NEUlIOPSYCHOPHARMACOLOGY 1993-VOL. 8, NO.3 187

Neuroendocrine and Cardiovascular Effects of MDE in Healthy Volunteers Euphrosyne Gouzoulis, M.D., Ulrich von Bardeleben, M.D., Armin Rupp, KIlrl-Arthur Kovar, Ph.D., and Leopold HermIe, M.D.

Thedrug 3,4-methylenedioxyethamphetamine ([MDE] every 20 minutes until 5:00 P.M. Administration of also known as "Eve") is a less toxic analog of 3,4- MDE was followed by statistically significant long-lasting mtthylenedioxymethamphetamine (also known as increases of serum cortisol, PRL, systolic blood pressure, "Ecstasy") with similar psychotropic effects in humans. and heart rate, and by a trend toward blunting of GH In a double-blind placebo-controlled, cross-over study we secretion. The neuroendocrine and cardiovascular effects IIlministered 140 mg of MDE or placebo orally to eight of MDE are comparable to those of other phenethyl­ htaIthy male volunteers at 1:30 P.M. Serum cortisol, amines with the exception of the effect on GH secretion. prolactin (PRL), and growth hormone (GH) levels, as lNeuropsychopharmacology 8: 187-193, 1993J wellas blood pressure, and heart rate were measured

KEY WORDS: MDE; MDMA; Cortisol; Prolactin; out distortion of sensory perception and thought and Growth honnone; Cardiovascular effects without marked stimulation (Greer and Tolbert 1986, 1990; Peroutka et al. 1988). Pharmacologic studies on The phenethylamines 3,4-methylenedioxymetham­ the structure-activity relationships of MDMA and phetamine ([MDMA]also known as "Ecstasy") and 3,4- related compounds supported the view that MDMA methylenedioxyethamphetamine ([MDE] also known and MDE might constitute a new psychoactive sub­ as"Eve") are chemically related to amphetamines and stance class, which was named the "entactogens" psychedelics like mescaline and methylenedioxyam­ (Nichols 1986; Nichols and Oberlender 1990). phetarnine(MDA) (Oimko et al. 1987). However, they The reasons for the public controversy about werepurported to exert unique psychotropic effectsin MDMA are its growing popularity and illegal abuse dur­ humans,diff erentiating them from the aforementioned ing the past years (Seymour 1986; Beck and Morgan chemically related substances (Shulgin and Nichols 1986; Beck 1990), its reported medical usefulness as an 1978; Shulgin 1986). Both MDMA and MDE were adjunct in insight-oriented psychotherapy (Grinspoon reportedto possess antidepressant and anxiolytic prop­ and Bakalar 1986; Greer and Tolbert 1990), and its pos­ erties and to evoke a well-controllable emotional ex­ sible neurotoxicity in humans (Price et al. 1989; Grob perience with relaxation, peaceful feelings, increased et al. 1990). In experimental animals, MDA and MDMA empathy, and a drop in fear responses, mostly with- were shown to exert neurotoxic effects on central serotonergic neurons resulting in degeneration of axon terminals (Ricaurte et al. 1985, 1988; Battaglia et al. From the Department of Psychiatry, University of Freiburg (EG, 1988b, 1990; Insel et al. 1989; Gibb et al. 1990; Schmidt UV,lli), and Instituteof Pharmaceutics, University of Tiibingen(AR, K·AJ(), Federal Republic of Germany. et al. 1990). It is not yet clear whether this fmding has Address reprint requests: Euphrosyne Gouzoulis, M.D., Depart­ a relevance for humans (Peroutka et al. 1987; Price et ment ofPsychiatry, Medical Faculty of the RWTH, Pauwelsstrasse al. 1989; Grob et al. 1990), but it played an important ll, 0·5100 Aachen, Federal Republic of Germany. ReceivedAugust 5, 1991; revised March 11, 1992and June 10, 1992; role for the assignment of MDMA to Schedule I status KteptedJune 16, 1992. by the Drug Enforcement Agency in 1985. After the

C 1993 American College of Neuropsychopharmacology Publishedby Elsevier Science Publishing Co., Inc. 655A venue of the Americas, New York, NY 10010 0893-133X/93/$6.00 188 E. Gouzoulis et al. NEUROPSYCHOPHARMACOLOGY 1993-VOL. 8, NO.3

scheduling of MDMA its N-ethyl analog, MDE ("Eve"), MATERIALS AND METHODS became more popular and served as an MDMA substi­ Subjects tute for recreational use (Beck 1990). The action of MDE is supposed to be more subtle and shorter (3 to 4 hours), Eight physically and mentally healthy, drug-free, male but otherwise very similar to the action of MDMA. volunteers (all academics: seven physicians, one en­ Studies of animal behavior underlined the similarity be­ gineer), ranging in age from 29 to 50 years (mean 38 tween MDE and MDMA (Boja and Schechter 1987). years) were included in a randomized double-blind Neurochemical studies showed that MDE is far less toxic placebo-controlled cross-over study. They gave in­ than MDA and MDMA (Schmidt 1987; Ricaurte et al. formed written consent and did not receive any pay­ 1987; Stone et al. 1987; Gibb et al. 1990). ment for participating in the study. Three to 7 days prior Both MDMA and MDE show high affinities at ser­ to the trial they underwent extensive physical and men­ otonin (5-HT) uptake sites, and lower affinities at nor­ tal examinations (medical history, physical examina­ epinephrine and dopamine (DA) uptake sites of cen­ tion, electroencephalography, electrocardiography tral neurons (Battaglia et al. 1988a). They are taken up (ECG), freepsychiatric interview, structured clinical in­ into the neurons and cause release and reuptake in­ terview according to DSM-III-R, Freiburger Personal­ hibition of the endogenous transmitters (Johnson et ity Inventory (FPI), State-Trait Anxiety Inventory X2, al. 1986,1988; Steele et al. 1987; Schmidt 1987). In ad­ and a questionnaire for vegetative lability). The exclu­ dition, the substances have low affinities at 5-HT2-, sion criteria were any signifIcant physical illness requir­ 5-HT1-, and D2-binding sites, but those seem to be ing therapy, any mental illness, and alcohol or sub­ less important for the drugs' action (Lyon et al. 1986; stance abuse at present or in the past, as defIned by Battaglia et al. 1988a). DSM-IIJ criteria. Mental illness in fIrst degree relatives In our literature review, we found only anecdotal was also an exclusion criterion. No volunteer had previ­ reports about the psychotropic effects and no human ous experience with MDE. One subject reported one experimental data on neurobiologic effectsof the drugs. experience with MDMA 2 years before. Another sub­ The aim of our investigation was to study the phar­ ject reported sporadic experience with cannabis about macokinetics and metabolism, as well as the psycho­ 10 to 15 years before, and one experience with MDMA logic and neurobiologic effects(endocrine, polysomno­ 1.5 years before. A third subject reported sporadic graphic, cardiovascular) of MDE in healthy volunteers, experience with cannabis and one experience with and to attempt a characterization of the substance. In D-lysergic acid (LSD) about 7 to 10 years before. All this paper, we present the neuroendocrine and cardio­ psychometric measurements were within normal vascular studies. range, except for the FPI dimension "openness," in Studies of the neuroendocrine effects of centrally which a higher than average mean score was obtained. acting drugs may contribute to the pharmacologic char­ The complete psychometric data are reported in a sep­ acterization of these substances. Numerous studies arate paper (HermIe et al., 1993). demonstrate that 5-HT and 5-HT agonists stimulate hypothalamic neurons that regulate adrenocorticotropic Substances hormone and corticosterone secretion from the pitu­ itary and adrenocortex, respectively (Fuller 1981). The The MDE used in this study was synthesized at the In­ secretion of prolactin (PRL) from the anterior pituitary stitute of Pharmaceutics, University of Tiibingenand isregulated by inhibitory tuberoinfundibular dopamin­ was obtained in the form of 70 mg capsules. Placebo ergic neurons and by an indirect stimulatory serotoner­ capsules were obtained from the same institute. The gic mechanism (Gudelsky 1981; Van de Kar et al. 1985a). volunteers received 140 mg of MDE, a dose commonly The secretion of growth hormone (GH) is stimulated taken for recreational use (Greer and Strassman 1985; by enhanced catecholaminergic and serotonergic trans­ Beck and Morgan 1986; Seymour 1986; Peroutka 1990). mission (Brown et al. 1978; Matussek 1988; Meltzer and Nash 1988). Both MDMA and MDE provoke release and Experimental Design reuptake inhibition of 5-HT in the central nervous sys­ tem (CNS), and to a lesser extent also of norepineph­ Subjects arrived at the hospital at 12:00 A.M. They re­ rine and dopamine (Johnson et al. 1986,1988; Steele et ceived a standardized calorie- and electrolyte-balanced al. 1987). Thus, one might expect that the acute adminis­ diet for lunch, and then entered the laboratory. Sub­ tration of MDMA or MDE in healthy volunteers would jects had to stay awake and supine with head and up­ increase the secretion of corticosterone, GH, and prob­ per trunk elevated on a bed in a single sound-isolated ably PRL, resulting in elevated plasma levels. Such room during the trial while they were observed by a fIndingswould also be in line with animal experimen­ video camera with a monitor located in the neighbor­ tal data showing an enhancement of cortisol and PRL ing laboratory unit. An intravenous catheter was placed secretion induced by MDMA (Nash et al. 1988). in a forearm vein between 1:15 P.M. and 1:25 P.M. and NEUROPSYCHOPHARMACOLOGY 1993-VOL. 8, NO. 3 Endocrine Effects of MDE 189

was kept open during the trial by a slow infusion of macoat, Dade). Concentrations of PRL and GH were salineso lution. The cuffof the sphygmomanometer and measured by immunoradiometric assays (Irma, IDS). ECG rate meter for registration of blood pressure and The coefficients of variation were as follows. For cor­ heartrate wasplaced round the other forearm. The cath­ tisol: 4.4 to 7.9 (within assay) and 5.2 to 9.7 (between eter and the sphygmomanometer were connected to assay); for PRL 2.7 to 4.8 (within assay) and 3.9 to 7.3 longtubes that passed through an opening in the wall (between assay); and for GH 3.7 to 5.7 (within assay) into the adjacent laboratory. The taking of blood sam­ and 9.7 to 11.4 (between assay). plesand ca rdiovascular measurements were performed in the laboratory room. Either MOE or placebo was Statistical Analysis givenorally with some liquid at 1:30 P.M. Blood sam­ ples fo r the determination of serum cortisol, PRL, and Mean values and standard deviation (SO) were calcu­ GHconcentrations, as well as for the determination of lated for all data. The time course of hormone concen­ the MDE concentration were drawn every 20 minutes tration and cardiovascular data were analyzed by mul­ &om2:00 to 5:00 P.M. Blood samples for the determi­ tivariate analysis of variance (MANOYA) with repeated nation of cortisol were drawn into 10 ml heparinized measurements. Further analysis was performed with tubes(150 III heparin solution, C = 125 IE/ml). Blood two-tailed Student's t-tests, followed by the Bonferroni samples forde termination of GH and PRL were drawn procedure. Statistically signrncant p values were con­ into10 mlTrasylol and ethylenediaminetetraacetic acid sidered to be those less than 0.05. (EDTA)-treated tubes (150 III Trasylol solution, C = 333

KlE/mI, 250 III EDTA solution, C = 1 mg/ml). Blood samples were centrifuged immediately after drawing RESULTS at +4°C, 4000 U/min, for 10 minutes. Serum was sepa­ Neuroendocrine Data rated,transferred to glass tubes, and stored at -70°C untilthe time of assay. The subjects were examined for Following placebo administration, cortisol and PRL lev­ heartrate and blood pressure every 20 minutes from els were stable, except for a slight decrease in plasma 2:00p.M.to 5:00 P.M. After the end of the trial subjects cortisol during the registration period, which was in­ remained in the hospital for another 2 to 3 hours and terpreted as relief from stress. SignifIcant long-lasting weremonitored clinically and cardiovascularly. Ifneces­ increases in serum cortisol and PRL were produced by sary,transportation home was arranged for them, and MDE (MANOYA, P = .001 and .0197, respectively). Fol­ astaffmemb er stayed with them until the next day. The lowing placebo administration, four of the eight volun­ secondtrial (placebo/MOE) was performed 1 to 4 weeks teers showed one or two secretion peaks for GH during afterthe frrst trial. the registration period. Following MOE administration Theinv estigation was part of a pilot study on psy­ the GH level remained stable in all volunteers during chologic and neurobiologic effects of MDE on normal the entire registration period. However, the resulting control subjects and was performed in accordance with difference in GH levels after MDE and placebo, indicat­ the requirements of the Declaration of Helsinki. The ing a blunting of GH secretion after MOE administra­ study was approved by the local ethics committee of tion, was not statistically signifIcant (MANOY A, P = theUniversity of Freiburg. In addition to the above de­ .0870). The neuroendocrine data are shown in Figure scribed neuroendocrine and cardiovascular tests the 1 (t-test, Bonferroni procedure). volunteersparticipated in a series of psychometric tests, whichwere performed before ingestion of the drug, and Cardiovascular Data at 2, 5, and 24 hours after ingestion of the drug, as well as 7days after the trial. Pharmacokinetics and metabo­ Blood pressure and heart rate remained stable after lismof the drug were investigated in the blood and urine placebo administration. Long-lasting increases in sys­ samples of the subjects at the Institute of Pharmaceu­ tolic blood pressure and heart rate were produced by tics, University of Tiibingen. Evaluation of the phar­ MDE (MANOYA, P = .006 and .001, respectively). The maceutical/toxicological data is currently in progress. increase in diastolic blood pressure after MOE adminis­ The psychometric data are reported in a separate pa­ tration was not statistically signihcant (MANOYA, P = per (Hermle et al., 1993). .053). The cardiovascular data are shown in Figure 2 (t-test, Bonferroni procedure).

Hormone Determinations DISCUSSION Serum concentrations of cortisol, PRL, and GH were measured using commercial kits. Cortisol was mea­ Oral administration of 140 mg of MOE to eight healthy suredby the solid face method with 125J-Cortisol (Gam- male volunteers was followed by signifIcant increases 190 E. Gouzoulis et al. NEUROPSYCHOPHARMACOLOGY 1993-VOL. 8, NO.3

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Figure 2. The effects of 140 mg MDE or placebo on systolic Figure 1. The effects of 140 mg MDE or placebo on serum blood pressure (A), diastolic blood pressure (B), and heart levels of cortisol (A), prolactin (B), and growth hormone rate (C) in eight healthy male volunteers (x and SD; t-test; (HGH) (C) in eight healthy male volunteers (X and SD; t-test; Bonferroni procedure: .p < .05; ••p < .01; •••p < JXl1). Time Bonferroni procedure: .p < .05; "p < .01; ".p < .001). Time o = MDE/placebo administration. o = MDE/placebo administration.

in plasma cortisol and PRL concentrations and a trend to stimulate the secretion of cortisol and PRL (Laakmann toward decrease of GH secretion. 1990; Matussek 1988; Meltzer and Nash 1988). Nash et A probable explanation for the effects of MOE on al. (1988) and Nash and Meltzer (1990) showed that plasma cortisol and PRL levels might be an indirect MOMA stimulates the secretion of cortisol and PRL in serotonergic mechanism. This would be in line with ex­ the rat. In those studies the effectof MOMA on cortisol perimental data from animal studies. In vitro studies secretion was clearly shown to be mediated via on rat brain slices showed that MOMA and MOE evoke serotonergic mechanisms, as it was blocked or blunted release and inhibit reuptake of endogenous 5-HT and by 5-HT2 antagonists or pretreatment with fluoxetine catecholamines, the preferential effects being on the or p-chlorophenylalanine. The mechanism mediating serotonergic, and the weakest effects on the OA sys­ PRL secretion could not be entirely clarmed; however, tems (Johnson et al. 1986; Steele et al. 1987; Battaglia the authors of that case hypothesized that a serotoner­ et al. 1988a). Serotonin and norepinephrine are known gic mechanism was responsible, because the effectwas NEUROPSYCHOPHARMACOLOGY 1993-VOL. 8, NO. 3 Endocrine Effects of MDE 191

bluntedafter pretreatment withp-ch1orophenylalanine. similarities of MDE to stimulant amphetamines: in these Theycame to the conclusion that MDMA requires en­ studies a marked overall stimulation with increased vi­ dogenous5-HT to stimulate the secretion of PRL and gility was shown to be the most robust effect of MDE. corticosterone (Nash et al. 1988). In studies with other Also in those studies we found some potentially in­ amphetamine derivatives similar effectson plasma cor­ teresting trends (nonsuppression of slow-wave-sleep, tisoland PRL were also demonstrated (Mc Elroy et al. simultaneous appearance of increased psychomotor 1984;Van de Kar et al. 1985a, b). Finally, the phenethyl­ drive, subjective feelings of relaxation, diminished anxi­ aminepsy chedelic mescaline and the indole psychedelic ety, and depressed mood), that might indicate unique N,N-dimethyltryptamine (N,N-DMT), which act via effectpatterns of MDE, but those fIndingsalso did not 5-HT-dependent mechanisms, were also shown to in­ reach statistical signifIcance (unpublished data). Fur­ creaseplasma PRL (Demisch and Neubauer 1979; Melt­ ther investigations are needed in order to assess the zer et al. 1978, 1981). neurobiologic and subjective effectsof MDE and related Incont rast, the observed trend toward a decrease substances and thus contribute to the pharmacologic of serumGH following MDE administration is difficult characterization of the "entactogens." tointerpret. To our knowledge, there are no previous experimentaldata on the effectof MDMA or MDE on GH secretion. 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