What Is MDMA? by Alexander T

• 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). A program for hearings work lie between 100mg and 150 mg of the amine as continued on page 10 the hydrochloride salt. A typical dose would be 120 mg. The onset of transition occurs between 25 and 30 minutes following oral administration. The changes MDMA Analyzed stabilize at or just before the one-hour point and the A sample of alleged MDMArecently obtained plateau of effects persists for about 40 additional from a recreational user attending the Drug En- minutes. Ifdesired, the plateau can be extended for an forcement Administration hearings in Los additional hour with the use of a supplementary 40- Angeles was analyzed by PharmChem's Research 50 mg at the 1:30point of the session. Recovery to the and Development Laboratory. The tablet, weigh- ing 398 mg., was alleged to contain 125mg of presession baseline psychologically generally re- MDMA.Qualitatively and quantitatively analyzed quires an additional three hours. The complete dis- by gas chromatography, the sample contained pelling of physical residue (anorexia, for example) MDMAwithout adulteration plus inert material may take additional hours. as filler and binding agents. Quantitative results: Can MDMAbe abused? 26.3% MDMAHydrochloride (105 mg) 22.1% MDMAFree Base (88 mg) Certainly. When it is used therapeutically, the medical environment precludes much of the abuse poten- While the sample contained less MDMAby tial, but with indiscriminate availability on the "street" :se~~to~l~np~;~~~:~~~:e tf~~:!~~~~~ined MDMA it can, and will, be overused and will inevitably be as- This compares with a 50 percent validity rate sociated with abuse situations. for alleged MDMA samples submitted to A related question (of a more legal kind) is, does PharmChem's Analysis Anonymous service for MDMAhave a high abuse potential. This is, of course, qualitative analysis between 1978and 1 .Sixty the crux of the proposed scheduling of MDMAas a samples were submitted as MD cstasy, high-abuse-potential drug without medical utility. XTC, or Adam during the five year penod, ex- The FDAhas explicitly stated that the use of any drug cluding 1979 because of incomplete data. not approved by them constitutes drug abuse. Their There is no way of knowing if clie implicit stand is that any drug that can be pleasurable ting samples under street names or "ADAM"actually understoo has a high abuse potential. The questions posed here supposed to be. These street n lie outside of the pharmacologist's territory. come popular synonyms for MD recent widespread icity a Half of the aUeg How would you classify PharmChem cont MDMAclinically? 27 percent, were There is no existing clinical classification for MDMA. other drugs The research currently exploring the use of MDMAin sa es (2 psychotherapy more closely resembles a medical M , sample cou e identi procedure such as hypnosis or acupuncture. There is Six alleged MDMAs no therapeutics classification for this drug although MDE [2-Ethylamino- efforts have been made to define one (14). The existing propane], which some classification of "anti-depressant" could be justified, I substitute f remembering that the effects are relatively abrupt following a single application, rather than being gradual following chronic medication. 5 What is MDMA? saline, MDMAdid not look like DOM(19). However, in rats trained to distinguish MDAfrom saline, or dex- continued from page 5 troamphetamine from saline, MDMAin both cases was distinguished from saline (20). across the country was agreed upon, and arguments and rebuttals were filed. This judicial process was aborted by an evocation of the Emergency Act (S- Can MDMAcause brain damage? 5656) on May 31,1985 (17), which proclaimed MDMA The answer is not known. No one has reported any as being an "imminent hazard to public safety" thus study that addresses this question. One of the major demanding that it be immediately scheduled as a Schedule Idrug, such action to be effective in 30 days. arguments prsented supporting the emergency sched- As of the moment, it must be assumed that MDMAwill uling of MDMAas an imminent hazard (17) was an be illegal on July 1, 1985.Apparently, the public hear- unpublished study (by Ricaurte et al., ref. 21) on MDA ings will still be held, and judicial recommendations in rats. Here the exposure of rats, acutely, to MDAled will be made as a result of those hearings. to the observation of degeneration of nerve terminals (possibly serotoninergic) in the hippocampus and the striatum. No dopaminergic problems were observed What will be the eventual although these were reported earlier (22) for amphetamine and methamphetamine. From these obser- fate of MDMA? vations,it has been extrapolated that MDMA (a This is conjecture into untested legal area. The different drug than MDAor amphetamine) is likely to emergency scheduling will place MDMAinto Schedule cause brain damage in man (a different species than rat). I for a full year, with an allowed six-month extension. Many states automatically parrot the federal drug Are there other drugs with laws in the rewriting of their own statutes, and it must actions similar to MDMA? be assumed that several states will amend their nar- cotics laws to include MDMAas a Schedule Idrug. Ac- None are known at the present time. Several drugs tion in this direction has already been initiated in are being studied that have some properties in com- Texas. Although hearings must be allowed at the end mon, but often there is either the absence of the be- of a year (federal law), the current hearings will have nign "freedom from fear" property, or the presence of been concluded by then and some decision will have some disturbing "psychedelic" side-effects. As of the been made regarding a more modest scheduling. moment, MDMAremains unique. However, there are no legal precedents at hand that permit the reevaluation of state law to reflect recon- What are the side effects of MDMA? siderations of federal assignment. It must be assumed that MDMAwill remain a Schedule I drug in many A number of side-effects have been reported with states regardless of any modification of federal stand. some regularity as a corollary to MDMAusage. In an extensive clinical study involving some score subjects (23) there was a consistent pressor response re- How does MDMAact? sulting in a blood pressure increase of some 15 or so mmlHg observed at the onset of action, although this The current consensus is that MDMAacts through disappeared shortly thereafter. There were some some effect on the serotoninergic nervous system. A complaints of bruxism (teeth clenching) and nystag- number of animal models have been studied to both mus (eye twitching). Some subjects reported a explain its mechanism of action, and to compare it to lethargy and headache the following day. These were structurally related analogs. A major focus in all of held by most subjects as being minor problems. these studies has been the fact that the optically active isomer of all the psychedelic drugs (LSD, MDA, DOM,DOET,and DOB)is the "R"(or levo) isomer, and How can one tell if one has valid MDMA? the optically active isomer of MDMA(and several The record of analytical sophistication relating to stimulants such as amphetamine) is the "S" (or dex- the verification of a sample as being MDMAhas not tro) isomer (5). This isomeric difference between been good. Tools such as gas chromatography (GC) or MDMAand MDAhas been shown to be true in the re- gas chromatography/mass spectrometry (GCMS),and lease of serotonin from rat-brain synaptosomes (18). infra-red are excellent, but they have been rarely In rat discrimination studies (train a rat to respond employed. The earliest report of analysis of seized differently to drug A or no drug, and then challenge material (24) showed color tests and U'V. to be in- with drug B). In rats trained to distinguish DOMfrom adequate, but reported that infra-red spectroscopy 10 and GCretention times to be satisfactory for identifi- nomenclature (MDMAvs. MMDA,ref 25) and as to pre- cation. TLCproperties suggest that MDAcan be effec- cursor identification (piperonylacetone vs. piperonyl- tively distinguished from MDMA(6). Some mis-iden- methyl ketone, ref 26). tifications have been reported, both as to compound

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