.19 mg/L, respec-tively. Alcohol and/or other drugs were present in seven ofthe nine cases, and included ethanol (range 0.02-0.11 g/100 mL), amphetamine, MDEA, cocaine or benzoylecgo-nine, and cannabinoids. Specific behaviors noted includeddisturbance of equilibrium, confused speech, disorienta-tion to time and place, aggressive behavior, dilated pupils,slow reactions, and drowsiness. The metabolite MDA wasnot detected in any of the cases. The authors cite recklessdriving, disturbance of equilibrium, and impaired track-ing ability as the primary effects resulting in the accidentsfrom which these cases arose.

Crifasi and Long [15] report a case of a traffic fatalityattributed to MDMA impairment, in which the driversuddenly veered off the roadway, and rolled over anembankment. The MDMA concentration in preservedwhole blood was 2.14 mg/L, and the MDA was less than0.25 mg/L. Urine and vitreous MDMA concentrationswere 11S.8 mg/L and 1.11 mg/L, respectively. Marijuanametabolites were present in the urine but were not detectedin the blood. The authors note the difficulty in assessingthe relationship between the drug use, which in this caseclearly results from overdosage, and the causation of theaccident.

Hooft et al. [49] have reported the case of a death, inwhich the decedent fell from the roof of a moving vehicle.They attribute this bizarre and reckless behavior to the useof MDMA, based on the history and the toxicology data.The MDMA concentration in blood was 0.63 mg/L, andethanol was also detected at a concentration of 0.123 g/100 mL.

Davies et al. [22] report their experience in treating 16ecstasy abusers over a 3-month period, all of whom hadbeen injured in road traffic accidents. They note thatreckless driving had been the cause of all 16, and note thatimpaired neurological function resulting from use of thedrug complicated the assessment of the patients for pur-poses of treatment

Cadier and Cl arke [11] report a case of severe burns inan individual who had been using ecstasy and amphet-amine, when a gasoline container in a vehicle ignited,although the exact circumstances were unclear.

Dowling et al. [276] reported five deaths in subjectstesting positive for MDMA or MDEA. One of these wasa man who was fatally injured in a traffic accident after histruck hit a curb, then a utility pole. His injuries were minorand the cause of death was determined to have resultedfrom ASCVD; however, his postmortem toxicology re-vealed 0.95 mg/L of MDEA, and 0.8 mg/L of butalbital.

22

Henry et al. [48] reported on a series of deaths andintoxications resulting from MDMA use, including fiveroad traffic accidents (three drivers, a passenger, and onepedestrian). The authors attribute the accidents in part tothe use of the drug and the associated behavioral distur-bances.

Morland [7S] reviews some of the above reports andnotes that epidemiologically there are not as many inci-dences of MDMA-related traffic fatalities as might beexpected given the extent of its use. A possible explana-tion for this could be that the population of MDMA usersis relatively young and accordingly may perform lessdriving. He notes, however, that the prevalence ofMDMAin cases of reckless driving and the associated bloodconcentrations measured indicate an accident risk in-crease comparable to that observed after use of amphet-amines.

Logan and Couper [62] reported a series of 18 cases ofapparentMDMA-impaired driving. The subjects displayeda variety of driving behaviors that brought them to theattention of the police. Ofthe 18 drivers identified, 5 wereinvolved in collisions (various causes), S displayed erraticdriving (usually lane travel) and at least 5 were speeding.A common feature of these cases and others reportedelsewhere is the presence of multiple drugs and/or alcoholin most cases. Six tested positive for THC or its metabo-lite, four for alcohol, three for diazepam (although for atleast one subject this was likely administered in hospital),and one each for methamphetamine, PCP, ephedrine andLSD. This pattern of polysubstance use undoubtedlycontributes to the overall presentation, but makes theisolation of effects specific to MDMA difficult.

Six subjects tested positive for MDMA only. Bloodconcentrations in these subjects were < 0.05, <0.05,0.33,0.36, 0.39, and 0.58 mg/L, respectively. All six subjectsappeared cooperative and "laid back," and all but oneadmitted using ecstasy. Most subjects displayed muscletwitching and body tremors, dilated pupils, elevated pulse,slow reaction to light, and profuse perspiration.

The concentrations in the majority of these reportsrepresent the low- to mid-range of blood concentrations inrecreational MDMA users, consistent with peak concen-trations from the use of 50-200 mg. This suggests thatthese subjects are engaging in patterns of typical recre-ational use and are not MDMA overdoses. This agreeswith the observation by Mueller and Korey [79] that mostcases ofMDMA intoxication appear idiosyncratic and arenot associated with massive overdose.

Akram and Forsyth [1] have performed a meta reviewof European epidemiological studies of driving associatedwith dance drugs, and failed to find evidence of a signifi-cant number of impaired or fatally injured drivers testing


-- --.- ._- ----

23

You can drive while on E, but l don't recommendit. Thelast two times I did it, I ended up "accidentally"running about 3 red lights in a row in downtownBuffalo. I don't know if my reaction time was impairedor if I wasl1 'tpaying attention, but I usually don't blowmore than 1 during a single drive.Don't do this: Take an E, wait 15 minutes, and thenstart or an hour long drive. If the E is good you willhave a hard to very hard time focussing 011 the road etc.Despite the danger you probably wont get off the roadbecause you feel so good. Reaction time is also worse

than normal because your not given all the attention tothe road. I guess what is o.k. is to drive after the firstrush (MDMA) has passed, i.e., 30 minutes after the pillhit you. On MDEA you will feel fucked up the wholetime (not as much as on an MDMA rush), so this is notso good.Driving on E isfun. Except when your eyes won 'tfocuson a central point.Relatively easy to get pulled over when you drive weirdunder the influence ofMDMA. Man ever been to a ravewith people under the influence of X? They get abnor-mally happy, boisterous and social. So you mightbecome one and starts talking to a pedestrian out awindow and slam into a pole.I've gone through many roadtrips on E ... a lot of emwere inner city cruises at dawn, as i head back forhome from a real fun party. if you're a responsibleenough type of a user, you 'd just enjoy a true sense ofcomplete control and power overthe road - given thatyou do have that sense of responsibility, you'll findyourselfbeing careful and watching out for your safetyeven if you're driving 180-200 kph as you're tripping.E can only bring out the true you if you do it in aresponsible, self-discovering context.E is a psychedelic drug, and driving on psychedelics isfucking STUPID and irresponsible. You could easilykill yourself or someone else, and you make all otherE users look bad.Depends on how many you take and over what period.If I do one at 1 am and don't leave till 7-8 am then I'mfine. lf I do more I tend to be more flicked up whichmakes driving harder.Yeah. it's not the E that impairs your driving necessar-ily, it's the lack of sleep associated with its use. i'veseen people hitting each other in their cars leavingdance parties at lOam in the morning.No, it's the ecstasy that impairs your driving. it impairsvour sense of vision, your equilibrium, and your reac-tion times. lack of sleep is also part of the problem, butdon't lie to yourself when you say that the actualchemical is not at fault.I thought I was all good to drive home on E ... actually[felt I had completely come down. I came up to an exiton the highway ... it was sharper turn than I hadanticipated. I stepped on the brakes and the car skid-ded out of control and we slammed through a bunch ofthose sand barrells. No one was hurt. I don't know if itwas just the road was slippery or my reactions wereslow from dancing and drugs ... or maybe just thegoddess teaching me a lesson.Well yo i drove home cande flippn [authors note: inthis thread "candy flipping" generally implies com-bined MDMA and LSD use] from a rave once when ihadn't sobered up and it was the funniest experience inthe world my car was packed full of wasted youthplaying with glow sticks and lasers and bumps sometrance in the background (dj micro) when I was drivingit felt like iwas in a video game its not hard to drive atall just make sure u got either a binky or blo pop inurmouth for when u want to bite down or chew some-thing

positive for MDMA. The studies they reviewed, however,had their own limitations, were not consistent in method-ology, tested for different drugs at different thresholds andin differing matrices, and some predated the explosion indance culture in the 1990s. They also ignored the majorityof smaller studies cited above in which MDMA had beenspecific ally implicated in bad or unusual driving or crashes.

In summary, there is objective evidence of MDMAusers being involved in crashes and displaying bad driv-ing, in which their drug use has been concluded to be afactor. Additionally, there are documented impairmentsin cognitive skills related to risk taking, and following tooclosely. Additionally, the laboratory-based studies haveexamined only relatively low doses of MDMA in acutedoes, and the effects of prolonged or repeated administra-tion, in large groups of subjects have not been studied.

3. User Self ReportsStatements made by subjects arrested for drug-im-

paired driving can be informative, although potentiallyunreliable and self-serving. The users' frank discussion ofexperiences in a voluntary "peer" forum, however, can bemore enlightening and less subject to the same fear ofretribution or incrimination. In 2000, a thread entitled"Can you drive while high on ecstasy?" was started on theUsenet newsgroups alt.rave, alt.drugs, and alt.drugs.ecsta-sy. The initial posting read:

I've never tried E before, but I want to. I would like toknow the effects on reaction times. Is it like drivingstoned? Better? Worse? Any info would help. Thanksin advance.

There were about 60 postings in response. These weregenerally negative, with nobody expressing the opinionthat MDMA did not affect driving. Those indi viduals whobelieved they could drive safely stressed the need for extraattention and care to compensate for the drug effects.There seemed to be a general belief among users that oncethe acute effects had worn off (after a few hours), it wasrelatively safe to drive, but that the best advice was toavoid driving if possible. A sample of the comments(unedited) follow:

Logan and Couper s MDMA

You probably could drive, but remember that whilerolling, everything feels like it's going to be OK. Youmight be driving like a complete retard, but you thinkyou're the shit on the road (this goes for most situa-tions while rolling, I might add).Are you shitting me? most people can't walk straightwhile rolling ... let alone driving ...People will use ecstacy when they can be out of it fora while. People will use metli when they need toconcentrate and get work done. For example, I wouldnever drive on ecstacy, but don't think that it is aproblem driving on meth (although too much metli willmake you a dangerous driver and there have beentimes that I needed to get somebody else to drive for mein the past).The main trouble while rolling isn't physical, but yourmind tends to wander and it is Izard to concentrate ...makes it hard to pay attention to driving.Driving after your peak is ok ... I've driven on E and 1find it almost impossible to focus on the road furtherahead. I was totally unable to stay within Tny lane onthe highway, I was well aware of what was going on ...it takes a lot of concentration to drive onE. After a ravehowever ... 4-6 hours after you dropped YOU should befine. Unless you're one of those who go psycho on thehits.

4. MDMA and the Drug Recognition Expert (DRE)ProgramThe DRE program [29] classifies MDMA and related

compounds as stimulants; however, as noted above, theunique character ofMDMA with mood-altering, halluci-nogenic, and mild stimulant effects are quite distinct frompure stimulants like methamphetamine or cocaine. It ispossible therefore, depending on the dose and phase ofeffect, that MDMA may be misclassified according to thestrict guidelines of the DRE program. According to theDRE matrix, subjects under the influence of stimulantswould be expected to have elevated pulse and bloodpressure, normal to elevated temperature, dilated pupils,normal to tense muscle tone, no horizontal or vertical gazenystagmus, and no lack of convergence. Pupillary reac-tion to light would be expected to be slow.

Logan and Couper [62] reported DRE observations insix subjects testing positive only for MDMA. Behavioralindicators were consistent with the sympathomimetic/hallucinogenic character of the drug. Other signs includedconfusion, profuse sweating, muscle twitching, and bodytremors. Subjects were usually very cooperative and "laid-back". Five of the six subjects were given field sobrietytests (one leg stand, walk and turn test), and all fiveperformed poorly. Physiological indicators such as el-evated blood pressure and body temperature were notobserved, however, and pupil size was not markedlydilated. There was no con-elation between the bloodconcentration and the specific demeanor of the subject.The subject with the highest MDMA concentration (0.58

24

mgfL) fell asleep in the police car during the an-est. Thisdata strongly suggests that the impairing effects experi-enced by these subjects were a result of normal patterns ofrecreational use, and they may in fact be on the downside,or experiencing the after-effects of the drug. Thesymptomology in the remaining polydrug subjects wassimilar to the MDMA-only group.

CONCLUSIONS

MDMA is a unique drug, sharing properties of hallu-cinogens and stimulants. The acute effects of empathy,euphoria, and excitement for which it is usedrecreationallycan make it overwhelmingly distracting for the user in thecontext of driving. Laboratory studies show that usersexperience cognitive impairments, and may also act moreimpulsively while under the influence of the drug's sym-pathomimetic effects. Psychomotor impairment mayoccur with elevated doses or after repeated administra-tion, and residual psychomotor impairment during the"coming-down" phase may be compounded by fatigue,dehydration, combined drug use or other confoundingfactors. There is growing anecdotal information providingevidence of impaired driving, and it is evident that manyusers recognize and attempt to mitigate the effects bydelaying driving until the acute effects have dissipated.The drug inevitably may impair a subject's judgment andability to properly assess their fitness to drive. Bloodconcentrations in MDMA-impaired drivers suggest thatthis impairment is caused by normal patterns of recre-ational use, and MDMA use should be considered incon-sistent with safe driving immediately following ingestion,and for up to a day or longer following use.

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~~l··i. ,!..•...•.~

ABOUT THE AUTHORSB.K. Logan, F.J. Couper

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115. Weinmann W, Renz M, Vogt S, Pollak S: Automatedsolid-phase extraction and two-step derivatisation forsimultaneous analysis of basic illicit drugs in serum byGCIMS; Int I Legal Med 113:229; 2000.

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117. Zhao H, Brenneisen R, Scholer A, Mc ally AJ, EISohlyMA, Murphy TP, Salamone SJ: Profi les of urine samplestaken from Ecstasy users at Rave parties - Analysis byimmunoassays, HPLC, and GC-MS; I Anal Toxicol25:258; 2001.

BalTYK. Logan earned his bachelor's degree in chemistry and Ph.D. in forensic toxicology from the University ofGlasgow, Scotland. In 1986 he accepted a research fellowship in the Department of Toxicology and ChemicalPathology at the University of Tennessee in Memphis. In 1990he joined the faculty ofthe University of Washington(UW) in the Department of Laboratory Medicine and was appointed Washington State Toxicologist. In 1999 theWashington State Toxicology Laboratory merged with the Washington State Patrol, and Dr. Logan became directorof the newly created Forensic Laboratory Services Bureau. In addition to his duties as State Toxicologist and clinicalassistant professor at UW, he oversees operations of the seven State Patrol Crime Laboratories, Breath Test Section,and Drug Recognition Expert (DRE) program.

Dr. Logan has over 60 publications in the field of forensic toxicology and drug analysis, and is Board Certifiedby the American Board of Forensic Toxicology, where he currently serves on the Board of Directors. He has beenelected to the National Safety Council's Committee on Alcohol and Other Drugs and to the Intemational Councilon Alcohol, Drugs, and Traffic Safety, and has served as a consultant to the National Institute of Justice, the UnitedNations Drug Control Program, and numerous state agencies. He was recently named Executive Director of theCenter for Studies of Law in Action at Indiana University. He is a fellow of the American Academy of ForensicSciences, an active member ofthe Society ofForensic Toxicologists, and serves on the editorial boards ofthelournalof Forensic Sciences and the Journal of Analytical Toxicology. His current research interests include stimulant useand driving impairment, drug interactions, and postmortem toxicology.

Fiona J. Couper received her B.Sc. (Honors) degree in Pharmacology/Toxicology in 1992, and her Ph.D. degree inForensic Medicine/Toxicology in 1997, from Monash University (Melbourne, Australia). Dr. Couper is currentlythe Chief Toxicologist at the Office of the Chief Medical Examiner, Washington, D.C.

While pursuing her Ph.D. degree in Monash University, Dr. Couper also worked as a forensic toxicologist atthe Victorian Institute of Forensic Medicine (VIFM) in Melbourne. From 1997-1998, she held a postdoctoralfellowship position at the National Institute of Forensic Sciences and the VIFM, and in late 1998 became a seniorresearch fellow at the University of Washington and the Washington State Toxicology Laboratory (Seattle, WA).Dr. Couper's research has focused on the effects of prescription and illicit drugs on driving impairment, the use ofdrugs to facilitate sexual assaults, GHB and drug overdoses in the emergency room, and the prevalence of drug usein various community groups. She is also an active member of the Society of Forensic Toxicologists (Drugs andDriving Committee; Drug-Facilitated Sexual Assault Committee), the American Academy of Forensic Sciences, theIntemational Association of Forensic Toxicologists (Young Scientists Committee), and the Seattle-King CountyCommunity Epidemiology Working Group.

Forensic ScienceReview • Volume Fifteen Number One > January 2003

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