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Pharmacology Biochemistry & Behavior, Vol..38. pp. 135-139. _ Pergamon Press pie, 1991. Printed in the U.S.A. 0091-3057/91 $3.00 + .00

5-Iodo-2-Am inoindan, a Nonneurotoxic

Analogue of p-Iodoamphetamine

DAVID E. NICHOLS, t MICHAEL P. JOHNSON AND ROBERT OBERLENDER

Department of Medicinal ChemistD, and Pharmacognosy and Department of Pharmacology and Toxicology ,.

School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafaye?te, IN 47907

Received 16 August 1990

'_ NICHOLS, D. E., M. P. JOHNSON AND R. OBERLENDER. 5-1odo-2-aminoindan, a nonneurotoxic analogue °fp-iodoamphet-

amine. PHARMACOL BIOCHEM BEHAV 38(1) 135-139, 1991.--A rigid analogue, 5-iodo--2-aminoindau (5-IAI), of the sero-t on in neumtoxic halogenated amphetamine p-iodoamphetamine (PIA) was pharmacologically evaluated for production of serotonin

neurotoxiclty, A comparison was also made between 5-1Al and PIA in the two-lever drug di_rimination paradigm in rats trained to

di,scriminate saline from 3,4-methylenedioxymethamphetamine (MDMA) or saline Pfrom the a-ethyl hot:/_slogue of MDMA, MBDB.

PIA and 5-1AI were both behaviorally active, and fully substituted in both groups of animals, but were considerably less potent than

p-chloroamphetamlne (PCA). PIA had about twice the potency of PCA as an inhibitor of [3H]-5-HT uptake in rat brain cortical syn-aptosomes, while 5-1AI was only about 75% as potent as PCA in this assay. A single 40 rog/kg dose of PIA resulted in a 40% re.

duction of 5-HT and 5-HIAA levels and in the number of 5-HT uptake sites in rat cortex at fine week sacrifice. The same dose of5-IAI with one week sacrifice led to about a 15% deci'ease in 5-HIAA levels and number of 5.HT uptake sites, but only the latterwas statistically significant. In rat hippocampus, PIA gave significant decreases in all _rotonin markers examined, while 5-IAI

slightly but significantly decreased only5-HT levels. Neither compound produced any change in catecholamioe or catecbolaminemetabolite levels. The resultsconfirm earlier reports of the selective serotonin neurotoxicityof PIA, which is lesssevere than that

of PCA, and also demonstrate that its rigid analogue 5-IAIdoes not appear to cause significant serotonin deficits inthe rat.

p-todoamphetamine(PIA) p-Chlomamphetamine (PCA) Serotonin Neurotoxicity HPLC-EC Iodoaminoiodan

IT is now well established that p-chloroamphetamine (PCA) pro- p-fiuoro, p°bromo and more recently p-iodoamphetamine (3,7).

:_ duces a short-term reversible and a long-term irreversible deple- p-lodoamphetamine (PIA) resembled PCA in many respects, in-

t ion of serotonin (5-HT)and 5-hydroxyindoleacetic acid (5-HIAA) cluding its tissue distribution, half-life, and ability to inhibit

i (5, 6, 10). More recent work has suggested that the long-term ir- [t4C]-5-HT uptake and block degradation of 5-HT by mitochon-

! reversible depletion of 5-HT is due to a selective degeneration of drial monoamine oxidase. The long-term depletion of 5-HT char-ine axons originating from the dorsal raphe nucleus (13). In ad- acteristic of PCA alsb occurred with PlA and, as with PCA, these

dition to the extensive work with PCA itself, certain studies have long-term deficits were prevented by pretreatment with the 5-HT

reported on both the short-term and long-term effects of structural uptake inhibitor, fluoxetine (7).

analogues of PCA, For example, the conformationally rigid aaa- The present report describes pharmacological data for a rigidlogue '6-chloro-2-aminotetralin retains acute serotonergic actions, analogue of PlA, 5-iodo-2-aminoindan (5-1AI; Fig. 1). It was

but does not cause long-term irreversible depletion of 5-HT sim-

ilar to PCA (4). These results have been recently confirmed inour laboratory (unpublished results). The loss of serotonin neuro-

toxicity following rigidification of the side chain of substituted - -}}_'cJ_rf_ NH2 _[,_.._/_)'_J_xamphetamines was further i llustrated when applied to 3,4-meth- NH 2

ylenedioxy-substituted compounds. Specifically, 3,4-methylene- i.._ 2J CH3 I" _dioxyamphetamine (MDA) causes serotonin neurotoxicity similar

to PCA (18), but the rigid analogues, 5,6-methylenedioxy-2-ami-

noindan (MDAI) and 6.7-methylenedioxy-2-aminotetralin (MDAT) PlA 5-IAIdo not appear to.possess this action (14).

Another series of structural analogues of PCA results when

the chlorine atom is replaced to give other p-halogenated amphet- FIG, 1. Structures of p-iodoamphetamine (PIA) and 5-iodo-2-aminoindanamines. Earlier studies have included comparisons of p-chloro, (5-IAI).

_Requests for reprints should be addressed to David E. Nichols, Department of Medicinal Chemistry and Pharmacognosy, Purdue University, West

Lafayette, tN 47907.

135 9 9_ '_'

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136 NICHOLS, JOHNSON AND OBERLENDER

_X BL _ lASUBSTITUTION IN MDMA-TRAINED ANIMALS

Dose EDso§

Drug (mg/kg;xM/kg) N* D'J' %SDL_ mg/kg IxM/kg

PCA 0.17¶ 0.84

(mol.wt. = 207) (0.09-0.32) (0.46--1.55)

PIA 0.5; 1.68 8 0 13 1.16 3.91

(mol.wt. = 298) 1.0; 3.36 8 0 _. 38 (0.78-1.74) (2.61-5.85)1.5; 5.04 9 1 50

2.0; 6.72 9 I 88

5-1AI 0.125;0.42 9 0 22 0.65, 2.19

(mol.wt.=296) 0.25; 0.85 9 1 38 (0.25-1.70) (0.83-5.75)0.5; 1.69 9 I 50

1.0; 3.38 8 0 50

2.0; 6.77 lO 2 50

3.0; 10.14 I1 3 88

envisioned that 5-IAI might retain the short-term actions of PlA one saline maintenance session. Test sessions ended after 5 rain

but lack the long-term neurodegeneration associated with PIA and or when 50 responses we,e m ade on either lev er, whichev er cam e

PCA . In addition, it was anticipated that radiolabel led [_ 25I]-PIA firs t. If 5 m in pas sed w ithout the rat em itting 50 responses , the

[as suggested by Fuller et al. (7)], and [J2Sl]-5-lAI might be use- animal was scored as disrupted and was not used in the calcula-

ful to visualize binding sites in brain utilizing autoradiography tion of the EDr,o. Animals were not tested if, in the preceding

techniques, maintenancesessions,the rat gaveless than 85%respondingon

the correct lev er prior to the firs t reinforcem ent. Follow ing the

METHOD procedureof Colpaert et al. (2), test data were discarded and the

Materials condit ion later retested if the rat responded incorrectly in either of

PIA .HCI, 5 -IA I.HCI, MDMA .HCI and (+)-MB DB 'HCI were the fol low ing two maintenance ses s ions . A t leas t eight rats w ere

synthesized in our laboratories using standard procedures (15). tested at each dose.

All spectral and elemental analyses were consistent with the ex-

pected s tru ctures . Fl uoxe tin e. HCl w as kindl y prov ided by E li L il ly HPLC Wi th E le ct ro ch emi ca l Det ec ti onlaboratories (Indianapo lis , IN ). The HPL C-EC s tandards were

purchased from Sigma Chemical Co. (St. Louis, MO). [3H]-Par- The frontal cortex or hippocampal regions from one hemi-oxetine was purchased from New England Nuclear (Boston, MA) sphere in each rat were weighed, and homogenized in 0.5 ml of

at a specific activity of 28.8 Ci/mmol. [3H]-5-HT was purchased 0.4 N HC104 containing 0.05% Na2EDTA, and 0.1% Na2S20 _from Amersham (Arlington Heights, IL) at a specific activity of using a motor-driven teflon pestle and Eppendorf 1.5 ml centrif-

u ga tion tu be s. A n in tern al s tan dard o f 3-(3,4-d ihy dro xy phe ny l)

9.3 Ci/mmol. propionic acid (100 ng/ml, DHPPA) was used. The samples were

centrifuged fro:4 min at 14,000× g and the supematant was as-

Animals sayed for the levels of NE, DA, DOPAC, HVA, 5-HT, and 5-

Male Sprague-Dawley rats (175 to 200 g) were used in all ex- HIAA. The HPLC-EC system consisted of a Brownlee CI8

perim en ts . A nim als w ere indiv idual ly caged in a tem perature- analy tica l cartridge colum n (A nspec, A nn A rbor, MI), a refriger-controlled room with a 12/12 h lighting schedule. Rats used in ated autosampler (TosoHass, Philadelphia, PA) and a Model 400

neurotoxicity tests were given food and water ad lib, while rats EG&G Princeton electrochemical detector (Princeton, NJ). The

used for drug discrimination testing were given free access to dual electrode potentials were set at E l = - 200 mV and E, -- 850

water and enough food to maintain them at about 80% of their mV versus the Ag/AgCI reference electrode. The mobile phase

free-feeding weight. Animal brain dissections were done over consisted of 0.05 M NaHePO4, 0.03 M citric acid, 0. I mMice and the areas removed according to the procedure of Glowin- Na2EDTA, 0.034% sodium octyl sulfate and 25% methanol (pH =

ski and Iversen (8). Brain areas from each hemisphere were sep- 2.75), at a flow rate of 1.0 ml/min. The monoamine and metab-arated and frozen w ith l iquid n itrogen before s toring at -70°C o lite lev el s were quantitated us ing the Dynam ax Method Manager

untilassay, software(Rainin,Woburn,MA)with an AppleMacintoshSEcomputer.

Drug Discr imination[SH]-Paroxetine Binding

The procedures and equipm ent em ploy ed hav e been described

in detail (17). Briefly, rats were trained to discriminate either The procedure of Habert et al. (9) as adopted by Battaglia et

MDMA'HCI (1.75 mg/kg) or S-MBDB.HCI (16) (1.75 mg/kg) al. (1) was employed with minor modifications. Briefly, the fron-

from saline using a fixed ratio (FR-50) schedule of food rein- tal cortex and hippocampus from one hemisphere were thawed.

forcem ent. Intraperitoneal injections were giv en 30 m in prio r to weighed , and hom ogenized w ith a B rinkm an poly tron (setting 6.

sessions. Test sessions were separated by at least one drug and 2x 20 s) in 5 ml of 50 mM Tris HCI containing 120mM NaCI

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IODOAMINOINDAN 137

TABLEB

SUBSTITUTIONIN ( + )-MBDB-TRAINEDANIMALS

Dose EDco§

Drug (rog/kg; ixM/kg) N* D'I' %SDL:I: mg/kg g,M/kg

PCA 0.17¶ 0.82

(0.10-O.28) (0.50-1.36)

PIA 0.25; 0.84 8 0 25 0.54 1.81

0.50; 1.68 9 I 25 (0.35--0.82) 1.18--2.74)

0.75; 2.52 10 2 63

1.00; 3.36 8 0 88 ,.

5-1Al 0.25; 0.85 9 I 0 0.79 _ 2.67

0.50; 1.69 8 0 50 (0.42-1.48) (1.43-5.00)

1.00;3.38 10 2 63

2.00;6.77 12 4 75

2.50:8.46 10 2 88 ',

Animals were trained to discriminate either MDMA or (+)-MBDB from saline using a two-lever drug dis-

crimination paradigm. At least eight ra ts were tested at each dose as indicated. The EDCovalues for substitu-tion in MDMA-trained (Table lA) and (+)-MBDB-trained (Table lB) animals were calculated according to

the method of Litchfield and Wilcoxon (12). ,

*N =Total number of rats tested. -_

tD = Number of disruptions (50 presses not completed in 5 rain).

$Percentage of responding (N-D) rats selecting the drug lever,

§95% confidence limits in parentheses.

¶Values taken from Johnson et al. (I l). ,

and 5 mM KCI (pH = 7.4). The homogenates were centrifuged at was added, and the vials were allowed to sit overnight before

30,000 x g for 10 min, and washed in the same buffer and recen- counting at an efficiency of 54%.

trifuged. The resulting pellet was resuspended and chilled on ice

until assay. Uptake Inhibition of [_HI-5-HTThe binding of a single saturating concentration (1 nM) of

[3H]-paroxetine in tissue homogenates was examined. Specific The procedure of Steele et al. (19) was employed with minor

binding was defined as that displaceable with I txM fluoxetine, modifications. Briefly, the whole cortex was homogenized in 15

Incubations commenced with the addition of tissue to the buffer volumes of 0.32 M sucrose Wth a glass mortar and motor-driven

described above to give a total volume of 2 mi. The tubes were teflon pestle. The homogenate was then centrifuged at 11300x g

equilibrated at 24°C for 1 h before filtering through GF/C' filters for 10 min at 4°C and the resulting supematant centrifuged at

presoaked with 0.05% PEI, using a Brandel Cell Harvestor 17,000xg for 10 min. The resulting pellet was resuspended in

(Gaithersburg, MD). The tubes were then rapidly washed twice the same volume of s0crose and placed.in an ice bath until used.

with ice-cold buffer. The filters were allowed to air dry and were A 200 $xl aliquot of the above tissue homogenate was added

then placed in scintillation vials, I0 mi of scintillation cocktail to 1.65 mi ofOe-saturated Krebs-Henseleit buffer (I 18 mM NaCl,

4.8 mM KC1, 1.3 mM CaCl2, 1.2 mM KHePO 4, 1,2 mM

: MgSO4,25mMNaHCO3, 10mMglucose,0.06mMascorbic

acid and 0.03 mM Na2EDTA), 50 $xl drug, and 50 gl pargyline

TABLE 2 (final concentration, 1 IxM). Following a 5-rain preincubation at

UPTAKE INHIBITIONOF [3HI-5-HT 37°C, [3HI-5-HT was added in 50 $xl aliquots to give a final con-centration of 10 nM. Tubes were allowed to equilibrate for an

additional 5 rain at 37°C before cooling in an ice bath. The syn-lCso (nM)

aptosomes were collected by filtering through Whatman GF/Bfilters utilizing a Brandel cell harvestor (Gaithersburg, MD). The

FCA 184 +- 12 filters were washed twice with 5 ml of cold buffer and allowed

PlA 82 _ 8* to air dry before preparing the samples for counting as described5-1Al 241 _ 21'I' above.

The in hibition of [JH ]-5 -H T u ptake was exam in ed in rat brain cortica l

synaptosomes. The IC_o values represent the mean ± S.E.M. of three to Statistical Analysis

four s eparate experim en ts . Each experim en t u til ized 5 or 6 concen tra-

tions, nm in triplicate, on the linear portion of the dose-response curve. In drug discrimination experiments, EDso values and 95%

*Indicates significantly different from PCA (p<0.05, ANOVA followed confidence intervals were determined from quantal dose-response

by post hoc comparison), curves according to the procedure of Litchfield and Wilcoxon

tlndicates significantly different from PIA (p<0.05, ANOVA followed (12). The ICao values for uptake inhibition were calculated from

by post hoc comparison), a graded dose-response curve by the method of Tallarida and

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138 NICHOLS,OHNSONNDOBERLENDE

A. Ez3 $olin_ Murray (20). For neurochemical analyses, comparisons betweenP_ treatment groups utilized an analysis of variance followed by a

EZa 5-INpos t hoc comparison, a s em bodied in the EPISTAT softw are

!0 0, (EPISTATServices. Richardson, TX).

'_ 80 RESULTSANDDISCUSSIONt-O

o 60 Both PlA and 5-IAI were behaviorally active in the drug dis-

'E criminationparadigm.AsseeninTable1,bothtestcompounds

40 fully substituted in rats trained to discriminate MDMA or (+)-MBDB from saline. Interestingly, 5-IAI is significantly less po-

m tentthanPIAatinhibitinghesynaptosomalptakeof[3H]-5-HT

20, in vitro (Table 2)'. In addition, PlA was significantly less potentthan PeA in M DMA -trained rats . Fuller et al . (7) hav e prev ious lY '

0 shownthatPIAisa lesspotentdepictorof5-HTand5-HIAA

5-HT 5-HIAA U )take than is PeA. This occurs despite the fact that PIA has equal or

Frontal Cortex greater potency than PCA in a number of in vitro assays. For ex-

ample, PlA is slightly more potent than PCA at inhibiting synap-

[3. E3 Sa,ne tosomal ['4C]-5-HT uptake (7). In our laboratory, PlA is alA

· eZa 5-_ significantly more potent inhibitor Of synaptosomal uptake oflower concentrations of [3H]-5-HT (Table 2). In addition, Fuller00-

· et al. (7) have repo_rtedhatPIA is substantiallymorepotent than

'_ 80 PCA as an inhibitor of monoamine oxidase. Given the similar.,., half-life and distribution .of PlA and PCA (7), the reason for the

c apparent discrepancy between the in viva and in vitro potencieso 6o is not readily apparent.

'_ As seen in Fig. 2, PIA caused a significant decrease in sero-

o 40 tonergic markers one week after a single 40 rog/kg (0.13 mmol/kg) dose. This was a selective serotonergic effect since no changes

20 in NE, DA or their metabolites were seen with any drug treatment

(T abl e 3). A s p rev io us ly in dicated (7), th e re lativ e n eu ro to xicity

o of PIA is substantially less than that of PCA. While PCA (0.05

5-HT 5-HIAA Uptake mmol/kg) causes a 75% reduction in serotonergic markers (I I),0.13 retool/kg of PIA caused only a 40% reduction (Fig. I). Pre-

Hippocompus viously, 0.10 mmol/kg (30 mg/kg) of PlA has been reported tocause a 20 to 30% reduction in 5-hydroxyindoles (7).

As anticipated, 5-IAI appears to be significantly less neuro-FIG. 2. Serotoninergic markers following acutedosing with PIA or 5-1AI. toxic than PIA (Fig. 2). Only slight decreases of serotonergicSaline. 40 mg/kg PIA, or 40 rog/kg 5-IAI was injected subcutaneouslyand animals were sacrificed one week later. Serotonin and 5-HIAA lev- markers (15% or less) were seen one week following a single 40

els were determined in frontal cortex (A) and hippocampal (B) areas us- rog/kg (0.13 mM/kg) SC dose of 5-IAI. The only statisticallylng HPLC-EC techniques. The number of uptake sites remaining was significant decreases were in the number of cortical uptake sitesdeterminedbyexamining the abilityof a saturatingconcentrationof [3H]- and the hippocampal levels of 5-HT (Fig. 2). One could specu-paroxetineto bind to tissue homogenatesas describedin the Method sec- late that higher doses might lead to significant decreases in all the

tion. Values arerepresented as the mean+ S.E.M. for n = 8.Saline control serotonergic parameters. However, a 40 rog/kg dose is already

values were as follows: cortical 5-HT, 366+_27; 5-HIAA, 296'-.27 pg! some 20- to 40-fold higher than a behaviorally active dose, and

mgwet wt.; uptake sites, 16.8'-.0.6 final/rogwet wt.; and hippocampal it has been our experience that doses of many amphetamine ana-5-HT. 400+-22; 5-HIAA, 558+-18pg/mgwet wt.; uptake sites 16.1 '4-1.1 logues greater than 40 mg/kg are approaching lethal levels. Inter-fmbl/mg wet wt. estingly, we have found that similar doses of 6-chloro-2-

aminotetralin (0.17 mmol/kg) resulted in slight reductions

TABLE 3

CATECHOLAMINE AND METABOLITE LEVELS

Cortical

(pg/mgwet wt.)Hippocampal

Treatment NE DA DOPAC HVA NE

Saline 508__21 40___ 16+-3 23+-I 590+ 28

PIA 504 +- 29 36 -- 3 16 __3 20 _+2 547 +- 42

5-IAI 540 +- 22 47 4- 5 13 _+2 19 +- 1 557 +- 26

Saline, 40 rog/kgPIA, or 40 mg/kg 5-1Al was injected subcutaneously and animalswere s acrific ed o ne w ee k l ate r. T he fro nta l c orte x a nd h ip po camp al a re as w ere a nal yze d

for N E, DA , DO PAC, and HV A lev els util izing HPL C-EC techniques . V al ues are re-ported as the m ean +- S.E.M. for N = 8.

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IODOAMINOINDAN 139

in serotonergic markers at one week, while a statistically signifi- nificant serotonin deficits in the rat, presumably reflecting a re-

cant decrease only occurred with the number of hippocampal 5- duced potential to induce serotonin neuron degeneration.

HT uptake sites (unpublished results).

In conclusion, the results indicate that both PIA and 5-IAt are ACKNOWLEDGEMENTSbehaviorally active in rats. PIA also appears to cause the same

type of serotonJn neurotoxicity that occurs with PCA, although We thank Stewar t Frescas for car rying out the syntbems of PIA'HCIPlA is somewhat less potent in this respect. Third, at the doses and 5-1AI.HCI. This work was supported by USPHS Grant DA-04758

examined, the rigid analogue 5-IAI does not appear to cause sig- from the National Institute on Drug Abuse.

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I. Battaglia, G.; Yeh, S. Y.; De Souza, E. B. MDMA-induced neuro- ethyl homologue of p-chloroamphetamine (PCA). Eur . J. Pharma-toxicity: Parameters of degeneration and recovery of brain serotonin col., in press; 1990. 'neurons. Pharmacol. Biochem. Behav. 29:269-274; 1988. 12. Litchfield, J. T., Jr.; Wilcoxon,' F. A simplified method of evaluat- '-

2. Colpaert, F. C.; Niemegeers, C. J. E.; Janssen, P. A. J. A drug dis- lng dose-effect experiments. J. Pharmacol. Exp. Ther. 96:99-I 13;

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antagonists and ofpirenpirone, a LSD-antagonist. J. Pharmacol. Exp. projections to neocortex: Axons from the dorsal and median rapheTher. 221:206-214; 1982. nuclei are differentially vulnerable to the neurotoxin p-chloroamphet-

3. Fuller, R. W.; Baker, J. C.; Perry, K. W.; Molloy, B. B. Compari- amine (PCA). Exp. Neurol. 102:23-36; 1'988.

son of 4-chloro-, 4-bromo- and 4-fluoroamphetamine in rats: Drug 14. Nichols, D. E.; Brewster, W. K.; Johnsofl, M. P.; Oberlender, R.;

levels inbrain and effects onbrain serotonin metabolism Neurophar- Riggs, R. M. Nonneurotoxic tetralin and indan analogues of 3,4-

macology 14:483--,188; 1975. (methylenedioxy)amphetamine (MDA). J. Med. Chem. 33:703-710;4. Fuller, R. W; Perry, K. W; Baker, J. C.; Molloy, B. B. 6-Chloro- 1990.

2-am inotetral in , a rigid conform ational analogue of 4-chlo roam phet- 1 5. N icho ls , D. E.; Hoffm an, A . _ .', O beriender, R.; Jacob, P., III; Shul-amine: Pharmacologic properties of i t and related compounds in rats. gin, A. T. Derivatives of I-(1,3-benzodioxol-5-yl)-2-butanamine: Rep-

Arch. Int. Pharmacodyn. Ther. 212:141-153; 1974. resentatives of a novel therapeutic class. J. Med. Chem. 29:2009-5. Fuller, R. W.; Perry, K. W.; Molloy, B. B. Effect of 3-(p-trifluoro- 2015; 1986.

methylphenoxy)-N-methyl-3-phenylpropylamine on the depletion of 16. Nichols, D. E.; Oberlender, R. Structure-activity relationships of

brain serotonin by 4-chloroamphetamine. J. Pharmacol. Exp. Ther. MDMA and related compounds: A new class of psychoactive agents?193:796-803;1975. In: Peroutka,S. J., ed. Ecstasy:Theclinical, pharmacologicalnd

6. Fuller, R. W.; Perry, K. W.; Molloy, B. B. Reversible and irrevers- neumtoxicological effects of the drag MDMA. Boston: Kluwer Aca-

ible pha_s of serotonin depletion by 4-cbloroamphetamine. Eur. J. demJc Publishers; 1990:t05-131.

Pharmacol.33:119-124; 1975. 17. Oberlender, R.; Nichols, D. E. Drug discriminationstudies with

7. Fuller, R. W.; Snoody, H. D.; Snoody, A. M.; Hemrick, S.K.; MDMA and amphetamine. Psychopharmacology (Berlin) 95:71-76;

: Wong, D. T.; Molloy, B. B. p-lodoamphetamine as a serotonin de- 1988.letor in rats. J. Pharmacol. Exp. Ther. 212:115-119; 1980. 18. O'Hearn, E.; Battaglia, G.; De Souza, E. B.; Kuhar, M. J.; Mol-

8. Glowinski, J.; lversen, L. L. Regional studies of catecholamines in l iver, M. E. MethylenedioxyamphetamJne (MDA) and methylene-

the rat brain. I. The deposi tion of [3H]-norepineprine, [3H]-dopamine dioxymethamphetamine (MDMA) cause selective ablation of[3H]-DOPA in various regions of the brain. J. Neurochem. 13:665- serotonergic axon terminals in forebrain: Immunocytochemical evi -

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LETFERS TO THE EDITOR

listened to their own heartbeats, developed exquisitely sen- Kueny, 1980 unpublished manuscript). Greer described onesitJve hearing and smell, or concentrated on their pain. case (out of 80) of a man with a prior history of panic attacks

Patients reported that their depersonalization and loss of self who experienced a recurrence of the symptoms after usingbecame more severe when they were not "allowed" pain MDMA; his symptoms resolved after he reentered psycho-

(becat,se of the narcotic administration). Four patients had therapy. Generally, subjects describe an increase in mood

had visual and auditory hallucinations (e.g., a deceased and in the ability tocommunicate in individual and conjoint

mother returning from the grave to sit at the bedside), but psychotherapy, and enhanced introspective ability.

retrospectively it was difficult to'tell whether these phenom- MDMA has a brief duration of action (4-6 hours), is

cna were directly related to the patient's being paralyzed or usually administered in a dose of 75-150 mg orally as anif thcy were secondary to the delirium accompanying phys- adjunct to psychotherapy, and has acute side effects that are

ical illness, primarily sympathomimetic in nature.

The posttraumatic stress disorders were characterized by MDMA has been placed in schedule I (with heroin and

screaming nightmares, intrusive recollections, irritability, LSD) on an emergency basis by the U.S. Drug Enforcement

suspiciousness toward caretakers, anger at the hospital and Agency (DEA). This apparently was done because of the

consenting relatives, withdrawal from visitors, suppressed increasing frequency of street use and because of concerns

and shameful memories of "having gone crazy," and a that MDMA's chemical similarity to methylenedioxy-

reluctance to return for aftercare. Four patients had had amphetamine (MDA), another schedule I drug, bespoke

suicidal ideation without immediate intent; they linked this similarities in clinical effects. An unpublished manuscript

ideation to the depressive realization that they had the that described serotinergic terminal degeneration in the CNS

capacity to lose control of their minds. Only one patient was was quoted from by the DEA in making its decision.

grateful for what he considered a "lifesaving" procedure; the However, that study used MDA, not MDMA. Even in the

other five said they would rather die than go through it best of circumstances, establishing a direct causal relation-ag_ml, ship between the use of a psychoactive drug and subsequent

The prevalence of panic during pancuronium administra- "adverse reactions" is quite difficult (3). Abuse of a drug oftion and of iatrogenic posttraumatic stress disorder is un- unknown purity, strength, and contaminants, in combina-

known and requires further investigation. Based on our tion with any number of other drugs and alcohol, in unpre-

evaluation of these six patients, we suggest that diazepam be pared subjects with an unknown degree of psychopathology

generously prescribed during the procedure, that staff and in an uncontrolled setting is not a test of whether or not the

relatives continually touch and talk to the patients, that drug has any potential therapeutic use or even high potential

tape-recorded explanationsfrom staff and reassurances from for abuse.

family be played when more personal contact is not avail- A number of psychotherapists who use MDMA as anable, and that, following the treatment, patients be assessed adjunct to their psychotherapeutic practice, as well as a

and, if necessary, treated for posttraumatic stress disorder, number of other concerned parties, have called on the DEA

Our six patients responded to the psychotherapeutic inter- for an administrative law hearing with regard to classifying

ventions described by Horowitz (1). MDMA as a schedule I substance. These hearings are now in

progress and will not be completed until next year, when afinal decis ion wil l be m ade.

REFERENCE We hope the furor in the media and legislatures that made

1. Horowitz MJ: Stress Response Syndromes. New York, Jason research with psychedelic compounds so difficult (if notAronson,1976 impossible) to pursue in the 1960s will not have the same

effect on further rational inquiry into the mechanisms of

SAMUEL W. PERRY, M.D. action and clinical utility of MDMA.New York, N.Y.

REFERENCES

Information on "Ecstasy" 1. Harman HF, Haavik CO, SeeversMH: Relationshipto the

structure of mescaline and seven analogues to toxicity and

,q,_: We read with interest Richard J. Alexander, M.D.'s behavior in five species of laboratory animals. Toxicol Appl

reqm_st for information regarding the drug "Ecstasy" (June Pharmacol 25:299-309, 19731985 i_suc). 2. Shulgin AT, Nichols DE: Characterizatiml of three new

"Ecs tasy " is the s treet name for 3,4-m ethy lenedioxymeth- psy chotom im etics , in The Pharmacology of Hal lucinogens . Ed-

amphetamine (MDMA), a psychoactive phenylisopropyla- ited by Stilman RC, Willette RE. New York, Pergamon Press,1978

mine, synthesized in Germany in the early twentieth century. 3. Strassman R: Adverse reactions to psychedelic drugs: a reviewh was investigated by the U.S. Army as a potential psy- of the literature. J Nerv Meat Dis 172:577-595, 1984chomxic compound in the'mid-1950s (1).

MDMA has been labeled a psychedelic drug, but the scant GEORGE GREER, M.D.

pul_lished literature comparing the subjective effects of this RICKJ. STRASSMAN,M.D.

compound to those of the "classic" psychedelic drugs, such Santa Fe, N.M.

as L SD, ps ilocy bin , m es ca line, or d im ethy ltry ptam ine, does

not clearly support the placem ent of MDMA in this category

(2). Anecdotal clinical reports describe a lack of the disori- Common Misconceptions About the Mental Status

entation, ego disruption, perceptual distortions, and tran- Examination

sient psychotic states that can occur with the more powerful

psy&edelics, whenMDMA is used in a controlledenviron- SIR:As examiners for part II of the American[loam ofmeat with careful supervision (Greet, 1983 unpublished Psychiatry and Neurology examination, we have observed

manuscript; Downing, 1984 unpublished manuscript; yearafteryearthatcandidatesmisconstruetheintentofmany

Am ! Psychiatry 142:li, November 1985 1391

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