sign in sign up
<<
Home , Tyramine

The Background and Chemistry ofMDMA

ALEXANDER T. SHULGIN, PH.D.*

This article will present the factual material that up to 1972, MDMA was entered with the exists in the literature representing the results of labora- name. Since then, the heterocyclic term benzodioxole-5- 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 struc- mon name applied to an organic compound, a secondary ture as a substituted . Other terms that amine. 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 Chemical these 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 (+) 66142-89-0

CllH1SN02, and its structural formula is given in Figure S-MDMA ( +) HC!. 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) 69610-10-2 structure. With that defining portion named as a stem MDMA HCI (racemic) 64057-70-1 word, the full chemical name is apparent by the additions to this base fragment. In Figure I, the fragments (with CHEMISTRY their names) are drawn on the left and the extended name Synthesis that applies to MDMA is given on the right. The use of the There are six methods of preparation to be found in simplest aliphatic chain (i.e., ethyl amine 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 of mine or methamphetamine. These terms are 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 a cals being described, according to his/her discipline: the German patent issued to the firm E. Merck (1914) in chemist sees the carbon chain, the pharmacologist sees the Darmstadt, dated December 24, 1912, and made avail- , and the policeman sees the drug laws. The able May 16,1914. Here, MDMA was synthesized in two names that are to be used in the searching of Chemical steps from safrole. The addition of aqueous hydrobromic Abstracts depend on the date of the search. In the earliest acid provides an impure intermediate (1- files, the homopiperonylamine name was used, and then methylenedioxyphenyl-2-bromopropane) that is con- verted with an alcoholic solution of methylamine to *1483 Shulgin Road, Lafayette, California 94549. MDMA. The same process, except for the isolation and

Journal of Psychoactive Drugs 291 Vol. 18(4) Oct-Dee, 1986 SHULGIN CHEMISTRY

MDMA

FAMILY MDMA NAME

Structure Name

Propane 2-Methylamino-l-(3,~-methylene- , dioxyphenyl)-propane

CH3 ,/NH2 'CH Isopropyl amine N-Methyl-8-(3,4-methylenedioxy- , phenyl)-isopropylamine CH3

Ethyl amine N,a-Dimethyl-8-(3,4-methylene- dioxyphenyl)-ethylamine Phenethylamine N,a-Dimethyl-3,4-methylenedioxy- phenethylamine Benzeneethanamine N,a-Dimethyl-3,4-methylenedioxy- benzene ethan amine

Amphetamine N-Methyl-3,4-methylenedioxy-

Methamphetamine 3,~-Methylenedioxy-methamphetamine

Homopiperonylamine N,a-Dimethylhomopiperonylamine Benzodioxole-S- N,a-Dimethylbenzodioxole-S- ethan amine ethanamine

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

Journal of Psychoactive Drugs 292 Vol. 18(4) Oct-Dee, 1986 SHULGIN CHEMISTRY purification of the bromo 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 on with Red-AI (Davis & Borne 1984). Similarly, MDA can these two aminated homologues. One study (Kasuya be converted to the formarnide that is reduced with lithium 1958) has compared HMDMA with atropine and found it aluminum hydride in tetrahydrofuran (Braun, Shulgin & to be a weak spasmolytic. The toxicity and pharmacology Braun 1980a). One report (O'Brien, Bonicamp & Jones of this homologue in mice (and of the corresponding 1982) 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 HMDA ary amine and the trimethylated quarternary products was found to be inactive (in rats at 10 mg/kg) in both open were 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, and the reductive amination ofpiperonyl acetone with methyl- modest inhibition of (Fellows & amine. The reducing agents are either sodium cyanoboro- Bernheim 1950). hydride in methanol (Braun, Shulgin & Braun 1980a) or amalgamated aluminum in aqueous isopropanol (see PHYSICAL PROPERTIES Nichols, in Frith 1986b). The cyanoborohydride method OFMDMA has been used for the preparation of tritium-labeled The free base has a boiling point in vacuo of 155° at MDMA using labeled methylamine (Gehlert et al. 1985). 20 mmlHg (Merck 1914) and 110°-120° at 0.4 mmlHg Piperonyl acetone may also be reacted with N- (Braun, Shulgin & Braun 1980a). The hydrochloride salt methylformamide 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 risky derivative (Bailey et al. 1975). This N-formyl intermedi- value for identification and as criteria of purity. The ate is also the topic of an early German patent describing following melting points (rn.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), 150C-15 1°(Gaston & Rasmussen 1972), 151°-152° available commercially. (See comments below for label- (Braun, Shulgin & Braun 1980a), 152°-153° (Braun, ing misidentifications.) It can also be made either by the Shulgin & Braun 1980a), 158°-159° (Nichols, In: Frith reduction 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° and peroxide in formic acid. m.p. 138°-145° (Shulgin 1986); for three-quarter hydrate. soften 50° and m.p. 90°-132° (Shulgin 1986); formonohy- Synthetic Precautions drate, soften 80° and m.p. 107°-133° (Shu1gin 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 ing point is not an acceptable criterion of identity or of reaction with hydrogen bromide. to an isomeric bromo- purity. Each of these polymorphs has, however, a distinct propane intermediate that on amination with ammonia and characteristic crystalline polymorphic structure. The produces an a-aminated analogue of MDMA (Merck index of refraction has been determined: n\5= 1.5311 1914). Presumably, the substitution of the methylamine, (Biniecki & Krajewski 1960). as in the procedure above, would produce 1-(3,4-methyl- A considerable body of spectral data exists for enedioxyphenyl)-l-methylaminopropane, the benzyl- MDMA. As mentioned above, the several polymorphs of amine 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 spectra substitution of 1-(3,4-methylenedioxyphenyl)-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 1-(3,4- The latter are as KBr pellets, a spectral procedure that can meth y lenedixoxyphen y 1)- 3 -methy laminobu tane dehydrate a material during preparation. (HMDMA); with ammonia rather than methylamine, this The ultraviolet spectrum is characteristic of the

Journal of Psychoactive Drugs 293 Vol. 18(4) oa-o«. 1986 SHULGIN CHEMISTRY

AR-CHO -----I ••.~ AR-CH=CHCH3 ...•~J--- (Piperonal) / (Isosafrole) // (Safrole) i/ !// AR-CH=C,CH3 AR-CH2CCH3 (D2 0\u

AR-CH2CHCH3 - AR-CH2CHCH3 AR-CH2CHCH3 I I , NH2 NHC02Er / ~HCH3 A 7 ) \ CHO AR-CH2fHCH3 ~ AR-CH2fHCH3 ~ NHCHO NHCH3 (MDMA)

Piperonylacetone

AR-CH2CCH3 o" (the "right" ketone) AR-CH2CH2CCH3 (Piperonyl-) o" (the "wrong" ketone)

Figure 2. Synthetic routes to MDMA.

Journal of Psychoactive Drugs 294 Vol. 18(4) Oct-Dec, 1986

--_ .._----- _ .. -_. __ ..._._-- SHULGIN CHEMISTRY

Figure 3. MOM A spectra.

Journal of Psychoactive Drugs 295 Vol. 18(4) Oct-Dec. 1986

------tIl 2- ::z:: c:: e..:l'" 5 ~ 3.4-METHYLENEDIOXYMETHAMPHETRMINE HCL z ~ .;g.:J ',..", '":0. '" tJ'" ~ HJO ""'"

IV \0 0>

< £

00 ~ o ~ ::z:: 6 ~ Il ""1""-JIII,Jl~IIIJI~1~11~#I~~lwuJllllllujl~I'f""rJI~t"'IIIIIII,""",~lllll""."ll\r'"~lltt•..,\II,"",J~ ..~,.", ...... ,Vl \0 10 50 100 150 200 00 -< 0> Figure 4. MDMA mass spectrum. " SHULGIN CHEMISTRY methylenedioxyphenyl ring (as the hydrochloride in etha- with locomotor activities (Harris 1985). nol, 286 nm, e = 3843 [Bailey et al. 1975]; as the sulfate in water, 0.1 N, 284 nm, A 1% 1 cm= 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, nuclear magnetic resonance spectra have been published, however, MDMA is less toxic, with an LDso in rats of 325 in part, both as the free base in CDC 13 and as the HCI salt mg/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 Pigs been published (see Figure 4), both with electron impact The study by Hardman, Haavik and Seevers (1973) (Bailey et al. 1975) and with chemical ionization reported an LDso in guinea pigs of 98 mg/kg i.p. (Nichols, In: Frith 1986b). Dogs ANALYTICAL PROCEDURES In dogs, following intravenous injection, the LDso Chromatographic analytical schemes have been de- was reported to be 14 mg/kg (Hardman, Haavik & Seevers veloped. Two thin-layer chromatographic reports have 1973). The death of one dog was observed at an oral dose appeared, one with six solvent systems (Bailey et al. of 18 mg/kg in toxicity trials preliminary to behavioral 1975) and another with two, but with a progressive color studies (Frith 1986a). In this latter study, however, development technique (O'Brien, Bonicamp & Jones chronic oral treatment of 15 mg/kg led to no further 1982). A third study (Shaw & Peel 1975) was erroneously deaths. titled MDMA and actually investigated MMDA. Several reports of gas chromatographic analyses have been pub- Monkeys lished, and this technique appears to be an excellent Intravenous administration of MDMA to monkeys measure of both identity and purity (Nichols, In: Frith (Macaca mulatta) 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 toxicological TOXICOLOGY 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 subacutely determined in several 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 mglkg) led to extensive de- MDMA was conducted at the University of Michigan crease of hippocampal levels as seen in post- during the period 1953-54, and was supported by a con- mortem assays after a two-week wait. There was little tract from the Army Chemical Center. The results were change in either or levels declassified in 1969 and published four years later (Hard- (Woolverton et al. 1985). A single injection at the highest man, Haavik & Seevers 1973). In this study, a total level produced a similar depletion (76% rather than 88%, number of eight drugs were studied in five animal species. relative to control ). A preliminary report of these In all five species examined in this study, MDMA proved findings was submitted as evidence to the Drug Enforce- to be less toxic than MDA, but more toxic than . 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 aI. 1985) that al data. These are presented here by animal species. was used to support the emergency scheduling ofMDMA. 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, Haa vik and Seevers Lovenberg (1985) and later published as an abstract (1973) determined the LDso ofMDMA in mice to be 97 (Schmidt & Lovenberg 1986). They too found that admin- mg/kg following intraperitoneal (i.p.) administration. istration of high acute dosages of MDMA in rats depleted More recent studies by Davis and Borne (1984) provided serotonin. They also found that pretreatment of the the same value (98 mg/kg i.p.) in isolated test animals. test animal with an (citalopram) known to Aggregate toxicity, however, was found to be consider- 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 with delayed. This latter value was also reported in conjunction studies of the levels of brain that are involved

Journal of Psychoactive Drugs 297 Vol. 18(4) OCI-Dec, 1986 SHULGIN CHEMISTRY with the formation of (Stone et a1. of radio-labeled MDMA in rat brain homogenates has 1986). activity in rats treated been reported (Gehlert et al. 1985), and several drugs with MDA or MDMA (10 rug/kg subacutely) decreased were evaluated as inhibitors of binding or as displacing in certain brain areas, unlike the decrease in agents. Studies observing release in rat hydroxylase associated with high-level administration of brain striatal slices showed MDMA to have a potency methamphetamine. Rats administered MDMA (or separ- similar to the neurotoxin para-chloroamphetamine in the ately, MDA) subacutely (10 mg/kg subcutaneously) were release of serotonin. Dopamine was found to be less shown 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 in the mechanism of action of MDMA. In a separate study (Goad 1985) of subacutely treated rats (oral administrations daily in increasing increments of In vivo Studies 25 mglkg per day for 13 days), survivors were sacrificed Studies have been conducted on both restrained for tissue and brain pathology studies after a three-week (electrodes, thermocouples) and freely moving animals wait. There were blood indicators of damage to both liver (drug discrimination, behavioral pharmacology). A and , but histological studies of brain tissue re- single report involved brain biochemistry with indwelling vealed no pathology (Frith 1986b). electrodes (Takeda et al. 1986) measuring MDMA- Dogs administered MDMA on a chronic basis at oral induced efflux of neurotransmitters by voltammetry in dosages of up to 15 mglkg/day showed restricted weight anesthetized rats. It was felt that the small amount of gain, and in several males at the highest dosages, testicu- dopamine release seen might be due to the changes seen in lar atrophy. Observed possible central nervous system serotonin levels. (eNS) lesions were believed to be artifacts (Frith 1986a). An experimental procedure has been developed that shows a remarkably good correlation between the qualita- PHARMACOLOGY tive nature of a drug-induced rise in a rabbit's temperature In vitro Studies (measured rectally) and the stimulant or psychotomimetic Studies 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 a between MDMA and various neurotransmitters. Most psychoactive agent in humans (Aldous et al. 1974). This frequently, the neurotransmitter serotonin has been the assay, when applied in rabbits to the optical of focal point of these studies. Assaying the optical isomers MDA and MDMA, showed a reversal of potencies of the of MDMA (in rat brain synaptosomes), Nichols. and col- isomers (Anderson et a1. 1978). Thus, with MDA the R leagues (1982) have found that the enantiomer of MDMA (levo-, l-) isomer is more potent than either the S isomer or effective in humans (the S or + isomer) is the more the racemate, whereas the S (dextro-, d-) isomer of effective isomer in releasing serotonin. The study of the MDMA is the more potent. This is true in rabbit studies optical isomers of MDMA on the inhibition of the uptake and in human evaluations as well. This reversal of active not only of serotonin, but of other neurotransmitters, is the 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 mecha- Nichols & Yim 1986). Studies have been made to deter- nisms of action. mine the affinity of both MDA and MDMA for serotonin and dopamine receptors (Lyon, Glennon & Titeler 1986). Drug Discrimination Tritiated serotonin and ketanserin were used to label 5- A pharmacological technique that recently has been HT 1 and 5-HT 2 receptors respectively, and the dopamine quite popular as a tool for comparing psychoactive drugs receptors were labeled with N-methylspiperone. All stud- in experimental animals is the drug-discrimination assay. ies indicated a moderate affinity for the 5-HT2 receptors, In this assay, test animals are trained to discriminate with less for the 5-HT1 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 of tive 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 one against the other in order to determine their relative indicate a possible amphetamine-associated mechanism, quantitative ranking. rather than just serotonin involvement. Specific binding Studies with rats trained to discriminate between

Journal of Psychoactive Drugs 298 Vol. 18(4) Oct-Dec, 1986 SHULGIN CHEMISTRY

d-amphetamine and saline or, separately, between MDA and defecation. A picture of disorientation and fear was and saline, have shown MDMA in both cases to general- presented for mescaline, and MDMA (in adequate doses) ize to the drug in preference to the saline (Glennon & was said to parallel this picture, but no explicit details Young 1984). This, together with the findings that were given. These effects were apparently not seen in the MDMA did not (unlike MDA) generalize to animals monkey in this study. A similar study in the macaque trained to discriminate 2,5-dimethoxy-4-methyl- (Schlemmer, Montrell & Davis 1986) at doses of up to 10 amphetamine (DOM) from saline (Glennon et al. 1982), mg/kg showed some disruption of social behavior (i.e., suggested that N-methylation of MDA (to produce self-grooming, food foraging), but no actions that sug- MDMA) emphasizes the stimulant properties in prefer- gested hallucinatory effects. ence to the psychedelic properties. In separate studies, In rats, with orally administered MDMA, there were however, rats trained to discriminate between d- adverse clinical signs-largely related to excitability amphetamine and saline, MDMA was found to only par- (i.e., piloerection, uncontrolled urination)-seen in all tially mimic d-amphetarnine (Woolverton et al. 1985). In studies at or above 25 mglkg. At higher levels (to 300 rhesus monkeys trained to discriminate between d- mglkg) there were tremors and convulsions observed, amphetamine and saline, MDMA appeared to be amphet- with death resulting above this dose (Frith 1986b; Goad aminelike, whereas MDA showed only partial mimicking 1985). in similar studies with dogs administered near- of d-amphetamine (Woolverton et al. 1985). lethal levels ofMDMA orally, toxic behavioral signs were observed, such as rapid breathing, salivation and hyperac- Behavioral Pharmacology tivity (Frith 1986a). A number of studies were made of MDMA, in com- Two studies were solicited by the federal govern- parison to both the primary amine (MDA) and the higher ment to evaluate the abuse potential of MDMA through N-homologues, both as an analgesic and as a eNS stimu- reinforcement studies (self-administration) in - lant in mice (Braun, Shulgin & Braun 1980a, 1980b). trained primates. The first of these employed pretrained MDMA proved to be the most effective analgesic of all baboons (Griffiths, Lamb & Brady 1985) and found that compounds tested, especially in the test that measures the two out of three animals reinforced themselves with loss of stretch reflex as a response to injected acetic acid. MDMA, but with less intensity than with cocaine. The MDMA, and the immediate N-ethyl homologue MDE, third animal did not self-administer MDMA on initial were the most effective compounds in promoting motor trials, but appeared to do so on retrial. A second study activity. In this assay, they had more than twice the (Harris 1985) employed rhesus monkeys, also pretrained potency of MDA as . to self-administer cocaine. Again, some reinforcement Many of the observations on drug-induced behavior- was found in two out of three animals, suggesting a real al changes are natural consequences of toxicity studies, abuse potential for MDMA. and hence often reflect doses that approach, and in some cases exceed, the LDso levels. When near-lethal amounts PSYCHOP~COLOGY of MDMA are given to mice, the observed behavior has Nonclinical Studies 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 sions). Tonic seizures did not occur (Davis & Borne oriented. The first description of its action in humans 1984). In discriminative stimulus studies conducted in (Shulgin & Nichols 1978) stated that it evoked an easily rats (Glennon & Young 1984) doses in excess of 1.6-3.0 controlled altered state of consciousness, with emotional mg/kg could not be considered, due to behavior disruption and sensual overtones. It shared a property 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- Seevers (1973) made behavioral observations of MDMA quent report (Shulgin 1983) elaborated more on the qual- in the dog and in the monkey at substantially lethal doses ity of action. (in the dog, between five and 50 mg/kg, with the Most of the known psychedelic drugs suffer a major LD50= 14 mg/kg; in the monkey, between 10 and 75 loss of potency on N-methylation (Anderson et al. 1978). mg/kg, with the LDso=22 mg/kg). Under these condi- MDMA is the one exception to this rule as it, like amphet- tions, a spectrum of behavior similar to that of mescaline amine, maintains potency as the N-methyl homologue. was observed (mescaline dose range in the dog, five to 60 This pair is set apart also by the reversal of optical isomer 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 motion in the hind limbs) followed by salivation, emesis and MDMA (Anderson et al. 1978).

Journal of Psychoactive Drugs 299 Vol. 18(4) Oct-Dee, 1986

------.-~-- SHULGIN CHEMISTRY

From a large number of clinical trials, it became tests showed responses within normal limits. The usual increasingly apparent that MDMA was without the harsh- correlative side effects of nystagmus, bruxism and ness 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 reports of ment for optimum human response, led to a fmner state- MDMA use has recently appeared, describing more than ment 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 in cation 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 ries were written by the authors of the original scientific insight-oriented psychotherapy to facilitate communica- studies and there are additional data included in these tion and intimacy between people involved in emotional reviews. relationships as well as in the treatment of alcohol and other drug abuse. It was emphasized that MDMA does not LEGAL HISTORY lend itself to overuse, because its most desirable effects The initial proposal for the scheduling of MDMA diminish 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 (Greer 1985b) with the overseeing ing of an abused drug, and there was the pro forma request of an equal number of psychiatrists or psychotherapists, made for comments, with none expected. Comments most of whom were experienced with both MDMA and were indeed made, however, and a second entry appeared LSD actions in humans. An extensive subjective analysis on December 31, 1984, noting that hearings were to be was 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 ofMDMA 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 law because 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 all subjects sometimes experience transient delusional states, information concerning illicit trafficking and medical the 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 into employed in MDMA therapy has been written and submit- Schedule I by the invocation of the emergency scheduling ted as a chapter in a forthcoming book (Tolbert & Greer, powers granted by the Comprehensive Crime Control Act In press). of 1984. The effective date for this scheduling was July 1, More quantitative values for these stimulant side 1985. This occurred in the middle of the hearings that effects 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- changes, 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 and diastolic pressure at the first hour followed by a gradual Drug Administration (Randolph 1984) for comments con- decrease to below baseline level by the sixth hour. At cerning 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. MDMA ered 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 neurological

Journal of Psychoactive Drugs 300 vor. 18(4) Oct-Dec, 1986 SHULGIN CHEMISTRY

recognizing the values of psychopharmacological agents POPULAR OPINIONS in any of several medical problem areas that are without An unusually large amount of commentary and opin- good current therapy. Doblin (1984), who personally ion has appeared in the popular press and in both profes- served as a principle information distribution center dur- sional as well as lay journals. Occasionally there may be ing the earliest days of the MDMA controversy, published some statements of fact, but usually there is much mis- the widely circulated book Murmers in the Heart of the 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 the sensationalism. There were sounds and shades of the LSD chilling effect of legal scheduling on medical research, notoriety of the 1960' s in that each reporter obtained some but were reminded in rebuttal (Holsten & Schieser 1985) facts, but also borrowed details from other writers. The that the exploratory use of new drugs outside of the results were an oft-repeated story, generally moderately controls that apply to the pharmaceutical industry carry accurate and somewhat favorable. An issue of Brain- real risks as to the safety and quality of the product. Mind Bulletin (April 15, 1985) was devoted to the con- Nichols (1985) submitted an essay to participants at the troversy, and a short critical review appeared in the DEA searings arguing that, according to the published PharmChemNewsletter (Seymour 1985). In addition, the literature, MDMA should not be considered either a hallu- 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 Articles or commentary also appeared in magazines recent history of MDMA and speculated on a number of and newspapers, such as Daily Californian (Marks 1986), areas of potential value. Grinspoon and Bakalar (1986a) High Times (Smith & Seymour 1986), New Age (Abram- presented an argument to the medical community support- son 1985), Newsweek (Adler 1985), Chemical and En- ing the need of drugs as adjuncts to psychotherapy, as well gineering News (Baum 1985), San Francisco Chronicle as having editorialized (Grinspoon & Bakalar 1986b) on (Butler 1985), Oakland Tribune (Dentinger 1985), Life the relationship between designer drugs and the law, using (Dowling 1985), San Francisco Examiner (Flinn 1985), MDMA as an illustration. The broader question touching 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 point 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 tracts 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- (Siegel 1985), Oklahoma Gazette (Siens 1985), Detroit tended to simply provide information (Greer 1985a; Greer News (Tessler 1985), Time (Toufexis 1985), Scientific & Strassman 1985; Grinspoon & Bakalar 1985). American (Unsigned 1985b), San Francisco Bay Guard- On the let's-discourage-drug-use-and-abuse side, 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's the comics page, in Doonesbury (Trudeau 1985), and the APA Monitor (Turkington 1986) quotes statements (see editorials on KCBS Radio (Barnett 1985). Two long below) ascribed to the authors of the rat serotonin studies. essays (Beck 1986; Ehrlich 1986) and a complete book Another example is a newsletter on drug abuse (Cohen (Seymour 1986) have appeared covering the subject. 1985) that equated all claims for MDMA to those that One of the first promotional hypes for MDMA gave LSD and other psychedelics such glowing press 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-attestrnent 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 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. information where much detail that applies to MDA is In addition, some organizations and federal agencies ascribed to MDMA. have produced tracts and flyers that are directed to the 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 Now but emphasize the clinical virtue and highlight the need of Foundation's MDA/MDM (Dye 1982), and NIDA's

Journal of Psychoactive Drugs 301 VoL 18(4) Oct-Dee, 1986

------SHULGIN CHEMISTRY

"MDMA" (NIDA 1985), a government bulletin warning above: "Repeated use of designer drugs such as Ecstasy of potential psychotic episodes (wherein most informa- produces potentially irreversible brain damage." And an tion has been taken from the MDA record). embarrassing elaboration of this misinformation was given in a newspaper interview, in which the following is CONCLUSION 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 system MDMA, 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 a From 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 be and aware of their own strength and loveliness, they are showing central nervous system degenerative signs that able to drop many of the usual barriers. Habitual users of ordinarily would not be seen until they get to be 70 or 80. " have no need to smoke. Chain smokers of mari- 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. And fingers alone. Compulsive talkers become quiet," and on from the NIDA bulletin: "MDMA-Ieads to psychotic and 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

REFERENCES

Abramson, D.M. 1985. The new drug underground. New Age October: (3 ,4-methylenedioxyamphetamine). Journal of Pharmaceutical Sci- 35. ences Vol. 69(2): 192-195. Adamson, S. 1985. Through the Gateway of the Heart. San Francisco: Braun, U.; Shulgin, A.T. & Braun, G. 1980b. Prufung auf zentrale Four Trees Publications. aktivitat und anlgesie von N-substituierten analogen des Adler, 1. 1985. Getting high on "Ecstasy." Newsweek April 15: 96. amphetarnin-derivates 3,4-methylenedioxyphenylisopropylarnin. Aldous, F.A.B.; Barrass, B.C.; Brewster, K.; Buxton, D.A.; Green, Arzneimiuel-Forschung Vol. 30(5): 825-830. D.M.; Pinder, R.M.; Rich, P.; Skeels, M. & Tull, K.J. 1974. Butler, K. 1985. Outlaw drug more popular. San Francisco Chronicle Structure-activity relationships in psychotomimetic phenylalkyla- August 26. mines. Journal of Medicinal Chemistry Vol. 17(10): 1100-1111. Buxton, D.A. 1972. Behavioral actions of some substituted ampheta- Anderson, G.M., III; Braun, G.; Braun, U.; Nichols, D.E. & Shulgin, mines. Progress in Brain Research Vol. 36: 171-181. A.T. 1978. Absolute configuration and psychotomimetic activity. Cohen, S. 1985. They call it Ecstasy. Drug Abuse and ALcoholism In: Barnett, G.; Trsic, M. & Willette, R. (Eds.). QUASAR: Quanti- Newsletter Vol. 14(6): 1-3. tative Structure Activity Relationships of Analgesics. Narcotic Davis, W.M. & Borne, R.F. 1984. Pharmacological investigation of Antagonists, and . NIDA Research Monograph 22. compounds related to 3,4-methylenedioxyarnphetamine (MDA). Rockville, Maryland: NIDA. Substance and Alcohol Actions/Misuse Vol. 5: 105-110. Associated Press. 1986. Researchers say "Ecstasy" is dangerous. Jan- Doblin, R. 1984. Murmurs in the Heart of the Beast: MDMA and the uary 16. DEA. HHS. NIDA, NIMH. ADAMHA, FBI and the WHO. Sarasota: Bailey, K.; By, A.W.; Legault, D. & Verner, D. 1975. Identification of Self-published. the N-methylated analogs of the hallucinogenic arnphetamines and Dentinger, J. 1985. "Ecstasy" worked so well it had to be made illegal. some isomers. Journal-Association of Official AnalyticaL Chemists Oakland Tribune July 31. Vol. 58( 1): 62-69. Dowling, C.G. 1985. The trouble with Ecstasy. Life August: 88. Barnett, R.M. 1985. DEA: RSVP re MDMA. Editorial, KCBS Radio. Downing, J. & Wolfson, P. 1985. Clinical study ofMDMA in normal July 29 & August 3. subjects. Unpublished findings. Baum, R.M. 1985. New variety of street drugs poses growing problem. Dye, C. 1982. MDA/MDM: The Chemical Pursuit of Ecstasy. Phoenix, Chemical and Engineering News September 9: 7. Arizona: Do It Now Foundation. Beck, J. 1986. The popularization and resultant implications of a recent- Ehrlich, B. 1986. Understanding Ecstasy: The MDM Story. Santa Cruz, ly controlled psychoactive substance. Contemporary Drug Prob- California: Self-published. lems Vol. 13(1): 23-63. Eichhorn, D.P. 1984. Ecstatic! XTC may be the sex drug of the '80s. If Biniecki, S. & Krajewski, E. 1960. Preparation of dL-I-(3,4- it's so good, why isn't it illegal? The Rockel December: 20. methylenedioxyphenyl)-2-(methylamino)propane and dL-(3,4- Fellows, E.J. & Bernheim, F. 1950. The effect of a number of aralkyl- dimethoxyphenyl)-2-(methylarnino)propane. Acta PoLoniae Phar- arnines on the oxidation of tyramine by amine oxidase. Journal of maceutica Vol. 17: 421425. PharmacoLogy and Experimental Therapeutics Vol. 100: 94-99. Braun, U.; Shulgin, A.T. & Braun, G. 1980a. Centrally active N- Flinn, J. 1985. "Ecstasy" causes agony for doctors, government. San substituted analogs of 3,4-methylenedioxyphenylisopropylarnine Francisco Examiner May 19.

Journal of Psychoactive Drugs 302 Vol. 18(4) Oct-Dec, 1986 SHULGIN CHEMISTRY

Foreman, J. 1985. Boston psychiatrists say drug aids therapy. Boston Other Drug Dependencies News Vol. 12: 14-15. Globe April 18. Hudson, G.E. 1985. The drug they call Ecstasy. Vanguard Press (Ver- Frith, C.H. 1986a. Report: 28-Day Oral Toxicity of Methylenedioxy- mont), June 16-23. methamphetamine Hydrochloride (MDMA) in Dogs. Protocol No. Jubera, D. 1985. Latest "designer" drug makes officials war, users EMD-SC-001. Little Rock, Arkansas: Toxicology Pathology Asso- heady; but everyone is calling it Ecstasy. Dallas Times Herald April ciates. 22: 10-11. Frith, C.H. 1986b. Report: 28-Day Oral Toxicity of Methylenedioxy- Kasuya, Y. 1958. Chemicopharmacological studies on antispasmodic methamphetamine Hydrochloride (MDMA) in Rats. Protocol No. action. XII. Structure-activity relationships of aralkylamine. Chem- EMD-SC-002. Little Rock, Arkansas: Toxicology Pathology Asso- ical and Pharmaceutical Bulletin Yol. 6: 147-154. ciates. Klein, J. 1985. The new drug they call "Ecstasy." New York Magazine Gaston, T.R. & Rasmussen, G.T. 1972. Identification of 3,4- May 20: 38-43. methylenedioxymethamphetamine. Microgram Vol. 5: 60-63. Lawn, J .C. 1985. Schedules of controlled substances; temporary place- Gehlert, D.R.; Schmidt, C.J.; Wu, L. & Lovenberg, W. 1985. Evidence ment of 3,4-methylenedioxymethamphetamine (MDMA) into for specific methylenedioxymethamphetamine (Ecstasy) binding Schedule l. Federal Register Yol. 50(105): 23118-23120. sites in the rat brain. European Journal of Pharmacology Vol. Leavy, J. 1985. Ecstasy: The lure and the peril. Washington Post June I. 119(1-2): 135-136. Levin. J.A.; Schmidt, C.J. & Lovenberg, W. 1986. Release of [3H] Glennon, R.A.; Rosencrans, J.A. & Young, R. 1983. Drug-induced monoamines from superfused rat striatal slices by methylenedioxy- discrimination: A description of the paradigm and a review of its metbamphetamine (MDMA). (Abstract 5265). Federation Proceed- specific application to the study of hallucinogenic agents. Medical ings Vol. 45(4): 1059. Research Reviews Vol. 3: 289-340. Lyon, R.A.; Glennon, R.A. & Titeler, M. 1986. 3,4- Glennon, R.A.; Young, R.; Rosencrans, J.A. & Anderson, G.M., III. Methylenedioxymethamphetamine (MDMA): Stereoselective in- 1982. Discriminative stimulus properties of MDA and related teractions at brain 5-HT I and 5HT 2 receptors. Psychopharmacology agents. Biological Psychiatry Vol. 17: 807-814. Vol. 88(4): 525. Glennon, R.A. & Young, R. 1984. Further investigation of the discrimi- Marks, R. 1986. Designer drug use on campus is on the rise. Daily native stimulus properties of MDA. Pharmacology, Biochemistry Californian Vol. 18(31): 1,8. and Behavior Vol. 20: 501-505. Merchant, K.; Letter, A.A.; Stone, D.M.; Gibb, J.W. & Hanson, G.R. Goad, P.T. 1985. Report: Acute and Subacute Oral Toxicity Study of 1986. Responses to brain neurotensin-like immunoreactivity to 3,4- Methylenedioxymethamphetamine in Rats. Protocol No. EMD-AT- methylenedioxymethamphetamine (MDMA) and 3,4- 001. Redfield, Arkansas: lntox Laboratory. methylenedioxyamphetamine (MDA). (Abstract 5268). Federation Gold, M. 1985. Ecstasy, etc. Alcoholism and Addiction September- Proceedings Vol. 45(4): 1060. October: II. Merck, E. 1920. Formyl derivatives of secondary bases. German patent Greer, G. 1985a. Recommended Protocol for MDMA Sessions. Albu- #334,555. querque, New Mexico: Self-published. Merck, E. 1914. Verfahren zur darstellung von alkyloxyaryl-, Greer, G. 1985b. Using MDMA in psychotherapy. Advances Vol. 2(2): dialyloxyaryl- und alkylenedioxyarylarninopropanen bzw. deren am 57. stickstoff monoalkylierten derivaten. German patent #274,350. Greer, G. 1983. MDMA: A new psychotropic compound and its effects Mullen, F.M. 1984a. Schedules of controlled substances proposed on humans. Unpublished manuscript. Santa Fe, New Mexico. placement of 3,4-methylenedioxymethamphetamine into Schedule Greer, G. & Strassman, R.J. 1985. Information on Ecstasy. American 1. Federal Register Vol. 49(146): 30210-30211. Journal of Psychiatry Vol. 142(11): 1391. Mullen, F.M. 1984b. Schedules of controlled substances proposed Griffiths, R.R.; Lamb, B. & Brady, J.V. 1985. A preliminary report on placement of 3,4-methylenedioxymethamphetamine into Schedule the reinforcing effects of racemic 3,4- I. Hearing. Federal Register Vol. 49(252): 50732-50733. methylenedioxymethamphetamine in the baboon. Submitted as a Nichols, D.E. 1985. MDMA represents a new type of pharmacologic preprint to the DEA for the MDMA Hearings, October. agent and cannot be considered to be either a hallucinogenic agent or Grinspoon, L. & Bakalar, J. 1986a. A potential psychotherapeutic drug? an amphetamine-type stimulant. Submitted as part of testimony to Psychiatric Times January: 4-5, 18. the DEA and WHO through the offices of Richard Cotton, lawyer for Grinspoon, L. & Bakalar, J. 1986b. An op-ed: Designer drugs and the the plaintiffs in the MDMA Hearings. law. Unpublished editorial, January 31. Nichols, D.E. & Glennon, R.A. 1984. Medicinal chemistry and Grinspoon, L. & Bakalar, J. 1985. What is MDMA? Harvard Medical structure-activity relationships of hallucinogens. In: Jacobs, B.L. School Mental Health Letter Vol. 2(2): 8. (Eds.). Hallucinogens: Neurochemical, Behavioral, and Clinical Gupta, R. C. & Lundberg, G. D. 1977. Application of gas chromatogra- Perspectives. New York: Raven Press. phy to street drug analysis. Clinical Toxicology Vol. 11(4): 437-442. Nichols, D.E.; Lloyd, D.H.; Hoffman, A.J.; Nichols, M.B. & Yim, Hagerty, C. 1985. "Designer Drug" Enforcement Act seeks to attack G .K. W. 1982. Effects of certain hallucinogenic amphetamine ana- problem at source. American Pharmacy Vol. NS25(10): 10. logues on the release of pH]serotonin from rat brain synaptosomes. Hardman, H.F.; Haavik, C.O. & Seevers, M.H. 1973. Relationship of Journal of Medicinal Chemistry Vol. 25: 530-535. the structure of mescaline and seven analogs to toxicity and behavior NIDA. 1985. MDMA. NlDA Capsules July. in five species of laboratory animals. Toxicology and Applied Phar- O'Brien, B.A.; Bonicamp, J.M. & Jones, D.W. 1982. Differentiation macology Vol. 25(2): 299-309. of amphetamine and its major hallucinogenic derivatives using thin- Harris, L.S. 1985. Preliminary report on the dependence liability and layer chromatography. Journal of Analytical Toxicology Vol. 6: abuse potential of methylenedioxymethamphetamine (MDMA). 143-147. Submitted as a preprint to the DEA for the MDMA Hearings. O'Rourke, P.J. 1985. Tune in. Turn on. Go to the office late on Holsten, D.W. & Schieser, D.W. 1985. Controls over the manufacture Monday. Rolling Stone December 19: 109, 176. of MDMA. California Society for the Treatment of Alcohol and Randolph, W.F. 1984. International drug scheduling: Convention on

Journal of Psychoactive Drugs 303 Yol. 18(4) Oct-Dee, 1986

.-f· SHULGIN CHEMISTRY

Psychotropic Substances: Stimulants and/or hallucinogenic drugs. Pharmacology of Hallucinogens. New York: Pergamon. Federal Register Vol. 49(140): 29273-29274. Siegel, R.K. 1985. Chemical ecstasies. Omni Vol. 7: 27. Ricaurte, G.; Bryan, G.; Strauss, L.; Seiden, L. & Schuster, C. 1985. Siens, K. 1985. Ecstasy. A flurry of abuse in OKC. Oklahoma Gazette Hallucinogenic amphetamine selectively destroys brain serotonin June 5. nerve terminals. Science Vol. 229: 986-988. Smith, D.E. & Seymour, R.B. 1986. Abuse folio: MDMA. High Times Riedlinger, J.E. 1985. The scheduling of MDMA: A pharmacist's May: 30. perspective. Journal of Psychoactive Drugs Vol. 17(3): 167-171. Smith, D.E.; Wesson, D.R. & Buffum, J. 1985. MDMA: "Ecstasy" as Roberts, T.B. 1986. The MDMA question. Associationfor Humanistic an adjunct to psychotherapy and a street drug of abuse. California Psychology Perspective May: 12. Society for the Treatment of Alcohol and Other Drug Dependencies Schlemmer, R.F.;Montrell, S.E. & Davis, J.M. 1986. MDMA-induced News Vol. 12(2): 1-3. behavioral changes in members of primate social colonies. (Abstract Stafford, P. 1983. Psychedelics Encyclopedia. Revised ed. Los 5263). Federation Proceedings Vol. 45(4): 1059. Angeles: J.P. Tarcher. Schmidt, C.J. & Lovenberg, W. 1986. (+ / -) Methylenedioxy- Steele, T.D. 1986. Stereoselective effects of 3,4- methamphetamine (MDMA): A potentially neurotoxic ampheta- methylenedioxymethamphetamine (MDMA) and related com- mine analogue. (Abstract 5264). Federation Proceedings Vol. pounds on inhibition of neurotransmitter uptake into synaptosomes 45(4): 1059. from different regions of rat brain. Master of Science thesis, Purdue Schmidt, c.r.. Wu, L. & Lovenberg, W. 1985. Methylenedioxy- University, April 28. methamphetamine (Ecstasy): A potential neurotoxic amphetamine Steele, T~.; Nichols, D.E. & Yim, G.K.W. 1986. Stereoselective analogue. Submitted as a preprint to the DEA for the MDMA effects of MDMA on inhibition of monoamine uptalce. (Abstract Hearings. 5262). Federation Proceedings Vol. 45(4): 1059. Schulman, R. 1985. The losing war against "designer drugs. "Business Stevens, J.K. 1985. MDMA and the psychedelic movement. Vanguard Week June 24: 101-104. Press (Vermont). Seiden, L. S. 1985. Report of preliminary results on MDMA. Submitted Stone, D.M.; Stahl, D.C.; Hanson, G.R. & Gibb, J.W. 1986. Effects of as a preprint to the DEA for the MDMA Hearings, October. 3,4-methylenedioxyamphetamine (MDA) and 3,4- Seymour, R.B. 1986. MDMA. San Francisco: Haight-Ashbury Publica- methylenedioxyrnethamphetamine (MDMA) on tyrosine hydroxy- tions. lase and tryptophane hydroxylase in the rat brain. (Abstract 5267). Seymour, R.B. 1985. MDMA: Another view of Ecstasy. PharmChem Federation Proceedings Vol. 45(4): 1060. Newsletter Vol. 14(3): I. Talceda, H.; Gazzara, R.A.; Howard, S.G. & Cho, A.K. 1986. Effects Shafer, J. 1985. MDMA: faces regulation. Psychology of methylenedioxymethamphetarnine (MDMA) on dopamine (DA) Today May: 68. and serotonin (5-HT) efflux in the rat neostriatum. (Abstract 5266). Shaw, M.A. & Peel, H.W. 1975. Thin-layer chromatography of 3,4- Federation Proceedings Vol. 45(4): 1059. methylenedioxyamphetamine, 3,4-methylenedioxymethamphet- Tessler, S.R. 1985. Paradise lost? Wonder drug in bad graces. Detroit amine and other phenethylamine derivatives. Journal of Chroma- News July I: I. tography Vol. 104: 201-204. Tolbert, R. & Greer, G. In press. The clinical use ofMDMA. In: Forte, Shulgin, A.T. 1986. Unpublished data. R. & Grof, S. (Eds.). Psychedelics and the New Paradigm. Shulgin, A.T. 1985. What is MDMA? PharmChem Newsletter Vol. Toufexis, A. 1985. A crackdown on Ecstasy. Time June 10: 64. 14(3): 3. Trudeau, G.B. 1985. Doonesbury. A two-week series (12 strips and Shulgin, A.T. 1983. Twenty years on an ever-changing quest. In: Sunday) satirizing MDMA. Universal Press Syndicate, August 12- Grinspoon, L. & Bakalar, J.B. (Eds.). Psychedelic Reflections. 24. New York: Human Sciences Press. Turkington, C. 1986. Brain damage found with designer drugs. APA Shulgin, A.T. 1982. Chemistry of psychotomimetics. In: Hoffmeister, Monitor March. F. & Stille, G. (Eds.). Psychotropic Agents. Part III. Alcohol and Unsigned. 1985a. Request for information. Microgram Vol. 18: 25. Psychotomimetics; Psychotropic Effects of Centrally Acting Drugs. Unsigned. 1985b. lllegal Ecstasy. Scientific American Vol. 253: 59. Berlin: Springer-Verlag. Unsigned. 1984a. DEA proposal to ban psychedelic protested. Subst- Shulgin, A.T. 1978. Psychotomimetic drugs: Structure-activity rela- ance Abuse Report Vol. 15(12): 4-5. tionships. In: Iversen, L.L.; Iversen, S.D. & Snyder, S.H. (Eds.). Unsigned. 1984b. Ecstasy: 21st Century Entheogen. Self-published. Handbook of Psychopharmacology. Vol. 11. Stimulants. New York: Unsigned. 198L Ecstasy: Everything looks wonderful when you're Plenum. young and on drugs. Wet September-October: 76. Shulgin, A.T. & Jacob, P., III 1982a. 1-(3,4-Methylenedioxyphenyl)- Weil, A.T. & Rosen, W. 1983. Chocolate to Morphine: Understanding 3-aminobutane: A potential toxicological problem. Journal of Tox- Mind-active Drugs. Boston: Houghton Mifflin. icology Vol. 19: 109-1I0. Wolfson, A. 1985. Making Ecstasy illegal. San Francisco Bay Guard- Shulgin, A.T. & Jacob, P., III 1982b. Potential misrepresentation of ian Vol. 19(33): 28. 3,4-methylenedioxyamphetamine (MDA). A toxicological warn- Woolverton, W.L.; Virus, R.M.; Kamien, J.B.; Nencini, P.; Johansen, ing. Journal of Analytical Toxicology Vol. 6: 71-75. C.E.; Seiden, L.S. & Schuster, C.R. 1985. Behavioral and neuro- Shulgin, A.T. & Nichols, D.E. 1978. Characterization of three new toxic effects of MDMA and MDA. Abstract from the American psychotomimetics. In: Stillman, R.C. & Willette, R.E. (Eds.). The College of Neuropsychopharmacology Meeting, Honolulu.

Journal of Psychoactive Drugs 304 Vol. 18(4) Oct-Dee, 1986