The Neuropsychopharmacology and Toxicology of 3,4-methylenedioxy-N-ethyl-amphetamine (MDEA)

The Neuropsychopharmacology and Toxicology

of 3,4-methylenedioxy-N-ethyl-amphetamine (MDEA)

Roland W. Freudenmann and Manfred Spitzer

Department of Psychiatry, University of Ulm, Germany

Keywords: Amphetamine derivatives — Amphetamine toxicity — Ecstasy — Eve — MDE —

MDEA — MDMA — RSA — Street drugs.

ABSTRACT

This paper reviews the pharmacology and toxicology of 3,4-methylenedioxy-N-ethyl-

amphetamine (MDEA, “eve”). MDEA is a ring-substituted amphetamine (RSA) like

MDMA, its well known N-methyl analog. Both have become very popular substances of

abuse in the techno- and house-music scene. They can evoke psychomotor stimulation,

mild alterations of perception, sensations of closeness and a positive emotional state as

well as sympathomimetic physical effects. At present, the name “ecstasy” is no longer

used only for MDMA, but for the whole group of RSAs (MDA, MDMA, MDEA and

MBDB) as they are chemically and pharmacologically nearly identical; moreover, many

ecstasy pills contain mixtures of the RSAs. Hence, for a selective review on MDEA, it is

crucial to strictly differentiate between: 1) street and chemical names, and 2) studies with

or without chemically defined substances. In order to present MDEA-specific infor

mation, the pharmacodynamics and kinetics are described on the basis of MDEA chal

lenge studies in animals and humans. In the toxicology section, we present a collection of

case reports on fatalities where MDEA was toxicologically confirmed. On the question of

serotonergic neurotoxicity and possible long-term consequences, however, MDEA-spe

cific information is available from animal studies only. The neurotoxic potential of MDEA

in humans is difficult to estimate, as ecstasy users do not consume pure substances. For

future research, challenge studies in animals using dosing regimens adapted to human

consumption patterns are needed. Such challenge studies should directly compare indi

vidual RSAs. They will represent the most viable and fruitful approach to the resolution

of the highly controversial issues of serotonergic neurotoxicity and its functional

consequences.

CNS Drug Reviews

Vol. 10, No. 2, pp. 89–116

Address correspondence and reprint requests to Dr. R. Freudenmann, MD, Department of Psychiatry, Uni

versity of Ulm, Leimgrubenweg 12, 89075 Ulm, Germany.

Tel.: +49 (731) 500-21451; Fax: +49 (731) 500-26751; E-mail: [email protected]

INTRODUCTION

Ecstasy has become the party and club drug of the 1990s, particularly in the techno-

musical scene (78,122). In many users, ecstasy produces psychomotor stimulation, eu

phoria and alterations of perception, obviously intensifying the “rave” experience. Ecstasy

received considerable medical and mass media attention because of its increasing popu

larity (75), indications of neurotoxic effects in the brain (133,136) and intoxications with a

fatal outcome (78).

Usually, the term ecstasy refers to pills containing 3,4-m

ethylenedioxy-methamphet

amine (MDMA). However, based on a proposal by the World Health Organization (181),

the name ecstasy is currently used for the whole group of ring-substituted amphetamines

(RSAs), since the single substances: MDA (for 3,4-m

ethylenedioxy-amphetamine,

“love”), MDMA (for 3,4-m

ethylenedioxy-methamphetamine, “XTC,” “E,” “adam”),

MDEA (for 3,4-m

ethylenedioxy-ethylamphetamine, “eve”) and MBDB (for N-methyl-1-

[1,3-b

enzodioxol-5-yl]-2-butanamine, “eden”)

are pharmacologically very similar. “Ent

actogens” is another name commonly used for these drugs, although it was originally

coined for MDMA and MBDB only (113); the name is based on the belief that the sub-

stances help individuals to experience a “touching within” (from Greek “en” = in(side),

Latin “tangere” = touch, Greek “gennan” = create).

Numerous reviews and handbooks have been published on MDA and MDMA, the two

RSAs that entered the market first (22,31,52,54,57,60,78,102,109,110,120,122,127,137).

The present paper reviews the pharmacology and toxicology of MDEA, a newer member

of the family. The “PubMed”-Medline was searched (search termes MDE(A), eve, but

also MDMA, ecstasy, MDA), and the retrieved papers were reviewed to identify MDEA-

specific information. However, it would be rather artificial to focus on MDEA without

mentioning MDA and MDMA, since 1) they have been far better investigated, 2) MDA is

the active metabolite of MDMA and MDEA (35,82,90), and most importantly, 3) ecstasy

tablets de facto often contain mixtures of different RSAs (163). Hence, studies based on

retrospective user reports cannot provide information on a single RSA. In the following,

we strictly distinguish chemical from street names, and differentiate between studies with

defined (i.e., challenge or in vitro studies, case reports with chemical or toxicological

workup) and undefined chemical compounds (i.e., epidemiological studies, retrospective

studies with self-reported use, case reports without toxicological workup).

CNS Drug Reviews, Vol. 10, No. 2, 2004

90 R. W. FREUDENMANN AND M. SPITZER

Abbreviations: I) neurotransmitters: 5-HT, serotonin (5-hydroxytryptamine); DA, dopamine; NA, norad

renaline (norepinephrine); ii) ring-substituted amphetamines

: MDA, (R,S)-3,4-methylenedioxy-amphetamine =

1-(3,4-methylenedioxyphenyl)-2-aminopropane; MDMA, (R,S)-3,4-m

ethylenedioxy-methamphetamine = N-me

thyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane; MDE(A), (R,S)-3,4-m

ethylenedioxy-(N)-eth(yl)amphetamine

= (R,S)-N-ethyl-3,4-methylenedioxy-amphetamine, N-ethyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane;

MBDB, (R,S)-N-m

ethyl-1-(1,3-benzodioxol-5-yl)-2-butanamine; iii) other substances: DOM, 2,5-dimethoxy-4-

ethylamphetamine = 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane = “STP” (for serenity, tranquility,

and p

eace); DOE, 2,5-dimethoxy-4-ethylamphetamine; DOB, 2,5-dimethoxy-4-bromo-amphetamine = 1-(2,5-

dimethoxy-4-bromophenyl)-2-aminopropane; DOI, 1-(2,5-d

imethoxy-4- iodophenyl)-2-aminopropane; THC, te

trahydrocannabinol; LSD, lysergic acid diethylamide.

CHEMISTRY, CLASSIFICATION, AND SYNTHESIS

Chemistry

To better understand MDEA and the other RSAs we briefly review some of their

chemical properties. The common mother substance of all RSAs, classic amphetamines

and some hallucinogens is phenylethylamine (Fig. 1). It consists of an aromatic ring and

an aliphatic side chain with an asymmetric (chiral) C-atom in alpha-position to the nitro

gen. Accordingly, phenylethylamine and its derivatives are racemic, i.e., exist as a mixture

of two enantiomers [R(–) and S(+)], which have some distinct stereospecific pharmaco

dynamic and pharmacokinetic properties.

CNS Drug Reviews, Vol. 10, No. 2, 2004

MDEA 91

phenylethylamine

OCH

HCO

Amphetamines

(stimulants)

Entactogens

Phenylethylamine

hallucinogens

amphetamine (R = H)

methamphetamine (R = CH )

MDA(R=H,R=CH)

MDMA (R = CH , R = CH )

MDEA (R = C H , R = CH )

MBDB (R = CH , R = C H )

123

1323

1252 3

13225

DOM (R = CH , R = CH )

DOE (R = C H , R = CH )

DOB (R = Br, R = CH )

DOI(R =I,R =CH)

132 3

1252 3

123

methamphetamine: meth, chalk,

tweak, crank (as hydro-

chloride), ice, crystal, glass)

MDA: love (drug pill)/

MDMA: ecstasy, XTC, E, adam,

M&M, california sunrise,

hug drug, clarity, essence,

lover’s speed, stacy

MDEA: eve, intellect

MBDB: methyl-J, eden

DOM: “STP” ( erenity,

ranquility, and eace)

Street names:

amphetamine: speed, uppers

FIG. 1. Phenylethylamine and its derivatives. Three important classes of substances of abuse are derived from

phenethylamine: 1) Amphetamines (stimulants) lack any ring-substitution, 2) Ring-substituted amphetamines

(RSAs) with an aromatic substitution in ring position 3 and 4 (methylenedioxy-group), 3) Phenylethylamine hal

lucinogens with a 3-fold ring-substitution (for the long names see Footnote 1). The pharmacological properties

of the single RSAs (MDA, MDMA, MDEA, MBDB) overlap with those of the other two classes: MDA has

stronger hallucinogen-like effects and shares the R(–) > S(+) order in psychotropic potency with the phenylethyl

amines with hallucinogenic activity; in contrast, MDMA has slightly more amphetamine-like effects (as indi

cated by discrimination studies in animals) and shares the S(+) > R(–) order in central effects with stimulants.

Classification

As illustrated in Fig. 1, RSAs take an intermediate position between amphetamines and

phenylethylamine hallucinogens (54), sharing many chemical and pharmacological prop

erties with the other two classes (partly overlapping effects). Some authors call all RSAs

or even all amphetamines “designer drugs.” According to the original definition by

G. L. Henderson (65), however, this term is restricted to substances synthesized to bypass

legal sanctions by modifying an illicit drug. MDA and MDMA were first synthesized as

legally unrestricted byproducts; in contrast, MDEA entered the market to substitute for

MDMA after its federal ban in the late 1980s (33,63), followed by MBDB in the early

1990s (29). Hence, only these two newer RSAs are designer drugs (not MDMA and

MDA).

Nomenclature

Phenylethylamines have a babel of names (Fig. 1). For MDEA, the usual street name

(apart from ecstasy) is “eve,” while “intellect” is much less common. Apart from several

other names used in the literature (see Footnote 1), the proper chemical name according to

the International Union of Pure and Applied Chemistry is 1-(1,3-benzodioxol-5-yl)pro

pan-2-yl(ethyl)azan (www.iupac.org).

Synthesis

MDEA and the other phenylethylamines can be easily synthesized in clandestine labo-

ratories without expensive or bulky equipment (mainly in Belgium and The Netherlands).

Instructions for the synthesis are readily available from books (158) or the internet. More

than 20 pathways are known for the synthesis of MDMA or MDEA, the easiest starts from

the illicit MDA (by simple N-alkylation). Popular precursors are safrole (available from

natural sources like sassafras, nutmeg, dill etc.) or MDP2P (= 3,4-methylenedioxyphenyl-

2-propanone, used by the fragrance and food industry). For further details see refs. 15,35,

97,153,158.

Usually, ecstasy and eve are marketed as pills (78) based on excipients like sorbitol,

cellulose or glucose (10). The manufacturers stamp the tablets with signs alluding to the

“rave” way of life (106). However, the symbols create a false sense of security as the psy

choactive agents in the tablets vary greatly in terms of quality and quantity [(78,106,165),

cf. www.ecstasydata.org].

Qualitatively, an eve pill may contain pure MDEA, but in recent years mixtures of

MDA, MDMA, MDEA, and MBDB are increasingly common. Moreover, countless adul

terants have been detected in ecstasy pills, including other abused drugs, e.g., amphet

amine, methamphetamine, pseudoephedrine, cocaine, opiates, benzodiazepines, LSD,

caffeine, 4-bromo-2,5-dimethoxyphenylethylamine (2C-B, “nexus”), paramethoxyam

phetamine (PMA), phencyclidine (PCP), ketamine, gamma-hydroxy-butyrate (GHB,

“liquid ecstasy”), and a variety of other drugs, e.g., chloroquine, vasodilators, dextrometh

orphan (43,106), which is associated with the danger of fatal drug interactions. Hence, re

sults from studies based on user reports and street names (ecstasy, eve) cannot be linked to

a defined substance (MDMA, MDEA).

The amounts of MDEA detected in pills varied from almost nothing to 75 mg (106).

In a recent report 64 to 175 mg of MDEA were present in various samples

CNS Drug Reviews, Vol. 10, No. 2, 2004

92 R. W. FREUDENMANN AND M. SPITZER

(www.ecstasy.org/testing/mde.html). The actual MDEA content in street pills should be

considered unknown, unless a specific toxicological analysis is carried out.

HISTORY AND LEGAL ISSUES

The role of MDEA within the RSA group is best understood in the context of their

history. Contrary to common beliefs, MDA and MDMA are rather old substances.

MDMA, for example, was first synthesized at the pharmaceutical company E. Merck in

Darmstadt, Germany, in 1912 as an intermediate product in a chemical pathway aiming at

a new styptic agent. MDEA, however, was introduced to the scientific community only in

the 1970s by the seminal work of the American experimental psychopharmacologist Alex

ander T. Shulgin (15,158,159). In the European and North American club scene MDEA

gained importance only after MDMA, its famous N-methyl analog, became federally

banned in the late 1980s (33,63). But the MDEA heyday was short. In the US, it became a

controlled drug already on August 13

1987 on the basis of a new law prohibiting analogs

of controlled substances [MDEA as an analog of the already controlled substances MDA

and MDMA; the law came into force in order to stop the “designer drug” problem

(9,63,117)]. In Germany, it remained legal until 1991, and in The Netherlands until 1993

(117). Today, it is listed along with MDA, MDMA, and MBDB in the most restrictive cat-

egory of abused substances in the US (Schedule I according to the Controlled Substances

Act), Canada (Schedule III of the Controlled Drugs and Substances Act), the UK (Class A

according to the Misuse of Drugs Act), Germany (appendix 1 of the Law on Hypnotics)

and other countries (26,54,78,86, 117). Table 1 summarizes the history of MDEA and the

other RSAs (for further details we recommend refs. 8,9,75,76,86,122,158,160).

CNS Drug Reviews, Vol. 10, No. 2, 2004

MDEA 93

TABLE 1. Short history of MDEA and other ring-substituted amphetamines

Date Event

1909/10

German chemists C. Mannich and W. Jacobsohn first synthesized MDA

1912/14

MDMA (not under this name) first synthesized in 1912 at pharmaceutical company

E. Merck, Darmstadt, Germany, as an intermediate byproduct in a chemical pathway

for a styptic agent; patent assigned to Merck April 27

1914

1978/1980

MDEA first mentioned in scientific publications by A. Shulgin and co-workers

1985–1988 MDMAlisted as a Schedule I controlled substance in the US in 1985 /8; it is also fed

erally banned in other countries; MDEA surfaced as a legal substitute (“designer

drug”), but became Schedule I on August 13th 1987 as well in the US

1986ff Techno-music and ecstasy use become a mass phenomenon in Europe in the 1990s;

mass production of ecstasy in Belgium, The Netherlands, Germany, Poland

1987 Dowling et al.: first report of fatalities after polydrug intoxication including MDEA

Jan 28

1991 MDEA federally controlled in Germany

1996 Iwersen & Schmoldt: first report of a fatal MDEA mono-intoxication

2003 currently MDA, MDMA, MDEA and MBDB are listed in the most restrictive cat

egory of abused substances in the USA (Schedule I), UK (Class A), and Germany

(appendix 1 of the BTM, 16

edition from Nov 28

2001), as well as other countries

Abbreviations. See Footnote 1.

EPIDEMIOLOGY

Ecstasy, as commonly known, became a quantitatively important drug of abuse in the

1990s with the emergence of the “rave” culture (techno- and house- music). Belonging to

this youth culture has been shown to be the best predictor for ecstasy use (42), indicating

strong sociocultural influences. However, there is a paucity of valid epidemiological infor

mation on illicit drugs in general. The best epidemiological study available in the US is

“Monitoring the Future“ [MTF, www.monitoringthefuture.org (75,76)]. MTF covers all

important classes of drug of abuse. According to MTF the use of MDMA in the USA for

the year 2002 was as follows: 1) life-time use in 10

grade students 6.6%, in college stu

dents 12.7%, and in young adults 14.6%; 2) annual use in 10

graders 4.9%, in college

students 6.8%, in young adults 6.2%; 3) 30 day-prevalence in 10

grade students 1.4%, in

college students 0.7%, and in young adults 1.3%.

In Europe a similar annual use of ecstasy of 0.5–3.0% was estimated for adults in 1998

(19). In a Spanish sample a life-time prevalence of 4.5% for designer drugs has been

found, a point prevalence of 0.6% (29).

The content of MDEA in the ecstasy pills is lower than that of MDMA or MDA. In

Spain, for example, the National Institute of Toxicology found that ~48% of the seized ec

stasy pills contained MDMA, ~41% MDA, ~7% para-methoxymethamphetamine, and

only 4% MDEA (2). A similar rank order was found in Denmark in 1995–1999 (163) and

in England (25).

The temporal consumption pattern of ecstasy is very typical. Usually, one to three pills

are taken during a rave weekend (124), while the rest of the week remains drug-free. The

subjective effects of this regimen have been eloquently termed “weekend high followed

by mid-week low“ (28). Often, there is no increase in either dosage or frequency of intake

(123,126). On the long run, however, 76% of the ecstasy users note less rewarding and

more unpleasant side and after-effects (126). This leads to two user groups: 1) those

quitting “E“ (self-limiting use, often interpreted as sign of a small addictive potential); and

2) those increasing dose and/or frequency of intake in order to overcome the loss of ef

fects (“stacking“).

Some new epidemiological trends include 1) increased drug trafficking, more profes

sional production and distribution that lead to: a higher availability and greater use of ec

stasy worldwide (87); 2) change in consumption patterns: growing street market for home

use, no longer a mere party drug for weekends, simultaneous use of other substances in

order to modulate effects (“flipping”) (149); and 3) change in user profile: ecstasy con

sumers tend to be older, more multidrug users (173,180). So-called “safe use recommen

dations” (see www.dancesafe.org) contributed to the use of refreshing drinks and regular

“chill-outs“ during rave weekends. This positive development is, however, counteracted

by a growing number of substance mixtures in ecstasy pills and multidrug use, which

raises clinical concern due to possible drug interactions (see below).

PHARMACODYNAMICS

Because of their chemical similarity to norepinephrine (NE, noradrenaline), dopamine

(DA) and serotonin (5-hydroxytryptamine, 5-HT), all phenylethylamines, including

CNS Drug Reviews, Vol. 10, No. 2, 2004

94 R. W. FREUDENMANN AND M. SPITZER

MDEA, interact with the corresponding transmitter systems in the central nervous system

(CNS). While amphetamines elicit psychomotor stimulation predominantly by a net re

lease of DA due to a “reverse transport” in the plasmalemmal DA transporter, i.e., an in

direct agonism [S(+)-enantiomer more potent than R(–), in the body sympathomimetic ac

tions (77,171)], phenylethylamine hallucinogens induce psychotomimetic effects by direct

interactions with neuronal 5-HT

receptors (44,143), with an inverse order in stereospeci

fic potency [R(–) > S(+)].

RSAs (e.g., MDEA) act mainly by indirect serotonergic mechanisms in the CNS

(6,27,54,78,94,101,113,160). Recent studies have shown, however, that RSAs also release

DA (157) and NE (141) from intracellular stores (rank order 5-HT > DA > NE). In the

5-HT system, RSAs trigger a 5-HT net release and inhibit its reuptake (54,78,101). These

findings are supported by studies in different laboratory settings (in vitro, cell culture,

drug discrimination studies in animals

), different species (rodents, non-human primates

and humans), and different experimental time schedules (acute and long term treatments)

(Table 2).

The primary site of action of MDMA has been identified at the molecular level as the

ser

otonin transporter (SERT), a membrane-bound protein in 5-HT vesicules and the

presynpatic plasmalemma (83,111,140), where it acts as a “substrate-type 5-HT-releaser”

(140). The plasmalemmal SERT is also the target site for antidepressants like selective

serotonin reuptake inhibitors (SSRIs) (111). Therefore, co-administration of a SSRI

attenuates MDA, MDMA and MDEA effects in vitro (73,101,179) and in humans in vivo

(citalopram with MDMA) (89).

In contrast to the selective mechanism of action of SSRIs, RSAs evoke their effects by

several mechanisms. Apart from their predominant indirect agonistic effects in serotoner-

gic neurotransmission, RSAs also act by inhibiting MonoAmine Oxidase (MAO) (88).

They have also comparatively weak intrinsic activity at several neurotransmitter receptors,

acting as direct agonists at 5-HT

1A/D

, and 5-HT

, á

1/2

, â,D

1/2

, and H

1/2

receptors

(6,7,46,94,128)). The affinity to postsynaptic 5-HT

-receptors is likely to mediate the mild

hallucinogenic effects of RSAs (7,44). Furthermore, several neuroendocrine effects ob

served in animal (41,62) and human studies (40,50,51,55) are thought to contribute to the

central and peripheral effects of these drugs.

The S(+)-enantiomers of RSAs, like MDA and MDMA, have higher affinity for presy

naptic 5-HT transporters, resulting in a greater 5-HT releasing (7,101) and psychotropic

potencies (94,113,114,118,119,146). By contrast, the R(–)-enantiomer is more potent at

postsynaptic 5-HT

-receptors which mediate the hallucinogenic effects of RSAs (7).

In addition, RSAs have substantial peripheral sympathomimetic, serotonergic, and

neuroendocrine effects (see below for clinical and toxicological details).

Animal and in vitro studies on the mechanism of MDEA action are summarized in

Table 2. In respect to its 5-HT releasing action MDEA is as potent as other RSAs (121,

153). Its overall neuropsychotropic potency is, however, controversial. In a rat study

MDEA has been reported to be as potent as MDMA, but weaker than MDA (45). In an

other study MDEA was found to be less potent than MDMA in inducing acute hyper

thermia (23). MDEA has a greater selectivity for 5-HT release than other RSAs (101,150).

CNS Drug Reviews, Vol. 10, No. 2, 2004

MDEA 95

Drug discrimination (DD) studies use animal models to compare behavioral effects of different drugs. First,

animals are trained to discriminate the stimulus properties of drugs from vehicle (saline), in a second step (chal

lenge), other drugs are administered and the degree of stimulus generalization is analyzed (generalization sug

gests similar stimulus cues in the animal).

It is weaker than MDA and MDMA in blocking the neuronal tryptophan hydroxylase

(TPH, the enzyme responsible for de novo 5-HT synthesis) (73,151,152,168,169). Conse

quently, tissue levels of 5-HT and of its main metabolite 5-hydroxyindoleacetic acid

(5-HIAA) (23,168,169) are lowered to a lesser extent by MDEA than by MDA or MDMA.

Therefore, the risk of inducing long-term toxic effects to serotonergic neurons is pre

sumably less with MDEA (23,101,121).

Pharmacodynamically, MDEA and the other RSAs are “dirty drugs.” Their predomi

nant mechanism of action is an increased release of 5-HT (probably responsible for emo

tional changes). Direct effects at 5-HT

receptors may account for DOM-like alterations of

perception.

PHARMACOKINETICS

The pharmacokinetic propertiess of RSAs, like those of MDEA, are determined by

their chemistry, which includes stereospecific differences. Animal studies revealed several

major aspects of MDEA kinetics, fostering further research in humans.

Animals

The challenge study by Boja & Schechter in rats (12) reported substantially faster ki-

netics of MDEA as compared to MDMA. The onset of action of MDEA is 10 min, peak

effect at 10 to 20 min, the effects are starting to decrease after 60 min, the duration of

action does not exceed 120 min, and the calculated half life is about 60 min. The duration

of action of MDMA, by contrast, is ~240 min, and the calculated half life ~100 min.

Hegadoren et al. (64) showed stereospecific differences in brain levels of MDEA enan-

tiomers with a R/S-ratio < 1 after administration of racemic MDEA (10 mg/kg i.p.) to rats

(after MDA, however, the R/S-ratio was > 1). MDA was detected as an active metabolite

of both MDEA and MDMA; surprisingly, the enantiomer ratios in the brain were inverse

to the ratio of the respective parent compounds (i.e., R/S-ratio of MDA after MDEA > 1,

after MDMA < 1).

Further evidence of stereospecific kinetics in animals was yielded by a study of the

urinary excretion of MDA, MDMA, and MDEA in rats (96). After administration of

racemic MDA, MDMA, or MDEA, a preferential excretion of the R(–)-enantiomer was

demonstrated with MDA and MDMA. This finding was in contrast to a higher excretion

rate of the S(+)-enantiomer after MDEA (30 mg/kg) administation.

Another study directly compared the metabolism and distribution of racemic MDMA

and MDEA (20 mg/kg, s.c.) in rats (103). MDEA (the racemic form and each isomer) was

significantly less metabolized than MDMA, resulting in significantly less neurotoxic

metabolites (e.g., S(+)-MDA). In the plasma, a R/S-ratio > 1 was found for MDEA as

well as for its metabolite MDA.

Humans

The pharmacokinetics of MDEA and other RSAs in humans has been the subject of

extensive research during the last decade in Kovar’s laboratory in Tübingen, Germany

(16,17,34,35,50,54,68,82,84,97–99,166).

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96 R. W. FREUDENMANN AND M. SPITZER

CNS Drug Reviews, Vol. 10, No. 2, 2004

MDEA 97

TABLE 2. Molecular mechanism of action of MDEA (animal and human in vitro studies, challenge studies only)

Study Main finding

(74) rats [

H]5-HT-release: MDA = MDMA,R=S;[

H]DA-release: S-MDA > S-MDMA; MDEA does not release DA

(72) rats single dose (MDEA (10 mg/kg): after 1 h: frontal cortical and hippocampal 5-HT concentration reduced (no effect on hypothalamic and neostriatal

5-HT, 5-HIAA and neostriatal TPH); after 3 h: 5-HT functions (incl. TPH) disturbed in most brain areas; the DA system, however, is almost unaffected

(only neostriatal DOPAC reduction after 3 h)

repeated dose: stronger decrease of 5-HT concentration and TPH; after 18 h: partial recovery (TPH activity), no more effects in DA system (transient);

hence, MDEA mainly affects the 5-HT, but not the DA system, effects are only transient

(134) rats MDEA selectively depletes 5-HT neurons, but not DA and NA; MDEA is factor 4 less toxic than MDMA

(150) rats 3 h after baseline: MDA = MDMA = MDEA deplete 5-HT in cortex neurons to <30% of baseline; MDA > MDMA > MDEA affect DA in striatum cells

(longer side chain => less effects)

1 week after baseline: cortical 5-HT & synaptosomal [

H]5-HT uptake normalized in MDEA, but still decreased in MDA & MDMA; hence, toxicity to

5-HT nerve terminals: MDA = MDMA (S>Rinboth), MDEA: no such effects

(168) rats MDA and MDMA (10 mg/kg, repeated dose): selectively alter 5-HT neurotransmission (decreased TPH, 5-HT & 5-HIAA tissue concentration),

MDEA: 5-HT & 5-HIAA is less reduced and TPH unaffected; hence, serotonergic neurotoxicity: MDA = MDMA >> MDEA

(12) rats, in vivo MDEA and MDMA have identical effects (drug discrimination task), but different potencies: MDMA > MDEA

(91) mice, rats first indication of species-specific long-term effects in MDMA and MDEA

(147) rats,

in vivo

acute effects: MDMA = MDEA (full generalization in drug discrimination task)

(128) human,

in vitro

first study in human cells investigates direct agonistic effects in 5-HT and NA systems; affinities at “DOB-binding site” are high (MDA = MDMA =

MDEA); at 5-HT

1A/D

- and alpha

-receptors, however, MDA has moderate, MDMA and MDEA little or no affinity

(73) rats MDEA (10 mg/kg) transiently reduces hippocampal 5-HT concentration and TPH activity (after 1 h, return to baseline after 12 h) as well as 5-HIAA

(decrease within 2 h, rebound to 22% above control after 12 h, returned to control after 24 h);

SSRI co-administration (fluoxetine) protects tissue 5-HT concentration and TPH activity (except for neostriatal TPH), in contrast to MAOI; hence,

MAO-related H

does not explain TPH activity changes

(112) pigeons,

in vivo

as measured by response rates in fixed-interval, fixed-ratio schedule controlled behavior (key pecking under food presentation): MDA is stronger than

MDMA and MDEA;

MDA effects can be blocked by metergoline (5-HT

1/2

-blocker) and ketanserine (5-HT

-blocker) but not prazosin (alpha

-blocker), MDMA: opposite

effects, MDEA: no effect of the co-administered drugs; the differential effects indicate different mechanisms of action

(47) rats,

in vivo

rats learned to discriminate S-amphetamine and R/S-DOM (i.e., a classic stimulant and a phenylethylamine hallucinogen); DOM stimulus did not

generalize to S-MDMA, R-MDMA, R-MDEA, S-MDEA, R/S-MDEA; amphetamine-stimulus generalized to S-MDMA, but not R-MDMA, or any

MDEA-form; hence, RSAs (except for S-MDMA) differ from stimulants and hallucinogens

(45) rats,

in vivo

MDMA-stimulus (0.75 mg/kg) generalized to MDEA (0.73 mg/kg) and MDA (0.47 mg/kg); hence, MDMA, MDA and MDEA have similar prop-

erties, but different potencies (MDA > MDMA = MDEA); MDMA partially generalized to S-amphetamine, however MDEA and MDA neither gener-

alized to amphetamine nor DOM; hence, MDA, MDMA and MDEA differ from amphetamine, S-MDMA is the most amphetamine-like substance

CNS Drug Reviews, Vol. 10, No. 2, 2004

98 R. W. FREUDENMANN AND M. SPITZER

Study Main finding

(95) rats, in vivo S-MDEA > R-MDEA in reducing prepulse inhibition in acoustic startle (stereoselective effects)

(101) rats acute effect:[

H]5HT-release: MDA = MDMA (both S > R), partially blocked by fluoxetine; [

H]DA-release: MDA = MDMA (both SR); R/S-MDEA:

5-HT release > DA release

long-term effect: only S-MDA produced a significant loss of [

H]paroxetine-labeled 5-HT-uptake sites, while MDMA and MDEA did not, indicating

differences in neurotoxicity

(148) rats block of 5-HT synthesis with TPH-antagonist p-chlorophenylalanine interferes with discrimination of serotonergic substances like MDMA, MDEA,

and fenfluramine, but neither dopaminergic (amphetamine) nor adrenergic drugs (yohimbine)

(13) rats stimulus generalization to MDEA was achieved by some 5-HT-receptor agonists, but not buspirone, norfenfluramine; partial generalization by ACh ag-

onist arecoline and amphetamine; amphetamine plus fenfluramine fully generalized to MDEA; 5-HT-blockers (cinanserin, metergoline) and a

dopamine-blocker (haloperidol) did not fully inhibit discrimination, only multiple pretreatments with TPH-blocker p-chlorophenylalanine; hence,

MDEA-stimuli are 5-HT and DA-dependent

(125) rats S-MDMA and R/S-MDEA change the quantity, but not the quality of motor behavior

(156) rats not single, only repeated high doses of MDEA (40 mg/kg, 8 times over 2 weeks) evoked a significant reduction of serotonin-immunoreactive axons,

particularly in fine-type varicosities (posterior cortex, hippocampus: CA1)

(144) baboons,

in vivo

after stopping cocaine i.v. self-injection MDEA and MDA were consistently continued by baboons

(23) rats acute effects: to induce hyperthermia 35 mg/kg MDEA i.p. and 15 mg/kg MDMA i.p. were needed; hence, potency MDEA < MDMA (~ factor 2)

long-term effects: after MDMA (7 days, 15 mg/kg) 50% decrease of 5-HT, 5HIAA (cortex, hippocampus, striatum) and [

H]paroxetine-binding sites

(cortex), whereas after MDEA (15, 25, 35 mg/kg i.p.) — even in the highest dose — only a 20% reduction of 5-HT parameters in cortex and hippo-

campus was found (only weak dose-dependent effects); in contrast, MDMA (15 mg/kg) and MDEA (35 mg/kg) had no effect in the DA system; hence,

neurotoxic potency in 5-HT neurons: MDEA < MDMA (~ factor 4); however, as human users need higher MDEA doses for the desired effects than in

MDMA, MDEA still is no safe substance

(5) rats single dose (MDEA 10, 20, or 40 mg/kg i.p.): induced dose-related hyperthermia and corticosterone increase; only the highest dose reduced 5-HT and

transporter density after 7 days (frontal cortex, hippocampus)

repeated doses (MDEA, 40 mg/kg i.p., b.i.d., for 4 consecutive days): stronger serotonergic deficits as compared with single dose

(121) rats single dose: MDMA and MDEA (20 mg/kg i.p.): increased locomotion, decreased rearing, induced stereotypy, Straub tail and head weaving as well

as hyperthermia (MDBA: no effects); [

H]5-HT-release (cortex, hippocampus): MDA = MDMA = MDEA >> MDBA; [

H]DA-release (striatum):

MDA > MDMA > MDEA = MDBA

repeated dose:20mg/kg, twice daily for 4 days): loss of forebrain [

H]paroxetine binding, 5-HT and 5-HIAA tissue concentration after 14 days (no ef-

fects on NA and DA systems), rank order: MDMA > MDEA >> MDBA > or = saline

(153) rats,

in vivo

haloperidol-induced catalepsy was used as a model for parkinsonian symptoms; MDMA (1.0–5.0 mg/kg) dose-dependently counteracted catalepsy

(S > R) with a much weaker effect in MDEA (2.5–5.0 mg/kg) or its two enantiomers (5.0 mg/kg), putatively based on less striatal dopamine release

(21) rats, in vivo cardiac toxicity of MDA, MDMA, and MDEA depends on a noradrenergic mechanism

Abbreviations. S, S(+)-enantiomer; R, R(–)-enantiomer; TPH, tryptophan hydroxylase; DOPAC, dihydroxyphenylacetic acid; MAOI, monoamine oxidase in-

hibitor; MDBA, N-butyl-analog of MDMA and MDEA.

TABLE 2 (continued)

Routes of administration

MDEA, like the other RSAs, is usually taken orally, rarely nasally or as a suppository.

As amines, all RSAs are soluble in water and alcohol (22,78) and can, therefore, be in

jected. Their inhalation as a vapor is impossible due to their high boiling points (160).

Dosage

A regular dose of ecstasy in “recreational use” ranges from 1 to 3 pills. For the defined

chemical substances in ecstasy pills the dose ranges are as follows: MDEA [100 to 200 mg

(158), or about 2 mg/kg (17)] > MDMA [80 to 150 mg (158), “best“ around 120 to

130 mg, or about 1.5 mg/kg (61)] > MDA [60–120 mg (63)]. These dose ranges appear to

correlate inversely with their psychotropic potencies (MDEA < MDMA < MDA).

Absorption and distribution

After consumption, MDEA is readily available and distributed in the body; data on oral

bioavailability and plasma protein binding in man are not available.

Course of action

According to human challenge studies the onset of action of pure MDEA, 140 mg, is

20–85 min (54), with 160 mg it is 40 min (158). The duration of action ranged from 2 to

3 h after intake of 140 mg MDEA (54) to 3 to 5 h after 160 mg (158), indicating shorter ef-

fects as compared with 4 to 6 h for MDMA and 8 to 12 h for MDA (158). Other major

pharmacokinetic parameters of MDEA obtained from challenge studies in healthy volun-

teers are summarized in Table 3 (17,166). These parameters include maximal plasma con-

centrations (C

max

) after usual “recreational“ doses (Study 1, 2) and the time of maximal

plasma levels (t

max

). Note that the study by Spitzer et al. (Study 3) gave first indications

for stereospecific pharmacokinetics in humans, e.g., the longer elimination half life in

R(–)-MDEA and the higher total clearance in S(+)-MDEA.

Metabolism and elimination

The hepatic metabolism of MDEA and of other RSAs is rather complex; two partly

overlapping phase I metabolic pathways have been identified by Ensslin et al. (35)

(Fig. 2). The major pathway is responsible for splitting the aromatic ring by O-dealkyla

tion; via 3,4-dihydroxy-metabolites. N-ethyl-4-hydroxy-3-methoxyamphetamine (HME)

is formed as the main metabolite (35,129). The second path breaks down the side chain of

the MDEA molecule by N-dealkylation. Quantitatively, this path is less important, but

N-deethylation leads to MDA as an active metabolite; after several further intermediates

the pathway leads to benzoic acids which are subsequently conjugated with glycine, re

sulting in substituted hippurates. In urine (after 140 mg racemic MDEA p.o.) unchanged

MDEA and 3,4-dihydroxyethylamphetamine (DHE) can be detected for 33 to 62 h after

ingestion, MDA for 32 to 36 h, and HME for 7 days. Initially detectable are also traces of

3,4-dihydroxyamphetamine (DHA), 4-hydroxy-3-methoxyamphetamine (HMA), pipero

nyl acetone, 3,4-dihydroxyphenyl acetone, and 4-hydroxy-3-methoxyphenyl acetone (34).

More profound insight into the metabolic breakdown of RSAs has been gained by the

identification of the cytochrome P450 isoenzymes (CYP) that catalyze the two aforemen

tioned pathways in animals and humans (98) (Fig. 2). In humans, MDEA catabolism de

pends on CYP 2D6 and 3A4 (2D6 mediates ring degradation only, 3A4 ring and side

chain degradation). This is of major clinical importance, since: 1) about 10% of the Cau

CNS Drug Reviews, Vol. 10, No. 2, 2004

MDEA 99

casian population have a CYP 2D6 “poor metabolizer” phenotype (30,84,106); 2) CYP

2D6 and 3A4 can be saturated by high doses of MDEA (84,175); and 3) P450 isoenzymes

can be inhibited by numerous drugs metabolized by the same isoenzymes, causing dispro

portionally high plasma levels of MDEA (non-linear kinetics) (30).

The effects of different activities of these “bottleneck enzymes” can be seen, for ex

ample, in the 10-fold variation in the levels of HME, the major metabolite of MDEA after

CNS Drug Reviews, Vol. 10, No. 2, 2004

100 R. W. FREUDENMANN AND M. SPITZER

MDEA

(R = C H , R = CH )

1252 3

ring degradation by

0-demethylenation:

2D1

2D6

3A2

3A4

side chain degradation

by N-dealkylation:

(1A2) (2D1)

3A2

3A4

rat:

man:

FIG. 2. Hepatic metabolism of MDEA in rat and man. Two major pathways, ring or side chain break down, and

the respective cytochrome P 450 isoenzymes in rat and man (2D1 = CYP 2D1). Data are adapted from Maurer et

al. (2000) (ref. 98).

TABLE 3. Pharmacokinetics of MDEA in man (challenge studies, healthy human subjects)

Study 1

Brunnenberg

et al. (1998)

N = 6, fixed dose:

140 mg MDEA

Study 2

Brunnenberg et al. (1998)

N = 8, dose adjusted

to2mg/kg body mass

(max. 140 mg) MDEA

Study 3

Spitzer et al. (2001)

N = 5, fixed dose: 70 mg

R(–) and S(+)-MDEA

R(–) S(+)

max

(ng/mL)

MDEA 260 (203–333) 332 (235–465) 127 ± 34 80 ± 30

MDA 21 (15–32) 23 (7–33)

HME 436 (285–615) 389 (67–673)

max

(h) MDEA 2.2 (1.6–2.9) 2.9 (1.8–5.0) 2.8 ± 0.9 2.6 ± 0.6

MDA 3.4 (15.0–32.0) 5.5 (4.0–7.0)

HME 2.8 (1.6–3.9) 2.7 (1.5–5.0)

1/2

(h) MDEA — (—) — (—) 7.5 ± 2.4 4.2 ± 1.4

MDA

HME

AUC

(ng/h/ mL)

MDEA — (657–875) — (832–1935) 1707 ± 897 535 ± 263

MDA — (38–95) — (19–120)

HME — (665–1976) — (218–3028)

Total Cl

(mL/min)

MDEA — (—) — (—) 718 ± 3404 2258 ± 1032

MDA

HME

Numbers given as mean and range (studies 1 and 2) or mean ± S.D. (study 3).

Abbreviations. C

max

, maximum plasma concentration; t

max

, time at maximum plasma concentration;

1/2

, elimination half life; AUC, area under curve; Total Cl, Total Clearance (cleared volume per time

unit).

administration of bodyweight-adjusted doses of MDEA to healthy subjects (Table 3, Study

2) (17). It can be concluded that interindividual differences in toxic MDEA doses can be

explained partially by genetically determined CYP activities and pharmacokinetic interac

tions (for further details on RSA metabolism see refs. 82,84,98).

Drug interactions

The dependence of MDEA metabolism on CYP 2D6 and 3A4 implies that substances

acting as CYP 2D6- and 3A4-inhibitors may substantially block hepatic MDEA degra

dation. CYP 2D6-blockers that have caused harm when used with ecstasy are fluoxetine,

paroxetine (132,175), moclobemide (79,164), and dextromethorphan (14,131,132,182),

but haloperidol, thioridazine and quinidine should be avoided as well. Among CYP

3A4-blockers, ritonavir has been repeatedly reported to interfere with ecstasy (1,3,32,66,

155), but also fluoxetine, nefazodone, cimetidine, grapefruit juice, verapamil, erythromy

cin, ketoconazole and metronidazole inhibit CYP 3A4. The SSRIs, fluoxetine and paroxe

tine, as well as the MAO-inhibitor moclobemide cause not only pharmacokinetic, but also

pharmacodynamic interactions, which may lead to the serotonin syndrome and arterial

hypertension.

Use in pregnancy

The use of ecstasy in pregnancy may lead to teratogenic effects including congenital

heart disease and malformations (24, 80,100). No specific information on the relative tera-

togenicity of MDA, MDMA, MDEA or MBDB is available.

LABORATORY AND TOXICOLOGICAL ANALYSIS

The laboratory and toxicological analytical procedures applied for classic amphet-

amines (108,139) and the different RSAs, including MDEA, are very similar. Reliable

methods are needed for the legal prosecution of the use of these illicit substances and the

clinical management of the growing number of intoxications (97,183). The analytical pro

cedures can be separated into two groups: 1) different types of immunoassays (85,92,142,

183), and 2) chromatographic and spectroscopic methods like high-performance liquid

chromatography (HPLC) (105), liquid chromatography-mass spectrometry (LC-MS) (11),

and gas chromatography-mass spectrometry (GC-MS) (97,170).

For screening purposes and routine sample testing, simple, cost-effective, but rather

sensitive methods, like immunoassays, are used (85,139). In contrast, for confirmatory

testing, forensic issues and quantitative analyses, GC-MS is considered to be the reference

method (107,183). For further information see refs. 11,20,98,107,142,170,183.

HUMAN NEUROPSYCHOPHARMACOLOGY

AND CLINICAL TOXICOLOGY

Amphetamine derivatives are primarily known as substances of abuse. Their effects

can be classified in several ways (e.g., acute vs. long-term, neuropsychiatric vs. physical,

CNS Drug Reviews, Vol. 10, No. 2, 2004

MDEA 101

and desired vs. undesired). We emphasize below MDEA challenge studies as being the

most MDEA-specific.

Acute Effects

The subjective experience under ecstasy varies greatly and depends on several factors,

such as the dose, presence of additional substances in the pill, frequency of previous ex

posure to ecstasy, baseline mood, concomitant use of other drugs, etc. In general, the expe

rience consists of “amphetamine-like” stimulation, mild “DOM-like” alteration of per

ception and “entactogenic” effects. The psychotropic effects of RSAs seem to lie in

between classic amphetamines and phenylethylamine hallucinogens which are derived

from the same parent compound (161,162) (Fig. 1).

Anecdotal Data

The differences between individual RSAs are subtle (54,78). Reports from some expe

rienced users indicate, however, a lower psychotropic potency, a shorter duration of

action, but stronger suppression of appetite for MDEA as compared to MDMA (54,158).

Users describe that under the influence of ecstasy they develop peculiar feeling of

“closeness” to other people (126), the loss of boundaries, sensation of unification with the

inner self, others or the environment. Since this experience depends to a great extent on

the environment during drug consumption, i.e., “trance”-like mass dancing, psychosocial

factors seem to contribute to the overall effect.

A certain sequence of subjective effects is considered typical for ecstasy use. The first

phase is a short rush called “coming on”. It is followed by a “plateau phase” with a

pleasant emotional state and increased physical energy. The plateau phase adds to the

“rave experience” and seems to be associated with a central serotonin rush and sympatho-

mimetic effects. In more than half of the cases, however, untoward effects accompany the

plateau phase: jaw clenching (trism), tachycardia, tooth grinding (bruxism), and dry

mouth (126). The third phase of the response is “coming down” and return to baseline,

often with “negative” emotions. The fourth and the last phase is characterized by psychic

and physical “aftereffects” that include muscle aches and stiffness, headache, depressed

mood, anxiety, cognitive dysfunctions and fatigue (126). This “nadir” represents pre

sumably neuronal serotonin depletion; the time of its onset is variable, the estimates range

from one (126) to 5 days (28) after ingestion.

MDEA Challenge

The best information on desired and unwanted psychotropic and somatic effects of

MDEA can be derived from challenge studies with pure MDEA in healthy subjects in a

controlled setting (49,50,54,68,166). According to Gouzoulis-Mayfrank et al. (54) MDEA

effects in humans as seen in several challenge studies can be summarized as follows: After

administration of 140 mg MDEA per os, there is a sudden onset of effects (after a few

minutes), but with a different delay (20 to 85 min). Initial signs of drug action are mainly

somatic, e.g., nausea, blurred vision and deep breathing, sometimes also anxiety; subse

quently, most subjects report strong relaxation, pleasant peacefulness and loss of anxiety,

contrasting with objective stimulating effects that subjects were unaware of (psychomotor

activation, logorrhea, tachycardia, elevated blood pressure, tremor). In at least half of the

CNS Drug Reviews, Vol. 10, No. 2, 2004

102 R. W. FREUDENMANN AND M. SPITZER

subjects, MDEA caused psychomotor stimulation, a positive emotional state and mild al

terations of perception (visual, acoustic and tactile), impaired cognitive functioning and

sympathomimetic effects. Surprisingly, only a minority of subjects reported “entactoge

nic” experiences. Still, MDEA challenges demonstrate amphetamine-like and hallucinoge

nic effects in a unique blend.

In 1992 Gouzoulis et al. reported the results of a double-blind, placebo-controlled sleep

EEG study involving six individuals (49). It was the first in a series of studies that used

140 mg racemic MDEA synthesized in the Kovar’s laboratory. In the sleep laboratory,

MDEA was given to the subjects at 11 p.m.; at 1 to 2 h later all subjects awakened, indi

cating the onset of the stimulant effect. Total sleep time and rapid eye movement (REM)

sleep were significantly reduced. The study revealed alterations of sleep architecture at

tributed to MDEA’s amphetamine-like properties.

Another study by Gouzoulis et al. (50) investigated on the effects of MDEA on neuro

endocrine and cardiovascular parameters. The study was double-blind, placebo-con

trolled, crossover and involved eight male volunteers. In addition to marked sympathomi

metic effects on blood pressure and heart rate, MDEA produced significant elevation of

serum cortisol and prolactin, supporting serotonergic actions in the hypothalamus, al

though the attenuated growth hormone secretion did not fit this interpretation.

CNS Drug Reviews, Vol. 10, No. 2, 2004

MDEA 103

TABLE 4. Psychotropic effects of MDEA in healthy humans (challenge studies)

Pooled

data

(%)

Study 1

N = 8 (males)

day-time, personal

contact to scientist,

systematic ratings

Study 2

N = 6 (3 female)

night, no personal

contact, no

systematic ratings

Hypervigilance, increased drive 100 8/86/6

Euphoria, relaxation, peaceful satisfaction 50 4/83/6

Dysphoria, irritation 7 1/80/6

Feeling of happiness 21 2/81/6

“Entactogenic effects”: introspection, empathy,

loss of anxiety, happy self acceptance, con

trolled communicative openness

21 3/80/6

Altered perception of time 21 2/81/6

Altered visual, tactile, acoustic perception:

colors more intense, blurred contours, things

bigger/smaller, sounds louder, haptic impres

sions “as if through cotton wool”

50 4/83/8

Depersonalization, derealization 7 0/81/6

Religious-mystique experiences 21 1/82/6

Psychotic state: acoustic/visual hallucinations,

delusions, loss of control, anxiety

70/81/6

No loss of control 93 8/85/6

Disturbed concentration (subjective) 43 4/82/6

Severe cognitive dysfunction NA 0/0NA

Adapted from Gouzoulis-Mayfrank et al. (1996) (ref. 54).

Abbreviations. NA, not available.

In order to further characterize MDEA effects in humans, Gouzoulis et al. directly com

pared MDEA with amphetamine (stimulant) and psilocybin (hallucinogenic substance).

One study systematically assessed the effects of the three substances on psychopathologi

cal, cardiovascular and vegetative functions (56). In addition to significant increases in

serum cortisol and prolactin, as well as an increase in body temperature, MDEA challenge

evoked subjective “relaxation” in a surprising blend with the sympathomimetic cardiovas

cular effects. This pattern clearly differed from that induced by either amphetamine or psi

locybin. Another study compared the same substances using positive emission tomog

raphy with

fluorodexoglucose (FDG-PET) (55,154). MDEA challenge led to changes in

the regional cerebral blood flow (rCBF), most prominently a rCBF decrease in frontal

cortex and cerebellum, and an increase in the right anterior cingulum. This pattern of ef

fects was different from that of the other two substances. The authors interpreted the re

sults of the two studies as a support of the earlier drug discrimination studies in animals

that classified “entactogens” (here MDEA) as a separate entity between stimulants and

hallucinogens.

The most comprehensive study of the psychotropic effects of MDEA was carried out

by Spitzer et al. (166). The double blind, crossover study addressed stereospecific effects

by the administration of the two MDEA enantiomers (70 mg) in five male physicians and

involved systematic controls of plasma levels. In addition to standardized rating scales to

assess subjective effects (mood, well-being, somatic symptoms, and hallucinogenic ef-

fects) the authors used a battery of neuropsychological tests (a task on basic visual pro-

cessing, the Wisconsin Card Sorting Test), and functional magnetic resonance imaging

(fMRI) to measure drug action. Despite the rather small doses used substantial stereospe-

cific differences were found. Significantly higher scores for well-being (Bf-S) were noted

with the S(+)-enantiomer. A trend for more somatic symptoms was reported for R(–)-

MDEA. Higher maximal plasma levels of R(–)-MDEA (p < 0.05) and a trend for a longer

elimination half-time (p < 0.08) resulted in a greater area under the curve (p < 0.04). In

contrast, S(+)-MDEA was preferentially excreted in urine (p < 0.04) (Table 3). A signifi-

cantly shorter reaction time in pop-out search (low level visual processing) was shown for

R(–)-MDEA. Higher switch costs in the Wisconsin Card Sorting Test were found for

S(+)-MDEA. In fMRI, semantic judgments were associated with significant BOLD “acti

vations“ of right visual and left frontal areas under R(–)-MDEA, in contrast to right

frontal and bilateral temporoparietal “activations“ under S(+)-MDEA. The study sug

gested that S(+)-MDEA is responsible for pleasant subjective effects, while the higher

plasma levels of R(–)-MDEA contribute to unpleasant somatic sensations and may also

enhance bottom-up processes in the visual system, possibly being the basis for visual

alterations of perception.

Complications

The possible acute complications of MDEA use range from psychiatric problems to

severe medical conditions and eventually fatal intoxications.

Acute psychiatric complications

MDEA has the potential to trigger acute psychotic disorders and induce dysphoric

mood, anxiety as well as panic attacks (48,68,70,176). These are the known complications

CNS Drug Reviews, Vol. 10, No. 2, 2004

104 R. W. FREUDENMANN AND M. SPITZER

of amphetamines, hallucinogens and cocaine (63,78). Accidents and misadventures under

the influence of MDEA and the other RSAs are also frequent.

Physical complications

In general, the physical problems associated with MDMA (63,78) have also been de

scribed for MDEA. Either of the two drugs can elicit a variety of symptoms, including

mild unwanted effects, like nausea or headache, as well as more serious conditions re

quiring medical treatment:

— One of the serious conditions is the serotonin syndrome (167) that involves hyper

thermia (often aggravated by environmental heat, overcrowding, and dancing), neuro

muscular signs (hyperreflexia, tremor, trism), psychopathology (hyperactivity, agitation,

confusion), and gastrointestinal symptoms (nausea, vomiting, diarrhea).

— In severe cases this syndrome leads to rhabdomyolysis, disseminated intravascular

coagulation (DIC), acute renal and eventually multiorgan failure (36,37,67,172,174,178),

that require referral to an intensive care unit.

— MDEA use may cause hyponatremia and the Syndrome of Inappropriate

AntiDiuretic Hormone secretion (SIADH) (18,41).

— Cardiovascular problems due to sympathomimetic effects after MDEA intake in

clude: arterial hypertension, tachycardia, arrhythmias, acute heart failure and myocardial

lesions (33,70,106,178); possibly also fenfluramine-like valvular heart disease mediated

by 5-HT

-receptors as shown by recent in vitro studies (157). Other reported complica-

tions include

— respiratory failure (26,93,178),

— intracranial hemorrhage due to ruptured aneurysms (106), cerebral seizures and

convulsions (174), as well as

— subacute toxic hepatitis (67,70,106,174).

The diagnostic and therapeutic measures in MDEA intoxications are the same as for

amphetamines and MDMA (67,78,139,177).

MDEA-related fatalities

The most comprehensive collection of lethal intoxications associated with the use of

ecstasy has been presented by Kalant (78, appendix 1). Table 5 summarizes 20 fatalities in

which the presence of MDEA was toxicologically confirmed (2,4,26,33,36,37,39,70,93,

106,130,178).

These fatalities clearly highlight the pathophysiological patterns mentioned above.

Note the rather large number of accidents as compared to the direct toxic effects. Most

cases are polydrug intoxications. The relative contribution of MDEA to the fatal outcome

cannot be exactly determined. The dangers of MDEA were, however, documented by four

lethal intoxications with the drug alone (70,93,178). The blood levels of MDEA in these

individuals ranged between 12 and over 20 mg/L.

Chronic Effects

Definitive information on the chronic effects of pure MDEA is not available, since

users do not usually consume MDEA alone, but various mixtures of RSAs and other

neurotoxic substances, such as amphetamine and methamphetamine. We will, therefore,

CNS Drug Reviews, Vol. 10, No. 2, 2004

MDEA 105

briefly review the issues of substance dependence, neurotoxic effects, and long-term neu

ropsychiatric consequences for RSAs in general, rather than for MDEA alone.

Substance dependence

In general, the addictive potential of ecstasy is considered to be low. This conclusion is

based on the lack of tolerance and withdrawal effects after discontinuation, as well as on

CNS Drug Reviews, Vol. 10, No. 2, 2004

106 R. W. FREUDENMANN AND M. SPITZER

TABLE 5. MDEA-related fatalities

Case

No.

Subject, clinical details,

detected substances (mg/L=ìg/mL), comments

Reference

1 male/25y, car accident probably due to cardiac arrest; blood: MDEA (0.95),

butalbital (0.8), underlying coronary heart disease

(33)

2 male/21y, found unconscious, CPR unsuccessful; blood: MDEA (2.0), propo

xyphene (0.26), norpropoxyphene (1.0), underlying idiopathic cardiomyopathia

(33)

3 male/21y, found dead in bed; blood: MDEA (3.5), MDMA (2.1), MDA (8.5),

amphetamine (0.256)

(39)

4 male/19y, cardiac arrest, CPR unsuccessful; blood: MDEA (20.2 or 22.2 on ad

mission, 45 post mortem), no other drugs, cerebrospinal fluid: MDEA (40.6)

first report of a fatal MDEA monointoxication, previously healthy person

(70)

5 male/24y, suicide by stabbing under the influence of drugs; blood: amphet-

amine (0.75), MDEA (0.22), alcohol (0.46)

(70)

6 male/22y, tachykardia, hyperthermia (41.8°C), metabolic acidosis, DIC, pete-

chial and subendocardial hemorrhages, lung edema, pleural effusion; blood:

MDEA (0.49 on admission, 0.30 post mortem), MDMA (0.55, 0.43), MDA

(0.24, 0.25), LSD (neither THC nor alcohol), healthy person

(26)

7 male/24y, collapsed dead at disco, focal necrosis in heart and liver;

blood (post mortem): amphetamine (0.453), MDEA (0.187)

(106)

8 male/21y, found dead in bed, focal necrosis of liver and brain, inhalation of

vomit; blood (post mortem): MDA (8.5), MDEA (3.5), MDMA (2.1), amphet-

amine (0.256)

(106)

9 male/23y, MDEA and amphetamine, violence (93)

10 male/17y, MDEA (alone), respiratory arrest/asphyxia? (93)

11 male/39y, MDMA and MDEA, cardiovascular death (93)

12 male/21y, MDEA (alone), traffic accident (93)

13 male/19y, MDEA (alone), traffic accident (93)

14 male/19y, MDEA (alone), “adverse drug reaction” (93)

15 male/20y, found dead in bed, hyperthermia and DIC; blood: MDEA (1.596),

MDMA (0.185), brain: MDEA (8.430), MDMA (12.794), urine: MDEA

(183.737), MDMA (263.132), intoxication with MDEA >> MDMA

(37)

16 female/27y, psychiatric patient, cardiac arrest; blood: MDEA (1.2), benzodiaze

pines and caffeine positive, other common drugs and phenelzine (last treatment)

negative

(2)

17 male/19y, profuse sweating, muscular spasms, aggression, hallucinations, loss

of consciousness, CPR unsuccessful, severe vascular congestion of all internal

organs, multiple subserous petechial hemorrhages, lung emphysema;

blood: MDEA (12), MDMA (0.016), MDA (0.32), brain: MDEA (28), no

MDMA, MDA (0.65) urine: MDEA (201), MDMA (0.135), MDA (7.1), other

drugs of abuse incl. alcohol negative, well documented lethal monointoxication

with about 1.3 g MDEA (and traces of MDMA) in normal ambient temperature

(178)

18 ??; blood: MDMA (2.0), MDEA (0.7) (130)

19+20 two more cases are mentioned in the literature, no details available (4,36)

Abbreviations. THC, tetrahydrocannabinol; LSD, lysergic acid diethylamide.

its consumption pattern (use on weekends only, often self-limiting, strong influence of

sociocultural factors) (71,78,104,126). Criteria for substance dependence according to the

current edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)

are not met in many users of ecstasy. However, some recent case reports indicate that ec

stasy has indeed the potential to evoke substance dependence (71). As the experimental

and epidemiological data basis is still limited, it is currently impossible to resolve the

issue of the addictive potential of ecstasy (63,78,122). For clinical purposes ecstasy use,

including complications, can be classified according to DSM-IV.

Neurotoxic effects

An even more intricate topic is the existence of neurotoxic effects after repeated ec

stasy use. Animal and in vitro studies (Table 2) showed selective alterations of serotoner

gic neurotransmission after repeated exposure to RSAs in the form of reduced levels of

5-HT and 5-HIAA in brain and liquor, reduced tryptophan hydroxylase activity, loss of

paroxetine-labeled binding sites, immunological and histological signs of damage to 5-HT

nerve terminals, and delayed “neuronal pruning” or “sprouting” (38,121,134,135,168).

Some authors argue that this evidence suffices to conclude that ecstasy has serotonergic

neurotoxic effects in humans. Others, by contrast, question the applicability of findings

from animal studies to humans and the significance of the results from human studies be-

cause of methodological limitations (retrospective design, possible exposure to other

neurotoxic agents, lack of toxicological workup, etc.) (78,81,145).

Most in vitro and animal studies suggest a lower serotonergic neurotoxicity with

MDEA than with other RSAs (MDEA < MDMA < MDA) (72,73,91,101,115,116,121,

134,150,168) with only a few exceptions (5,156).

The mechanism responsible for the toxic effects of RSAs to 5-HT neurons is not well

understood (60, 69). The proposed mechanisms include: 5-HT depletion, an increased stri-

atal dopamine release, calcium-influx, inhibition of tryptophan hydroxylase, hyperther-

mia, formation of free radicals, effects of excitatory amino acids, increased turnover of

cytoskeletal protein tau, impaired axonal transport, prolonged translocation and activation

of protein kinase C, etc. (for reviews see refs. 52,53,60, 63,121,184). The paper by

Ricaurte et al. describing dopaminergic neurotoxicity of MDMA in primates was recently

retracted (138). Future research is needed to elucidate the neurophysiological changes in

duced by RSAs.

Chronic psychiatric complications

The discussion about neurotoxic effects is not only of academic but also of clinical im

portance. There is a substantial evidence that many former ecstasy users seek professional

help because of various neuropsychiatric symptoms. They suffer from cognitive problems

that affect verbal and visual memory, decision-making and problem-solving as well as af

fective (atypical depression or anxiety, 68) and psychotic symptoms (paranoid ideas, al

tered visual or acoustic perception, depersonalization and flashbacks). Their appetite and

sexual functions can be impaired as well. The combined presence of these symptoms, to

gether with the experimental finding of a reduced 5-HIAA concentration in the liquor, is

very indicative of a chronic serotonergic depletion (123). Some research groups, however,

failed to demonstrate neurocognitive deficits in former ecstasy users (122). Little is

known about the treatment of the possible long-term complications of ecstasy use. To our

knowledge, no controlled clinical trials have been carried out to establish evidence-based

CNS Drug Reviews, Vol. 10, No. 2, 2004

MDEA 107

strategies. An important but open question is how many of the vast number of ecstasy con

sumers of the 1990s will need treatment.

Therapeutic Use

MDEA and the other RSAs are not approved for medical use. However, between 1960

and the late 1980s MDA and MDMA have been used as pharmacological tools to an in

sight-oriented psychotherapy. Some experimental psychotherapists tried to stop the

federal control of MDMA in the 1980s and celebrated its therapeutic potential (58,59,113,

116,119). In 2001, about 15 years after MDMA was banned in the USA, the FDA ap

proved controlled clinical trials of MDMA in the psychotherapy of Posttraumatic Stress

Disorder (PTSD). These trials were proposed by the USA-based Multidisciplinary Associ

ation for Psychedelic Studies (MAPS) and are currently in progress.

CONCLUSIONS

The aim of this review was to summarize the current knowledge of pharmacology and

toxicology of MDEA. MDEA is chemically and pharmacologically similar to the other

ring-substituted amphetamines (MDA, MDMA, and MBDB), and all these substances can

be present in ecstasy pills. A regular ecstasy user does not consume pure MDEA or any

other RSA in a pure form. Therefore, user reports cannot be used for definitive conclu-

sions on the effects of pure chemical substances. Hence, we used primarily drug challenge

studies in this review. Many properties of MDEA are well understood, even though the lit-

erature provides less information on MDEA than on MDMA or MDA. The best experi-

mental data comes from in vitro studies on MDEA pharmacodynamics and drug discrimi-

nation in animals. Knowledge on the effects of pure MDEA in humans is based mainly on

a series of challenge studies conducted in Germany which investigated its pharmacokine-

tics and several neurobehavioral effects. MDEA was selected for these studies, instead of

other RSAs, because of its suggested lower toxicity to serotonergic neurons in animals

(54). This research required special approval by the legal authorities, because MDEA is a

federally controlled substance.

A possible goal for future research on MDEA is to investigate on stereospecific aspects

in kinetics and central effects, which are not yet completely understood. This may be ad

dressed in further enantioselective MDEA challenge studies.

Other important yet unanswered questions refer to the whole group of RSAs, not only

MDEA. They include the characterization of the neurotoxic effects, their selectivity for

the serotonergic neurons, and their prevention. The long-term neuropsychiatric complica

tions after repeated ecstasy use and their treatment have to be studied clinically. The dif

ferences between individual RSAs in relation to neurotoxicity and clinical complications

should also be elucidated.

From the methodological point of view, it is impossible to answer these questions

solely by studies in abstinent ecstasy users and to define the relative contribution of an in

dividual RSA, when other possible neurotoxic agents are ingested in unknown doses.

Such studies will have to be carefully controlled to exclude possible simultaneous use of

amphetamine or cannabinoids (51). More promising are challenge studies in non-human

primates using the enantiomers and racemic forms of different RSAs at doses comparable

CNS Drug Reviews, Vol. 10, No. 2, 2004

108 R. W. FREUDENMANN AND M. SPITZER

to those used by ecstasy users. Challenges in humans should only be carried out in experi

enced laboratories, approved by the local authorities. Further research on neurotoxicity

and long-term neuropsychiatric deficits after ecstasy is urgently needed because ecstasy is

still very popular, despite legal sanctions.

Acknowledgment. The authors would like to thank Georg Grön and Roberto Viviani for helpful

comments on earlier versions of the manuscript.

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