AN ANNOTATED BIBLIOGRAPHY OF THE SCIENTIFIC LITERATURE REFERRING TO MDMA (including a sampling of the popular literature) ALEXANDER T. SHULGIN 1483 SHULGIN ROAD LAFAYETTE.CA 94549 JULy 1.1988 2 MDMA BIBLIOGRAPHY TABLE OF CONfENTS (1) Chemistry 3 (2) In Vitro Studies 5 (3) BiochemiStry 7 (4) Phannacology (behavior and drug discrimination studies) 9 (5) Neurochemistry 15 (6) Toxicology 23 (7) Clinical Studies 27 (8) Analysis 31 (9) Reviews and Commentaries (including books and magazine articles) 35 (10) Legal History 47 SECTION 1: CHEMISTRY 3 (1) CHEMISTRY Anon: Verlahren rur Darstellung von Alkyloxyaryl-. Dialkyloxyaryl- und Alkylendioxyarylamino­ propanen bzw. deren am SHckstoif monoalkylierten Derivaten. German Patent. 274.350; Filed December 24. 1912. issued May 16. 1914. Assigned to E. Merck in Dannstadt. A chemical process is described for the conversion of several allyl- and propenyl­ aromatic compounds to the corresponding beta- or alpha-bromopropanes. These. in tum. react with ammonia or primary arn1nes to produce the corresponding prtmary or secondary propylamines. Specifically. safrole was reacted with aqueous HBr. and the impure reaction product reacted with alcoholic methylamine to produce MDMA in an unstated yield. Also described and characterized are MDA and DMA. as well as the corresponding 1-phenyl-1­ aminopropanes. No pharmacology. Anon: Fonnyl Derivatives of Secondary Bases. German Patent 334.555. assigned to E. Merck 1920. CA: 17: 1804a. A chemical conversion ofMDMA to its fonnyl derivative. and the properties of the latter. are described. Biniecki. S. and Krajewski. E. Preparation of DL-l-(3,4-Methylenedioxy)-2-(methylamino)propane and DL-1-(3.4-dimethoxyphenyl)- 2-(methylamino)propane. Acta Polon. Pharm. 11 pp. 421-425 (1960). CA: (1961) 14350e. A chemical procedure is given for the conversion of safrole to the beta-bromopropane with HEr. and its subsequent conversion with alcoholic methylamine to MDMA. 4-Allylvera­ trole was similarly converted to 3.4-dimethoxy- methamphetamine. Braun. U .. Shulgin. AT. and Braun. G., Centrally Active N- Substituted Analogs of 3.4-Methylene­ dioxyphenyl1sopropylamine (3.4-Methylenedioxyamphetaminel. J. Phann. Sci.. ~ pp 192-195 (1980). Twenty two homologs and analogs of MDA were synthesized and their physical properties presented. Twelve ofthem were assayed in man as psychotomimetic agents. Three of them were found to be active: MDMA with a human potency of between 100 and 160 rug orally; MDE somewhat less potent at a dosage requirement of 140-200 mg orally; and MDOH. which was similar to MDMA in potency. Some animal phannacology is reviewed. and a comparison between MDMA and MDA (toxicology. CNS pharmacology. and human effective­ ness) Is tabulated. FUjisawa. T. and Deguchi. Y. (Concerning the Commercial Utilization ofSafrole). J. Pharm. Soc. Japan 74 975 (1954). CA: ~: 109581. The conversion of safrole to piperonylacetone 15 described, using fonnic acid and hydrogen peroxide. in acetone. The yield is satisfactory. and this is probably the most direct and efikient conversion of a natural product to an immediate precursor to MDMA Janesko, J .L. and Dal Cason. T.A. Seizure of a Clandestine Laboratory: The N-Alkyl MDA Analogs Paper presented at the 39thAImual Meeting of the AmertcanAcademy ofForensic Sciences. San Diego. 4 MDMA BIBLIOGRAPHY CA Feb. 16-21 (1987). See Microgram, 2.Q 52 (1987). Several clandestine laboratortes have been seized. revealing the illicit preparation ofnot only MDMA. but the N-ethyl (MDEJ. the N-propyl (MDPR). the N-isopropyl (MDIP) and the N}'J­ dimethyl (MDDM) homologues. These were all synthesized by the NaCNBH3 reduction method from the appropriate amine salt and piperonylacetone. Also. the N- ethyl-N-methyl, and the N.N-diethyl homologs were found. prepared by catalytic hydrogenation. i'.'ichols. D.E., SyntheSiS of3,4-Methylenedioxymetharnphetamine Hydrochloride. FDA Master File on MDMA 1986. A detailed synthesis of MDMA from piperonylacetone is presented. including all the spectroscopic and physical detail, bibliographies, CVs. and such that define the final product for medical needs. Shulgin. A.T. and Jacob III. P., Potential Misrepresentation of 3,4-Methylenedioxyarnphetamine (MDA). A Toxicological Warning. J. Anal. Tox., 2. pp 71-75 (1982). The commercial availability and overt misrepresentation of3,4-methylenedioxybenzyl­ acetone as 3,4-methylenedioxyphenylacetone might well suggest that an unsuspecting attempt to synthesize MDMA may yield a new and unexplored base. 1-(3,4-methylenedioxy­ phenyl)-3-(methylamino)butane. This compound was synthesized. and characterized in compartson to MDMA. The analogous relationship between MDA and its comparable homolog. 1-(3,4-methylenedioxyphenyI1-3- aminobutane. was also explored. SECTION 2: ~N VI1RO STUDIES 5 (2) IN VI1RO STUDIES Brady. J.F.. Di Stephano. E.W. and Cho. AK.. Spectral and Inhibitory Interactions of (+/-)-3.4­ Methylenedioxyamphetamine (MDA) and (+/-)-3.4-Methylenedioxymethamphetam1ne (MDMA) with Rat Hepatic Microsomes. Life Sciences lli! 1457-1464. Both MDA and MDMA were shown to form complexes with cytochrome P-450 that were inhibitory to its function as to demethylation ofbenzphetam1ne and carbon monoxide bindmg. Liver microsome studies showed the metabolic demethylation ofMDMA and the N-hydroxyla­ tion ofMDA Frye. G. and Matthews. R Effect of 3.4-methylenedioxymethamphetam1ne (MDMA) on Contractive Responses in the G. Pig Ileum. The Pharmacologist 2E 149 (#318) (1986). Using the longitudinal muscle of the guinea pig ilium. MDMA evoked dose-related. transient contractions. but failed to reduce contractions produced by serotonin. acetylcholine. or GABA. The MDMA contractions were blocked by atropine. and do not appear to involve serotonin receptors. Gehlert. D.R. Schmidt. C.J.. Wu. L. and Levenberg. W .. Evidence for Specific Methylenedioxymetham­ phetamine (Ecstasy) Binding Sites in the Rat Brain. Europ. J. Pharmacol.lli 135-136 (1985). Evidence is presented from binding to rat brain homogenate studIes. The use of the serotoninerglc re-uptake inhibitor. active in vivo. does not antagonize this binding. nor in studies with uptake into striatal microsomes. Levin. JA.. Schmidt, C.J. and Levenberg. W. Release of [3H)_ Monoamines from Superfused Rat Striatal Slices by Methylenedioxymethamphetam1ne (MDMA). Fed. Proc. ~ 1059 (#5265) April 13­ 18. 1986. The release oftritiated serotonin and dopamine from superfused rat striatal slices was observed for three amphetamine derivatives. MDMA and p-chloroamphetam1ne were equiva­ lent. and about lOx the potency ofmethamphetam1ne. ThIs last compound was. however. some lOx more effective than MDMA in the relase of dopamine. Lyon. RA.. Glennon. RA. and TIteler, M. 3.4-Methylenedioxymethamphetam1ne (MDMA): Stereo­ selective Interactions at Brain 5- HT) and 5-HT2Receptors. Psychopharmacology.a8 525-526 (1986). Both MDMA and MDA, and their respective opUcalisomers, were assayed as to their affinity at radio-labelled serotonin (5-HT) and 5-HT2) and dopamine (D 2) binding sites. The "R" isomers of both drugs showed a moderate affinity at the 5-HT:z receptor (labelled with 3H ketansertn). and the MS" isomers were lower. Affinities for the 5-HT) site were similar. but that for D2 sites were very low. Since the MS" isomer ofMDMA is the more potent in man. it may not work primarily through a direct interaction at 5-HT receptors. Nichols, D.E., Lloyd. D.H., Hoffman, AJ.• Nichols. M.B. and Yim. G.K.W. Effects of Certain Hallucinogenic Amphetamine Analogues on the Release of PHI Serotonin from Rat Brain Synapto­ somes. J. Med. Chern. ~. pp 530-535 (1982). 6 MDMA BIBLIOGRAPHY The optically active isomers of MDMA (as well as those for MDA. PMA) and the corresponding phenterm1ne analogs, have been evaluated as to their effect on the release of serotonin from rat brain synaptosomes. The (+) isomer of MDMA was the more effective (this is the acUve isomer in humans) suggesting that serotonin release may play some role in the psychopharmacological activity. The alpha-alpha dimethyl homologues were inactive even at the highest concentrations studied. Steele, T.P., Nichols, D.E. and Yim, G.K.W. StereoselecUve Effects of MDMA on Inhibition of Mono­ amine Uptake. Fed. Proc. ~ 1059 (# 5262) April 13-18 1986. In the investigation ofthe opUcalisomeric difference ofactivities seen for amphetamtne, MDMA. and DOM (the more potent isomers being the WS", WS" and WR" resp.) their abilities to inhibit the uptake ofradio-labelled monoamines into synaptosomeswere studied, The findings are discussed, and it is concluded that MDMA exhibits stereoselecUve effects similar to those of amphetamine on monoamine uptake inhibition, a parameter that is unrelated to the mechanism of action of the hallucinogen DOM. Steele, T.D., Nichols, D.E. and Yim. G.K.W. Stereochemical Effects of 3,4-Methylenedioxymetham­ phetamtne (MDMA) and Related Amphetamine Derivatives on Inhibition ofUptake of [3H]Monoamtnes into Synaptosomes from Different Regions of Rat Brain. Biochem. Pharmacol. aG 2297-2303 (1987). MDA. MDMA. and the alpha-ethyl homolog MEDE were found to inhibit serotonin uptake in brain synaptosomes. The conclUSiOns to a broad series of studies were that MDMA and its homologs are more closely related to amphetamine than to DOM in their biochemical actions. Wang, 5.5., Ricaurte, GA. and Peroutka, S.J.. [3Hl 3,4 Methylenedioxymethamphetamtne (MDMA) Interactions with Brain Membranes and Glass Fiber Filter Paper, Europ. J. Pharmacol. .!.J.8 439-443 (1987). Tritiated MDrvIA appears to give a pharmacological