• What is MDMA? By Alexander T. Shulgin (Dr. Alexander Shulgin is a chemist and phar- to be on many occasions the same as the MDMAas macologist who has been active in research in described above. There have been some misrepre- the area of psychotropic drugs for many years. sentations. This paper is to bepresented at the summer meet- ing of the California Association of Toxicologists Is MDMArelated to MDA? in Sacramento, California, August 3, 1985.) Yes, it is very closely related to MDA.MDAis the MDMAhas been thrust upon the public awareness abbreviation for 3,4-methylenedioxyamphetamine, as a largely unknown drug which to some is a medical currently listed as a Schedule I drug, under the class- miracle and to others a social devil. Many Questions ification of "hallucinogenic substances." But this is a have been asked. It is sad that most of these Questions structural relationship, not a pharmacological re- have received answers which have been Quite con- lationship. A structural relationship invokes slight tradictory, and often untrue. I have had innumerable rearrangements of atomic features. calls from reporters and magazine staff writers, most MDMAis related to MDA(a hallucinogen) by being of whom have bemoaned the fact that they always its N-methyl analog. It is similarly related to N-methyl- 3,4-methylenedioxy-phenethylamine (an antitussive) seem to encounter one of two extreme positions. There have been the born-again protagonists who say that by being its alpha-methyl homolog. It is similarly re- once you have tried it you will see the light and will de- lated to methamphetamine (a stimulant) by being its fend it against any attack, and there have been the 3,4-methylenedioxy-analog. However, pharmacologi- staunch antagonists who say that this is nothing but cally, it bears little resemblance to any of these drugs. LSD revisted and it will certainly destroy our youth. There are many voices to be heard presenting the Is MDMAa psychedelic drug? modest inventory of facts that are known, but there is Not in the sense of the popular definition of no one who will answer Questions in a way that can be psychedelic drugs where one makes immediate as- heard by both camps. Let me distill several reporter sociation with drugs such as mescaline or LSD.There interactions into a hypothetical interview which is neither the visual distortion nor the interpretive parallels the many telephone inquiries I have had to problems that have been reported with most psyche- field in the last few months. The Questions are typical. delic drugs. Some Questions call for opinions, but many have fac- tual answers which are documented. How is MDMAmade? What is MDMA? There are published procedures for its production. The earliest literature describes the use of safrole as MDMAis the abbreviation given to a chemical with an intermediate (1,2). More recently published proce- the full name 3,4-methylenedioxymethamphetamine. dures have employed piperonylacetone as a starting It has also been called in recent literature N-methyl-2- material (3,4). The optical isomers have been pre- (3,4-methylenedioxyphenyl)-isopropylamine and 2- pared by the reduction of the amides prepared by methylamino-l-(3,4-methylenedioxyphenyl)-propane. formulation of the enantiomers of MDA(5). In one In Beilstein it is called methyl-[beta-(3,4-methylene- analytical report, MDMAwas prepared (with byproduct dioxyphenyl)-isopropyl]-amine; in the early Chemical impurities) from MDAby reaction with methyl iodide (6). Abstracts it is called N,alpha-dimethyl-homopiper- onylamine, in the pre-!972 Chemical Abstracts it is known as N,alpha-dimethyl-3,4-methylenedioxyphen- Where can one get MDMA? ethylamine; and in the most recent Chemical Abstracts, It appears to be readily available on the street. But it is N.alpha-dimethyl-I ,3-benzodioxole-5-ethaneamine. most of the psychiatrists who have reported on its Although it has many names, to a chemist there is a clinical utility have prepared it themselves, a proce- single chemical structure represented. dure which in many states meets the legal require- ments for drug manufacture. MDMAhas recently been What is Ecstasy (or MDM, or Adam, offered to researchers by NIDA(National Institute on or XTC, or E, or Doctor)? Drug Abuse), Rockville, MD. These are names of street drugs, which have proven continued on next page 3 What is MDMA? Is it true that the effective level continued from previous page is close to the toxic level? Is MDMAtoxic? As the toxic level in man is not known, this close- ness cannot be determined. The term "therapeutic There are two interpretations of the word "toxic." In index" has been used as a measure of comparative the strict medical sense, toxic means "Is the drug safety; i.e., how far apart are the effective levels and poisonous; i.e., is it lethal?" In the popular language, the lethal levels? The toxicity in mammals following toxic means "Does the drug have poisonous effects; parenteral administration lies between 14and 100mg/ i.e., are there unwanted side-effects." Kg.Oral toxicity has never been reported. The orally In answer to the first meaning, yes, MDMAis toxic, effective dosage in man is about 1.5 mglKg so the ef- as is every chemical known if sufficiently high levels fective safety factor is greater than ten-fold. are administered. In an extensive toxicity study (7) the lethality of MDMAwas compared with seven other related phenethylamines (including MDAand mescal- What does MDMAdo in animals? ine) in fiveanimal species. The comparative toxicity is given below for these three compounds, as their LD- There have been two in vivo studies ofMDMAin ani- 50 values in mg/Kg: mals. The earlier of these was the toxicology study by Hardman et al. (7) wherein several behavioral studies MDMA MDA Mescaline were reported in several animal species. Comparisons Mouse 97 68 212 of MDMA with seven other structurally related Rat 49 27 132 phenethylamines, in the areas of motor activity, auto- Guinea Pig 98 28 328 nomic activity, and CNSactivity, showed that it was, in Dog 14 7 54 general, similar to the other related compounds. Behavioral effects were observed at levels that ap- Monkey 22 130 6 proached the toxic levels. No particular effect de- served special mention in the discussion section of The toxicity thus lies as less than that for MDA,and this paper. more than that for mescaline. The latter study (10) has reported both stimulant A second study of toxicity in isolated and aggre- and analgesic effects of MDMA,in comparison to MDA gated mice (8) has reported the LD-50(i.p.) to be 106 and several higher homologs and analogs. It proved to mglKg(and 30 mgIKgin aggregated colonies). The LD- be among the most potent of all compounds studied. 50s for MDAwere given (again in mice, i.p.) as 90 mg! No extrapolation to human psychotropic response Kg and 45 mgIKg(aggregate). These values are good was made. agreement with the reference (7) data above. Atypical human dosage of MDMA(120 mg) is about 1.5mg/Kg. As to the second meaning of toxicity (toxic side- effects) there are some side-effects that have been fre- What does MDMAdo in man? quently reported. See the "side-effects" question below. It provides, at least within a therapeutic setting, a brief period of openness and freedom from fear and defensiveness that allows a trust to be established Have there been deaths ascribed to between a therapist and a patient. There is no amnesia and no loss of control. An excellent summing-up can the use of MDMA? be found in a quote from a recent report by an admit- Yes. There have been three deaths ascribed to the ted proponent (11). use of MDMA,but the role that MDMAmight have "The drug takes away all your neuroses. It takes played, or whether MDMAwas even involved, is un- away the fear response. There is an overwhelming certain. Two DAWNreports imply association, one in feeling of peace; you're at peace with the world. You San Francisco, and one in Seattle. The San Francisco feel open, clear, loving. I can't imagine anyone being report was mis-entered in the DAWNnetwork, and has angry under its influence, or feeling selfish or mean, or been verified as a death involving MDAand alcohol (9). even defensive. Youhave a lot of insights into yourself, The Seattle report contained evidence that the mate- real insights; that stay with you after the experience is rial present was similar to, but not the same as, MDA.It over. It doesn't give you anything that isn't already was assumed to be MDMA,but not verified as such. I there. It's not a trip. You don't lose touch with the have not been able to get any information on the third world. You could pick up the phone, call your mother, alleged death. and she'd never know." 4 -----_._" ----.---~ .--"--"------------ Two clinical studies have been reported that em- Is MDMAillegal? phasize the qualitative aspects of MDMAtherapy. A At the moment, no. (Editor's Note: Dr. Shulgin pilot study by Kueny on nine subjects (12) and prepared this article before the DEA's emergency another by Greer on 29 subjects (13) have both shown scheduling became effective. As of July 1, MDMA therapeutic value. is a Schedule I drug and its possession is poten- tiallya felony.) It was proposed for scheduling in the Controlled Substances Act by notice in the Federal What is the chronology of Register in 1984(15). However, there were several pe- titions filed requesting hearings to determine the ap- effects of MDMAin man? propriate schedule for listing, and this process was The usual dosages of MDMAemployed in clinical agreed to by the DEA(16).