(

The Background and ChemistryofMDMA

ALEXANDER T. SHULGIN, PH.D.*

This article will present the factual material that up to 1972, MDMA was entered with the phenethylamineexists in the literature representing the results of labora- name. Since then, the heterocyclic term benzodioxole-5- i

tory studies and scientific experimentation with ethanamine has been the root name. The common abbre-methylenedioxymethamphetamine or MDMA, the com- viation MDMA is based on the consideration of the stmc-mon name applied to an organic compound, a secondary ture as a substituted methamphetamine. Other terms thatamine. As a free base it is a white, musty smelling oil with have been used to refer to this drug include MDM, Ec- _,a searing taste, insoluble in water but soluble in most stasy, XTC, Adam, and EA-1475 (the last, by the Edge-organic solvents. It forms salts with several acids, and wood Arsenal). The computer searching of Chemicalthese are white solids or oils that are readily water soluble Abstracts employs the following registry numbers: _'and bitter to the taste. It has an empirical formula S-MDMA (+) ................... 66142-89-0Cl iHlsNO2, and its structural formula is given in Figure S-MDMA (+) HCI ............... 69558-32-3

1. R-MDMA(-) .................. 81262-70-6 _MDMA has a number of correct chemical names, R-MDMA (-) HCI .............. 69558-31-2

each based on one portion or another of the chemical MDMA (racemic) ................ 69610-10-2structure. With that defining portion named as a stem MDMA HC1(racemic) ............ 64057-70-1word, the full chemical name is apparent by the additionsto this base fragment. In Figure 1, the fragments (with CHEMISTRYtheirnames)aredrawnontheleftandtheextendedname Synthesis t/

that applies to MDMA is given on the right. The use of the There are six methods of preparation to be found insimplest aliphatic chain (i.e., ethylamine or isopropyl- the scientific literature. In all cases, the starting material

amine) occurs in part to avoid the generic name ampheta- carries the preformed methylenedioxy ring, in the form ofmine or methamphetamine. These terms arc so frequently safrole, isosafrole, or of the derived aldehyde, piperonal.used that each listener conjures up an image of the chemi- The first preparation and description of MDMA was acals being described, according to his/her discipline: the German patent issued to the firm E. Merck (1914) inchemist sees the carbon chain, the pharmacologist sees the Darmstadt, dated December 24, 1912, and made avail-stimulant, and the policeman sees the drug laws. The able May 16, 1914. Here, MDMA was synthesized intwonames that are to be used in the searching of Chemical steps from safrole. The addition of aqueous hydrobromicAbstracts depend on the date of the search, ln the earliest acid provides an impure intermediate (l-files, the homopiperonylamine name was used, and then methylenedioxyphenyl-2-bromopropane) that is con-

verted with an alcoholic solution of methylamine to· 1483Shulgin Road, Lafayette, California94549. MDMA. The same process, except for the isolation and

Journal of Psychoactive Drt_gs 291 Vol. 18(4) Oct-Dec, 1986 !

SHULGIN CHEMISTRY

CH2 MD_

FAMILY MDMANAME

Structure Name

CH_iCH 2 Propane 2-Methylamino-l-(3,_-methylene-

CH3 dioxyphenyl)-propane

CH3'CH/NH2 Isopropyl amine N-Methyl-B-(3,_-methylenedioxy-I phenyl)-isopropylamine

CH5

CH_cH{NH2 Ethyl amine N,a-Dimethyl-B-(3,_-methylene-dioxyphenyl)-ethylamine

{NH2 Phenethylamlne N,a-Dimethyl-3,_-methylenedioxy-

CH2'CH phenethylamine

Benzeneethanamine N,=-Dimethyl-3,4-methylenedioxy-benzeneethanamine

CH2'CH/rlH2 Amphetamine N-Methyl-3,_-methylenedio×y-

CH_ amphetamine

CH2.?fNHCH5 Methamphetamine 3,4-Methylenedioxy-methamphetamine

CH5

jO_CH2'cH_NH2 Homopiperonylamine N,=-Dimethylhomopiperonylamine

C i O_ Benzodioxo le-5-ethanamine N ,=-Dimethylbenzodioxole-5-ethanamine

Figure 1. Chemical structures of MDMA and its fragments, with extended MDMA names.

Journal of PsychoactiveDrugs 292 Vol. 18(4)Oct-Dec, 1986

SHULGIN CHEMISTRY

purification of thebromo intermediate, was described by incorrect starting material would lead to 1-(3,4-

Polish chemists almost 50 years later (Biniecki & methylenedioxyphenyl)-3-aminobutane (HMDA)(Shul-Krajewski 1960). gin & Jacob 1982a, 1982b). The structure for this alter-

MDMA has also been synthesized from MDA by nate "piperonylacetone" is also given in Figure 2.reaction with ethyl chloroformate, followed by reduction Only a modest pharmacological literature exists onwith Red-Al (Davis & Borne 1984). Similarly, MDA can these two aminated homologues. One study (Kasuyabe converted to the formamide that is reduced with lithium 1958) has compared HMDMA with atropine and found italuminum hydride in tetrahydrofuran (Braun, Shulgin & to be a weak spasmolytic. The toxicity and pharmacologyBraun 1980a). One report (O'Brien, Bonicamp & Jones of this homologue in mice (and of the corresponding1982) described the methylation of MDA with methyl MDA homologue HMDA) have been studied and pub-iodine. MDMA was obtained, but the dimethylated terti- lished (Davis & Borne 1984). The primary amine HMDAary amine and the trimethylated quarternary products was found to be inactive (in rats at 10 rog/kg) in both openwere also generated as contaminants, field testing and as a stimulant (Buxton 1972), but at

Two procedures exist for the synthesis of MDMA by higher doses caused slight stimulation with tremors, andthe reductive amination ofpiperonyl acetone with methyl- modest inhibition of monoamine oxidase (Fellows &amine. The reducing agents are either sodium cyanoboro- Bemheim 1950).hydride in methanol (Braun, Shulgin & Braun 1980a) oramalgamated aluminum in aqueous isopropanol (see PHYSICAL PROPERTIESNichols, in Frith 1986b). The cyanoborohydride method OF MDMA

has been used for the preparation of tritium-labeled The free base has a boiling point itl vacuo of 155° at

MDMA using labeled methylamine (Gehlert et al. 1985). 20 mm/Hg (Merck 1914) and l 10°-120° at 0.4 mm/HgPiperonyl acetone may also be reacted with N- (Braun, Shulgin & Braun 1980a). The hydrochloride saltmethylformamide in the Leuckart reaction, and MDMA can occur in a number of hydrated crystalline forms,obtained by the hydrolysis of the intermediate N-formyl making the physical properties and solid spectra of riskyderivative (Bailey et al. 1975). This N-formyl intermedi- value for identification and as criteria of purity. Theate is also the topic of an early German patent describing following melting points (m.p.) are given: for anhydrous,its formation from MDMA and chloral hydrate (Merck 147°-148 ° (Bailey et al. 1975), 148°-149 ° (Biniecki &1920). Krajewski 1960), 148°. 150° (Davis & Borne 1984: Merck

The piperonyl acetone required for these syntheses is 1914), 150°-151°(Gaston& Rasmussen 1972), 151°-152 °

available commercially. (See comments below for label- (Braun, Shulgin & Braun 1980a), 152%153° (Braun,lng misidentifications.) It can also be made either by the Shulgin & Braun 1980a), 158°- 159° (Nichols, In: Frithreduction of the nitroethane adduct of piperonyl with 1968b); for quarter-hydrate, soften 132° and m.p. 135°-elemental iron or the oxidation of isosafrol with hydrogen 139° (Shulgin 1986); for hemihydrate, soften 92° andperoxide in formic acid. m.p. 138°-145 ° (Shulgin 1986); for three-quarter hydrate,

soften 50° and m.p. 90°- 132° (Shulgin 1986): for monohy-Synthetic Precautions drate, soften 80° and m.p. 107°-133 ° (Shnlgin 1986).

Some potential synthetic mishaps should be consid- It is apparent that with uncertain hydration, the melt-ered. Substitution of isosafrole for safrole leads, in the lng point is not an acceptable criterion of identity or of

e reaction with hydrogen bromide, to an isomeric bromo- purity. Each of these polymorphs has, however, a distinctpropane intermediate that on amination with ammonia and characteristic crystalline polymorphic structure. Theproduces an a-aminated analogue of MDMA (Merck index of refraction has been determined: n_= 1.5311

1914). Presumably, the substitution of the methylamine, (Biniecki & Krajewski 1960).as in the procedure above, would produce l-(3,4-methyl- A considerable body of spectral data exists forenedioxyphenyl)-1 -methylaminopropane, the benzyl- MDMA. As mentioned above, the several polymorphs ofamine isomer of MDMA. the hydrated hydrochloride salts have distinct infrared

In the syntheses starting with piperonylacetone, the spectra. Some of these are shown in Figure 3. The spectrasubstitution of 1-(3,4~methylenedioxyphenyi)-3- of the free base (Nichols, In: Frith 1986b; Bailey et al.butanone for 1-(3,4-methylenedioxyphenyl)-2-propane 1975) and the anhydrous hydrochloride salt (Bailey et al,(an error that as been made by commercial suppliers of 1975; Gaston & Rasmussen 1972) have been published,piperonylacetone) leads to the formation of I-(3,4- The latter are as KBr pellets, a spectral procedure that canmethylenedixoxyphenyl)-3-methylaminobutane dehydrate a material during preparation.(HMDMA); with ammonia rather than methylamine, this The ultraviolet spectrum is characteristic of the

_6 Journalof PsychoactiveDrugs 293 Vol. 18(4)()ct-Dec. 1986

1SHULGIN CHEMISTRY i

AR-CHO _ AR-CH=CHCH3_ AR-CH2CH=CH2

(Piperon al ) (I so safrole ) (Safr_le )

j/ j/

AR-CH=CCH3j AR-CH2CCH3NO2 0 i

AR-CH2CHCH3 AR-CH2CHCH3 AR-CH2CHCH3

(MDA) CHO

A.-CH2CHCH3 '- A_-CH2CHCH3_ A.-CH2FHCH3NHCHO NHCH3 BR

(MDMA)

Piperonylaeetone

CH2/0,,,,_

ARAR-CH2CCH3 (the "right" ketone)

AR-CH2CH2CCH3 (the(Piperonyl-) "wrong" ketone)0

Figure 2. Synthetic routes to MDMA.

Journal qf I','vchoactive Drugs 294 Vol. 18(4) Oct-Dec, 1986 _.

1

SHULGIN " v : .., : ,: .., : ,, .' : . CHEMISTRY

_' " _l , _r'jmi;

MI_AHCL AN.Y_ROUS

ffiJ U_J ............

/ '

i

x,_' .............}i

Figure 3. MDMA spectra.

Jourtud of Psychoactive Drugs 295 Vol. IH(4) Oct-Dec. 1986

SHULGIN CHEMISTRY

Z ,E

Z

--7 [

CE_

CD --= LF__- .z----a

L.t.3

l,J ._

Z --=

LL3 ¢-_- -t-

I

ED, E

.<

!_j Journal of Psychoactive Drugs 296 Vol. 18(4)Oct-Dec. 1986

SHULGIN CHEMISTRYRY

methylenedioxyphenyl ring (as the hydrochloride in etha- with locomotor activities (Harris 1985).nol, 286 nm, e = 3843 [Bailey et al. 1975]; as the sulfate inwater, 0.1 N, 284 nm, A I% 1 em= 164 [Gaston & Rats

Rasmussen 1972]). It is excellent for quantitative analy- The study by Hardman, Haavik and Seevers (1973)sis, but is of little value for qualitative identification. The reported the LDso in rats to be 49 mg/kg i.p. Orally,

e nuclear magnetic resonance spectra have been published, however, MDMA is less toxic, with an LDso in rats of 325in part, both as the free base in CDC13 and as the HC! salt rog/kg being reported (Goad 1985).in D20 by Bailey and colleagues (1975) and, in full, by

Nichols (In: Frith 1986b). Mass spectral data have also Guinea Pigsbeen published (see Figure 4), both with electron impact The study by Hardman, Haavik and Seevers (1973)

d (Bailey et al. 1975) and with chemical ionization reported an LDso in guinea pigs of 98 mg/kg i.p.(Nichols, In: Frith 1986b).

DogsANALYTICAL PROCEDURES In dogs, following intravenous injection, the LDso

Chromatographic analytical schemes have been de- was reported to be 14 mg/kg (Hardman, Haavik & Seeversveloped. Two thin-layer chromatographic reports have 1973). The death of one dog was observed at an oral doseappeared, one with six Solvent systems (Bailey et al. of 18 mg/kg in toxicity trials preliminary to behavioral1975) and another with two, but with a progressive color studies (Frith 1986a). In this latter study, however,

3 development technique (O'Brien, Bonicamp & Jones chronic oral treatment of 15 mg/kg led to no further1982). A third study (Shaw & Peel 1975) was erroneously deaths.titled MDMA and actually investigated MMDA. Severalreports of gas chromatographic analyses have been pub- Monkeyslished, and this technique appears to be an excellent Intravenous administration of MDMA to monkeysmeasure of both identity and purity (Nichols, In: Frith (Macaca rnulatta) provided an LDso of 22 mg/kg (Hard-1986b; Gupta & Lundberg 1977; Bailey et al. 1975; man, Haavik & Seevers 1973).Gaston & Rasmussen 1972).

Several studies have been made of toxicologicalTOXICOLOGY changes in chemistry or body condition of both rats and

The mean lethal dose (LDso) of MDMA has been dogs at sublethal levels of MDMA. Studies in subacutelydetermined in several animal species. The first thorough treated rats (subcutaneous administrations twice daily for

study of the toxicity and behavioral pharmacology of four days at 10, 20 and 40 mg/kg) led to extensive de-l MDMA was conducted at the University of Michigan crease of hippocampal serotonin levels as seen in post-

I during the period 1953-54, and was supported by a con- mortem assays after a two-week wait. There was littletract from the Army Chemical Center. The results were change in either norepinephrine or dopamine levels

, declassified in 1969 and published four years later (Hard- (Woolverton et al. 1985). A single injection at the highest

Ii ; man, Haavik & Seevers 1973). In this study, a total level produced a similar depletion (76% rather than 88%,

number of eight drags were studied in five animal species, relative to control animals). A preliminary report of theseIn all five species examined in this study, MDMA proved findings was submitted as evidence to the Drug Enforce-

' to be !ess toxic than MDA, but more toxic than mescaline, ment Administration (DEA) hearings on MDMA (Seiden

A number of other studies, often to determine behavioral 1985), and it was a report of parallel findings in the rat,_ responses or sublethal morbidity, have provided addition- following MDA administration (Ricaurte et al. 1985) that

al data. These are presented here by animal species, was used to support the emergency scheduling of MDMA.Similar findings were reported, as a preprint to the DEA,/ Mice for use at the MDMA hearings, by Schmidt, Wu and

The seminal study of Hardman, Haavik and Seevers Lovenberg (1985) and later published as an abstract_ (1973) determined the LDso of MDMA in mice to be 97 (Schmidt & Lovenberg 1986). They too found that admin-

rog/kg following intraperitoneal (i.p.) administration, istration of high acute dosages of MDMA in rats depletedMore recent studies by Davis and Borne (1984) provided brain serotonin. They also found that pretreatment of the

the same value (98 mg/kg i.p.) in isolated test animals._,, test animal with an antidepressant (citalopram) known to

Aggregate toxicity, however, was found to b_consi_[_ block serotonin uptake mechanisms prevented this de-ably higher (20 mg/kg), with a number of deaths being crease in serotonin. These findings are in agreement withdelayed. This latter value was also reported in conjunction studies of the levels of brain enzymes that are involved

!

986 , Journal of Psychoactive Drugs 297 Vol. 18(4) Oct-Dec, 1986

SHULGIN CHEMISTRY

with the formation of neurotransmitters (Stone et al. of radio-labeled MDMA in rat brain homogenates has1986). Tryptophan hydroxylase activity in rats treated been reported (Gehlert et al. 1985), and several drugswith MDA or MDMA (10 rog/kg subacutely) decreased were evaluated as inhibitors of binding or as displacingin certain brain areas, unlike the decrease in tyrosine agents. Studies observing neurotransmitter release in ratbydroxylase associated with high-level administration of brain striatal slices showed MDMA to have a potencymethamphetamine. Rats administered MDMA (or separ- similar to the neurotoxin para-chloroamphetamine in theately, MDA) subacutely (10 mg/kg subcutaneously) were release of serotonin. Dopamine was found to be lessshown to have an increased neurotensinlike immunoreac- affected (Levin, Schmidt & Lovenberg 1986). In general,tivity level in certain regions of the brain (Merchant et al. these studies tend to imply some functional role of seroto-1986). nin inthemechanismof actionofMDMA.

In a separate study (Goad 1985) of subacutely treatedrats (oral administrations daily in increasing increments of In vivo Studies

25 mg/kg per day for 13 days), survivors were sacrificed Studies have been conducted on both restrainedfor tissue and brain pathology studies after a three-week (electrodes, thermocouples) and freely moving animalswait. There were blood indicators of damage to both liver (drug discrimination, behavioral pharmacology). Aand kidney, but histological studies of brain tissue re- single report involved brain biochemistry with indwellingvealed no pathology (Frith 1986b). electrodes (Takeda et al. 1986) measuring MDMA-

Dogs administered MDMA on a chronic basis at oral induced effiux of neurotransmitters by voltammetry indosages of up to 15 mg/kg/day showed restricted weight anesthetized rats. It was felt that the small amount ofgain, and in several males at the highest dosages, testicu- dopamine release seen might be due to the changes seen inlar atrophy. Observed possible central nervous system serotonin levels.(CNS) lesions were believed to be artifacts (Frith 1986a). An experimental procedure has been developed that

shows a remarkably good correlation between the qualita-PHARMACOLOGY tire nature of a drug-induced rise in a rabbit's temperature

In vitro Studies (measured rectally) and the stimulant or psychotomimeticStudies have been conducted using various in vitro character of the tested drug. The extent of this temperature

systems for the purpose of evaluating the relationship rise is proportional to the potency of the tested drug as abetween MDMA and various neurotransmitters. Most psychoactive agent in humans (Aldous et al. 1974). Thisfrequently, the neurotransmitter serotonin has been the assay, when applied in rabbits to the optical isomers offocal point of these studies. Assaying the optical isomers MDA and MDMA, showed a reversal of potencies of theof MDMA (in rat brain synaptosomes), Nichols and col- isomers (Anderson et al. 1978). Thus, with MDA the Rleagues (1982) have found that the enantiomer of MDMA (levo-, l-) isomer is more potent than either the S isomer oreffective in humans (the S or + isomer) is the more the racemate, whereas the S (dextro-, d-) isomer ofeffective isomer in releasing serotonin. The study of the MDMA is the more potent. This is true in rabbit studiesoptical isomers of MDMA on the inhibition of the uptake and in human evaluations as well. This reversal of activenotonlyofserotonin, butofotherneurotransmitters, isthe isomer assignment, coupled with the absence of cross-subject of a recently completed master of science thesis tolerance between MDMA and MDA in humans, supports(Steele 1986), which has been publicly presented (Steele, the hypothesis that these two drugs have different mocha-Nichols & Yim 1986). Studies have been made to deter- nisms of action.

mine the affinity of both MDA and MDMA for serotoninand dopamine receptors (Lyon, Glennon & Titeler 1986). Drug DiscriminationTritiated serotonin and ketanserin were used to label 5- A pharmacological technique that recently has beenHT_ and 5-HT2 receptors respectively, and the dopamine quite popular as a tool for comparing psychoactive drugsreceptors were labeled with N-methylspiperone. All stud- in experimental animals is the drug-discrimination assay.les indicated a moderate affinity for the 5-HT2 receptors, In this assay, test animals are trained to discriminatewith less for the 5-HTj and very much less for the dopa- between a given active compound and (usually) saline.mine receptors. In all cases the R isomer was more effec- Then the behavior seen resulting from varying dosages ofrive than the S isomer, with the racemate being intermedi- a trial drug allows some qualitative assignment of action.ate in effectiveness. As the S isomer of MDMA is the Furthermore, two experimental drugs may be compared

more effective in humans, it was felt that these findings _._t the other in order to determine their relativeindicate a possible amphetamine-associated mechanism, quantitatit_e ranking.rather than just serotonin involvement. Specific binding Studies with rats trained to discriminate between

Journalof PsychoactiveDrugs 298 Vol. 18(4)Oct-Dec, 1986

t_['RY _ SHULGIN CHEMISTRY

s has _ d-amphetamine and saline or, separately, between MDA and defecation. A picture of disorientation and fear wasdrugs and saline, have shown MDMA in both cases to general- presented for mescaline, and MDMA (in adequate doses)acing ! ize to the drag in preference to the saline (Glennon & was said to parallel this picture, but no explicit details

in rat Young 1984). This, together with the findings that were given. These effects were apparently not seen in thetency MDMA did not (unlike MDA) generalize to animals monkey in this study. A similar study in the macaque

n ttm I trained to discriminate 2,5-dimethoxy-4-methyl- (Schlemmer, Montrell & Davis 1986) at doses of up to 10less ¢ amphetamine (DOM) from saline (Glennon et al. 1982), rog/kg showed some disruption of social behavior (i.e.,

leral, _; suggested that N-methylation of MDA (to produce self-grooming, food foraging), but no actions that sug-roto- _ MDMA) emphasizes the stimulant properties in prefer- gested hallucinatory effects.

i ence to the psychedelic properties. In separate studies, In rats, with orally administered MDMA, there were

t however, rats trained to discriminate between d- adverse clinical signs--largely related to excitabilityamphetamine and saline, MDMA was found to only par- (i.e., piloerection, uncontrolled urination)--seen in ali

fined tially mimic d-amphetamine (Woolverton et al. 1985). In studies at or above 25 mg/kg. At higher levels (to 300reals rhesus monkeys trained to discriminate between d- rog/kg) there were tremors and convulsions observed,L A amphetamine and saline, MDMA appeared to be amphet- with death resulting above this dose (Frith 1986b; Goad!ling aminelike, whereas MDA showed only partial mimicking 1985). In similar studies with dogs administered near-_dA- of d-amphetamine (Woolverton et al. 1985). lethallevels of MDMA orally, toxic behavioral signs werey in observed, such asrapid breathing, salivation and hyperac-

of Behavioral Pharmacology tivity (Frith 1986a).,'nin A number of studies were made of MI)MA, in eom- Two studies were solicited by the federal goveru-

parison to both the primary amine (MDA) and the higher ment to evaluate the abuse potential of MDMA throughIhat N-homologues, both as an analgesic and as a C'NS stimu- reinforcement studies (serf-administration) in cocaine-!its- lant in mice (Braun, Shulgin & Braun 1980a, 1980b). trained primates. The fu'st of these employed pretrainedmm MDMA proved to be the most effective analgesic of all baboons (Caiffiths, Lamb & Brady 1985) and found thatctic compounds tested, especially in the test that measures the two out of three animals reinforced themselves withture i_i loss of stretch reflex as a response to injected acetic acid. MDMA, but with less intensity than with cocaine. Theas a MDMA, and the immediate N-ethyl homologue MDE, third animal did not self-administer MDMA on initial

['his were the most effective compounds in promoting motor trials, but appeared to do so on retrial. A second studys of activity. In this assay, they had more than twice the (Harris 1985)employed rhesus monkeys, also pretrainedthe potency of MDA as stimulants, to self-administer cocaine. Again, some reinforcemente R Many of the observations on drug-induced behavior- was found in two out of three animals, suggesting a realrot .._ al changes are natural consequences of toxicity studies, abuse potential for MI)MA.

of i and hence often reflect doses that approach, and in somelies I cases exceed, the LD.solevels. When near-lethal amounts PSYCHOPHARMACOLOGYire { of MDMA are given to mice, the observed behavior has Nonclinical Studies_ss- t_ been described as being excitatory in nature (tremors, The earliest reports of human activity of MDMA

jerking, head clonus that progressed to clonic convul- were from research studies that were not clinically

ha- sions). Tonic seizures did not occur (Davis & Borne oriented. The first description of its action in humans1984). In discriminative stimulus studies conducted in (Shulgin & Nichols 1978) stated that it evoked an easilyrats (Glennon & Young 1984) doses in excess of 1.6-3.0 controlled altered state of consciousness, with emotional

rog/kg could not be considered, due to behavior disruption and sensual overtones. It shared aproperty with low levels(i.e., lack of any response at all). Hardman, Haavik and of MDA in that it had little hallucinatory effect. A subse-

Igs Seevers (1973) made behavioral observations of MI)MA quent report (Shulgin 1983) elaborated more on the qual-ry. in the dog and in the monkey at substantially lethal doses ity of action.ate (in the dog, between five and 50 mg/kg, with the Most of the known psychedelic drugs suffer a majorJe. LDso= 14 rog/kg; in the monkey, between 10 and 75 loss of potency on N-methylation (Anderson et al. 1978).

of rog/kg, with the LDso-- 22 mg/kg). Under these condi- MDMA is the one exception to this rule as it, like amphet-a. lions, a spectrum of behavior similar to that of mescaline amine, maintains potency as the N-methyl homologue.ed was observed (mescaline dose range in the dog, five to 60 This pair is set apart also by the reversal of optical isomerye mg/kg, with the LDso = 54 mg/kg). This spectrum initial- configuration required for human activity, and the fact

ly included motor effects (a weakness and a fluttering that there is no observed cross-tolerance between MDA ....m motion in the hind limbs) followed by salivation, emesis and MDMA (Anderson et al. 1978).

_6Journal of Psydtoacti_ Drugs 299 Vol. 18(4) Oct-Dec, 1986

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SHULGIN CHEMISTRY

From a large number of clinical trials, it became tests showed responses within normal limits. The usualincreasingly apparent that MDMA was without the harsh- correlative side effects of nystagmus, bruxism andness and complexity usually seen with MDA. This, anorexia were occasionally noted.coupled with the reversal of the optical isomer require- A remarkable collection of anecdotal repons ofment for optimum human response, led to a fu'mer state- MDMA use has recently appeared, describing more thanment of the differences between these two drugs (Braun, 20 personal experiences. These first-hand accounts will

Shulgin & Braun 1980a). be of keen interest to students of psychology (Adamson '1985).

Clinical Studies The pharmacological and psychopharmacological

The most complete publication of the clinical appli- findings related to MDMA have been summarized incation of MDMA in therapy appeared in 1983 (Greer several reviews (Nichols & Glennon 1984; Glennon,1983). It described the results of the administration of Rosencrans & Young 1983; Stafford 1983; Weil & Rosen

MDMA to 29 patients in a therapeutic setting. It con- 1983; Shulgin 1982, 1981, 1978). Most of these summa-cluded that the best use of MDMA is as an adjunct to ties were written by the authors of the original scientific

insight-oriented psychotherapy to facilitate communica- studies and there are additional data included in thesetion and intimacy between people involved in emotional reviews.

relationships as well as in the treatment of alcohol andother drug abuse. It was emphasized that MDMA does not LEGAL HISTORYlend itself to overuse, because its most desirable effects The initial proposal for the scheduling of MDMAdiminish with frequency of use. appeared on July 27, 1984 (Mullen 1984a). Here was

A study involving 13 experimental subjects was con- presented the usual body of justifications for the schedul-ducted in March 1985 (Greet 1985b) with the overseeing lng of an abused drug, and there was thepro forma request

of an equal number of psychiatrists or psychotherapists, made for comments, with none expected. Commentsmost of whom were experienced with both MDMA and were indeed made, however, and a second entry appearedLSD actions in humans. An extensive subjective analysis on December 31, 1984, noting that hearings were to bewas made to develop a comparison between MDMA and held (Mullen 1984b). The date of February 1, 1985, was

LSD as potential therapeutic adjuncts. The principle set as a time to hold a hearing to establish procedures,effects of MDMA lasted three to five hours, while those of dates and locations. These hearings were held in 1985 in

LSD are known to extend up to 14 hours. The clinicians Los Angeles, Kansas City, Missouri, and Washington,

agreed that MDMA was much easier to use than LSD, and D.C., and were presided over by an administrative lawbecause MDMA did not threaten ego control, involving judge, Francis L. Young.

little psychological risk to a naive subject. While LSD A request appeared in March 1985 for any and allsubjects sometimes experience transient delusional states, information concerning illicit trafficking and medicalthe only complications of using MDMA, according to the problems associated with MDMA use (Unsigned 1985a).clinicians and researchers, are occasional anxiety and This was followed, at the end of May 1985, by a notice

various physical symptoms due to the sympathomimetic that appeared in the Federal Register (Lawn 1985)effects of the drug. A description of the clinical protocol announcing the temporary placement of MDMA intoemployed in MDMA therapy has been written and submit- Schedule I by the invocation of the emergency schedulingted as a chapter in a forthcoming book (Tolbert & Greer, powers granted by the Comprehensive Crime Control Act !,In press), of 1984.TheeffectivedateforthisschedulingwasJuly1, i

More quantitative values for these stimulant side 1985. This occurred in the middle of the hearings thateffects were obtained in a similar study conducted earlier were designed to determine the legal fate of MDMA as to

on 21 subjects (Downing & Wolfson 1985). Here the its potential scheduling.subjects were continuously monitored for cardiovascular In an administrative development initially indepen- ichanges, neurological sensitivity and blood chemistry, dent from the scheduling procedures initiated by the DEA /Noteworthy was a relatively large rise in both systolic and in 1984, there was a request made through the Food anddiastolic pressure at the first hour followed by a gradual Drag Administration (Randolph 1984) for comments con-decrease to below baseline level by the sixth hour. At ceming the medical usefulness and abuse potential of

24-hour follow-up, both signs were still somewhat de- some 28 drugs that were being considered by the World

pressed. Pulse rate also rose over the first hour and recov- Health Organization for international restriction. MDMAered during the next five hours. At no point did it drop was explicitly included on this list.below baseline during the next 24 hours. All neurologicalt

Journalof Psychoactive Drugs 300 Vol. 18(4)Oct-Dec,1986

,y SHULGIN CHEMISTRY

al POPULAR OPINIONS recognizing the values of psychopharmacological agents_d inanyof severalmedicalproblemareasthatarewithout

An unusually large amount of commentary and opin- good current therapy. Doblin (1984), who personallyof ion has appeared in the popular press and in both profes- served as a principle information distribution center dur-tn sional as well as lay journals. Occasionally there may be ing the earliest days of the MDMA controversy, publishedill some statements of fact, but usually there is much mis- the widely circulated book Murmers in the Heart of them statement of fact. Beast that made available legal and technical correspon-

The popular press has shown a blend of curiosity and dence. Smith, Wesson and Buffum (1985) addressed theal sensationalism. There were sounds and shades of the LSD chilling effect of legal scheduling on medical research,in notoriety of the 1960's in that each reporter obtained some but were reminded in rebuttal (Holsten & Schieser 1985)

l, facts, but also borrowed details from other writers. The that the exploratory use of new drugs outside of the·n results were an oft-repeated story, generally moderately controls that apply to the pharmaceutical industry carry

a- i accurate and somewhat favorable. An issue of Brain- real risks as to the safety and quality of the product.ic _ Mind Bulletin (April 15, 1985) Was devoted to the con- Nichols (1985) submitted an essay to participants at the;e troversy, and a short critical review appeared in the DEA hearings arguing that, according to the published

PharmChem Newsletter (Seymour 1985). In addition, the literature, MDMA should not be considered either a hallu-

i author of the present article has written a hypothetical cinogenic agent or an amphetaminelike stimulant.question-and-answer interview (Shulgin 1985). A perspective article (Riedlinger 1985) reviewed the

A Articles or commentary also appeared in magazines recent history of MDMA and speculated on a number ofis and newspapers, such as Daily Californian (Marks 1986), areas of potential value. Grinspoon and Bakalar (1986a)

1- High Times (Smith & Seymour 1986), New Age (Abram- presented an argument to the medical community support-st son 1985), Newsweek (Adler 1985), Chemical andEn- ingtheneedofdrugsasadjunctstopsychotherapy, aswellts gineering News (Baum 1985), San Francisco Chronicle as having editorialized (Grinspoon & Bakalar 1986b) on_d (Butler 1985), Oakland Tribune (Dentinger 1985), Life the relationship between designer drags and the law, using,e (Dowling 1985), San Francisco Examiner (Flinn 1985), MDMA as an illustration. The broader question touchingts Boston Globe (Foreman 1985), Alcoholism & Addiction on the need of an acknowledgment of the value of con-

;, (Gold 1985), Vanguard Press (Hudson 1985; Stevens sciousness alteration in society (using MDMA as a pointn 1985), Dallas Times Herald (Jubera 1985), New York of departure) has been presented to the lay community

_, Magazine (Klein 1985), Washington Post (Leavy 1985), (Roberts 1986b). Several informational articles or tractsN Rolling Stone (O'Rourke 1985), Business Week (Schul- have appeared that seem reasonably neutral, but empha-

man 1985), Psychology Today (Shafer 1985), Omni size clinical utility nonetheless; they are apparently in-11 (Siegel 1985), Oklahoma Gazette (Siens 1985), Detroit tended to simply provide information (Greer 1985a; Greerfi News (Tessler 1985), Time (Toufexis 1985), Scientific & Strassman 1985; Grinspoon & Bakalar 1985).1. American (Unsigned 1985b), San Francisco Bay Guard- On the let's-discourage-drug-use-and-abuse side,:e ian (Wolfson 1985), The Rocket (Eichhorn 1984) and there have been some noteworthy examples. A short re-

;) Substance Abuse Report (Unsigned 1984a). It even made view article in the American Psychological Association'so the comics page, in Doonesbury (Trudeau 1985), and the APA Monitor (Turkington 1986) quotes statements (see

g i editorials on KCBS Radio (Barnett 1985). Two long below) ascribed to the authors of the rat serotonin studies.

:t I! essays (Beck 1986; Ehrlich 1986) and a complete book Another example is a newsletter on drag abuse (Cohen, _ (Seymour 1986) have appeared covering the subject. 1985) that equated all claims for MDMA to those that

_t One of the first promotional hypes for MDMA gave LSD and other psychedelics such glowing presso appeared in an underground magazine titled Wet (Un- years ago. It is stated that any attempts to set MDMA apart

signed 1981), in which the name Ecstasy was used and from MDA, DOM or PMA (or from the user-attestment

_- I availability was implied as early as 1976. Another irre- record, from LSD or opium) reflects a lack of knowledge_, ] sponsible tract appeared (Unsigned 1984b) that was styled about these drugs. Furthermore, it indicated that MDMA

d { to disarm and discourage the potential user of MDMA. appears to be less safe than LSD, and even LSD was a__ This is an excellent example of inaccurate and misleading failure.,f information where much detail that applies to MDA is In addition, some organizations and federal agencies

d I ascribed to MDMA. have produced tracts and flyers that are directed to thei In a more balanced vein, a number of reviews and potential MDMA user, but have been written without

evaluations acknowledge the abuse potential of MDMA, much factual accuracy. Two examples are Do It Nowbut emphasize the clinical virtue and highlight the need of Foundation's MDA/MDM (Dye 1982), and NIDA's

6 i Journalof Psychoactivel_rugs 301 Vol. 18(4)Oct-Dec.1986

SHULGIN CHEMISTRY

"MDMA" (NIDA 1985), a government bulletin warning above: "Repeated use of designer drags such as Ecstasy

of potential psychotic episodes (wherein most informa- produces potentially irreversible brain damage." And antion has been taken from the MDA record), embarrassing elaboration of this misinformation was

given in a newspaper interview, in which the following isCONCLUSION a verbatim quotation from Dr. Charles Schuster (Associ-

One of the inescapable facts of life is that with ated Press 1986): "It can poison the nervous systemMDMA, as with everything that combines both promise probably irreversibly. It may very well be that a young,and threat, there are intense protagonists and intense healthy adult who is exposed to these drugs is not going to

antagonists. And both groups are vocal, show frank symptoms that are going to be picked up by aFrom the promotional flyer (Dye 1982) mentioned clinician. But what we don't know is whether 20 or 30

above: "When people feel well, centered, unthreatened years from now, at the age of 45, they may begin to beand aware of their own strength and loveliness, they are showing central nervous system degenerative signs thatable to drop many of the usual barriers. Habitual users of ordinarily would not be seen until they get to be 70 or 80."tobacco have no need to smoke. Chain smokers of marl- It further quotes that this is the first demonstration of a

juana do not need their weed. Nail biters leave their neurotransmitter being modified to a neurotoxin. Andfingers alone. Compulsive talkers become quiet," and on from the NIDA bulletin: "MDMA--leads to psychoticand on: pretty much a glowing picture, without negatives, episodes." All this is an equally inaccurate negative pic-

And the opposite extreme is just as unrelenting, ture, without positives.From the APA Monitor (Turkington 1986) mentioned

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