E is for Ecstasy by Nicholas Saunders

Appendix 4: Bibliography

1970

Sreenivasan, V.R. Problems in Identification of Methylenedioxy and Methoxy Amphetamines. J. Crim. Law 63 304-312 (1972).

In a study of the spectral properties of several substituted amphetamine analogs, the properties of an unknown sample seized from an apparent drug abuser were recorded. The evidence indicated that this material was MDMA. As this report was initially presented to a group of crime laboratory chemists in August, 1970, this is probably the earliest documentation of illicit usage of MDMA.

1972

Gaston, T.R. and Rasmussen, G.T. Identification of 3,4-Methylenedioxymethamphetamine. Microgram 5 60-63 (1972).

Several exhibits were encountered in the Chicago area, which were identified as MDMA as the hydrochloride salt. Chromatographic and spectrographic properties are presented.

1982

Anonymous. Request for Information, Microgram 15 126 (1982).

The Drug Control Section of the DEA (Drug Enforcement Administration) has solicited information concerning the abuse potential of both MDMA and MDE. The request covered the abuse potential, the illicit trafficking and the clandestine syntheses, since 1977.

1984

Randolph, W.F. International Drug Scheduling; Convention on Psychotropic Substances; Stimulant and/or Hallucinogenic Drugs. Federal Register 49 29273-29274 (1984).

A request has been made from the Food and Drug Administration for information and comments concerning the abuse potential, actual abuse, medical usefulness and trafficking of 28 stimulants and/or hallucinogenic drugs, including MDMA. International restrictions are being considered by World Health Organization.

Mullen, F.M. Schedules of Controlled Substances Proposed Placement of 3,4-Methylenedioxymethamphetamine into Schedule I. Federal Register 49 30210-30211 (1984).

A request has been made for comments, objections, or requests for hearings concerning the proposal by the Drug Enforcement Administration (DEA) for the placement of MDMA into Schedule I of the Controlled Substances Act.

Cotton, R. Letter from Dewey, Ballantine, Bushby, Palmer & Wood, 1775 Pennsylvania Avenue, N.W., Washington, D.C. 20006 to F. M. Mullen, Jr., DEA. September 12, 1984.

This is a formal request for a hearing concerning the listing of MDMA as a Schedule I drug. The retaining parties are Professor Thomas B. Roberts, Ph.D., George Greer, M.D., Professor Lester Grinspoon, M.D. and Professor James Bakalar.

Mullen, F.M. Schedules of Controlled Substances. Proposed Placement of 3,4-Methylenedioxymethamphetamine into Schedule I. Hearings. Federal Register 49 50732-50733 (1984).

This is a notice of an initial hearing in the matter of the placement of MDMA into Schedule I of the Controlled Substances Act. This is to be held on February 1, 1985 and is intended to identify parties, issues and positions, and to determine procedures and set dates and locations for further proceedings.

1985

Young, F.L. Memorandum and Order. Docket No. 84-48. February 8, 1985.

A formal Memorandum and Order is addressed to the Drug Enforcement Administration, laying out the ground rules for the hearings to be held in the matter of the scheduling of MDMA.

Anon : Request for Information, Microgram 18 25 (1985).

A brief review is presented of the requests for hearings regarding the scheduling of MDMA. A request is made for any information that might be found concerning illicit trafficking, clandestine synthesis, and medical emergencies or deaths associated with the use of MDMA. All such information is to be sent to the Drug Control Section of the DEA.

Young, F.L. Opinion and Recommended Decision on Preliminary Issue. Docket No. 84-48. June 1, 1985.

The question of where to schedule a drug such as MDMA is considered. The Schedules have only one place for drugs without currently accepted medical use, Schedule I. But a second requirement that must be met is that the drug have a high abuse potential. There is no place for a drug without currently accepted medical use and less-than-high abuse potential.

The first opinion is that such a drug cannot be placed in any schedule. And if that is not acceptable to the administrator, then into Schedule III, IV or V, depending upon the magnitude of the less-than-high abuse potential.

Lawn, J.C. Schedules of Controlled Substances; Temporary Placement of 3,4-Methylenedioxymethamphetamine (MDMA) into Schedule I. Federal Register 50 23118-23120 (1985).

The DEA invoked the Emergency Scheduling Act powers, to place MDMA into Schedule I on a temporary basis, effective July 1, 1985. This move is valid for a year, and can be extended for six months. This occurred just before the first hearing was to take place, to determine the appropriate schedule for MDMA.

[The chronology of the hearings was as follows:]

June 10, 1985: Los Angeles, California
July 10,11, 1985: Kansas City, Missouri
October 8,9,10,11, Nov. 1, 1985: Washington, DC.
February 14, 1986: (submitting briefs, findings, conclusions, and oral arguments) Washington, DC.

1986

Anon: Verordnung des BAG uber die Bet=E4ubungsmittel und andere Stoffe und Pr=E4parate. March 17, 1986.

Effective April 22, 1986, MDMA has been entered into the Controlled Law structure of the Narcotics Laws of Switzerland.

Young, F.L. Opinion and Recommended Ruling, Findings of Fact, Conclusions of Law and Decision of Administrative Law Judge. Docket 84-48. May 22, 1986.

This 70 page decision was handed down as a product of the three hearings held as outlined above. A careful analysis is given of the phrase "currently accepted medical use" and of the phrase "accepted safety for use." The final recommendation was that MDMA be placed in Schedule III.

Stone, S.E. and Johnson, C.A. Government's Exceptions to the Opinion and Recommended Ruling, Findings of Fact, Conclusions of Law and Decision of the Administrative Law Judge. Docket No. 84- 48. June 13, 1986.

The attorneys for the DEA reply to the decision of Judge Young with a 37 page document, including statements that he had given little if any weight to the testimony and document proffered by the DEA, and had systematically disregarded the evidence and arguments presented by the government. Their statement was a rejection of the suggestion of the Administrative Law judge, in that they maintained that MDMA is properly placed in Schedule I of the CSA because it has no currently accepted medical use, it lacks accepted safety for use under medical supervision, and it has a high potential for abuse.

Lawn, J.C. Schedules of Controlled Substances; Extension of Temporary Control of 3,4-Methylenedioxymethamphetamine (MDMA) in Schedule I. Federal Register 51 21911- 21912 (1986).

The provision that allows MDMA to be placed in Schedule I on an emergency basis (due to expire on July 1, 1986) has been extended for a period of 6 months or until some final action is taken, whichever comes first. The effective date is July 1, 1986.

Anon: Zweite Verordnung zur =C4nderung bet=E4ubungsmittelrechticher Vorschriften. July 23, 1986.

Effective July 28, 1986, MDMA was added to the equivalent of Schedule I status, in the German Drug Law. This was in the same act that added cathenone, DMA, and DOET.

Lawn, J.C. Order. Docket 84-48 August 11, 1986.

In reply to a motion by the respondents (Grinspoon, Greer et al. to strike portions of the DEA exceptions that might allege bias on the part of the Administrative Law Judge, and to request an opportunity for oral presentation to the Administrator. The bias was apologized for, and struck. The opportunity for oral presentation was not allowed.

Kane, J. Memorandum and Opinion. Case No. 86-CR-153. In the United States District Court for the District of Colorado. Pees and McNeill, Defendants. October 1, 1986.

The is an early decision dismissing a prosecution charge for unlawful acts involving MDMA, on the basis that MDMA had been placed into Schedule I using the Emergency Scheduling Act, and the authority to invoke this Act was invested in the Attorney General, and the Attorney General had never subdelegated that authority to the DEA. This transfer had not occurred at the time of the charges being brought against the defendants, and the charges were dismissed.

Lawn, J.C. Schedules of Controlled Substances; Scheduling of 3,4-Methylenedioxymethamphetamine (MDMA) into Schedule I of the Controlled Substances Act. Federal Register 51 36552-36560 (1986).

A complete review of the scheduling process history of MDMA, including the receipt of Administrative Law Judge Young's recommendations and a 92 point rebuttal of it, is presented. There is an equating of standards and ethical considerations concerning human research, with legal constraints. It is maintained that the original stands taken, that there is no currently accepted medical use, and there is a high abuse potential, were both correct, and this then is the final placement of MDMA into Schedule I, on a permanent basis. The effective date is November 13, 1986.

1987

Coffin, Torruella, and Pettin. United States Court of Appeals for the First Circuit. Lester Grinspoon, Petitioner, v. Drug Enforcement Administration, Respondent. September 18, 1987.

This is the opinion handed down in answer to the appeal made by Grinspoon (Petitioner) to the action of the DEA (Respondent) in placing MDMA in a permanent classification of a Schedule I drug. Most points were found for the DEA, but one specific claim of the petitioner, that MDMA has a currently accepted use in the United States, was accepted. The finding of the court was that the FDA approval was not the sole criterion for determining the acceptability of a drug for medical use. An order was issued to vacate MDMA from Schedule I.

1988

Lawn, J.C. Schedules of Controlled Substances; Deletion of 3,4-Methylenedioxymethamphetamine (MDMA) From Schedule I of the Controlled Substances Act. Federal Register 53 2225 (1988).

Notice is posted in the Federal Register that MDMA has been vacated from Schedule I of the Controlled Substances Act and now falls under the purview of the Analogue Drug Act. It is no longer a Scheduled Drug. This ruling was effective December 22, 1987, and will be effective until such time as the Administrator reconsidered the record in the scheduling procedures, and issues another final ruling.

Lawn, J.C. Schedules of Controlled Substances; Scheduling of 3,4-Methylenedioxymethamphetamine (MDMA) into Schedule I of the Controlled Substances Act; Remand. Federal Register 53 5156 (1988).

Notice is posted in the Federal Register that MDMA has been placed again into Schedule I. The DEA has accepted the Appellate Court's instruction to develop a standard for the term "accepted medical use," and they have done so. The conclusion is that MDMA is properly assigned to Schedule I, and as there have already been hearings, there is no need for any further delay. Effective date, March 23, 1988.

Meyers, M.A. In the United States District Court for the Southern District of Texas, Houston Division, The United Sates of America v. A.E. Quarles, CR. No. H-88-83. Memorandum in Support of Motion to Dismiss. March 25, 1988.

This memorandum (13 pages and attached literature) is an instructive vehicle addressing the applicability of the Analogue laws to MDMA, and the possible unconstitutional vagueness of the Act itself.

Hug, Boochever and Wiggins, Ninth Circuit Court of Appeals, California. United States, Plaintiff-Appellee v. W.W. Emerson, Defendant-Appellant.

An appeal was made, and was allowed, by three defendants, that the use of the Emergency Scheduling Act by the DEA for the placement of MDMA into Schedule I was improper, in that this power was invested specifically in the Attorney General, and that he had failed to subdelegate this authority to the DEA for its use.

Harbin, H. MDMA. Narcotics, Forfeiture, and Money-Laundering Update, U.S. Department of Justice, Criminal Division. Winter, 1988. pp. 14-19.

A brief legal history of MDMA is presented, detailing its changing status from emergency schedule, to permanent schedule, to non-schedule, to schedule again, a case against its occasional status in-between as an analogue substance. In U.S. v. Spain (10th Circuit, 1987, 825 F.2d 1426), the MDMA conviction was undermined both by the absence of sub- delegation of emergency scheduling powers by the Attorney General to the DEA, and by the failure of the DEA to publish a formal scheduling order 30 days after the publication of its "notice-order", as required by statute. This latter failure was successful in overturning the conviction in the U.S. v. Caudel (5th Circuit, 1987, 828 F.2d 1111)

These reversals were based on the temporary scheduling status of MDMA. The vacating of the permanent scheduling Grinspoon v. DEA (1st Circuit 1987, 828 F.2d 881), coupled with these successful appeals of the temporary scheduling action, will certainly serve to allow further challenge to be made to any and all legal action that took place prior to the final and unchallenged placement of MDMA in Schedule I on March 23, 1988.

1990

Shulgin, A.T. How Similar is Substantially Similar? J. Forensic Sciences, 35 8-10 (1990).

MDMA, illegal under Federal law, can only be charged in the State of California (where it is not a Scheduled drug) as an analogue of some drug that is Scheduled. It must be shown to be substantially similar to known Scheduled drugs in structure or in activity. This similarity definition is discussed.

1991

People v. Silver. Statute Defining Controlled Substance Analog as "Substantially Similar" to Controlled Substance not Unconstitutionally Vague. 91 C.D.O.S. 3801., 2d App. Dist; May 21, 1991.

The question has been brought to the Appeals Court as to a possible vagueness in the wording of the California State Law concerning the definition of Analogue. MDMA was the focus of the appeal. The court found that there was no problem in the definition of the term "substantially similar" but they did not, themselves, define it.

Fromberg, E. Letter to R. Doblin from the Netherlands Institute for Alcohol and Drugs. April 4, 1991.

An explanation of the Schedule I and Schedule II structure of Dutch Law is given. All new drugs must go into Schedule I, and yet MDMA was prosecuted (and defended on appeal) as a (rather minor) Schedule II drug.

Gilbert, J., Stone, P.J. and Yegan, J. Controlled Substance Analog Law is Not Unconstitutionally Vague. Finding of the Second Appellate District Division Six. Daily Appellate Report, May 24, 1991, page 5993-5995.

The appellate Court considered an appeal concerning the classification of MDMA as an analog of methamphetamine. This is question raised under the California Health and Safety Code section 11401, concerning analogs of scheduled drugs, as MDMA is not a scheduled drug in California. The appeal was based (in part) on the statement that "substantially similar" was unconstitutionally vague.

It was concluded that all that was required would be that the statute be reasonably certain, so that a person of common intelligence need not guess at its meaning. They found against the appeal

1994

del Arco, M.A., La Batalla del Extasis: Su Inventor Convencio al Juez de Que es una Droga Blanda. Tiempo, Espana, February 7, 1994.

A consensus of experts presents MDMA as a drug with little hazard associated with it's use. This directly addresses the "rave" scene (La Ruta del Bakalao) in Spain, and removes much of the judicial penalties from this social phenomenon.

Argos, E. and Castello, L. El MDMA es Valioso en Medicina. El Pais, Espana, January 30, 1994 pp. 28-29.

A tribunal court in Madrid found that the material, MDMA, should be classified as a low-hazard drug akin to marijuana, rather than a high-hazard drug such as cocaine, heroin, or LSD. It has a well-defined medical value.

Elayan, I., Gibb, J.W., Hanson, G.R., Lim, H.K., Foltz, R.L. and Johnson, M. , Short-term Effects of 2,4,5-Trihydroxyamphetamine, 2,4,5-Trihydroxymethamphetamine and 3,4-Dihydroxymethamphetamine on Central Tryptophan Hydroxylase Acticity. J. Pharm. Exptl. Therap. 262 813-8 (1993).

The short term effects of the three title metabolites of MDMA (THA, THM and DHM) on tryptophan hydroxylase are reported. The first two metabolites were quite effective, but the third (DHM) had no effect. In vitro studies were unsuccessful in reversing these changes.

Gibb, J.W., Hanson, G.R. and Johnson, M. Effects of (+)-3,4-Methylenedioxymethamphetamine [(+)MDMA] and (-)-3,4-Methylenedioxymethamphetamine [(-)MDMA] on Brain Dopamine, Serotonin, and their Biosynthetic Enzymes. Soc. Neurosciences Abstrts. 12 169.2 (1986).

The optical isomers of MDMA were studied in rats, as to the extent of serotonin and dopamine depletion, and the changes in their respective biosynthetic enzymes TPH (tryptophane hydroxylase) and TH (tyrosine hydroxylase). The (+) was the more effective in reducing serotonin levels at several sites in the brain, and was the more effective in reducing the TPH levels at all sites. Striatal TH was not effected by either isomer.

Hanson, G.R., Hanson, G.R. and Johnson, M. Effects of (+)-3,4-Methylenedioxymethamphetamine [(+)MDMA] and (-)-3,4-Methylenedioxymethamphetamine [(-)MDMA] on Brain Dopamine, Serotonin, and their Biosynthetic Enzymes. Soc. Neurosciences Abstrts. 12 169.2 (1986).

The optical isomers of MDMA were studied in rats, as to the extent of serotonin and dopamine depletion, and the changes in their respective biosynthetic enzymes TPH (tryptophane hydroxylase) and TH (tyrosine hydroxylase). The (+) isomer was the more effective in reducing serotonin levels at several sites in the brain, and was the more effective in reducing the TPH levels at all sites. Striatal TH was not effected by either isomer.

Hanson, G.R., Merchant, K.M., Johnson, M., Letter, A.A., Bush, L. and Gibb, J.W. Effect of MDMA-like Drugs on CNS Neuropeptide Systems. The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Kluwer, New York. (1990) Ed: S.J. Peroutka.

An increase in both neurotensin and dynorphin in selected areas of rat brain following single administrations of MDMA has been observed. The ramifications of these changes are discussed.

Johnson, M., Bush, L.G., Stone, D.M., Hanson, G.R. and Gibb, J.W. Effects of Adrenalectomy on the 3,4-Methylenedioxymethamphetamine (MDMA)-induced Decrease of Tryptophan Hydroxylase Activity in the Frontal Cortex and Hippocampus. Soc. Neurosci. Abstr. 13, 464.6 (1987).

The tryptophan hydroxylase (TPH) activity of rat frontal cortex and hippocampus was found to decrease seven days following an acute large dosage of MDMA. The latter area was spared enzyme loss with adrenalectomy.

Johnson, M., Hanson, G.R. and Gibb, J.W. Effect of MK-801 on the Decrease in Tryptophan Hydroxylase Induced by Methamphetamine and its Methylenedioxy Analog. Europ. J. Pharmacol. 165 315-318 (1989).

Repeated injections of methamphetamine or MDMA in rats reduced neostriatal TPH activity. If MK-801 is administered concurrently the methamphetamine depletion of enzyme is attenuated, but the MDMA induced depletion is not. There may be some involvement of NMDA receptors.

Johnson, M., Mitros, K., Stone, D.M., Zobrist, R., Hanson, G.R. and Gibb, J.W. Effect of Flunarizine and Nimodipine on the Decrease in Tryptophan Hydroxylase Activity Induced by Methamphetamine and 3,4-Methylenedioxymethamphetamine. J. Pharm. Exptl. Therap. 261 586-591 (1992).

The effects of calcium channel blockers on the decrease of central tryptophan hydroxylase activity and serotonin concentration induced by repeated large doses of methamphetamine and MDMA were evaluated. The results suggest that calcium influx may participate in these responses.

Kumagai, Y., Lin, L.Y., Schmitz, D.A. and Cho, A.K. Hydroxyl Radical Mediated Demethylenation of (Methylenedioxy)phenyl Compounds. Chem. Res. Toxicol. 4 330-334 (1991).

The oxidative demethylation of methylenedioxybenzene, MDA and MDMA was achieved with two hydroxy iron-containing radical systems, one with ascorbate and one with xanthine oxidase. Hydrogen peroxide alone was not effective in producing the metabolite catechols.

Kumagai, Y., Wickham, K.A., Schmitz, D.A. and Cho, A.K. Metabolism of Methylenedioxyphenyl Compounds by Rabbit Liver Preparations. Biochem. Pharmacol. 42 1061-1067 (1991).

The demethyleneation of methylenedioxbenzene, MDA and MDMA is a major metabolic pathway, and is achieved in the microcome fraction by the action of P-450. Studies involving inducers and suppressors indicate that several isozymes are involved in the formation of the product catechols.

Letter, A.A., Merchant, K., Gibb, J.W. and Hanson, G.R. Roles of D2 and 5-HT2 Receptors in Mediating the Effects of Methamphetamine, 3,4-Methylenedioxymethamphetamine, and 3,4-Methylenedioxyamphetamine on Striato-Nigral Neurotensin Systems. Soc. Neurosciences Abstrts. 12 1005 (# 277.7) 1986.

The chronic treatment of rats with methamphetamine, MDA or MDMA leads to a 2-3x increase of the neurotensin-like immunoreactivity in the striato-nigral areas of the brain. Efforts to assign neurotransmitter roles led to the simultaneous administration of serotonin and dopamine antagonists. These interrelationships are discussed.

Merchant, K., Letter, A.A., Stone, D.M., Gibb, J.W. and Hanson, G.R. Responses of Brain Neurotensin-like Immunoreactivity to 3,4-Methylene-dioxymethamphetamine (MDMA) and 3,4-Methylenedioxyamphetamine (MDA). Fed. Proc. 45 1060 (# 5268) (1986).

The administration of MDA and MDMA profoundly alters the levels of neurotensin-like immunoreactivity (NTLI) concentrations in various portions of the brain of the rat. Increases of up to a factor of 3x are observed in some regions of the brain.

Nash, J.F. and Meltzer, H.Y. Neuroendocrinological Effects of MDMA in the Rat. The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Kluwer, New York. (1990) Ed: S.J. Peroutka.

MDMA has been observed to increase plasma ACTH and corticosterone concentrations in a dose-dependent manner. A series of pharmacological challenges suggests that serotonin release may be a responsible factor.

Poland, R.E. Diminished Corticotropin and Enhanced Prolactin Responses to 8-Hydroxy-2-(di-n-propylamino)tetralin in Methylenedioxymethamphetamine Pretreated Rats. Neuropharmacology 29 1099-1101 (1990).

Pretreatment of rats with a single, modest dose of MDMA followed by a challenge with the serotonin agonist 8-OH DPAT led to a decrease corticotropin and an enhanced prolactin response. This suggests that MDMA produces abnormal serotonin receptor-coupled neuroendocrine responses.

Schmidt, C.J. and Taylor, V.L. Acute Effects of Methylenedioxymethamphetamine (MDMA) on 5-HT Synthesis in the Rat Brain. Pharmacologist 29 ABS-224 (1987). See also: Biochemical Pharmacology 36 4095-4102 (1987).

Acute exposure of MDMA dropped the tryptophane hydroxylase activity of rats, and this persisted for several days. Subsequent administration of Fluoxetine recovered this activity, but reserpine or alpha-methyl-tyrosine did not.

Stone, D.M., Hanson, G.R. and Gibb, J.W. GABA-Transaminase Inhibitor Protects Against Methylenedioxy-methamphetamine (MDMA)-induced Neurotoxicity. Soc. Neurosci. Abstr. Vol. 13, Part 3 (1987). # 251.3.

The neurotoxicity of MDMA (in the rat) was protected against by GABA-transaminase inhibitors.

Stone, D.M., Johnson, M., Hanson, G.R. and Gibb, J.W. A Comparison of the Neurotoxic Potential of Methylenedioxyamphetamine (MDA) and its N-methylated and N-ethylated Derivatives. Eur. J. Pharmacol. 134 245-248 (1987).

Multiple doses of MDA and MDMA decreases the level of brain tryptophan hydroxylase (TPH). The N-ethyl homologue was without effect. It is argued that although the studies here were well above human exposures, the cumulative effects of repeated exposures, the differences between rat and human metabolism, and increased human sensitivity to this drug, could present a serious threat to human abusers of this drug.

Stone, D.M., Johnson, M., Hanson, G.R. and Gibb, J.W. Acute Inactivation of Tryptophan Hydroxylase by Amphetamine Analogs Involves the Oxidation of Sulfhydryl Sites. Europ. J. Pharmacol. 172 93-97 (1989).

MDMA, Fenfluramine and methamphetamine, separately, reduced the tryptophan hydroxylase activity in rat brain. The enzyme activity could be restored, in the cases of the latter two drugs, by treatment that suggested that some reversible oxidation of sulfhydryl groups was involved. With MDMA, the changes were irreversible, and serotonergic toxicity is suggested.

Stone, D.M., Stahl, D.C., Hanson, G.R. and Gibb, J.W. Effects of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphet-amine (MDMA) on Tyrosine Hydroxylase and Tryptophane Hydroxylase Activity in the Rat Brain. Fed. Proc. 45 1060 (# 5267) April 13-18, 1986.

The effects of rats treated chronically with either MDA or MDMA on the enzymes involved with neurotransmitter synthesis is reported. The levels of tryptophane hydroxylase (TPH, involved with serotonin synthesis) were markedly reduced, differently in different areas of the brain. The tyrosine hydroxylase (TH, involved with dopamine synthesis) remains unchanged. This is in contrast to the documented reduction of TH that follows high dosages of methamphetamine.

Wilkerson, G. and London, E.D. Effects of Methylenedioxymethamphetamine on Local Cerebral Glucose Utilization in the Rat. Neuropharmacology 28 1129-1138 (1989).

MDMA was found to influence glucose utilization at some 60 different areas in the rat brain, as determined by the employment of radioactive 2-deoxyglucose. A thorough tally has been made of these areas, and the changes that follow four different dose levels of exposure.

Cho, A.K., Hiramatsu, M., Distefano, E.W., Chang, A.S and Jenden, D.J. Stereochemical Differences in the Metabolism of 3,4-Methylenedioxymethamphetamine in vivo and in vitro: A Pharmacokinetic Analysis. Drug Metabol. Disposition 18 686-691 (1990).

The optical isomers of MDMA were demethylated to form MDA, with the active (+)-isomer being 3x more extensively degraded. The loss of the methylenedioxy group gave N-methyl-alphamethyldopamine proved to be the major metabolite.

Fitzgerald, R.L., Blanke, R., Narasimhachari, N., Glennon, R. and Rosecrans, J. Identification of 3,4-Methylenedioxyamphetamine (MDA) as a Major Urinary Metabolite of 3,4-Methylenedioxymethamphetamine (MDMA). NIDA Research Monograph, #81 321 (1988).

Rats were administered MDMA chronically and, from both the plasma and the excreta, unchanged MDMA and the demethylation product MDA were detected by GCMS as the trifluoroacetamide derivatives.

Fitzgerald, R.L., Blanke, R.V. and Poklis, A. Stereoselective Pharmacokinetics of 3,4-Methylenedioxymethamphetamine in the Rat. Chirality 2 241-248 (1990).

The optical isomers of MDMA and MDA were assayed in the rat, following the administration of MDMA by two different dosages and by two different routes. The S-isomer of MDMA was found to clear more rapidly, resulting in a preferred presence of its metabolite, the S-isomer of MDA. Blood levels, isomer ratios, and half-lives are given.

Fukuto, J.M., Kumagai, Y. and Cho, A.K. Determination of the Mechanism of Demethylenation of (Methylenedioxy)phenyl Compounds by Cytochrome P450 Using Deuterium Isotope Effects. J. Med. Chem. 34 2871-2876 (1991).

Kinetic studies of the demethylenation of several methylenedioxy compounds (including MDMA) have shown, by isotope effects, to be mediated by different mechanisms.

Helmlin, H. -J., Bracher, K., Salamone, S.J. and Brenneisen, R., Analysis of 3,4-Methylenedioxymethamphetamine (MDMA) and its Metabolites in Human Plasma and Urine by HPLC-DAD, GC-MS and Abuscreen-Online. Abstracts from CAT/SOFT Joint Meeting, October 10-16, 1993, Phoenix, Arizona.

Urine and plasma samples were taken from a number of patients being administered 1.5 mg/Kg MDMA for psychotherapy research purposes. Maximum plasma levels (300 ng/mL) were seen at 140 minutes. The main urinary metabolites were 4-hydroxy-3-methoxymethamphetamine and 3,4-dihydroxymethamphetamine, both excreted in conjugated form. The two N-demethylated homologues of these compounds were present as minor metabolites. The cross-reactivity of the Abuscreen immunoassay for both the metabolites (including MDA, another metabolite) and the parent drug were determined.

Hiramatsu, M., DiStefano, E., Chang, A.S. and Cho, A.K. A Pharmacokinetic Analysis of 3,4-Methylenedioxy-methamphetamine Effects on Monoamine Concentrations in Brain Dialysates. Europ. J. Pharmacol. 204 135-140 (1991).

The role of the MDMA metabolite, MDA, in the releasing of dopamine, was studied in brain dialysates. It was noted that the plasma levels of MDA were higher following the administration of (+)-MDMA as compared to (-)-MDMA, to the rat.

Hiramatsu, M., Kumagai, Y., Unger, S.E. and Cho, A.K. Metabolism of Methylenedioxymethamphetamine: Formation of Dihydroxymeth-amphetamine and a Quinone Identified as its Glutathione Adduct. J. Pharmacol. Exptl. Therap. 254 521-527 (1990).

Studies were made of the in vitro metabolism of MDMA by rat liver microsomes, of the optical isomers of MDMA. A P- 450 dependent hydrolysis to N,alpha-dimethyl was observed, which was further converted by superoxide oxidation to a metabolite that formed an adduct with glutathione. It is speculated that this pathway may account for some of the irreversible action on serotoninergic neurons.

Kumagai, Y., Lin, L.Y., Schmitz, D.A. and Cho, A.K. Hydroxyl Radical Mediated Demethylenation of (Methylenedioxy)phenyl Compounds, Chem. Res. Toxicol. 4 330-334 (1991).

The oxidative demethylenation of several methylenedioxy compounds such as MDMA has been studied, with two hydroxyl radical generating systems. The various requirements for this metabolic transformation are defined.

Lim, H.K. and Foltz, R.L. Metabolism of 3,4-Methylenedioxymeth-amphetamine (MDMA) in Rat. FASEB Abstracts Vol. 2 No. 5 page A-1060. Abst: 4440.

The metabolism of MDMA in the rat is studied. Seven metabolites have been identified from urine. These are: 4-hydroxy-3-methoxymethamphetamine; 3,4-methylenedioxyamphetamine; 4-hydroxy-3-methoxyamphetamine; 4-methoxy-3-hydroxymethamphetamine; 3,4-methylenedioxyphenylacetone, 3,4-dihydroxyphenyl acetone and 4-hydroxy-3-methoxyphenylacetone

Lim, H.K. and Foltz, R.L. In Vivo and In Vitro Metabolism of 3,4-Methylenedioxymethamphetamine in the Rat: Identification of Metabolites using an Ion Trap Detecor. Chem. Res. Toxicol. 1 370-378(1988).

Four metabolic pathways for MDMA metabolism in the rat have been identified. These are N-demethylation, O-dealkylation, deamination, and conjugation. A total of eight distinct metabolites have been observed and identified.

Lim, H.K. and Foltz, R.L. Identification of Metabolites of 3,4-Methylenedioxymethamphetamine in Human Urine. Chem. Res. Toxicol. 2 142-143 (1989).

The metabolites observed in the rat following MDMA administration are, to a large degree, identical to those found in man. The metabolic paths observed are N-demethylation, O-dealkylation, deamination, and conjugation. The major metabolite in this one individual (an undocumented MDMA user accident victim) is 3-methoxy-4-hydroxymethamphetamine.

Lim, H.K. and Foltz, R.L. Application of Ion Trap MS/MS Techniques for Identification of Potentially Neurotoxic Metabolites of 3,4-Methylenedioxymeth-amphetamine (MDMA). Paper presented at the CAT Quarterly Meeting, February 3, 1990, San Jose, California.

The GCMS analysis of the rat liver metabolites of MDMA has given evidence of ring hydroxylation. Employing MS/MS techniques and unresolved synthetic mixtures, tentative structural assignments have been presented for the hydroxylation of MDMA at all three available ring positions. Another possible metabolite is ring-hydroxylated MDA. A possible neurotoxic role of such products is suggested by their structural relationship to 6-hydroxydopamine.

Lim, H.K. and Foltz, R.L. In vivo Formation of Aromatic Hydroxylated Metabolites of 3,4-Methylenedioxymeth-amphetamine in the Rat: Identification by Ion Trap Tandem Mass Spectrometric (MS/MS and MS/MS/MS) Techniques. Biological Mass Spectrometry 20 677-686 (1991).

Metabolism studies in the rat have shown that MDMA can be hydroxylated at all three possible aromatic positions. The three corresponding compounds with N-demethylation also are formed. The 6-position is favoured. All metabolites are observed in the liver, only the 6-hydroxyl isomer in the brain, and none can be found in urine.

Lim, H.K., Zeng, S., Chei, D.M. and Foltz, R.L. Comparitive Investigation of Disposition of 3,4-(Methylenedioxy)methamphetamine (MDMA) in the Rat and the Mouse by a Capillary Gas Chromatography-Mass Spectrometry Assay based on Perfluorotributylamine-enhanced Ammonia Positive Ion Chemical Ionization . J. Pharmaceut. Biomed. Anal. 10 657-665 (1992).

An assay is described that allows a quantitative measure of MDMA and three of its primary metabolites, methylenedioxamphetamine, 4-hydroxy-3-methoxymethamphetamine and 4-hydroxy-3-methoxyamphetamine. The latter two metabolites were excreted mainly as the glucuronide and sulfate conjugates. The metabolic patterns of the rat and the mouse are compared.

Lin, L., Kumagai, Y., Cho, A.K. Enzymatic and Chemical Demethylenation of (Methylenedioxy)amphetamine and (Methylenedioxy)methamphetamine by Rat Brain Microsomes. Chem Res. Tox. 5 401-406 (1992)

Metabolism of MDA and MDMA by microsomal preparation from rat brains. The products observed were the corresponding catechol derivatives. The oxidizing agents appear to involve both a cytochrome P-450 component and hydroxyl radical.

Yousif, M.Y., Fitzgerald, R.L., Narasimhachari, N., Rosecrans, J.A., Blanke, R.V. and Glennon, R.A. Identification of Metabolites of 3,4-Methylenedioxymethamphetamine in Rats. Drug and Alcohol Dependence. 26 127-135 (1990).

Two metabolites of MDMA have been established as being present in rat urine, by both HPLC and GCMS; these were MDA and 4-hydroxy-3-methoxy-N-methylamphetamine. From HPLC alone, evidence was found for the positional isomer 3-hydroxy-4-methoxy-N-methyl- amphet-amine, for 4-hydroxy-3-methoxy-amphet amine, and for 3,4-dihydroxy- amphetamine, but these were not confirmed by GCMS. MDA was identified in both plasma and brain extracts.

Azmitia, E.C., Murphy, R.B. and Whitaker-Azmitia, P.M. MDMA (Ecstasy) Effects on Cultured Serotonergic Neurons: Evidence for Ca 2+ -Dependent Toxicity Linked to Release. Brain Research 510 97-103 (1990).

The relationship of MDMA with serotonin neurons, and with calcium cation release has been determined in the fetal cells of newborn rats. Long-term serotonin changes are blocked by 5-HT re-uptake blockers, and the interactions between MDMA and caffeine have been reported. It has been suggested that Ca cation release may play a role in MDMA toxicity.

Battaglia, G., Brooks,B.P., Kulsakdinum, C. and De Souza, E.B. Pharmacologic Profile of MDMA 3,4-Methylenedioxymeth-amphetamine at Various Brain Recognition Sites. Eur.J.Pharmacol. 149 159-163 (1988).

The affinity of MDMA for various neurotransmitter receptor and uptake sites was studied in vivo, using competition with various radioligands. Comparisons with MDA, MDE, amphetamine and methamphetamine are reported.

Berger, U.V., Gu, X.F. and Azmitia, E.C. The Substituted Amphetamines 3,4-Methylenedioxymethamphetamine, Methamphetamine, p-Chloroamphetamine and Fenfluramine Induce 5-Hydroxytryptamine Release via a Common Mechanism Blocked by Fluoxetine and Cocaine. Eur. J. Pharmacol. 215 153-60 (1992).

An in vitro assay has been used to compare several drugs for their ability to induce synaptosomal serotonin release. Para-chloroamphetamine and fenfluramine were equally effective, MDMA less so, and methamphetamine very much less so still. Evidence is presented that the serotonin release produced by these drugs employs a common mechanism.

Bradberry, C.W., Sprouse, J.S., Aghajanian, G.K. and Roth, R.H. 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Release of Endogenous Serotonin from the Rat Dorsal Raphe Nucleus in vitro: Effects of Fluoxetine and Tryptophan. Neurochem. Int. 17 509-513 (1990).

Brain slices of the dorsal raphe nucleus were exposed to a medium containing MDMA and the released serotonin was measured. A serotonin transport inhibitor (Fluoxetine) reduced the amount released, whereas the addition of tryptophan increased the amount released.

Bradberry, C.W., Sprouse, J.S., Sheldon, P.W., Aghajanian, G.K. and Roth, R.H. In Vitro Microdialysis: A Novel Technique for Stimulated Neurotransmitter Release Measurements. J. Neuroscience Methods. 36 85-90 (1991).

A novel technique allowing measurement of neurotransmitter release and single unit recordings from brain slices is described. The effects of MDMA on slices of dorsal raphe nucleus and frontal cortex were used to demonstrate it.

Brady, J.F., Di Stephano, E.W. and Cho, A.K. Spectral and Inhibitory Interactions of (+/-)-3,4-Methylenedioxyamphetamine (MDA) and (+/-)-3,4-Methylenedioxymethamphetamine (MDMA) with Rat Hepatic Microsomes. Life Sciences 39 1457-1464 (1986).

Both MDA and MDMA were shown to form complexes with cytochrome P-450 that were inhibitory to its function as to demethylation of benzphetamine and carbon monoxide binding. Liver microsome studies showed the metabolic demethylation of MDMA and the N-hydroxylation of MDA.

Frye, G. and Matthews, R. Effect of 3,4-Methylenedioxymethamphetamine (MDMA) on Contractive Responses in the G. Pig Ileum. The Pharmacologist 28 149 (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 Lovenberg, W. Evidence for Specific Methylenedioxymethamphet-amine (Ecstasy) Binding Sites in the Rat Brain. Europ. J. Pharmacol. 119 135-136 (1985).

Evidence is presented from binding to rat brain homogenate studies. The use of the serotoninergic re-uptake inhibitor, active in vivo ,does not antagonize this binding, nor in studies with uptake into striatal microsomes.

Levin, J.A., Schmidt, C.J. and Lovenberg, W. Release of [3H]-Monoamines from Superfused Rat Striatal Slices by Methylenedioxymethamphetamine (MDMA). Fed. Proc. 45 1059 (#5265) April 13-18, 1986.

The release of tritiated serotonin and dopamine from superfused rat striatal slices was observed for three amphetamine derivatives. MDMA and p-chloroamphetamine were equivalent, and about 10x the potency of methamphet amine. This last compound was, however, some 10x more effective than MDMA in the release of dopamine.

Lyon, R.A., Glennon, R.A. and Titeler, M. 3,4-Methylenedioxymethamphetamine (MDMA): Stereoselective Interactions at Brain 5- HT1 and 5-HT2 Receptors. Psychopharmacology 88 525-526 (1986).

Both MDMA and MDA, and their respective optical isomers, were assayed as to their affinity at radio-labelled serotonin (5-HT1 and 5-HT2) and dopamine (D2) binding sites. The "R" isomers of both drugs showed a moderate affinity at the 5-HT2 receptor (labelled with 3H ketanserin), and the "S" isomers were lower. Affinities for the 5-HT1 site were similar, but that for D2 sites were very low. Since the "S" isomer of MDMA 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, A.J., Nichols, M.B. and Yim, G.K.W. Effects of Certain Hallucinogenic Amphetamine Analogues on the Release of [3H] Serotonin from Rat Brain Synaptosomes. J. Med. Chem. 25 530-535 (1982).

The optically active isomers of MDMA (as well as those for MDA, PMA and the corresponding phentermine 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 active 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.

Rempel, N.L., Callaway, C.W. and Geyer, M.A. Serotonin-1B Receptor Activation Mimics Behavioral Effects of Presynaptic Serotonin Release. Neuropsychopharm. 8 201-11 (1993).

The locomotor hyperactivity induced by MDMA in rats appears to be due to the drug-induced release of presynaptic serotonin. It appers to act as indirect serotonin agonist, acting probably at the 5-HT1B receptor.

Ricaurte, G.A., Markowska, A.L., Wenk, G.L., Hatzidimitriou, G., Wlos, J. and Olton, D.S. 3,4-Methylenedioxymethamphetamine, Serotonin, and Memory. J. Pharmacol. Exptl. Therap. 266 1097-1105 (1993).

A series of behavioral studies in the rat were conducted to assay the effect of serotonin neuron lesions on memory. MDMA was used for selective reduction of serotonin, and 5,7-dihydroxytryptamine for more extensive nerve damage than can be achieved with MDMA. The MDMA treated rats had no impairment of memory, but the more extensively damaged animals (involving both serotonin and norepinephrine systems) showed a disruption of recently aquired memory.

Robinson, T.E., Castaneda, E. and Whishaw, I.Q. Effects of Cortical Serotonin Depletion Induced by 3,4-Methylenedioxymethamphetamine (MDMA) on Behavior, Before and After Additional Cholinergic Blockade. Neuropsychopharmacology 8 77-85 (1993).

Studies in rats describe the effects of MDMA on a number of behavioral tests. The serotonergic denervation that resulted is not sufficient to produce marked and lasting behavioral deficits.

Romano, A.G. and Harvey, J.A. MDMA Enhances Associative and Nonassociative Learning in the Rabbit. Pharmacol. Biochem. Behav. 47 289-93 (1994).

Conditioned response studies in rabbits have shown that MDMA, like MDA, enhances the learning process. The effects seen are not known for other psychedelic drugs, and may be unique to this chemical class.

Rudnick, G., Wall, S.C. The Molecular Mechanism of "Ecstasy" [3,4-Methylenedioxymethamphetamine(MDMA)]: Serotonin Transporters are Targets for MDMA-Induced Serotonin Release. Proc. Natl. Acad. Sci USA, 89 1817-1821 (1992)

The mechanisms of MDMA action at serotonin transporters from plasma membranes and secretory vesicles isolated from human platelets have been studied and are reported.

Rudnick, G., and Wall, S. Non-Neurotoxic Amphetamine Derivatives Release Serotonin through Serotonin Transporters. Molecular Pharmacology, in press (1992).

MDMA was compared to MMA (3-methoxy-4-methylamphetamine) and MMAI ( both non-neurotoxic analogues) as to their effects on several serotonin and dopamine properties in in vitro studies.

Schuldiner, S., Steiner-Mordoch, S., Yelin, R., Wall, S.C. and Rudnick, G. Amphetamine Derivatives Interact with Both Plasma Membrane and Secretory Vesicle Biogenic Amine Transporters. Mol. Pharmacol. 44 1227-31 (1993).

The interaction of fenfluramine, MDMA and p-chloroamphetamine (PCA) with brain transporter systems have been studied. The mechanisms of inhibition are discussed.

Steele, T.P., Nichols, D.E. and Yim, G.K.W. Stereoselective Effects of MDMA on Inhibition of Monoamine Uptake. Fed. Proc. 45 1059 (# 5262) April 13-18 1986.

In the investigation of the optical isomeric difference of activities seen for amphetamine, MDMA, and DOM (the more potent isomers being the "S", "S" and "R" resp.) their abilities to inhibit the uptake of radio-labelled monoamines into synaptosomes were studied. The findings are discussed, and it is concluded that MDMA exhibits stereoselective 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-Methylenedioxymethamphetamine (MDMA) and Related Amphetamine Derivatives on Inhibition of Uptake of [3H]Monoamines into Synaptosomes from Different Regions of Rat Brain. Biochem. Pharmacol. 36 2297-2303 (1987).

MDA, MDMA, and the alpha-ethyl homologue MBDB were found to inhibit serotonin uptake in brain synaptosomes. The conclusions to a broad series of studies were that MDMA and its homologues are more closely related to amphetamine than to DOM in their biochemical actions.

Wang, S.S., Ricaurte, G.A. and Peroutka, S.J. [3H]3,4 Methylenedioxymethamphetamine (MDMA) Interactions with Brain Membranes and Glass Fiber Filter Paper. Europ. J. Pharmacol. 138 439-443 (1987).

Tritiated MDMA appears to give a pharmacological "binding profile" in rat brain homogionate studies, even in the absence of brain tissue. This appears to result from an unexpected binding of the radioligand to glass filter paper. Pretreatment with polyethylenimine eliminated this artifact.

Anderson III, G.M., Braun, G., Braun, U., Nichols, D.E. and Shulgin, A.T. Absolute Configuration and Psychotomimetic Activity, NIDA Research Monograph #22, pp 8-15 (1978).

The "R" isomer of most chiral hallucinogenics is known to be the active isomer. This generality includes LSD, DOB, DOM, DOET, and MDA. This assignment has been demonstrated both in rabbit hyperthermia studies as well as in clinical evaluations. With MDMA, however, this assignment is reversed. In both rabbit and human studies, the more potent isomer of MDMA is the "S" form, similar to that of amphetamine and methamphetamine. The summed activity of the individual isomers did not satisfactorily reproduce the activity of the racemic mixture. Also, the addition of an N-methyl to a known hallucinogenic amphetamine routinely decreases the potency (as with DOB, DOM, TMA and TMA-2). The exception again is with MDA, which produces the equipotent MDMA. The relationship between the stimulants amphetamine and methamphetamine is similar. The two drugs MDA and MDMA appear not to be cross-tolerant in man. It is argued that the mechanisms of action of MDMA must be different from that of MDA and related hallucinogenics.

Beardsley, P.M., Balster, R.L. and Harris, L.S. Self-administration of Methylenedioxymethamphetamine (MDMA) by Rhesus Monkeys. Drug and Alcohol Dependence 18 149-157 (1986)

In monkeys trained to self-administer cocaine intravenously MDMA was found, in two out of four animals, to be an effective substitute.

Beaton, J.M., Benington, F., Christian, S.T., Monti, J.A. and Morin, R.D. Analgesic Effects of MDMA and Related Compounds. Pharmacologist 29 ABS 281 (1987).

Analgesia of several compounds (including MDMA and several close homologues) was measured by the tail-flick response in mice. All produced analgesia, with the (+) (S) MDMA being the most potent.

Bilsky, E.J. and Reid, L.D. MDL-72222, A Serotonin 5-HT3 Receptor Antagonist, Blocks MDMA's Ability to Establish a Conditioned Place Preference. Pharm. Biochem. Behav. 39 509-512 (1991).

MDMA has been shown to establish conditioned place-preference in rats. An experimental 5-HT3 antagonist MDL-72222 blocked the effect, suggesting that such antagonists might be of use in the evaluation the pharmacology of self-administer drugs.

Bilsky, E.J., Hubbell, C.L., Delconte, J.D. and Reid, L.D. MDMA Produces a Conditioned Place Preference and Elicits Ejaculation in Male Rats: A Modulatory Role for the Endogenous Opioids. Pharm. Biochem. Behav. 40 443-447 (1991).

The ability of rats to establish a conditioned place-preference was studied. This was blocked by the pre-administration of Naltrexone. This drug interaction was studied as to ejaculatory behaviour, urination, defecation and body weight change.

Bilsky, E.J., Hui, Y., Hubbell, C.L. and Reid, L.D. Methylenedioxymethamphet-amine's Capacity to Establish Place Preferences and Modify Intake of an Alcohol Beverage. Pharmacol. Biochem. Behav. 37 633-638 (1990).

Employing behavioural studies with experimental rats, it was found that MDMA led to a dose-dependent decrease of intake of sweetened ethanol. Another study showed a positive, but not dose dependent, "conditioned placement preference" test which, it is argued, provides further evidence for the drug's abuse liability.

Bird, M. and Kornetsky, C. Naloxone Antagonism of the Effects of MDMA "Ecstasy" on Rewarding Brain Stimulation. The Pharmacologist 28 149 (1986).

The lowering of the reward threshold (REBS, rewarding electrical brain stimulation) by the s.c. administration of MDMA to rats (as determined by implanted electrodes) was blocked by Naloxone. This suggests that MDMA affects the same dopinergic and opioid substrates involved in cocaine and d-amphetamine reward.

Braun, U., Shulgin, A.T. and Braun, G. Prufung auf zentral Aktivitat und Analgesie von N-substituierten Analogen des Amphetamin-Derivates 3,4-Methylenedioxyphenylisopropylamin. Arzneim.-Forsch. 30 825-830 (1980).

MDMA, and a large collection of N-substituted homologues, were assayed in mice for both analgesic potency and enhancement of motor activity. MDMA proved to be the most potent analgesic (compared with some 15 homologues) but was not particularly effective as a motor stimulant. The structure and pharmacological relationships to known analgesics are discussed.

Brodkin, J., Malyala, A. and Nash, J.F. Effect of Acute Monamine Depletion on 3,4-Methylenedioxymethamphetamine-Induced Neurotoxicity. Pharmacol. Biochem. Behav. 45 647-53 (1993).

The depletion of serotonin and dopamine induced by treatment of rats with acute exposure to high levels of MDMA has been explored. Several pharmacological probes have suggested that dopamine can play a major role in the neurotoxic effects of MDMA.

Callahan, P.M. and Appel, J.B. Differences in the Stimulus Properties of 3,4-Methylenedioxyamphetamine (MDA) and N-Methyl-3,4-methylenedioxmethamphetamine (MDMA) in Animals Trained to Discriminate Hallucinogens from Saline. Soc. Neurosci. Abstr.13, Part 3, p. 1720 (1987) No. 476.2.

The stimulant properties of MDA and MDMA (including the optical isomers) were studied in rats that were trained to discriminate mescaline or (separately) LSD, from saline. "R"-MDA appears similar to both hallucinogens, but the other isomers gave no clear-cut accord to the literature reports of behavioural activity.

Callahan, P.M. and Appel, J.B. Differences in the Stimulus Properties of 3,4-Methylenedioxyamphetamine and 3,4- Methylenedioxmethamphetamine in Animals Trained to Discriminate Hallucinogens from Saline. J. Pharmacol. Exptl. Therap. 246 866-870 (1988).

In animals trained to discriminate LSD from saline, DOM, mescaline, psilocybin and (+) MDA and both (+) and (-) MDMA, responses followed the LSD cue. With animals trained to mescaline (vs. saline), both isomers of both MDA and MDMA produced mescaline-like responses, as did DOM, LSD and psilocybin.

Callaway, C.W., Wing, L.L. and Geyer, M.A. Serotonin Release Contributes to the Locomotor Stimulant Effects of 3,4-Methylenedioxyamphetamine in Rats. J. Pharm. Exptl. Therap. 254 456-464 (1990).

The relative roles of dopamine and of serotonin have been evaluated, employing the MDMA-induced locomotor hyperactivity in the rat. It has been found that the observed activity calls upon mechanisms that depend upon the release of central serotonin, as opposed to the mechanisms believed to express amphetamine motor activity.

Callaway, C.W. and Geyer, MA. Stimulant Effects of 3, 4-Methylenedioxymethamphetamine in the Nucleus Accumbens of Rat. Eur. Journ. Pharm. 214 45-51 (1992)

This study examined the behavioural effects in rats of intracerebral administration of S-MDMA using an automated holeboard and open-field apparatus. Administration of S-MDMA into the nucleus accumbens septi produced locomotor hyperactivity.

Callaway, C.W. and Geyer, M.A. Tolerance and Cross-Tolerance to the Activating Effects of 3,4-Methylendioxymethamphetamine and a 5-Hydroxytryptamine1B Agonist. J. Pharmacol. Exptl. Therap. 263 318-326 (1992).

Two experiments were carried out. Changes in the response of rats to MDMA were studied following chronic pretreatment with serotonin agonists responsive to different receptor subtypes. And, following chronic pretreatment with MDMA, changes in responses to these separate receptor agonists were studied. There was an acute reciprocal cross-tolerance observed between MDMA and RU-24969, a 5-HT1B receptor agonist, in producing activating effects in the rat. This supports the hypothesis that the release of endogenous serotonin increases locomotor activity by the stimulation of 5-HT1b receptors.

Cho, A.K., Hiramatsu, M., Kumagal, Y. and Patel, N. Pharmacokinetic Approaches to the Study of Drug Action and Toxicity. NIDA Research Monograph #136, pp 213-225 (1993). Ed. Linda Erinoff.

Using rats as an experimental animal, the time courses of plasma MDMA and metabolite MDA were reported following the administration of (separately) (+) and (-) MDMA. The dideutero-analogue was used as an internal standard, and the analysis was performed on the trifluoroacetamides by selected ion monitoring. Microsomal metabolic pathways were also reported.

Elayan, I., Gibb, J.W., Hanson, G.R., Foltz, R.L., Lim, H.K. and Johnson, M. Long-term Alteration in the Central Monoaminergic Systems of the Rat by 2,4,5-Trihydroxyamphetamine but not by 2-Hydroxy-4,5-Methylenedioxymethamphetamine or 2-Hydroxy-4,5-Methylenedioxyamphetamine. Eur. J. Pharmacol. 221 281-288 (1992).

The effects of the i.c.v. administration of three metabolites of MDMA were studied in the rat. With 2,4,5-trihydroxyamphetamine there was a long-term decline in tryptophane hydroxylase and tyrosine hydroxylase activity, as well as a decrease in serotonin, dopamine and norepinephrin levels. This suggests that this metabolite may contribute to the neurotoxic action of MDMA on the serotonergic system.

Crisp, T., Stafinsky, J.L., Boja, J.W. and Schechter, M.D. The Antinociceptive Effects of 3,4-Methylenedioxymethamphetamine (MDMA) in the Rat. Pharmacol. Biochem. Behav. 34 497-501 (1989).

MDMA was compared to morphine as an analgesic drug in the rat, in both the tail-flick and the hot-plate tests. Both drugs were equipotent in the latter tests, but only morphine was effective in the former test. The effectiveness of MDMA was not attenuated by either the opiate antagonist naltrexone nor the adrenoreceptor antagonist Phentolamine. However, the serontin antagonist Methysergide did antagonise the MDMA effectiveness, suggesting a serotonin involvement in this action.

Davis, W.M. and Borne, R.F. Pharmacological Investigation of Compounds Related to 3,4-Methylenedioxyamphetamine (MDA), Subs. Alc. Act/Mis. 5 105-110 (1984).

MDA and MDMA, as well as the homologous 3-aminobutanes HMDA and HMDMA, were studied toxicologically in both isolated and aggregated mouse groups. Both MDA and MDMA were of similar lethality in isolated animals (ca. 100mg/Kg i.p.) which was enhanced 3 or 4 fold by aggregation. The homologues HMDA and HMDMA were approximately twice as toxic but showed no such enhancement. The prelethal behaviour characteristics and the effects of potential protective agents are described.

Dimpfel, W., Spuler, M. and Nichols, D.E. Hallucinogenic and Stimulatory Amphetamine Derivatives: Fingerprinting DOM, DOI, DOB, MDMA, and MBDB by Spectral Analysis of Brain Field Potentials in the Freely Moving Rat (Tele-Stereo-EEG). Psychopharmacology 98 297-303 (1989).

Recording from several areas of the brain of freely moving rats were made following the administration of several hallucinogens and other structurally related entactogens and stimulants. The recorded results show clear regional specificity of the various classes of drugs, and suggest that serotonin receptors in the striatum might be involved with hallucinogenic action.

Dragunow, M., Logan, B. and Laverty, R. 3,4-Methylenedioxymeth-amphetamine Induces Fos-like Proteins in Rat Basic Ganglia: Reversal with MK-801. Eur. J. Pharmacol. 206 205 (1991).

Administration of MDMA to rats leads to an accumulation of Fos proteins and Fos-related antigens. The NMDA antagonist MK-801 inhibited this induction, but Fluoxetine had no effect.

Evans, S.M. and Johanson, C.E. Discriminative Stimulus Properties of (+/-)-3,4-Methylenedioxymethamphetamine and (+/-)-Methylenedioxyamphetamine in Pigeons. Drug and Alcohol Dependence 18 159-164 (1986).

Pigeons were trained to discriminate (+) amphetamine from saline. Both MDA and MDMA substituted for amphetamine, and both were less potent.

Farfel, G.M., Vosmer, G.L. and Seiden, L.S. The N-Methyl-D-Aspartate Antagonist MK-801 Protects Against Serotonin Depletions Induced by Methamphetamine, 3,4-Methylenedioxymethamphetamine and p-Chloramphetamine. Brain Res. 595 121-127 (1992).

The NMDA receptor antagonist MK-801 attenuates the decrease in serotonin concentration brought about by MDMA and two other amphetamine derivatives, in rats. Changes in the serotonin metabolite 5-hydroxyindoleacetic acid concentrations were similar to the serotonin in changes observed.

Fellows, E.J. and Bernheim, F. The Effect of a Number of Aralkylamines on the Oxidation of Tyramine by Amine Oxidase. J. Pharm. Exptl. Therap. 100 94-99 (1950).

There were animal behavioural studies made on the chain homologue of MDMA, vis., 1-(3,4-methylenedioxyphenyl)-3-methylaminobutane. This is the amine that would result from the use of the "wrong" piperonylacetone in illicit synthesis. In the dose range 10-25 mg/Kg, toxic effects such as tremors and convulsions were seen.

Finnegan, K.T., Calder, L., Clikeman, J., Wei, S. and Karler, R. Effects of L-type Calcium Channel Antagonists on the Serotonin-depleting Actions of MDMA in Rats. Brain Res. 603 134-138 (1993).

Of several calcium channel blockers effective at increasing the convulsion threshold induced by NMDA, only flunarizine blocked the long-term serotonin depleting effects of MDMA. It is suggested that calcium channels are not involved in the neurotoxicity of MDMA.

Gazzara, R.A., Takeda, H., Cho, A.K. and Howard, S.G. Inhibition of Dopamine Release by Methylenedioxymethamphetamine is Mediated by Serotonin, Eur. J. Pharmacol. 168 209-217 (1989).

The administration of MDMA to rats produces a long-lasting decrease in extracellular dopamine in brain tissues. To determine if the known increased release of serotonin might be the cause of this, experimental animals were pretreated with PCA which effectively decreased the serotonin content and inhibited the dopamine decrease following MDMA treatment. The serotonin release by MDMA is argued as possibly being a mediating factor in the observed dopamine release.

Gibb, J.W., Johnson, M., Stone, D.M. and Hanson, G.R. Mechanisms Mediating Biogenic Amine Deficits Induced by Amphetamine and its Congeners. NIDA Research Monograph #136 226-241 (1993).

A large number of amphetamine-like derivatives, including MDMA, have been compared for their capacity for causing neurochemical deficits, in both the serotonin and the dopamine systems. Neurotoxicity is inferred in most cases as there is a long-term persistence of change.

Glennon, R.A. and Misenheimer, B.R. Stimulus Effects of N-Monoethyl-1-(3,4-Methylenedioxyphenyl)-2-aminopropane (MDE) and N-Hydroxy-1-(3,4-Methylenedioxyphenyl)-2-aminopropane (N-OH MDA) in Rats Trained to Discriminate MDMA from Saline. Pharmacol. Biochem. Behav. 33 909-912 (1989).

Both MDE and MDOH generalized to MDMA in rats trained to discriminate MDMA from saline. Amphetamine was less effective. Since MDMA substitutes for amphetamine, whereas neither MDE nor MDOH do so, these latter drugs appear to have less of an amphetamine-like component than MDMA.

Glennon, R.A. and Young, R. Further Investigation of the Discriminative Stimulus Properties of MDA. Pharmacol. Biochem. and Behaviour 20, 501-505 (1984).

In rats trained to distinguish between racemic MDA (and separately, "S"-amphetamine) and saline, MDMA (as well as either optical isomer of MDA) was found to generalize to MDA. Similarly, with rats trained to distinguish between dextro-amphetamine and saline, MDMA and "S"-MDA (but not "R"-MDA or "S"-DOM) produced generalization responses.

Glennon, R.A., Little, P.J., Rosecrans, J.A. and Yousif, M. The Effects of MDMA ("Ecstasy") and its Optical Isomers on Schedule-Controlled Responding in Mice. Pharmacol. Biochem. Behav. 26 425-426 (1987).

The effectiveness of several analogs of MDMA were evaluated in mice trained in a reinforcement procedure. Both (+) and racemic MDMA were 4x the potency of the levo-isomer; all were less potent than amphetamine.

Glennon, R.A., Young, R., Rosecrans, J.A. and Anderson, G.M. Discriminative Stimulus Properties of MDA Analogs. Biol. Psychiat. 17 807-814 (1982).

In rats trained to distinguish between the psychotomimetic DOM and saline, several compounds were found to generalize to DOM (including racemic MDA, its "R" isomer, and MMDA-2) Others did not generalize to DOM (including MDMA, the "S" isomer of MDA, and homopiperylamine). These results are consistent with the qualitative differences reported in man.

Glennon, R.A., Yousif, M. and Patrick, G. Stimulus Properties of 1-(3,4-Methylenedioxy)-2-Aminopropane (MDA) analogs. Pharmacol. Biochem. Behav. 29 443-449 (1988).

Rats were trained to discriminate between saline and DOM or d-amphetamine. They were challenged with "R" and "S" MDMA, with racemic, "R" and "S" MDE, and with racemic MDOH (N-OH-MDA). The amphetamine-trained animals generalized to "S" MDMA, but to neither "R" MDMA, any of the MDE isomers, MDOH, nor to homopiperonylamine. N-substituted amphetamine derivatives (N-ethyl and N-hydroxy) also gave the amphetamine response, but none of these compounds generalized to DOM. This study supports the suggestion that MDMA represents a class of compounds apart from the stimulant or the hallucinogenic.

Glennon, R.A. MDMA-Like Stimulus Effects of Alpha-Ethyltryptamine and the Alpha-Ethyl Homolog of DOM. Pharmacol. Biochem. Behav. 46 459-462 (1993).

The alpha-ethyl homologues of alpha-methyltryptamine and of DOM are a-ET and Dimoxamine. Whereas rats trained to discriminate MDMA from saline failed to generalize to DOM or alpha-methyltryptamine, they did to both of these homologues.

Glennon, R.A. and Higgs, R. Investigation of MDMA-Related Agents in Rats Trained to Discriminate MDMA from Saline. Pharm. Biochem. and Behav. 43 759-63 (1992).

A number of MDMA metabolites and related compounds were compared to MDMA in discrimination studies in the rat. Several gave MDMA-appropriate responses, but only 4-methoxymethamphetamine showed stimulus generalization. The intact methylenedioxy ring appears unneccessary for MDMA-like action

Glennon, R.A., Higgs, R., Young, R. and Issa, H. Further Studies on N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane as a Discriminative Stimulus: Antagonism by 5-Hydroxytryptamine3 Antagonists. Pharmacol. Biochem. Behavior 43 1099-106 (1992).

Rats were trained to discriminate MDMA from saline, and this response was evaluated with the study of antagonists of 5-HT1A (NAN-190), 5-HT2 (pirenperone), 5-HT3 (zacopride) and dopamine receptors (haloperidol). The results can give rise to several mechanistic interpretations, but it is concluded that MDMA produces it's stimulus effects via a complex mechanism involving both dopaminergic and serotonergic components.

Gold, L.H. and Koob, G.F. Methysegide Potentialtes the Hyperactivity Produced by MDMA in Rats. Pharmacol. Biochem. Behav. 29 645-648 (1988).

The hyperactivity that results from MDMA administration is significantly increased by methysergide. This latter drug was itself without effect, nor did it potentiate the hyperactivity induced by amphetamine administration.

Gold, L.H. and Koob, G.F. MDMA Produces Stimulant-like Conditioned Locomotor Activity, Psychopharmacology 99 352-356 (1989).

The administration of MDMA to rats concurrently with exposure to specific sensory clues (odours) produced a conditioned activity response to the clues alone. In this property, MDMA resembles other psychostimulants such as amphetamine and cocaine.

Gold, L.H., Geyer, M.A. and Koob, G.F. Psychostimulant Properties of MDMA. NIDA Monograph #95. Problems of Drug Dependence 345-346 (1989).

The pharmacological stimulant properties of MDMA are compared with those of amphetamine. But, as there are some hallucinogenic activity apparent as well, the overall action may be considered as unique mixture of these two properties.

Gold, L.H., Geyer, M.A. and Koob, G.F. Neurochemical Mechanisms Involved in Behavioural Effects of Amphetamines and Related Designer Drugs. NIDA Monograph #94. Pharmacology and Toxicology of Amphetamines and Related Designer Drugs, 101-126 (1989).

The dopaminergic aspects of the stimulatory action of MDMA, MDE and amphetamine in rats is discussed. This motor action has been evaluated in conjunction with several areas of brain neuroactivation.

Gold, L.H. , Hubner, C.B. and Koob, G.F. A Role for the Mesolimbic Dopamine System in the Psychostimulant Actions of MDMA. Psychopharmacology 99 40-47 (1989).

The stimulant action produced by MDMA in rats was studied with and without the brain lesions produced by 6-hydroxydopamine. The attenuation of responses was similar to that seen with amphetamine suggests that some involvement of presynaptic release of dopamine may be involved in its action.

Gordon, C.J., Watkinson, W.P., O'Callaghan, J.P. and Miller, B.D. Effects of 3,4-Methylenedioxymethamphetamine on Autonomic Thermoregulatory Responses of the Rat. Pharm. Biochem. Behav. 38 339-344 (1991).

The acute s.c. administration of 30 mg/Kg MDMA to rats led to a increase in body temperature. It is concluded that MDMA stimulates the serotonin pathways that control the metabolic rate and this, accompanied by peripheral vasostriction, lead to the observed hyperthermia.

Gough, B., Ali, S.F., Slikker, W. and Holson, R.R. Acute Effects of 3,4-Methylenedioxymethamphetamine (MDMA) on Monoamines in Rat Caudate. Pharmacol. Biochem. Behav. 39 619-623 (1991).

A number of neurotransmitter metabolites were assayed in the rat, following the i.p. injection of MDMA. It was concluded that MDMA affects both the dopaminergic as well as the serotoninergic systems.

Griffiths, R.R., Lamb, R. and Brady, J.V. A Preliminary Report on the Reinforcing Effects of Racemic 3,4-Methylenedioxymethamphetamine in the Baboon. Document entered into evidence Re: MDMA Scheduling Docket No. 84-48, U.S. Department of Justice, Drug Enforcement Administration, October 16, 1985.

In three baboons trained to respond to cocaine, MDMA maintained self-administration at a somewhat lower level than cocaine, d-amphetamine, and phencyclidine. There was the evocation of distinct behavioural signals, which suggested that MDMA had a high abuse potential.

Harris, L.S. Preliminary Report on the Dependence Liability and Abuse Potential of Methylenedioxymethamphetamine (MDMA). Document entered into evidence Re: MDMA Scheduling Docket No. 84- 48, U.S. Department of Justice, Drug Enforcement Administration, October 16, 1985.

MDMA and amphetamine were compared as to locomotor activity in mice, and in reinforcing activity in monkeys as compared to cocaine. MDMA showed a fraction (20-25%) of the stimulant activity of amphetamine, and was substituted for cocaine in some of the test monkeys.

Hashimoto, K. Effects of Benzylpiperazine Derivatives on the Acute Effects of 3,4-Methylenedioxymethamphetamine in Rat Brain. Neurosci. Let. 152 17-20 (1993).

The reduction of serotonin in rat brain following exposure to MDMA was significantly attenuated with the co-administration of weak inhibitors (several benzylpiperazines) of serotonin uptake into synaptosomes. The co-administration of the more potent inhibitors (desipramine, imipramine) did not attenuate this MDMA-induced reduction of serotonin, suggesting that the effects of the piperazines may employ a different neurological pathway.

Hashimoto, K., Maeda, H., Hirai, K. and Goromaru, T. Drug Effects on Distribution of [3H]3,4-Methylenedioxymethamphetamine in Mice. Eur. J. Pharmacol. - Environm. Tox. Pharmacol. Section 228 247-256 (1993).

The effectiveness of a number of drugs and other compounds carrying the methylenedioxyphenyl group on the distribution of radioactive MDMA in the mouse brain was determined. It is suggested that there may exist a specific mechanism for this group which rapidly alters the disposition and metabolism of MDMA.

Hegadoren, K.M., Baker, G.B. and Coutts, R.T. The Simultaneous Separation and Quantitation of the Enantiomers of MDMA and MDA using Gas Chromatography with Nitrogen-Phbosphorus Detection. Res. Commun. Subs. Abuse 14 67-80 (1993).

Following the administration of racemic MDMA to the rat, the levels of both MDMA and its demethylated metabolite MDA were determined in areas of the brain. Assays were made at 1,2,4 and 8 hrs., and with a chiral derivative system that allowed the determination of the amounts of the optical isomers resulting from selective chiral metabolism. For unmetabolized MDMA, the concentrations of the (-) isomer were greater than for the (+) isomer. The reverse was true for the demethylated metabolite MDA which, although present at much lower levels, was largely the (+) isomer in all regions studied.

Hiramatsu, M., Nabeshima, T., Kameyama, T., Maeda, Y. and Cho, A.K. The Effect of Optical Isomers of 3,4-Methylenedioxymethamphetamine (MDMA) on Stereotyped Behaviour in Rats. Pharmacol. Biochem. Behaviour 33 343-347 (1989).

The optical isomers of MDMA were compared as to their potencies in inducing stereotyped behaviour in rats. The "S", or (+) isomer was the more potent, which was consistent with this isomer's increased effectiveness in the release of neurotransmitters.

Hubner, C.B., Bird, M., Rassnick, S. and Lornetsky, C. The Threshold Lowering Effects of MDMA (Ecstasy) on Brain-stimulating Reward. Psychopharmacology 95 49-51 (1988). MDMA produced a dose-related lowering of the reward threshold, as

determined in rats with electrodes stereotaxically implanted in the medial forebrain bundle-lateral hypothalamic area. This procedure has been used as an animal model for drug-induced euphoria.

Huang, X. and Nichols, D. 5-HT2 Receptor-Mediated Potentiation of Dopamine Synthesis and Central Serotonergic Deficits. Eur. J. Pharm. 238 291-296 (1993).

Employing receptor agonists, releasing agents and enzyme inhibitors in rats, the hypothesis was tested that serotonin modulates the MDMA-induced increase in dopamine synthesis. The results indicate that the induced increases depend on both serotonin receptor stimulation and on dopamine efflux.

Jensen, K.F., Olin, J., Haykal-Coates, N., O'Callaghan, J., Miller, D.B. and de Olmos, J.S. Mapping Toxicant-Induced Nervous System Damage With Cupric Silver Stain: A Quantitative Analysis of Neural Degeneration Induced by 3,4-Methylenedioxymethamphetamine. NIDA Research Monograph #136 133-154 (1993).

An argument is made for the quantitative potential that could be realized from the cupric silver staining of degenerating neurons. This technique was applied to rats that had been treated with MDMA and a dose-response curve of neural degeneration was obtained.

Johnson, M., Bush, L.G., Gibb, J.W. and Hanson, G.R. Blockade of the 3,4-Methylenedioxymethamphetamine-induced Changes in Neurotensin and Dynorphin A Systems. Eur. J. Pharmacol. 193 367-370 (1991).

The increase in immunoreactivity in the neurotensin and dynorphin systems following a single s.c. injection of MDMA in the rat has suggested that both the dopaminergic and glutamatergic systems are involved.

Johnson, M.P., Frescas, S.P., Oberlender, R. and Nichols, D.E. Synthesis and Pharmacological Examination of 1-(3-Methoxy-4-methylphenyl)-2-aminopropane and 5-Methoxy-6-methyl-2-aminoindane: Similarities to 3,4-Methylenedioxymeth-amphetamine (MDMA). J. Med. Chem. 34 1662-1668 (1991).

The two title compounds have been viewed as analogues of DOM (missing a methoxyl group) or of alpha,4-dimethyltyramine (with O-methylation) and have been synthesized. Both compounds appear to be pharmacologically similar to MDMA, but are lacking any indications of neurotoxicity.

Johnson, M., Bush, L.G., Midgley, L., Gibb, J.W. and Hanson, G.R. MK-801 Blocks the Changes in Neurotensin Concentrations Induced by Methamphetamine, 3,4-Methylenedioxymethamphetamine, Cocaine, and GBR 12909. Ann. N.Y. Acad. Sci. 668 350-352 (1992).

A study of the neurotensin-like immunoreactivity in the rat has been shown to increase following the administration of several compounds, including MDMA. This can be blocked by the administration of a dopamine D1 receptor antagonist (SCH 23390).

Kamien, J.B., Johanson, C.E., Schuster, C.R. and Woolverton, W.L. The Effects of (+/-)-Methylenedioxymethamphetamine in Monkeys Trained to Discriminate (+)-Amphetamine from Saline. Drug and Alcohol Dependence 18 139-147 (1986).

In monkeys trained to discriminate between amphetamine and saline, MDMA substituted for amphetamine suggesting that there was an amphetamine-like component to its action. This similarity suggested a dependence potential.

Kasuya, Y. Chemicopharmacological Studies on Antispasmodic Action. XII. Structure-Activity Relationship on Aralkylamines. Chem. Pharm. Bull. 6 147-154 (1958).

In vitro studies on mouse intestinal segments were carried out for the chain homologue of MDMA, vis., 1-(3,4-methylenedioxyphenyl)-3-methylaminobutane. This is the amine that would result from the use of the "wrong" piperonylacetone in illicit synthesis. The compound shows weak atropine action.

Kehne, J.H., McCloskey, T.C., Taylor, V.L., Black, C.K., Fadayel, G.M. and Schmidt, C.J. Effects of the Serotonin Releasers 3,4-Methylenedioxymethamphetamine (MDMA), 4-Chloroamphetamine (PCA) and Fenfluramine on Acoustic and Tactile Startle Reflexes in Rats. J. Pharm. Exptl. Therap. 260 78-89 (1992).

The three amphetamine derivatives, MDMA, PCA and Fenfluramine share a common neurochemical action, of releasing central cerotonin, but the behavioural effects they evoke are dissimilar. Use of serotonin blockers was made to study the pharmacology of these compounds.

Krebs, K.M. and Geyer, M.A. Behavioral Characterization of Alpha-Ethyltryptamine, a Tryptamine Derivative with MDMA-like Properties in Rats. Psychopharmacology 113 284-287 (1993).

There have been a number of anecdotal comparisons between MDMA and alpha-ethyl tryptamine (AET). These have supported the scheduling of the latter compound in the United States. In rat studies, AET appears to produce an MDMA-like profile of behavioral changes apparently related to serotonin release.

Kulmala, H.K., Boja, J.W. and Schechter, M.D. Behavioural Suppression Following 3,4-Methylenedioxymethamphetamine. Life Sciences 41 1425-1429 (1987).

Rotation in rats was employed as an assay of the central dopaminergic activity of MDMA. At low doses it acts similarly to amphetamine, but at higher doses it appears to stimulate the dopamine receptor directly.

Lamb, R.J. and Griffiths, R.R. Self-injection of dl-3,4-Methylenedioxymethamphetamine in the Baboon. Psychopharmacolgy 91 268-272 (1987).

In monkeys conditioned to the self-administration of cocaine, MDMA produced a similar but less potent response. A decrease in food intake was also reported.

LeSage, M., Clark, R. and Poling, A. MDMA and Memory: The Acute and Chronic Effects of MDMA in Pigeons Performing under a Delayed-matching-to-sample Procedure. Psychopharmacol. 110 327-332 (1993).

The behavior-disruptive effectiveness of MDMA in the conditioned behavior of pigeons was found to be dose-dependent. Tolerance to the drug was observed, but there did not appear to be any long-lasting behavioral impairment.

Li, A., Marek, G., Vosmer, G. and Seiden, L. MDMA-induced Serotonin Depletion Potentiates the Psychomotor Stimulant Effects of MDMA on Rats Performing on the Differential-Reinforcement-of-Low-Rate (DRL) Schedule. Society of Neurosciences Abstracts 12 169.7 (1986).

This is a study of Serotonin depletion and motor response. The long term depletion following both acute and chronic administration of MDMA to rats, increased activity and decreased serotonin suggests some inhibitory action of this neurotransmitter.

Li, A.A., Marek, G.J., Vosmer, G. and Seiden, L.S. Long-Term Central 5-HT Depletions Resulting from Repeated Administration of MDMA Enhances the Effects of Single Administration of MDMA on Schedule-Controlled Behaviour of Rats Pharmacol. Biochem. Behaviour 33 641-648 (1989).

Experimental rats showed an increased response in schedule-controlled behaviour studies to the effect of a single dose of MDMA if this dose was preceded by a regimen of chronic exposure to MDMA. This sensitisation was typical of amphetamine and other stimulants.

Matthews, R.T., Champney, T.H. and Frye, G.D. Effects of (+/-)-Methylenedioxymethamphetamine (MDMA) on Brain Dopaminergic Activity in Rats. Pharmacol. Biochem. Behav. 33 741-747 (1989).

High levels of MDMA in rats increased locomotor activity, and decreased brain dopamine turnover rate as determined by dihydroxyphenylacertic acid levels. There were some similarities to amphetamine exposure in the effects seen on dopamine neurons.

Mansbach, R.S., Braff, D.L. and Geyer, M.A. Prepulse Inhibition of the Acoustic Startle Response is Disrupted by N-Ethyl-3,4-methylenedioxyam-phetamine (MDEA) in the Rat. Eur. J. Pharmacol. 167 49-55 (1989).

Both the optical isomers and the racemate of MDE, as well as racemic MDMA, were studied as to their effectiveness as prepulse inhibitors of the acoustic startle response, a measure of sensitivity to psychoactive drugs. The (+) isomer of MDE, and the racemate, and (less so) racemic MDMA were effective inhibitors, suggesting a psychostimulant component in their activities.

McKenna, D.J., Guan, X.-M. and Shulgin, A.T. 3,4-Methylenedioxyamphetamine (MDA) Analogues Exhibit Differential Effects on Synaptosomeal Release of 3H-Dopamine and 3H-5-Hydroxytryptamine. Pharm. Biochem. Behav. 38 505-512 (1991).

The in vitro effectiveness of a number of MDA analogues on the release of serotonin and dopamine from synaptosomes was determined.

Nash, J. F. Ketanserin Pretreatment Attenuates MDMA-induced Dopamine Release in the Striatum as Measured by in vivo Microdialysis. Life Sciences 47 2401-2408 (1990).

The systemic administration of MDMA to freely moving rats produces a dose-dependent extracellular concentration of dopamine in the striatum. The effects of administering the serotonin antagonist, Ketanserin, are reported.

Nash, J.F. and Brodkin, J. Microdialysis Studies on 3,4-Methylenedioxymethamphetamine-induced Dopamine Release: Effect of Dopamine Uptake Inhibitors. J. Pharm. Exptl. Therap. 259 820-825 (1991)

The effects of both dopamine and serotonin uptake inhibitors on the MDMA induced increase in dopamine efflux were studied by microdialysis techniques. The dopaminergic effects are believed to be independent of those resulting from serotonin release.

Nash, J.F. and Nichols, D.E. Microdialysis Studies on 3,4-Methylenedioxyamphetamine and Structurally Related Analogues. Europ. J. Pharmacol. 200 53-58 (1991).

MDA and three analogues (MDMA, MDE and MBDB) were studied in the free-moving rat by microdialysis. The effects on dopamine were observed, and they did not correlate well with serotonin. Structural relationships are discussed.

Nash Jr., J.F., Meltzer, H.Y. and Gulesky, G.A. Elevation of Serum Prolactin and Corticosterone Concentrations in the Rat after the Administration of 3,4-Methylenedioxymethamphetamine. J. Pharmacol. Exptl. Therap. 245 873-879 (1988).

The effects of acute i.p. administrations of MDMA were seen as an elevation of prolactin and corticosterone in rats. The effects of the serotonin uptake inhibitor Fluoxetine and of p-chlorophenylalanine on MDMA-induced neuroendocrine responses are similar to those induced by p-chloroamphetamine.

Nencini, P., Woolverton, W.L. and Seidin, L.S. Enhancement of Morphine-induced Analgesia after Repeated Injections of Methylenedioxymethamphetamine. Brain Research 457 136-142 (1988).

Chronic administration of MDMA to rats led to an enhancement of the analgesic effects of morphine administration. The changes in the serotonin and 5-hydroxytryptamine levels were confirmed.

Nichols, D.E., Hoffman, A.J., Oberlender, R.A., Jacob III, P. and Shulgin, A.T. Derivatives of 1-(1,3-Benzodioxol-5-yl-2-butanamine: Representatives of a Novel Therapeutic Class. J. Med. Chem. 29 2009-2015 (1986).

Animal discrimination studies (LSD versus saline) of the alpha-ethyl homologues of MDA and MDMA were performed. No generalization occurred with the N-methyl analogs of either group (MDMA and MBDB), and the latter compound was also found to be psychoactive but not hallucinogenic in man. It was found to be less euphoric than MDMA, but with the same sense of empathy and compassion. The term "entactogen" is proposed for the class of drugs represented by MDMA and MBDB.

Oberlender, R. and Nichols, D.E. Drug Discrimination Studies with MDMA and Amphetamine. Psychopharmacology 95 71-76 (1988).

Rats were trained to discriminate saline from either racemic MDMA or dextroamphetamine. The MDMA cue generalized to MDA and to all isomers of MDMA and MBDB, but not to LSD or DOM. The dextroamphetamine cue generalized to methamphetamine, but to none of the forms of either MDMA or MBDB. The "S" isomers of both MDMA and MBDB were the more potent.

Oberlender, R. and Nichols, D.E. (+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine as a Discriminative Stimulus in Studies of 3,4-methylenedioxymethamphetamine-Like Behavioural Activity. J. Pharm. Exptl. Therap. Vol. 255 pp.1098-1106 (1990).

A number of compounds (including the racemate and the optical isomers of MBDB) were studied in rats trained to discriminate between (+)-MBDB and saline. There was generalization to both MDMA and MDA, but not to DOM, LSD or mescaline, nor for either amphetamine or methamphetamine. Several aminoindanes were also assayed.

Park, W.K. and Azmitia, E.C. 5-HT, MDMA (Ecstasy), and Nimodipine Effects on 45Ca-Uptake into Rat Brain Synaptosomes. Ann. N.Y. Acad. Sci. 635 438-440 (1991).

The uptake of calcium ion into the rat brain, both basal and K+ stimulated, was increased by exposure to MDMA, a potent neuropathological drug of abuse. Interestingly, this same increase was seen with both serotonin and Fluoxetine.

Paulus, M.P. and Geyer, M.A. The Effects of MDMA and Other Methylenedioxy-substituted Phenylalkylamines on the Structure of Rat Locomotor Activity. Neuropsychopharm. 7 15-31 (1992).

The effects of acute s.c. injections of MDA, racemic, S(+) and R(-) MDMA, racemic MBDB, racemic MDEA, DOI, and methamphetamine were studied in the rat. Indirect 5-HT1 effects appear to contribute substantially to the differential changes in the amount and structure of motor behaviour induced by the phenylalkylamines. This conclusion may provide an encouraging rationale to develop postsynaptically effective "entactogens", a potential new drug category as adjunctive psychotherapeutics.

Paulus, M.P., Geyer, M.A., Gold, L.H. and Mandell, A.J. Application of Entropy Measurements Derived from the Ergodic Theory of Dynamical Systems to Rat Locomotor Behaviour. Proc. Natl. Acad. 87 723-727 (1990).

The observed activity of rats treated with MDMA followed paths with a different geometric distribution, than control animals treated with amphetamine.

Rezvani, A.H., Garges, P.L., Miller, D.B. and Gordon, C.J. Attenuation of Alcohol Consumption by MDMA (Ecstasy) in Two Strains of Alcohol-preferring Rats. Pharm. Biochem. Behav. 43 103-110 (1992)

The hypothesis that serotonin is involved in alcoholism has led to the design and carrying out of an experiment evaluating the action of MDMA, acutely and chronically, on the behaviour of alcohol-preferring rats. It was found to have an inhibitory action on alcohol preference, perhaps by the enhancement of serotonergic and/or dopaminergic systems in the CNS.

Rosecrans, J.A. and Glennon, R.A. The Effect of MDA and MDMA ("Ecstasy") Isomers in Combination with Pirenpirone on Operant Responding in Mice. Pharmacol. Biochem. Behav. 28 39-42 (1987). See also: Soc. Neurosci. Abstr. 13, Part 3, p. 905 (1987) No. 251.10.

The disruptive effects of the optical isomers of MDA and MDMA were studied for mice trained in a reinforcement schedule, both with and without pretreatment with Pirenpirone, a serotonin antagonist. Of the four isomers evaluated, only "R"-MDA behaviour responses were attenuated by Pirenpirone.

Scallet, A.C., Lipe, G.W., Ali, S.F., Holson, R.R., Frith, C.H. and Slikker Jr., W. Neuropathological Evaluation by Combined Immunohistochemistry and Degeneration-Specific Methods: Application to Methylenedioxymethamphetamine. Neurotoxicol. 9 529-539 (1988).

The combination of neurohistological and neurochemical evaluations suggests that the changes in serotonin levels following MDMA exposure in the rat is due to neural degeneration followed by axon loss, rather than a decrease in serotonin synthesis.

Scanzello, C.R., Hatzidimitriou, G., Martello, A.L., Katz, J.L. and Ricaurte, G.A. Serotonergic Recovery after (+/-)3,4-(Methylenedioxy)methamphetamine Injury: Observations in Rats. J. Parmacol. Exptl. Therap. 264 1484-1491 (1993).

In rats, as opposed to monkeys, the damage that is done by exposure to MDMA appears to be reversable. This study explored the permanence of this recovery, and in some cases it appears to be sustained for at least a year. Some rats, however, appeared not to show this recovery.

Schmidt, C.J., Sullivan, C.K. and Fadayel, G.M. Blockade of Striatal 5-Hydroxytryptamine(2) Receptors Reduces the Increase in Extracellular Concentrations of Dopamine Produced by the Amphetamine Analogue 3,4-Methylenedioxymethamphetamine. J. Neurochem. 62 1382-89 (1994).

MDMA stimulates the synthesis and release of dopamine, and serotonin receptor antagonists interfere with this action. Studies have been made to determine which receptors are responsible.

Schechter, M.D. Discriminative Profile of MDMA. Pharmacol. Biochem. Behav. 24 1533-1537 (1986)

Rats trained to discriminate several psychoactive drugs (against saline) were challenged with MDMA. The findings show that MDMA may act both as a dopamine and a serotonin agonist. This property is related to its abuse potential.

Schechter, M.D. MDMA as a Discriminative Stimulus: Isomeric Comparisons. Pharmacol. Biochem. Behav. 27 41-44 (1987).

Studies with rats trained to discriminate racemic MDMA from saline, showed generalization with both optical isomers of MDMA, with the "S" isomer being more potent. The chronological observations paralleled the reported human responses.

Schechter, M.D. Advantages and Disadvantages of a Rapid Method to Train Drug Discrimination. Pharmacol. Biochem. Behav. 31 239-242 (1988).

A exploration of training regimens was made for accelerating the development of discrimination protocols, using MDMA as a trial drug. The various findings are discussed.

Schechter, M.D. Effect of MDMA Neurotoxicity Upon Its Conditioned Place Preference and Discrimination. Pharmacol. Biochem. Behav. 38 539-544 (1991).

Two behaviour patterns, conditioned place preference and discrimination, were used as measures of the neurotoxicity induced by MDMA in rats. Dose-dependent changes were observed. The possible involvement of both serotonin and dopamine neurons is discussed.

Schlemmer Jr., R.F., Montell, S.E. and Davis, J.M. Fed. Proc. 45 1059 (1986).

The behavioural effects of MDMA have been studied in a primate colony, following multiple acute exposures. There was a decrease in activity, grooming, and food-searching, and an increase in staring. There was a disruption of social behaviour, that differed from the effects of other hallucinogens.

Schmidt, C.J. and Taylor, V.L. Reversal of the Acute Effect of 3,4-Methylenedioxymethamphetamine by 5-HT Uptake Inhibitors. Europ. J. Pharmacol. 181 133-136 (1990).

Re-uptake inhibitors of serotonin were administered at intervals following the administration of MDMA to rats. The inactivation of tryptophan hydroxylase activity that follows MDMA administration can be rapidly recovered by the early administration of such an inhibitor.

Schmidt, C.J., Fadayel, G.M., Sullivan, C.K. and Taylor, V.L. 5-HT2-Receptors Exert a State-Dependent Regulation of Dopaminergic Function - Studies with MDL-100,907 and the Amphetamine Analogue, 3,4-Methylenedioxymethamphetamine. Eur. J Pharmacol. 223 65-74 (1992).

The role of serotonin in the stimulation of dopaminergic function as produced by MDMA, was studied by the use of a selective serotonin receptor antagonist. The interactions between these receptors and dopamine activation are discussed.

Sharkley, J., McBean, D.E. and Kelly, P.A.T. Alterations in Hippocampal Function Following Repeated Exposure to the Amphetamine Derivative Methylenedioxymethamphetamine ("Ecstasy"). Psychopharmacology 105 113-118 (1991).

Studies with labelled deoxyglucose radiography techniques demonstrate that the loss of serotonin innervation resulting from MDMA exposure in the rat resulted in lasting change in hippocampus function.

Spanos, L.J. and Yamamoto, B.K. Acute and Subchronic Effects of Methylenedioxymethamphetamine [(+/-) MDMA] on Locomotion and Serotonin Syndrome Behaviour in the Rat. Pharm. Biochem. Behav. 32 835 (1989).

The behavioural effects of MDMA on rats were observed. There was a "serotonin syndrome" (low body posture, forepaw treading, headweaving) as well as autonomic signs (piloerection and salivation). These were dose-dependent, and were augmented with sub-acute exposure implying behavioural sensitisation.

Sprouse, J.S., Bradberry, C.W., Roth, R.H. and Aghajanian, G.K. MDMA 3,4-Methylenedioxymeth-amphetamine Inhibits the Firing of Dorsal Raphe Neurons in Brain Slices via Release of Serotonin. Eur. J. Pharmacol. 167 375-383 (1989).

Both optical isomers of MDMA as well as p-chloroamphetamine led to a reversible dose-dependant inhibition of serotonin cell firing. The (+) isomer was the more potent, and these effects were blocked by Fluoxetine. It was concluded that MDMA inhibits the raphe neurons through the release of endogenous serotonin.

Sprouse, J.S., Bradberry, C.W., Roth, R.H. and Aghajanian, G.K. 3,4-Methylenedioxymethamphetamine-induced Release of Serotonin and Inhibition of Dorsal Raphe Cell Firing: Potentiation by L-Tryptophane. Eur. J. Pharmacol. 178 313-320 (1990).

The relationship between L-tryptophan and the psychotropic and neurotoxic action of MDMA (in the rat) has been studied. A pretreatment with tryptophane appeared to increase the potency of MDMA, with the apparent release of serotonin.

Steele, T.D., Nichols, D.E. and Yim, G.K. MDMA Transiently Alters Biogenic Amines and Metabolites in Mouse Brain and Heart. Pharm. Biochem. Behav. 34 223-227 (1989)

The administration of MDMA to the mouse elevated the brain serotonin levels (rather than lowering them, as seen in the rat), but had little effect on the dopamine levels. The highest level depleted norepinephrine in both brain and heart. Mice appear to be resistant to the neurotoxic effects of MDMA.

Stone, D.M., Johnson, M., Hanson, G.R. and Gibb, J.W. Role of Endogenous Dopamine in the Central Serotonergic Deficits Induced by 3,4-Methylenedioxymethamphetamine. J. Pharm. Exp. Therap. 247 79-87 (1988).

The role of endogenous dopamine was examined in rats which had been subjected to both acute and chronic MDMA exposure. Potential mechanisms of dopamine-mediated toxicity are discussed.

Thompson, D.M., Winsauer, P.J. and Mastropaolo, J. Effects of Phencyclidine, Ketamine and MDMA on Complex Operant Behaviour in Monkeys. Pharm. Biochem. Behav. 26 401-405 (1987).

The loss of response to conditioned behaviour in monkeys was observed for the title drugs. All were effective i.m., with phencyclidine being the most potent, and MDMA being the least potent.

Winslow, J.T. and Insel, T.R. Serotonergic Modulation of Rat Pup Ultrasonic Vocal Development: Studies with 3,4-Methylenedioxymethamphetamine.J. Pharm. Exp. Therap. 254 212-220 (1990).

New-born rat pups voice a high frequency sound, an isolation call, when separated from their mothers. These calls were decreased in a dose-dependant manner following the administration of MDMA. Benzodiazepine and opioid agonists also show this response. A number of pharmacological challenges suggest that these effects may be related to serotonin changes.

Yeh, S.Y. and Hsu, F-L. The Neurochemical and Stimulatory Effects of Putative Metabolites of 3,4-Methylenedioxyamphetamine and 3,4-Methylenedioxymethamphetamine in Rats. Pharmacol. Biochem. Behav. 39 787-790 (1991).

Both MDA and MDMA, as well as their metabolites, were injected s.q. into rats. Brain analyses for serotonin and 5-hydroxyindoleacetic acid were conducted. Both MDA and MDMA appeared to have a stimulative action of the test animals.

Zacny, J.P., Virus, R.M. and Woolverton, W.L. Tolerance and Cross-Tolerance to 3,4-Methylenedioxymethamphetamine (MDMA), Methamphetamine and Methylenedioxyamphetamine. Pharmacol. Biochem. Behav. 35 637-642 (1990).

Using milk intake as a titrant of behaviour, rats were evaluated for their behavioural responses to MDMA, methamphetamine (MA) and MDA. These animals were then treated chronically with either MDMA or saline, and the degree of tolerance determined by challenges with the three drugs. MDMA produced a tolerance for MDMA, there was some tolerance for these animals to MDA, depending on the schedule established, and there was no tolerance of these animals to the administration of MA.

Ali, S.F., Scallet, A.C., Holson, R.R., Newport, G.D. and Slikker Jr., W. Acute Administration of MDMA (Ecstasy): Neurochemical Changes Persist up to 120 Days in Rat Brain. Soc. Neurosci. Abstr. 13 904 (1987).

Rats were given 40 mg/Kg MDMA twice daily for 4 days. After 120 days, some regions of the brain (frontal cortex, hippocampus) still had serotonin depletion. There was fighting behaviour noted between rats during the dosing and for up to two weeks following it.

Ali, S.F., Scallet, A.C., Newport, G.D., Lipe, G.W., Holson, R.R. and Slikker Jr., W. Persistent Neurochemical and Structural Changes in Rat Brain after Oral Administration of MDMA. Res. Commun. Subst. Abuse 10 225-236 (1989).

Rats were administered short-term intense levels of MDMA orally, and then assayed for neurological changes after a period of four months. Changes were seen in the levels of both serotonin and 5-hydroxyindoleacetic acid, and neurohistological changes in the brain step were observed.

Anon. Long-term Effects of "Ecstasy": Study Finds Brain Cell Destruction. NIDA Notes 2 # 3. p. 7 (1987).

A short distillation of the present state of MDMA research in relationship to serotonin neurochemistry is presented.

Battaglia, G. and De Souza, E.B. Pharmacologic Profile of Amphetamine Derivatives at Various Brain Recognition Sites: Selective Effects on Serotonergic Systems. NIDA Research Monograph Series #94 240-258 (1989).

A review is presented of the affinities for a large number of substituted amphetamine derivatives for several serotonin receptors. An addition, a pharmacologic profile of binding affinities of MDMA at a number of recognition sites is tabulated.

Battaglia, G., Kuhar, M.J. and De Souza, E.B. MDA and MDMA (Ecstasy) Interactions with Brain Serotonin Receptors and Uptake Sites: In vitro Studies. Soc. Neurosciences Abs. 12 336.4 (1986).

The receptor site uptake of the optical isomers, as well as the racemate, of both MDA and MDMA were measured by separate, selective labelling with appropriate radioligands. The relationships between the isomers depended on whether uptake sites or receptors were involved, and differed at different locations in the brain.

Battaglia, G., Sharkey, J., Kuhar, M.J. and De Souza, E.B. Neuroanatomic Specificity and Time Course of Alterations in Rat Brain Serotoninergic Pathways Induced by MDMA (3,4- Methylenedioxymethamphetamine): Assessment Using Quantitative Autoradiography. Synapse 8 249-260 (1991).

A quantitative measure of the change in serotonin uptake sites as a consequence of MDMA exposure in rats was determined by the use of radio labelled Paroxetine. Changes as a function of time were noted in defined areas of the brain.

Battaglia, G., Yeh, S.Y. and De Souza, E.B. MDMA-Induced Neurotoxicity: Parameters of Degeneration and Recovery of Brain Serotonin Neurons. Pharmacol. Biochem. Behav. 29 269-274 (1988).

A number of parameters were studied to define the nature of the neurotoxic effect on serotonin axons and terminals. Both the size and frequency of drug administration resulted in a dose-dependent response. Regeneration of these neurons was also time dependent, returning to control levels in 12 months. Pretreatment with a serotonin uptake blocker (Citalopram) prevented the neurodegenerative effects of MDMA. The rat and guinea-pig brains were affected, whereas the mouse brain was not.

Battaglia, G., Yeh, S.Y., O'Hearn, E., Molliver, M.E., Kuhar, M.J. and De Souza, E.B. 3,4-Methylenedioxymethamphetamine and 3,4-Methylenedioxyamphetamine Destroy Serotonin Terminals in Rat Brain: Quantification of Neurodegeneration by Measurements of [3H] Paroxetine-Labelled Serotonin Uptake Sites. J. Pharm. Exptl. Therap. 242 911-916 (1987),

The effects of repeated administration of MDMA and MDA on the levels of rat brain monoamines and their metabolites are reported. Only the serotonin-related systems were found to be affected.

Battaglia, G., Zaczek, R. and De Souza, E. MDMA Effects in Brain: Pharmacologic Profile and Evidence of Neurotoxicity from Neurochemical and Autoradiographic Studies. The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Kluwer, New York. (1990) Ed: S.J. Peroutka.

A series of in vitro and in vivo studies of MDMA in rats has allowed a thorough mapping of the sites of MDMA-induced neurotoxicity.

Bird, M.P., Svendsen, C.N., Knapp, C., Hrbek, C.C., Bird, E.D. and Kornetsky, C. Evidence for Dopaminergic and Not Serotonergic Mediation of the Threshold Lowering Effects of MDMA on Rewarding Brain Stimulation. Soc. Neurosci. Abstr. 13, Part 3, p. 1323 (1987) No. 365.13.

An effort was made to determine the rewarding aspect of MDMA by a combination of brain electrodes and specific neurotransmitter inhibitors. It is felt that MDMA reinforcing values may be mediated by the dopamine D2 receptor rather than the serotonin 5-HT2 receptor.

Callaway, C.W., Nichols, D.E., Paulus, M.P. and Geyer, M.A. Serotonin Release is Responsible for the Locomotor Hyperactivity in Rats Induced by Derivatives of Amphetamine Related to MDMA. Serotonin: Molecular Biology, Receptors and Functional Effects, Birkh=E4user Verlag, Basel. J.R. Fozard and P.R. Saxena, Eds. (1991).

In rats MDMA produces locomotor hyperactivity, but the spatial pattern of locomotion differs qualitatively from the pattern of exploration produced by other psychostimulants.

Callaway, C.W., Rempel, N., Peng, R.Y. and Geyer, M.A. Serotonin 5-HT1-Like Receptors Mediate Hyperactivity in Rats Induced by 3,4-Methylenedioxymethamphetamine. Neuropsychopharm. 7 113-127 (1992).

This study was designed to evaluate the role of different serotonin (5-HT) receptor subtypes in mediating the effects of MDMA on a rat's exploration of a novel environment. This study indicates that S-MDMA produces a characteristic form of locomotor hyperactivity in rats that depends upon activation of 5-HT1-like receptors, possibly of the 5-HT1b subtype.

Champney, T.H. and Matthews, R.T. Pineal Serotonin is Resistant to Depletion by Serotonergic Neurotoxins in Rats. J. Pineal Res. 11 163-167 (1991).

A comparison between MDMA and p-chloroamphetamine (pCA) has been made in the rat with a view to neurotoxicity. Both compounds reduced serotonin levels in several brain areas, but neither affected the neurotransmitter levels in the pineal. This gland does not appear to have the serotonin re-uptake system that is thought to be necessary for MDMA or pCA induced neurotoxicity.

Champney, T.H., Golden, P.T. and Matthews, R.T. Reduction of Hypothalamic Serotonin Levels after Acute MDMA Administration. Soc. Neurosciences Absts. 12 101.6 (1986).

Cortical, hypothalamic, and pineal levels of catecholamines, serotonin and 5-HIAA were determined shortly following an acute exposure of rats to each of several doses of MDMA. Dose-dependent decreases of serotonin and 5-HIAA were noted in some but not other areas of the brain. The catecholamine levels were unchanged.

Commins, D.L., Vosmer, G., Virus, R.M., Woolverton, C.R., Schuster, C.R. and Seiden, L.S. Biochemical and Histological Evidence that Methylenedioxmethamphetamine (MDMA) is Toxic to Neurons in Rat Brain. J. Pharm. Exptl. Therap. 241 338-345 (1987).

MDMA was administered chronically to rats and guinea pigs , and the neurotransmitter levels were assayed in several portions of the brain. These levels were found to be related to dosage, and to the extent of exposure. Anatomical morbidity is carefully described.

Defrese, G.D.R. (+/-)-3,4-Methylenedioxymethamphetamine (MDMA): Extending the Debate Regarding Clinical Implications of its Neurotoxicity. Unpublished manuscript, Department of Pharmacology, U.C. Davis, (1990).

An experimental approach is proposed, using experimental animals, to evaluate the toxicological risks to man that might result from the reintroduction of MDMA into clinical practice.

De Souza, E.B. and Battaglia, G. Effects of MDMA and MDA on Brain Serotonin Neurons: Evidence from Neurochemical and Autoradiographic Studies. NIDA Research Monograph Series #94 196-222 (1989).

A series of studies with both MDMA and MDA demonstrate dose-dependent changes in the brain serotonin neurons, which can blocked by pretreatment with a serotonin uptake blocker.

DeSouza, E.B., Battaglia, G., Shu, Y.Y. and Kuhar, M.J. In Vitro and In Vivo Effects of MDA and MDMA (Ecstasy) on Brain Receptors and Uptake Sites: Evidence for Selective Neurotoxic Actions on Serotonin Terminals. Amer. Coll. of Neuropsychopharm. p. 207 (Dec. 8-12, 1986).

MDA and MDMA both showed a relatively high affinity for both 5-HT2 serotoninergic and alpha-2 adrenergic brain receptors, but low affinities for 5-HT1, and for the alpha-1 and beta adrenergic receptors, as well as for dopamine, muscarinic, and opiate receptors. Chronic administration of either drug decreases the number of 5-HT2 receptors in various brain locations.

Dornan, W.A., Katz, J.L. and Ricaurte, G.A. The Effects of Repeated Administration of MDMA on the Expression of Sexual Behaviour in the Male Rat. Pharmacol. Biochem. Behav. 39 813-816 (1991).

The repeated s.c administration of MDMA to rats produced a disruption of copulatory behaviour. These effects disappeared within a week.

Finnigan, K.T., Ricaurte, G.A., Ritchie, L.D., Irwin, I., Peroutka, S.J. and Langston, J.W. Orally Administered MDMA Causes a Long-term Depletion of Serotonin in Rat Brain. Brain Research 447 141-144 (1988).

The oral and sub-cutaneous routes of MDMA toxicity to rat serotonergic neurons are studied. Both routes lead to a dose dependent serotonin depletion.

Finnegan, K.T., Skratt, J.J., Irwin, I. and Langston, J.W. The N-Methyl-D-aspartate (NMDA) Receptor Antagonist, Dextrorphan, Prevents the Neurotoxic Effects of 3,4-Methylenedioxymethamphetamine (MDMA) in Rats. Neuroscience Letters 105 300-306 (1990).

In in vivo rat studies with various levels of MDMA and dextrorphan, the latter drug, a NMDA antagonist, completely prevented the serotonin-depleting action of MDMA.

Gaylor, D.W. and Slikker Jr, W. Risk Assessment for Neurotoxic Effects. Neurotoxicology 11 211-218 (1990).

A mathematical basis is presented for the estimation of risk as a function of dose, with drugs that are neurotoxic. An illustration is given for MDMA, based on rat and monkey data.

Gehlert, D.R. and Schmidt, C.J. Acute Administration of Methylenedioxymethamphetamine (MDMA) Results in a Persistent and Selective Increase in 5-HT1 Receptor Binding in Rat Brain. Pharmacologist 29 ABS-44 (1987).

Acute administration of MDMA in the rat showed an increase in serotonin binding in 24 hours. This occurred in several parts of the brain.

Glennon, R.A., Titeler, M., Lyon, R.A. and Youssif, M. MDMA ("Ecstasy"): Drug Discrimination and Brain Binding Properties. Soc. Neurosciences Abstrac ts 12 250.11 (1986).

In rats treated chronically with MDMA (trained to discriminate racemic MDMA from saline), radioligand binding studies were conducted with both serotonin and dopamine sites. The Ki values for both 5-HT1 and 5-HT2 receptors were highest for the "S" isomers of MDMA and MDA, with the racemate lower, and the "R" isomer yet lower. There was no particular affinity for the dopamine receptors studied.

Gold, L.H., Hubner, C.B. and Koob, G.F. The Role of Mesolimbic Dopamine in the Stimulant Action of MDMA. Soc. Neurosci. Abstr., Vol. 13, Part 3, p. 833 (1987) No. 234.13.

The administration of MDMA to rats may involve (like amphetamine) the release of dopamine. Test animals with lesions induced by 6-hydroxydopamine showed less motor activity in response to MDMA than control animals.

Gold, L.H., Hubner, C.B. and Koob, G.F. A Role for the Mesolimbic Dopamine System in the Psychostimulant Actions of MDMA. Psychopharmacology 99 40-47 (1989).

MDMA was evaluated in rats as a stimulant. Lesions induced with 6-hydroxydopamine modified the amphetamine-like responses seen, suggesting that the drug's action may involve the presynaptic release of dopamine in the region of the nucleus accumbens.

Gollamudi, R., Ali, S.F., Lipe, G., Newport, G., Webb, P., Lopez, M., Leakey, J.E.A., Kolta, M. and Slikker Jr., W. Influence of Inducers and Inhibitors on the Metabolism in vitro and Neurochemical Effects in vivo of MDMA. Neurotox. 10 455-466 (1989).

A number of experiments were conducted on rats, with the optical isomers of MDMA. The metabolic formation of MDA by N-demethylation, in vitro, was greater for the "S" isomer in the female than the male. This effect was lost with prior phenobarbital induction, and may be related to P-450 isozymes. In in vivo studies, either isomer appeared to be equally effective in depleting serotonin, but pretreatment studies suggest that an active metabolite other than MDA is formed.

Hanson, G.R., Sonsalla, P., Letter, A., Merchant, K.M., Johnson, M., Bush, L. and Gibb, J.W. Effects of Amphetamine Analogs on Central Nervous System Neuropeptide Systems. NIDA Research Monograph Series #94 259-269 (1989).

The effects of a number of substituted amphetamines on polypeptides associated with extrapyrimidal structures, have been observed. Both MDA and MDMA are included, and a discussion is presented of their possible contribution to both motor and mood changes related to drug-exposure.

Hashimoto, K. and Goromaru, T. Reduction of [3H] 6-Nitroquipazine-labelled 5-Hydroxytrypatmine Uptake Sites in Rat Brain by 3,4-Methylenedioxymethamphetamine. Fund. Clin. Pharmacol. 4 635-641 (1990).

The administration of the selective serotonin uptake inhibitor 6-nitroquipazine prevented the MDMA-induced reduction of serotonin and 5-hydroxyindoleacetic acid in rat brain. Tritiated 6-nitroquipazine was used as a probe for determining the receptor sites that recognized by MDMA.

Hashimoto, K. and Goromaru, T. Reduction of in vivo Binding of [3H]Paroxetine in Mouse Brain by 3,4-Methylenedioxymeth-amphetamine. Neuropharmacol. 29 633-639 (1990)

Pretreatment of a mouse with MDMA significantly modifies the radioactivity distribution of tritiated Paroxetine, a potent serotonin re-uptake inhibitor. The relative decrease of binding to hypothallimus and to cerebral cortex appears to be dose dependent.

Hashimoto, K. and Goromaru, T. Study of 3,4-Methylenedioxymethamphetamine-Induced Neurotoxicity in Rat Brain Using Specific In Vivo Binding of [3H] 6-Nitroquipazine. Res Comm. Subst. Abuse 13 191-201 (1992).

MDMA-induced neurotoxicity in the rat was studied employing 6-nitoquipazine binding. This radioligand appears to be well suited for studying neuropathology and neurochemical changes associated with brain serotonin.

Hashimoto, K., Maeda, H. and Goromaru, T. Antagonism of 3,4-Methylenedioxymethamphetamine-induced Neurotoxicity in Rat Brain by 1-Piperonylpiperazine. Eur. J. Pharmacol. - Envir. Toxicol. and Pharmacol. Section, 228 171-174 (1992).

Several serotonin uptake inhibitors were evaluated for their effects on MDMA-induced neurotoxicity. 6-Nitroquipazine, Paroxetine and 1-piperonylpiperazine were effective, but the immediate homologue of MDMA (N,alpha-dimethylpiperonylamine) was not.

Hekmatpanah, C.R., McKenna, D.J. and Peroutka, S.J. Reserpine does not Prevent 3,4-Methylenedioxyamphetamine-induced Neurotoxicity in the Rat. Neuroscience Letters (in press) 1989.

The administration of reserpine to rats, which reduces the brain monoamine stores in rats, did not prevent the degeneration of serotoninergic nerve terminals.

Hiramatsu, M. and Cho, A.K. Enantiomeric Differences in the Effects of 3,4-Methylenedioxymethamphetamine on Extracellular Monoamines and Metabolites in the Striatum of Freely-Moving Rats: An in vivo Microdialysis Study, Neuropharm. 29 269-275 (1990).

The effects of para-chloroamphetamine and of the optical isomers of MDMA on the extracellular levels of the metabolites of dopamine and of serotonin were determined by dialysis. The level of dopamine was increased, and that of its metabolites decreased, with p-CPA, (+) MDMA and (-) MDMA showing decreased potency. The serotonin metabolite 5-HIAA was also decreased, but there was no difference between the two optical isomers of MDMA in the production of this effect.

Hoffman, B.J., Mezey, E. and Brownstein, M.J. Cloning of a Serotonin Transporter Affected by Antidepressants. Science, 254 579-580 (1991).

A DNA clone for a serotonin transporter has been isolated. The cell uptake of the complimentary DNA resembles platelet serotonin uptake, and it is sensitive to antidepressants, amphetamine derivatives and cocaine. MDMA has an exceptionally high affinity.

Insel, T.R., Battaglia, G., Johannessen, J.N., Marra, S. and De Souza, E.B. 3,4-Methylenedioxymethamphetamine ("Ecstasy") Selectively Destroys Brain Serotonin Terminals in Rhesus Monkeys. J. Pharm. Exptl. Therap. 249 713-720 (1989).

In rhesus monkeys, the subacute administration of MDMA decreased both serotonin and 5-HIAA levels. At high levels there was also a decrease in the number of serotonin uptake sites (implying serotonin terminal destruction). There appears to be a considerable specificity as to brain region where these effects are expressed.

Johnson, M.P. and Nichols, D.E. Neurotoxin Effects of the Alpha-Ethyl Homologue of MDMA Following Subacute Administration. Pharmacol. Biochem. Behav. 33 105-108 (1989).

MBDB, the alpha-ethyl homologue of MDMA, was compared with MDMA in rats, as to potential neurotoxicity. There was a similar decrease in the number of observed serotonin binding sites but, unlike MDMA, there were no significant decreases in dopamine levels observed.

Johnson, M.P., and Nichols, D.E. Combined Administration of a Non-Neurotoxic 3,4-Methylenedioxymethamphetamine Analogue with Amphetamine Produces Serotonin Neurotoxicity in Rats. Neuropharmacology 30 819-822 (1991).

Two drugs have been studied in combination, in the rat. MMAI (5-methoxy-6-methyl-2-aminoindan) and S-(+)-amphetamine by themselves do not change any serotonin parameters in the rat. However, in combination, there was a central serotonin neurotoxicity induced. It appears that dopamine release plays a critical role in the serotonin neurotoxicity expression of substituted amphetamine derivatives.

Johnson, M.P., Conarty, P.F. and Nichols, D.E. [3H]Monoamine Releasing and Uptake Inhibition Properties of 3,4-Methylenedioxymethamphetamine and p-Chloroamphetamine Analogues. Eur. J. Pharmacol. 200 9-16 (1991).

A number of analogues of MDMA and of PCA were studied to determine their effectiveness in inhibiting the uptake of serotonin into synaptosomes, with or without pretreatment with reserpine. A valid relationship between the serotonin neurotoxic potential and the dopamine releasing ability of these compounds was noted.

Johnson, M.P., Hoffman, A.J. and Nichols, D.E. Effects of the Enantiomers of MDA, MDMA, and Related Analogues on [3H]Serotonin and [3H]Dopamine Release from Superfused Rat Brain Slices. Eur. J. Pharmacol. 132 269-276 (1986).

The study of a series of MDA homologues (MDA, MDMA, MBDB) showed a dramatic dependence between chain length and dopamine release. The longer the chain, the less the release. It is concluded that dopamine release plays a minor role in the human activity of these compounds.

Johnson, M.P., Huang, X. and Nichols, D.E. Serotonin Neurotoxicity in Rats After Combined Treatment with a Dopaminergic Agent Followed by a Nonneurotoxic 3,4-Methylenedioxymethamphetamine (MDMA) Analogue. Pharm. Biochem. Beh. 40 915-922 (1991).

Further evidence has been found linking dopamine to the long-term serotonergic neurotoxic effects of certain substituted amphetamines such as MDMA. Studies were conducted with MDAI (5,6-methylenedioxy-2-aminoindan (itself with a low neurotoxic liability) with several MAO inhibitors (clorgyline and deprenyl), with a dopamine uptake inhibitor led to no long term changes. Pretreatment with a dopamine releaser (S-amphetamine) did produce changes, however.

Johnson, M.P., Huang, X., Oberlender, R., Nash, J.F. and Nichols, D.E. Behavioural, Biochemical and Neurotoxicological Actions of the alpha-Ethyl Homologue of p-Chloroamphetamine. Eur. J. Pharmacol. 191 1-10 (1990).

The alpha-ethyl homologue of PCA was studied. The relationship of this compound (CAB) to PCA is that of the non-dopamine releasing MBDB (N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine) to MDMA. Although CAB produces less disruption of the dopamine system, its effects on the serotonin system is similar to that of PCA.

Johnson, M., Elayan, I., Hanson, G.R., Foltz, R.L., Gibbs, J.W. and Lim, H.K. Effects of 3,4-Dihydroxymethamphetamine and 2,4,5-Trihydroxymethamphetamine, Two Metabolites of 3,4-Methylenedioxymethamphetamine, on Central Serotonergic and Dopaminergic Systems. J. Pharm. Exptl. Therap. 261 447-453 (1992).

Two metabolites of MDMA have been evaluated as to their contribution to neurotoxicity. The metabolite, 2,4,5- trihydroxymethamphetamine is toxic to both serotonin and dopamine nerve terminals, although it does not appear to explain the neurotoxic effects of MDMA.

Johnson, M., Hanson, G.R. and Gibb, J.W. Effects of Dopaminergic and Serotonergic Receptor Blockade on Neurochemical Changes Induced by Acute Administration of Methamphetamine and 3,4-Methylenedioxymethamphetamine. Neuropharm. 27 1089-1096 (1988).

By the use of specific neurorecptor ligands, the mechanisms of acute and long-term changes in the CNS from methamphetamine and MDMA exposure, have been investigated.

Johnson, M., Letter, A.A., Merchant, K., Hanson, G.R. and Gibb, J.W. Effects of 3,4-Methylenedioxyamphetamine and 3,4-Methylenedioxymethamphetamine Isomers on Central Serotonergic, Dopaminergic and Nigral Neurotensin Systems of the Rat. J. Pharm. Exptl. Therap. 244 977-982 (1988).

The difference of the isomers of MDA and MDMA in their ability to induce neurotransmitter changes and neurotensin immunoreactivity are reported. In general, the d-isomers of each were the more potent in affecting neurochemical systems.

Johnson, M., Stone, D.M., Bush, L.G., Hanson, G.R. and Gibb, J.W. Glucocorticoid and 3,4-Methylenedioxymethamphetamine (MDMA)-induced Neurotoxicity Eur. J. Pharmacol. 161 181 (1989).

A series of studies of the role of the glucocorticoids in the serotonin neurotoxicity of MDMA in rats has indicated some involvement in the hippocampal area.

Kalix, P. A Comparison of the Effects of Some Phenethylamines on the Release of Radioactivity from Isolated Rat Caudate Nucleus Prelabelled with 3H-Dopamine. Arzneim. Forsch. 36 1019-1021 (1986).

A number of phenethylamines were found to be able to release radioactive dopamine from prelabelled caudate nuclei. MDMA was not spectacular. The simplest unsubstituted amphetamine derivatives were the most effective.

Kalix, P., Yousif, M.Y. and Glennon, R.A. Differential Effects of the Enantiomers of Methylenedioxymeth-amphetamine (MDMA) on the Release of Radioactivity from (3H)Dopamine-Prelabeled Rat Striatum. Res. Commun. Subst. Abuse 9 45-52 (1988).

The S-isomer of MDMA (the more effective stimulant) is more effective than the R-isomer in releasing tritiated dopamine from rat striatum. It is about one sixth the potency of S-methamphetamine.

Kelland, M.D., Freeman,A.S. and Chiodo, L.A. (+/-)-3,4-Methylenedioxymethamphetamine- induced Changes in the Basal Activity and Pharmacological Responsiveness of Nigrostriatal Dopamine Neurons. Europ. J. Pharmacol. 169 11-21 (1989).

Studies of acute exposure of rats to MDMA showed an inhibition of the firing of dopamine neurons, and this effect is diminished following the depletion of either serotonin or dopamine. MDMA appears to exert direct functional effects on the nigrostriatal dopamine system.

Kleven, M.S., Woolverton, W.L. and Seiden, L.S. Evidence that both Intragastric and Subcutaneous Administration of Methylenedioxmethamphetamine (MDMA) Produce Serotonin Neurotoxicity in Rhesus Monkeys. Brain Research 488 121-125 (1989).

Subacute administration of MDMA to rhesus monkeys by both intragastric and subcutaneous routes was found to lead to depletion of both serotonin and 5-HIAA in various brain regions. Serotonin uptake sites were depleted following the oral route but not the subcutaneous route.

Kopajtic, T., Battaglia, G. and De Souza, E.B. A Pharmacologic Profile of MDA and MDMA on Brain Receptors and Uptake Sites. Soc. Neurosciences Abstrts. 12 336.1 (1986).

Both MDA and MDMA were studied at various brain recognition sites using radioligand binding techniques. The findings suggest that these drugs may express their effects at serotonin receptors or uptake sites and/or alpha-2 adrenergic receptors.

Logan, B.J., Laverty, R., Sanderson, W.D. and Yee, Y.B. Differences Between Rats and Mice in MDMA (Methylenedioxmethamphetamine) Neurotoxicity. Europ. J. Pharmacol. 152 227-234 (1988).

A single large administration of MDMA to the rat or the mouse caused only transient changes in serotonin, norepinephrine and dopamine levels (and those of their metabolites). Repeated administrations were required to establish long-lasting changes in the rat; the mouse remained relatively insensitive. It appears that the both the nature and the degree of neurotoxicity with MDMA is species-specific.

Lowe, M.T., Nash Jr., J.F. and Meltzer, H.Y. Selective Reduction of Striatal Type-II Glucocorticoid Receptors in Rats by 3,4-Methylenedioxymethamphetamine (MDMA). Eur. J. Pharmacol. 163 157-161 (1989).

A single large s.c. dose of MDMA to rats reduced, in addition to brain serotonin and 5-HIAA levels, the glucocorticoid levels in the striatum. No differences in the corticosterone levels were noted, however, suggesting that it may not play a role in the receptor reduction.

Lyon, R.A., Glennon, R.A. and Titeler, M. 3,4-Methylenedioxymethamphetamine (MDMA): Stereoselective Interactions at Brain 5-HT1 and 5-HT2 Receptors. Psychopharmacology 88 525-526 (1986).

The assay of the optical isomers of MDA and MDMA with isolated receptors of rat brains, suggested that MDMA does not work primarily through direct interaction with serotonin receptors.

Millan, M.J. and Colpaert, F.C. Methylenedioxymethamphetamine Induces Spontaneous Tail-flicks in the Rat via 5-HT1a Receptors. Eur. J. Pharmacol. 193 145-152 (1991).

MDMA, but not amphetamine, induced dose-dependent tail-flicks in restrained rats. These effects were blocked by serotonin uptake inhibitors, implicating these receptors in this response.

Mokler, D.J., Robinson, S.E. and Rosecrans, J.A. Differential Depletion of Brain 5-Hydroxytryptamine (5-HT) by (+/-) 3,4-Methylenedioxymethamphetamine (MDMA). Pharmacologist 29 ABS-273 (1987).

The sensitivity of specific brain areas for the 5-HT depleting effects of MDMA may relate to the metabolic activity of 5-HT neurones in that region.

Mokler, D.J., Robinson, S.E. and Rosecrans, J.A. (+/-) 3,4-Methylenedioxymethamphetamine (MDMA) Produces Long-term Reductions in Brain 5-Hydroxytryptamine in Rats. Eur. J. Pharmacol. 138 265-268 (1987).

Following chronic administration of MDMA to rats, both serotonin and 5-HIAA became depleted in the brain. It is suggested that MDMA can function as a neurotoxin.

Mokler, D.J., Robinson, S.E. and Rosecrans, J.A. A Comparison of the Effects of Repeated Doses of MDMA ("Ecstasy") on Biogenic Amine Levels in Adult and Neonate Rats. Soc. Neurosci. Abstr. 13No. 251.9 p.905 (1987).

MDMA was given to both adult and neonate rats in 10-40 mg/Kg doses over several days. The serotonin levels were decreased and the dopamine levels were significantly increased.

Molliver, M.E. Serotonergic Neural Systems: What Their Anatomic Organization Tells Us about Function. J. Clinical Psychopharm. 7 3S-23S (1987).

A review of the organization of the serotonin nervous system is presented. The findings associated with the neurotoxic effects of MDMA are used as instructive tools, and speculation is extended as to the role of these neurons in the generation of the affective state.

Molliver, M.E., Mamounas, L.A. and Wilson, M.A. Effects of Neurotoxic Amphetamines on Serotonergic Neurons: Immunocytochemical Studies. NIDA Research Monograph Series #94 270-305 (1989).

A highly detailed cytological mapping of the serotonin related structures in the rat brain, is presented. An immunocytological study, with anto-serotonin antibodies, has been made with several substituted amphetamines, including MDA and MDMA. The axon bodies are severely damaged, but the raphe cell bodies are spared. Some primate studies are discussed.

Molliver, M.E., O'Hearn, E., Battaglia, G. and De Souza, E.B. Direct Intracerebral Administration of MDA and MDMA Does Not Produce Serotonin Neurotoxicity. Soc. Neurosciences Abstrts. 12 336.3 (1986).

The microinjection of either MDA or MDMA directly in to the cerebral cortex resulted in no detectable cytotoxicity. This suggests that the neurotoxicity of both compounds may be due to some metabolite formed peripherally.

Monti, J.A., Beaton, J.M., Benington, F., Morin, R.D. and Christian, S.T. MDMA and MBDB Potentiate Phorbol Ester-Stimulated Catecholamine Release from PC-12 Cells. Soc. Neuroscience Abstrt. November 13-18, 1988.

The "S" isomer of both MDMA and MBDB are potent in stimulating catechol release from PC-12 cells. The norepinephrin and dopamine release was increased in the presence of phorbol dibenzoate. It is suggested that this release may be mediated by protein kinase-C.

Nader, M.A., Hoffmann, S.M. and Barrett, J.E. Behavioural Effects of (+/-) 3,4-Methylenedioxyamphetamine (MDA) and (+/-) 3,4-Methylenedioxymethamphetamine (MDMA) in the Pigeon: Interactions with Noradrenergic and Serotoninergic Systems. Psychopharmacology 98 183-188 (1989).

MDA, MDMA and MDE. were studied in a conditioned behaviour involving pigeons. MDA was the most potent of the three drugs. The use of serotonin and dopamine antagonists suggested that the actions of MDA and MDMA are mediated by different neurotransmitter systems.

Nash, J.F. and Yamamoto, B.K. Methamphetamine Neurotoxicity and Striatal Glutamate Release: Comparison to 3,4-Methylenedioxymethamphet- amine. Brain Research 581 237-243 (1992).

The neurotoxicity of methamphetamine and MDMA were compared by measuring the extracellular concentrations of several compounds by microdialysis in freely moving rats. The long term dopamine neurotoxicity from repeated methamphetamine administration is mediated, in part, by a delayed increase in extracellular glutamate. Repeated MDMA administration, at a dose that produced a long-term depletion of serotonin, had no effect on glutamate release.

Nash, J.F., Meltzer, H.Y. and Gudelsky, G.A. Effect of 3,4-Methylenedioxymethamphetamine on 3,4-Dihydroxyphenylalanine Accumulation in the Striatum and Nucleus Accumbers, J. Neurochem. 34 1062-1067 (1990).

The effect of MDMA on dopamine synthesis in rat brain was estimated by measuring DOPA accumulation following pretreatment with a decarboxylase inhibitor. It is suggested that dopamine plays a role in the serotonin depletion produced by MDMA.

Nash, J.F., Meltzer, H.Y. and Lowy, M.T. The Effect of Adrenalectomy on MDMA-Induced Dopamine Release in the Striatum as Measured by in vivo Microdialysis and Depletion of Serotonin. Res. Commun. Subst. Abuse 13 177-190 (1992).

The interaction of MDMA and corticosterone in neurotransmitter depletion was studied in adrenalectomized rats. There does not seem to be any significant role for corticosterone in the MDMA-induced depletionof serotonin and 5-hydroxyindoleacetic acid.

Nichols, D.E., Brewster, W.K., Johnson, M.P., Oberlender, R. and Riggs, R.M. Nonneurotoxic Tetralin and Indan Analogues of 3,4-Methylenedioxyamphetamine (MDA). J. Med. Chem. 33 703-710 (1990).

Four cyclic analogues of MDA were synthesized and evaluated pharmacologically. Two indanes and two tetralins were explored through discrimination studies relative to MDMA or LSD. They appear not to have serotonin neurotoxicity.

O'Hearn, E., Battaglia, G., De Souza, E.B., Kuhar, K.J. and Molliver, M.E. Systemic MDA and MDMA, Psychotropic Substituted Amphetamines, Produce Serotonin Neurotoxicity. Soc. Neurosciences Abstrts. 12 336.2 (1986).

Rats exposed chronically to either MDA or MDMA were found, on sacrifice, to have a reduced number of serotonin axon terminals. This was most evident in cerebral cortex, thalamus, olfactory bulb and striatum, but also occurred in other areas. This may be due to the binding of these drugs to the uptake sites. The serotonin cell bodies and the preterminal axons are spared.

O'Hearn, E., Battaglia, G., De Souza, E.B., Kuhar, M.J. and Molliver, M.E. Methylenedioxyamphetamine (MDA) and Methylenedioxymethamphetamine (MDMA) Cause Selective Ablation of the Serotoninergic Axon Terminals in Forebrain: Immunocytochemical Evidence for Neurotoxicity. J. Neuroscience 8 2788 (1988).

Following chronic administration of MDMA (or separately, MDA) to rats, there is observed a profound loss of serotoninergic neuron axons throughout the forebrain. Various regions of the brain are compared as to extent of damage. The catacholamine counterparts are not affected.

Pan, H.S. and Wang, R.Y. MDMA: Further Evidence that its Action in the Medial Prefrontal Cortex is Mediated by the Serotoninergic System. Brain Res. 539 332-336 (1991).

The administration of MDMA was found to suppress the firing rates of certain brain neurons in anaesthetized rats. The (+) isomer, but not the (-) isomer, mimics the racemate. These effects are blocked by the pretreatment with a serotonin uptake inhibitor.

Pan, H.S. and Wang, R.Y. The Action of (+/-)-MDMA on Medial Prefrontal Cortical Neurons is Mediated Through the Serotoninergic System. Brain Research 543 56-60 (1991).

Rats anaesthetized with chloral hydrate were given varying amounts of MDMA intravenously. Electrodes located in the brain showed decreased neuron excitement. Studies were extended to include pretreatment with para-chlorophenylalanine and alpha-methyl-paratyrosine. The action of MDMA apparently involves some endogenous serotonin release.

Paris, J.M. and Cunningham, K.A. Lack of Serotonin Neurotoxicity after Intraraphe Microinjection of (+) 3,4-Methylenedioxymethamphetamine (MDMA). Brain Res. Bull. 28 115-119 (1991).

Direct injection of MDMA into the dorsal and the median Raphe nuclei was followed, in two weeks, by assay for serotonin and catecholamine changes. No apparent neurotoxicity was found.

Peroutka, S.J. Relative Insensitivity of Mice to 3,4-Methylenedioxymethamphetamine (MDMA) Neurotoxocity. Res. Commun. Subst. Abuse 9 193-206 (1988).

The effects of MDMA were determined in mouse brain serotonin uptake sites using paroxetine binding as a measure. In distinction with rats, there were no effects that could be observed at dosages of up to 30 mg/Kg, administered chronically. These findings confirm that in the mouse, MDMA is not a neurotoxic agent.

Pierce, P.A. and Peroutka, S.J. Ring-substituted Amphetamine Interactions with Neurotransmitter Receptor Binding Sites in Human Cortex. Neuroscience Lett. 95 208-212 (1988).

Three psychotropic drugs, MDA, MDMA and MDE, were evaluated as to their affinities for the DOB binding site, as determined by the displacement of 77Br DOB as the labelled radioligand.

Piercey, M.F., Lum, J.T. and Palmer, J.R. Effects of MDMA ("ecstasy") on Firing Rates of Seroronergic, Dopaminergic, and Noradrenergic Neurons in the Rat. Brain Research 526 203-206 (1990).

MDMA is effective in the depression of serotonin neurons in the dorsal and median raphe. Noradrenalin neurons in the locus coeruleus were also depressed at moderate dosages, but dopamine neurons were unaffected.

Ricaurte G.A. and McCann, U.D. Neurotoxic Amphetamine Analogues: Effects in Monkeys and Implications for Humans. Ann. N. Y. Acad. Sci. 648 371-82 (1992)

A review is presented of the relationships between several amphetamine-related compounds (such as amphetamine, methamphetamine and MDMA) and changes in the neurotransmitter area. The changes seen in rodents are compared to those observed in non-human primates, and speculation is made concerning further extrapolation to humans. Research with these compounds should enhance our understanding of central monoaminergic systems in normal brain function, and their role in the pathophysiology of neuropsychiatric disorders

Ricaurte, G.A., Bryan, G., Strauss, L., Seiden, L. and Schuster, C. Hallucinogenic Amphetamine Selectively Destroys Brain Serotonin Nerve Terminals. Science 229 986-988 (1985).

MDA was studied and found to produce long lasting reductions in the level of serotonin, the number of serotonin uptake sites, and the concentration of 5-HIAA in the rat brain. It was suggested that these deficits were due to serotonin nerve terminal degeneration. This was the research report that had been submitted for publication at the time of the MDMA hearings, and that played a focal role in the emergency scheduling of MDMA.

Ricaurte, G.A., DeLanney, L.E., Irwin, I. and Langston, J.W. Toxic Effects of MDMA on Central Serotonergic Neurons in the Primate: Importance of Route and Frequency of Drug Application. Brain Research 446 165-169 (1988).

The toxicity of MDMA was studied in primates both by the oral and the subcutaneous routes, and in single and multiple doses. Multiple doses are more effective that single doses in depleting serotonin, and the s.c route is more effective than the oral route. However, a single, oral administration of MDMA still produces a long-lived depletion

Ricaurte, G.A., DeLanney, L.E., Wiener, S.G., Irwin, I. and Langston, J.W. 5-Hydroxyindoleacetic acid in Cerebrospinal Fluid Reflects Serotonergic Damage Induced by 3,4-Methylenedioxymethamphetamine in CNS of Non-human Primates. Brain Research 474 359-363 (1988).

The usefulness of 5-hydroxyindoleacetic acid in CSF as a marker for serotonergic damage induced by MDMA was evaluated in the monkey. Following toxic doses of MDMA, there was removal of CSF for the assay of this serotonin metabolite, followed by sacrifice of the animal for direct brain measurement. The resulting positive correlation supports this technique for the eventual search for MDMA-induced damage in humans.

Ricaurte, G.A., Finnegan, K.F., Nichols, D.E., DeLanney, L.E., Irwin, I. and Langston, J.W. 3,4-Methylenedioxymeth-amphetamine (MDE), a Novel Analogue of MDMA, Produces Long-lasting Depletion of Serotonin in the Rat Brain. Eur. J. Pharmacol. 137 265-268 (1987).

MDE was qualitatively similar to MDMA in the depletion of serotonin in rat brain, but was only one fourth as potent.

Ricaurte, G.A., Forno, L.S., Wilson, M.A., DeLanney, L.E., Irwin, I., Molliver, M.E. and Langston, J.W. (+/-) Methylenedioxymethamphetamine (MDMA) Exerts Toxic Effects on Central Serotonergic Neurons in Primates. Soc. Neurosci. Abstr. 13 No. 251.8 p. 905 (1987).

MDMA was given s.q. twice daily for four days to monkeys, at 2.5, 3.75 and 5 mg/Kg. Post-mortem brain analyses showed serotonin reduction (90%) and axon damage. Some was described as "striking" and involved morphological changes.

Ricaurte, G.A., Forno, L.S., Wilson, M.A., DeLanney, L.E., Irwin, I., Moliver, M.E. and Langston, J.W. (+/-) 3,4-Methylenedioxymethamphetamine Selectively Damages Central Serotonergic Neurons in Nonhuman Primates. J. Am. Med. Assn. 260 51-55 (1988).

The parenteral administration (subcutaneous, twice daily for four days) of MDMA to monkeys of three species produced both brain serotonin depletion and accompanying neuron damage upon autopsy following a two-week waiting period. Considerable microscopic detail is given. The evidence presented could imply, but does not established, that there may be actual neuron cell death. The humanpattern of use is oral rather than parenteral, but a warning for prudence is advanced for the human use of either MDMA or (the neurotoxicologically similar drug) Fenfluramine.

Ricaurte, G.A., Marletto, A.L., Katz, J.L. and Marletto, M.B. Lasting Effects of (+/-)-3,4-Methylenedioxymethamphetamine (MDMA) on Ventral Serotonergic Neurons in Nonhuman Primates: Neurochemical Observations. J. Pharm. Exptl. Therap. 261 616-622 (1992).

A study was made of the duration of the neurotoxic effects of MDMA on squirrel monkeys (5 mg/day, twice daily, for 4 days) as a function of time, from 2 weeks to a year and a half. A control blank was used. Serotonin deficits persisted, suggesting that MDMA produces lasting effects.

Scallet, A.C., Ali, S.F., Holson, R.R., Lipe, G.W. and Slikker Jr., W. Neurohistological Effects 120 Days after Oral Ecstasy (MDMA): Multiple Antigen Immunohistochemistry and Silver Degeneration Staining. Soc. Neurosci. Abstr. 13, Part 3 No. 251.6, p. 904 (1987).

Both silver degeneration procedures (Fink-Heimer) and immunohistochemical techniques have been applied to MDMA-treated rats long after dosing. There are indications of regional differences in recovery, and that some changes may be irreversible.

Scheffel, U. and Ricaurte, G.A., Paroxetine as an in vivo Indicator of 3,4-Methylenedioxymethamphetamine Neurotoxicity: A Presynaptic Serotonergic Positron Emission Tomography Ligand? Brain Research 527 89-95 (1990).

The value of Paroxetine as an indicator of serotonergic nerve axon damage was demonstrated by the effectiveness of 5,7-dihydroxytryptamine in decreasing specific binding. MDMA treatment of rats gave similar reduction in labelled Paroxetine binding.

Scheffel, U., Lever, J.R., Stathis, M., Ricaurte, G.A. Repeated Administration of MDMA Causes Transient Down-regulation of Serotonin 5-HT2 Receptors. Neuropharm. 31 881-893 (1992).

The repeated administration of MDMA to rats causes a down regulation of serotonin receptors ion the brain of the rat. N-methyl-2-iodolysergic acid diethylamide is a suitable ligand for the labelling of these receptors in vitro and in vivo..

Schlechter, M.D. Serotonergic-Dopaminergic Mediation of 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"). Pharmacol. Biochem. and Behav. 31 817-824 (1989).

The discriminative stimuli properties of MDMA in rats, were studied to explore the serotinergic, as contrasted to the dopaminergic, nature of the drug's action. In the early part of the behavioural responses, the effects appear to be exclusively serotinergic, but in the latter period, there are some believable dominergic actions.

Schmidt, C.J. Acute Administration of Methylenedioxymethamphetamine: Comparison with the Neurochemical Effects of its N-Desmethyl and N-Ethyl Analogs. Eur. J. Pharmacol. 136 81-88 (1987).

MDMA (and its two immediate homologues, MDMA and MDE) were studied in the serotoninergic systems in the rat brain. There was depletion of cortical serotonin which in the case of MDMA appeared to persist after at least a week.

Schmidt, C.J. Neurotoxicity of the Psychedelic Amphetamine, Methylenedioxymethamphetamine. J. Pharm. Exptl. Therap. 240 1-7 (1987).

Evidence is presented that MDMA has a complex effect on rat serotonergic neurons, that results in a neurotoxic change at the nerve terminals. A parallel is drawn to the neurotoxin para-chloroamphetamine.

Schmidt, C.J., Acute and Long-term Neurochemical Effects of Methylenedioxmethamphetamine in the Rat. NIDA Research Monograph Series #94 179-195 (1989).

An analysis of short and long-term brain serotonin-related changes was made, and interpreted. Comparisons were made to PCA, methamphetamine and Fenfluramine.

Schmidt, C.J. and Kehne, J.H. Neurotoxicity of MDMA: Neurochemical Effects. Ann. N. Y. Acad. Sci. 600 665-681 (1990).

A review of the experimental findings involving both serotonin and dopamine in the neurotoxic action of MDMA. The actual mechanism of action remains unknown.

Schmidt, C.J. and Lovenberg, W. (+/-)Methylenedioxymethamphetamine (MDMA): A Potentially Neurotoxic Amphetamine Analogue. Fed. Proc. 45 1059 (#5264) April 13-18, (1986). Note paper below, Schmidt et al., with this same title.

Rats were administered MDMA s.c. at various doses and sacrificed at three hours. Brain concentrations of dopamine and serotonin, and their major metabolites were determined. The serotonin concentrations were reduced in a dose-dependent manner. Co-administration of a serotonin uptake inhibitor, Citalopram, blocked the MDMA-induced decline in striatal serotonin concentrations suggesting a mechanism similar to that of the known serotonergic neurotoxin p-chloroamphetamine.

Schmidt, C.J. and Lovenberg, W. Further Studies on the Neurochemical Effects of 4,5-Methylenedioxymethamphetamine and Related Analogues. Soc. Neurosciences Abstrts. 12 169.5 (1986).

The racemate and optical isomers of MDMA produced depletion of cortical and striatal serotonin. The (+) isomer was the more effective material. MDA was similar to MDMA, but effects produced by the N-ethyl homologue (MDE) were reversed in a week. Whereas all three drugs caused an acute decrease in serotonin concentration, only MDA and MDMA reduced the uptake of tritiated serotonin at the dosages studied (20 mg/Kg).

Schmidt, C.J. and Taylor, V.L. Direct Central Effects of Acute Methylenedioxymethamphetamine on Serotonergic Neurons. Eur. J. Pharmacol. 156 121-131 (1988).

The optical isomers of MDMA were studied separately in the rat as to their effects on loss of brain tryptophan hydroxylase. This appeared to precede the drop of serotonin concentration in the same areas. Injections of MDMA directly into the brain had no effect on either measure.

Schmidt, C.J. and Taylor, V.L. Neurochemical Effects of Methylenedioxymethamphetamine in the Rat: Acute versus Long-term Changes. The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Kluwer, New York. (1990) Ed: S.J. Peroutka

A study is presented describing the changes in the brains of rats which had been administered MDMA. It is felt that the release of dopamine is a prerequisite for the neurotoxic effects seen.

Schmidt, C.J., Abbate, G.M., Black, C.K. and Taylor, V.L. Selective 5-Hydroxytryptamine-2 Receptor Antagonists Protect against the Neurotoxicity of Methylendioxymethamphetamine in Rats. J. Pharm. Exptl. Therap. 255 478-483 (1990).

The characteristic serotonin deficits produced in rats by MDMA were prevented by the simultaneous administration of serotonin antagonists such as Ritanserin. The action of such drugs may involve dopamine.

Schmidt, C.J., Black, C.K., Abbate, G.M. and Taylor, V.L. Methylenedioxymethamphetamine-induced Hyperthermia and Neurotoxicity are Independently Mediated by 5-HT2 Receptors. Brain Research 529 85-90 (1990).

In rats, MDMA produces a hyperthermia which can be partially antagonised, as can the induced neurotoxicity, by the administration of a serotonin antagonist.

Schmidt, C.J., Black, C.K., Abbate, G.M. and Taylor, V.L Chloral Hydrate Anesthesia Antagonizes the Neurotoxicity of 3,4-Methylenedioxymethamphetamine. Eur. J. Pharmacol. 191 213-216 (1990).

When chloral anesthesia is administered to rats that have been administered MDMA, there is an interference with the induced neurotoxicity. This may be due to some role played by dopamine release.

Schmidt, C.J., Black, C.K. and Taylor, V.L. Antagonism of the Neurotoxicity due to a Single Administration of Methylenedioxyamphetamine. Eur. J. Pharmacol. 181 59-70 (1990).

A complex series of experiments in the rat investigating MDMA has suggested that the release of both dopamine and serotonin are implicated in the observed neurotoxicity of MDMA.

Schmidt, C.J., Black, C.K. and Taylor, V.L. L-DOPA Potentiation of the Serotoninergic Deficits Due to a Single Administration of 3,4-Methylenedioxymethamphetamine, p-Chloroamphetamine or Methamphetamine to Rats. Eur. J. Pharmacol. 203 41-49 (1991).

The role of dopamine in the serotoninergic neurotoxicity of MDMA, PCA, methamphetamine, MDE, and Fenfluramine was assessed by their co-administration with L-DOPA. The findings reported support a role for dopamine release in the toxicity of the first three of these drugs.

Schmidt,C.J., Levin, J.A. and Loverberg, W. In Vitro and In Vivo Neurochemical Effects of Methylenedioxymethamphetamine on Striatal Monoaminergic Systems in the Rat Brain, Biochem. Pharmacol. 36 747-755 (1987).

This study compares the effects of MDMA and MDA on neurotransmitter release in vitro and the (+) isomer is the more effective. The (+) isomer is also the more effective in vivo.

Schmidt, C.J., Vicki, L., Taylor, G.M. and Nieduzak, T.R. 5-HT-2 Antagonist Stereoselectivly Prevents the Neurotoxicity of 3,4-Methylenedioxymethamphetamine by Blocking the Acute Stimulation of Dopamine Synthesis: Reversal by L-DOPA. J. Pharm. Exptl. Therap. 256 230-235 (1991).

The effects of the optical isomers of a serotonin antagonist (one active, the other inactive) on the interaction of MDMA with both the dopaminergic and the serotoninergic systems of the male rat were studied. The protective effects against forebrain serotonin deficit that was observed, was reversed by the administration of L-DOPA.

Schmidt, C.J., Wu, L. and Lovenberg, W. Methylenedioxymethamphetet-amine: A Potentially Neurotoxic Amphetamine Analogue. Eur. J. Pharmacol. 124 175-178 (1986).

Acute administration of MDMA to rats provide selective and long lasting serotonin and 5-HIAA depletion, similar to that produced by p-chlorophenylalanine. There was an elevation of neostriatal dopamine as well as it primary metabolite homovanillic acid. A typewritten draft of this paper was presented to the DEA in conjunction with the legal hearings held concerning the scheduling of MDMA.

Seiden, L.S. Report of Preliminary Results on MDMA. Document entered into evidence Re: MDMA Scheduling Docket No. 84-48, U.S. Department of Justice, Drug Enforcement Administration, October 16, 1985.

Rats were treated both acutely and chronically with MDMA, and the study of the decrease of serotonin receptors and the interpretation of neurological staining indicated a neurotoxicity similar to, but less dramatic than, that seen with MDA.

Slikker, Jr., W. and Gaylor, D.W. Biologically-Based Dose-Response Model for Neurotoxicity Risk Assessment. Korean J. Toxicol. 6 205-213 (1990).

A discussion of a model of risk assessment of neurotoxicity is presented, illustrated by published experimental details from MDMA in experimental rats.

Slikker Jr., W., Ali, S.F., Scallet, A.C. and Frith, C.H. Methylenedioxymethamphetamine (MDMA) Produces Long Lasting Alterations in the Serotonergic System of Rat Brain. Soc. Neurosciences Abstrts. 12 101.7 (1986).

The chronic treatment of rats with MDMA (orally) produced decreased levels of serotonin and 5-HIAA. At high dose levels there was a temporary decrease in homovanillic acid (HVA) but no change in dopamine levels.

Slikker Jr., W., Ali, S.F., Scallet, A.C., Firth, C.H., Newport, G.D. and Bailey, J.R. Neurochemical and Neurohistological Alterations in the Rat and Monkey Produced by Orally Administered Methylenedioxmethamphetamine (MDMA). Toxicol Appl. Pharmacol. 94 448-457 (1988).

A complete neurohistochemical study of chronically administered MDMA, orally, to either rats of monkeys, showed extensive indications of serotonin neuron involvement, but no changes in with either dopamine or its primary metabolites.

Slikker Jr., W., Holson, R.R., Ali, S.F., Kolta, M.G., Paule, M.G., Scallet, A.C., McMillan, D.E., Bailey, J.R., Hong, J.S. and Scalzo, F.M. Behavioural and Neurochemical Effects of Orally Administered MDMA in the Rodent and Nonhuman Primate. Neurotox. 10 529-542 (1989).

MDMA was compared to p-chloroamphetamine (PCA) in rats following short-term chronic oral administration. Observations were made on behavioural effects and on neurochemical changes. Both compounds showed the "serotonin motor syndrome" but these markers were not persistent, although the brain serotonin level decreases were maintained with time. Similar decreases were seen in monkeys, but there was no behavioural modification evident.

Spanos, L.J. and Yamamoto, B.K. Methylenedioxymethamphetamine (MDMA)-induced Efflux of Dopamine and Serotonin in Rat Nucleus Accumbens. Soc. of Neurosciences Abstr. 12 p. 609 (#169.6) (1986).

Following MDMA administration to rats, the efflux of dopamine was decreased but then it quickly recovered. Serotonin depletion does not recover even after 2 hours, thus MDMA may be neurotoxic.

Steele, T.D., Brewster, W.K., Johnson, M.P., Nichols, D.E. and Yim, G.K.W. Assessment of the Role of alpha-Methylepinine in the Neurotoxicity of MDMA. Pharm. Biochem. Behav. 38 345-351 (1991).

The catachol metabolite of MDMA, alpha-methylepinine, was evaluated as a potential contributor to the neurotoxicity of MDMA. It was formed metabolicially, and also assayed directly. No relationship to biogenic amines was observed, and it appears not to be responsible for the observed MDMA effects.

Stone, D.M., Hanson, G.R. and Gibb, J.W. Does Dopamine Play a Role in the Serotonergic "Neurotoxicity" Induced by 3,4-Methylenedioxymethamphetamine (MDMA)? Soc. Neurosciences Abstrt. 12 169.4 (1986).

The possibility that the negative serotonin effects of MDMA might be mediated by dopamine was investigated. Studies involving dopamine synthesis inhibitors and antagonists suggest less involvement of dopamine than is seen with methamphetamine.

Stone, D.M., Hanson, G.R. and Gibb, J.W. Differences in the Central Serotonergic Effects of Methylenedioxymethamphetamine (MDMA) in Mice and Rats. Neuropharm. 26 1657-1661 (1987).

A number of studies as to the brain serotonin responses to MDMA (in rats) suggest that the duration of exposure might be an important factor in the estimation of toxic effects. Mice are shown to be less susceptible to MDMA, neurotoxicologically, than rats.

Stone, D.M., Merchant, K.M., Hanson, G.R. and Gibb, J.W. Immediate and Long Term Effects of 3,4-Methylenedioxymethamphetamine on Serotonin Pathways in Brain of Rat. Neuropharmacology 26 1677-1683 (1987).

The time course for the decrease of markers of central serotonin function in the rat is reported. Changes were observed at 15 minutes following a 10 mg/Kg s.c. injection, and much recovery was observed at the 2 week point. Following multiple dose administration of MDMA, significant serotonin changes were still evident after 110 days.

Stone, D.M., Stahl, D.C., Hanson, G.R. and Gibb, J.W. The Effects of 3,4-Methylenedioxymethamphetamine (MDMA) and 3,4-Methylenedioxyamphetamine (MDA) on Monoaminergic Systems in the Rat Brain. Eur. J. Pharmacol. 128 41-48 (1986).

Single or multiple doses of either MDMA or MDA caused marked reduction in both serotonin and 5-HIAA, as well as in the associated enzyme tryptophane hydroxylase (TPH). Single injections elevated striatal dopamine concentrations, although after repeated injections, these values became normal. Striatal tyrosine hydroxylase (TH) was not changed.

St. Omer, V.E.V., Ali, S.F., Holson, R.R., Duhart, H.M., Scalzo, F.M. and Slikker, W. Behavioural and Neurochemical Effects of Prenatal Methylenedioxymethamphetamine (MDMA) Exposure in Rats. Neurotox. Teratol. 13 13-20 (1991).

Pregnant rats were treated repeatedly with MDMA. The progeny were completely normal as to litter size, birth weight, physical appearance, maturation parameters, and other measures of behaviour. No neurological deficit could be observed, although the mother showed some decrease in weight gain, and decreases in brain levels of serotonin at selected locations.

Takeda, H., Gazzara, R.A., Howard, S.G. and Cho, A.K. Effects of Methylenedioxymethamphetamine (MDMA) on Dopamine (DA) and Serotonin (5-HT) Efflux in the Rat Neostriatum. Fed. Proc. 45 1059 (#5266) April 13-18, 1986.

Employing electrodes implanted in the neostriatum of anaesthetized rats, the MDMA-induced efflux of dopamine and serotonin was measured. The serotonin efflux was significantly increased by MDMA, and had returned to normal by three hours. The dopamine efflux increased slightly, and then dropped below normal. MDA decreased the dopamine efflux.

Trulson, T.J. and Trulson, M.E. 3,4-Methylenedioxymethamphetamine (MDMA) Suppresses Serotonergic Dorsal Raphe Neuronal Activity in Freely Moving Cats and in Midbrain Slices in vitro. Soc. Neurosci. Abstr. Vol. 13, Part 3, p. 905 (1987) No. 251.7.

A study of the decrease of brain serotonin levels in cats given 0.25-5.0 mg/Kg MDMA is reported. Pretreatment with p-chloroamphetamine greatly attenuated the suppressant action of MDMA, and it is suggested that the action of the two drugs is similar.

Wagner, J. and Peroutka, S.J., Neurochemistry and Neurotoxicity of Substituted Amphetamines, Neuropsychopharm. 3 219-220 (1990).

MDMA was compared with Fenfluramine as a depletor of serotonergic nerve terminals, as determined by the reduction of the density of paroxetine binding sites in rat's brains. Single dosages of 30 mg/Kg and 10 mg/Kg were required of the two drugs, respectively, to achieve significant changes.

Whitaker-Azmitia, P.M. and Azmitia, E.C. A Tissue Culture Model of MDMA Toxicity. The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Kluwer, New York. (1990) Ed: S.J. Peroutka

A procedure is described for studying MDMA toxicity employing tissue cultures prepared from fetal rat brains. The similarities and the differences observed between this technique and the more common in vivo techniques, are discussed.

Wilson, M.A., Ricaurte, G.A. and Molliver, M.E. The Psychotropic Drug 3,4-Methylenedioxymethamphetamine (MDMA) Destroys Serotonergic Axons in Primate Forebrain: Regional and Laminar Differences in Vulnerability. Soc. Neurosci. Abstr., Vol. 13, Part 3, No. 251.8 p. 905 (1987).

The monkey shows a striking brain loss of serotonin terminals following exposure to MDMA twice daily for 4 days at 5 mg/Kg. The distribution and extent of this damage is reported.

Wilson, M.A., Ricaurte, G.A. and Molliver, M.E. Distinct Morphologic Classes of Serotoninergic Axons in Primates Exhibit Differential Vulnerability to the Psychotropic Drug 3,4-Methylenedioxymethamphetamine. Neuroscience 28 121 (1989).

An exacting study is presented describing the morphological changes seen in the serotoninergic axons in the monkey's brain following MDMA exposure.

Woolverton, W.L., Virus, R.M., Kamien, J.B., Nencini, P., Johanson, C.E., Seiden, L.S. and Schuster, C.R. Behavioural and Neurotoxic Effects of MDMA and MDA. Amer. Coll. Neuropsychopharm. Abstrts. p. 173 (1985).

In behavioural studies in rats and monkeys trained to distinguish amphetamine from saline, MDMA mimicked amphetamine. With chronic administration, MDMA caused a degeneration of serotonin uptake sites, but no change in affinity of the undamaged sites. These results were similar to, but greater than, those seen with MDA.

Yamamoto, B.K. and Spanos, L.J. The Acute Effects of Methylenedioxymethamphetamine on Dopamine Release in the Awake-behaving Rat. Eur. J. Pharmacol. 148 195-204 (1988).

The effects of MDMA on the caudate and nucleus accumbens dopamine release and metabolism were studied by in vivo voltammetry and HPLC with electrochemical detection. There was a dose-dependent dopamine release observed in both regions by both measures.

Yeh, S.Y. Lack of Protective Effect of Chlorpromazine on 3,4-Methylenedioxymethamphetamine Induced Neurotoxicity on Brain Serotonin Neurons in Rats. Res. Commun. Subst. Abuse 11 167-174 (1990).

Studies involving the administration of MDMA with or without chlorpromazine suggests have suggested that chlorpromazine does not protect MDMA-induced depletion of serotonin in rats.

Yeh, S.Y. and Hsu, F-L Neurotoxicity of Metabolites of MDA and MDMA (Ecstasy) in the Rat. Soc. Neurosci. Abstr., Vol. 13, Part 3, p. 906 (1987) No. 251.11.

MDA, MDMA, and a number of potential metabolites (4-OH-3-OMe- amphetamine, alpha-methyldopamine, alpha-methylnorepinephrine) were studied in the rat, and the serotonin decreases measured. These metabolites have a lower neurotoxicity than the parent compound.

Zaczek, R., Culp, S. and De Souza, E.B. Intrasynaptosomal Sequestration of [3H]Amphetamine and [3H]Methylenedioxyamphetamine: Characterization Suggests the Presence of a Factor Responsible for Maintaining Sequestration. J. Neurochem. 54 195-204 (1990).

The incorporation of tritiated amphetamine, MDA and MDMA into rat brain synaptosomes was studied. The observed dynamics is discussed in relationship to the mechanism of action of amphetamine-induced monoamine release.

Zaczek, R., Hurt, S., Culp, S. and DeSouza, E.B. Characterization of Brain Interactions with Methylenedioxyamphetamine and Methylenedioxymethamphetamine. NIDA Research Monograph Series #94 223-239 (1989).

Brain recognition sites have been described for labelled MDA and MDMA, and similarities between these and the corresponding amphetamine sites are noted.

Zhao, Z., Castagnoli Jr., N, Ricaurte, G.A., Steele, T. and Martello, M. Synthesis and Neurotoxicological Evaluation of Putative Metabolites of the Serotoninergic Neurotoxin 2-(Methylamino)-1-[3,4-(methylenedioxy)phenyl]propane [(Methylenedioxy)methamphetamine]. Chem. Res. Toxicol. 5 89-94 (1992).

A number of potential toxic metabolites of MDMA were synthesized and assayed as neurotoxins. One of these, 2,4,5-trihydroxymethamphetamine, was found to deplete both dopamine and serotonin.

Beck, J. The Public Health Implications of MDMA Use. The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Kluwer, New York. (1990) Ed: S.J. Peroutka.

This sociological paper brings together the street acceptance of, and the public health rejection of, MDMA as a tool for therapy and a vehicle of simple intoxication. The part that this drug has played in each of these roles is carefully defined.

Beck, J., Harlow, D., McDonnell, D., Morgan, P.A., Rosenbaum, M. and Watson, L. Exploring Ecstasy: A Description of MDMA Users. Report to NIDA, September 15, 1989. Grantee: Institute for Scientific Analysis, San Francisco, CA.

This is a 253 page report of a research project that conducted a broad and thorough analysis, through interview, of over 100 MDMA users. A fascinating picture emerges of the pros and cons of MDMA usage. This is the only analysis of this depth and candidness that has ever been done, and it is an essential reference volume for all social researchers in this area.

Buffum, J. and Moser, C. MDMA and Human Sexual Function. J. Psychoactive Drugs 18 355-359 (1986).

A survey of some 300 MDMA users produced a response of 25%. An analysis of the presented data is offered, organized as to types of activity and performance. There was a significant increase in intimacy, and a decrease (especially for males) in performance.

Downing, J. The Psychological and Physiological Effects of MDMA on Normal Volunteers. J. Psychoactive Drugs 18 335-340.

This is certainly the most complete clinical study on the effects of MDMA on the normal human subject. A total of 21 normal volunteers were administered known amounts of MDMA, orally. The entire group had analyses of blood chemistry, timed and frequent physiological measures, including pulse and blood pressure (for all) and as well as neurological and electrocardiographic tests (for some). The neurological and electrocardiogram evaluations were continued for 24 hours.

Physiologically, all subjects experienced an elevation in blood pressure and pulse rate, with a peaking on the average at about one hour. At the sixth hour, most subjects were at or below their pre-dose levels, and at 24 hours all were within their normal ranges. Eye dilation was seen in all subjects, more than half had jaw clench and an increased jaw reflex, which persisted in one subject to the 24 hour point. Some neurological reflexes were enhanced (deep tendon) or equivocal (planter reflex), and there were signs of incoordination (finger-nose testing, gait) in some subjects, giving a strong warning against motor vehicle operation. One subject was nauseous, with vomiting, but there were no difficulties with either urination or defecation, and there were neither headaches nor insomnia. Appetite was suppressed in all subjects to varying degrees.

At the psychological level, all subjects reported a heightened sensual awareness, and three reported sexual arousal. It is concluded that MDMA produces remarkably consistent psychological effects that are transient, and is free of clinically apparent major toxicity.

Greer, G. MDMA: A New Psychotropic Compound and its Effects in Humans. Privately Published, 333 Rosario Hill, Sante Fe, NM 87501. Copyright 1983. 15 pages.

The most complete study of the effects of MDMA published as of this date, describing the results of administration of MDMA to 29 human subjects (none with serious psychiatric problems) in a therapeutic setting. It is concluded that the best uses of MDMA are: facilitation of communication and intimacy between people involved in emotional relationships; as an adjunct to insight-oriented psychotherapy; and in the treatment of alcohol and drug abuse. It is explained why MDMA does not lend itself to over-use, since its most desirable effects diminish with frequency of use.

Greer, G. Recommended Protocol for MDMA Sessions. Privately Published. 333 Rosario Hill, Sante Fe, NM 87501. Copyright 1985. 6 pages.

This is a generalized protocol designed to cover the clinical use of MDMA. It reviews the issues of law, of safety, and of efficacy.

Greer, G. Using MDMA in Psychotherapy. Advances, 2 57-57 (1985).

A conference was held at Esalen March 10-15 1985, to discuss the potential of MDMA for therapy, and to evaluate its differences from earlier therapeutic tools such as LSD. A total of 13 subjects, with the supervision of several experienced psychiatrists, participated in a experiment designed to familiarize the potential clinician with the actions of MDMA. Most of the attendees had already known of the drug in a therapeutic context, and their collected comments are presented and discussed.

Greer, G. Ecstasy and the Dance of Death. British Med. J. 305 775 (1992).

A defence of MDMA is presented, in answer to published conclusions that no clinical benefits have been observed. There is a tallying of the benefits seen amongst the author's patients, in earlier clinical studies.

Greer, G. and Tolbert, R. Subjective Reports of the Effects of MDMA in a Clinical Setting. J. Psychoactive Drugs 18 319-327 (1986).

This article summarizes and gives additional detail on the collection of 29 therapeutic trials discussed earlier. The protocol of drug administration, a review of both the benefits and the undesirable effects, and an outlining of the changes seen in the patients, are presented. There is a considerable body of retrospective evaluation.

Greer, G. and Tolbert, R. The Therapeutic Use of MDMA. The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Kluwer, New York. (1990) Ed: S.J. Peroutka.

A structure is provided in detail for the clinical use of MDMA in a therapeutic setting. A number of the preferred procedured are illustrated with specific case examples.

Grob, C., Bravo, G., McQuade, J. and Doblin, R. Analgesic Efficacy of 3,4-Methylenedioxymethamphetamine (MDMA) in Modification of Pain and Distress of End-stage Cancer. Proposal submitted to the FDA for clinical approval, August 4, 1991.

A proposal has been submitted to the FDA for the evaluation of MDMA as an analgesic against clinical pain in advanced cancer patients.

Grob, C., Bravo, G., and Walsh, R., Second Thoughts on 3,4-Methylenedioxymethamphetamine (MDMA) Neurotoxicity. Arch. Gen. Psychiatry 47 288 (1990).

A letter to the editor presents a critique of studies done on alleged MDMA users in search for evidence of serotonin nerve damage (Price et al., Arch. Gen. Psychiatry 46 20-22 (1989). The fact that all nerve toxicity is based on animal studies, and that the long-used drug Fenfluramine is considerably more potent a neurotoxin than MDMA, might argue that studies into the potential therapy use should be encouraged.

Grob, C.S., Bravo, G.L., Walsh, R.N. and Liester, M.B. Commentary: The MDMA-Neurotoxicity Controversy: Implications for Clinical Research with Novel Psychoactive Drugs. J. Nerv. Ment. Dis. 180 355-356 (1992).

The points raised by Kosten and Price, in criticism to the retrospective interview paper, are answered.

Hastings, A. Some Observations on MDMA Experiences Induced Through Posthypnotic Suggestion. J. Psycho. Drugs 26 77-83 (1994).

A study is reported with subjects who were familiar with MDMA action. The techniques of hypnosis were employed toreinstitute MDMA-like effects, and the potential for post-hypnotic suggestion in therapy is explored.

Kosten, T.R. and Price, L.H. Commentary: Phenomenology and Sequelae of 3,4-Methylenedioxymethamphetamine Use. J. Nerv. Ment. Dis. 180 353-354 (1992).

The retrospective interview by Liester et al. is critically analysed, and found to be faulted both methodologically and as to the conclusions reached.

Liester, M.B., Grob, C.S., Bravo, G.L. and Walsh, R.N. A Study of MDMA Use Among Psychiatrists. Poster #NR-62, New Research Poster Session, American Psychiatric Association, San Francisco, CA May 8, 1989.

A survey was conducted among 20 psychiatrists who had previously taken MDMA, and a tally of the various responses made. There was a discussion of both the methodological problems and the ethical considerations of this type of study.

Liester, M.B., Grob, C.S., Bravo, G.L. and Walsh, R.N. Phenomenology and Sequelae of 3,4-Methylenedioxymethamphetamine Use. J. Nerv. Ment. Dis. 180 345-352 (1992).

Twenty psychiatrists experienced with MDMA were retrospectively interviewed as to side effects, insight gained, pleasure experienced, and intensity of effects.

McCann, U.D. and Ricaurte, G.A. MDMA ("Ecstasy") and Panic Disorder: Induction by a Single Dose. Biol. Psychiatry 32 950-953 (1992).

A patient is described with a lasting panic disorder syndrome that started during the course of an alledged MDMA experience. Alprazolam improved his condition, but it was reprecipitated by OTC cold remedies, suggesting that some catecholamine function had been disturbed.in the patient.

McCann, U.D. and Ricaurte, G.A. Reinforcing Subjective Effects of (+/-) 3,4-Methylenedioxymethamphetamine ("Ecstasy") May Be Separable from its Neurotoxic Actions: Clinical Evidence. J. Clin. Psychopharmacol. 13 214-217 (1993).

Four subjects who had voluntarily, and anecdotaly, exposed themselves to MDMA, report that pretreatment with Fluoxetine found some increased somatic distress, but no attenuation of the expected responses to the drug, including enhanced awareness and ease of communication. It is implied that a pretreatment with a serotonin uptake inhibitor attenuates the neurotoxic effects of the drug MDMA, but the thrust of the report might well be to suggest that there is a neurotoxic effect in man that can indeed be attenuated.

McCann, U.D., Ridenour, A., Shaham, Y. and Ricaurte, G.A. Serotonin Neurotoxicity After (+/-)3,4-Methylenedioxymethamphetamine (MDMA; "Ecstasy"): A Controlled Study in Humans. Neuropsychopharmacology 10 129-138 (1994).

A group of 30 MDMA users and 28 matched controls with no history of MDMA use were studied. The MDMA subjects had lower levels of 5-hydroxyindoleacetic acid in their cerebrospinal fluid, indicating some serotonin depletion. At the psychological level, the MDMA users showed a decreased impulsivity and hostility, and increased harm avoidance and constraint.

Moody, C.P. Facsimile letter to C.S. Grob concerning FDA approval of human Phase I study application. November 4, 1992.

This is an official statement from the Pilot Drug Evaluation Section of the Food and Drug Administration, that the Phase I study submitted by Dr. Grob, has been approved.

Peroutka, S.J. Recreational Use of MDMA, Ecstasy: The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Kluwer, New York. (1990) Ed: S.J. Peroutka.

There is a distillation from some 300 users of MDMA as to their experiences on the drug, both as to subjective mental effects, and as to physical difficulties. Although the reports are largely favourable, there is a mention of both panic attacks and of a lethal event, and several popular myths are itemized. It is concluded that recreational use should be avoided.

Peroutka, S.J., Newman, H. and Harris, H. Subjective Effects of 3,4-Methylenedioxymethamphetamine in Recreational Users. Neuropsychopharmacol. 1 273-277 (1988).

A survey has been made of about a hundred admitted MDMA users and has been organized into reports of subjective feelings such as "closeness" (the most often reported) to "blurred vision" (the least often reported). A brief review of the toxicological history is presented, and no unequivocal evidence of human toxicity could be concluded from this study.

Price, L.H., Krystal, J.H., Heninger, G.R. and Ricaurte, G.A., In Reply. Arch. Gen. Psychiatry 47 289 (1990).

The critique of Grob et al. is responded to. The self-claimed MDMA users had been assayed by urine EMIT screening for recent drug use prior to the experiments reported (Price et al., Arch. Gen. Psychiatry 46 20-22 (1989). The justification for continued Fenfluramine use was that it had no record of abuse (as contrasted to MDMA use), and that the claims for drugs serving as psychotherapeutic adjuncts have been made for many compound for many years, and have not bourn fruit. The recommendation is strongly made that clinical studies are inappropriate at this time.

Shulgin, A.T. and Nichols, D.E. Characterization of Three New Psychotomimetics, The Psychopharmacology of Hallucinogens, Eds. R.C. Stillman and R.E. Willette, Pergamon Press, New York. (1978).

The psychopharmacological properties of MDMA are presented, in company with two new compounds, para-DOT (2,5-dimethoxy-4-methylthioamphetamine) and alpha,O-DMS (5-methoxy-alpha-methyltryptamine). It is described as evoking an easily controlled altered state of consciousness with emotional and sensual overtones. It appears to be with little hallucinatory component. This is the first clinical report of the effects of MDMA in man.

Siegel, R.K. MDMA: Nonmedical Use and Intoxication. J. Psychoactive Drugs 18 349-354 (1986).

From a group of 415 acknowledged MDMA users, a sub-group of 44 were chosen for examinations and tests. They were interviewed, physically examined, and tested by several of a large battery of psychological evaluation procedures. From this, patterns of use and the nature of the intoxicating effects were deduced.

The author has concluded that the visual effects of MDMA intoxication were typical of the intoxications from the classical hallucinogens such as mescaline with imagery characteristic of drug-induced hallucinations, as well as those induced by isolation and stress. These are mollified when attention is directed towards external events. There were, nonetheless, no abnormal profiles on the psychological tests. It is felt that the MDMA intoxication is neither uniformly controllable nor uniformly predictable.

Tatar, A. and Naranjo, C. MDMA in der Gruppenpsychotherapie. Symposion "Uber den derzeitigen Stand der Forschung auf dem Gebiet der psychoaktiven Substanzen." Nov. 29 - Dec. 12, 1985, in Hirschhorn/Neckar, Germany.

Two independent reports of clinical utility are presented. Both investigators report MDMA use in group settings. The groups consisted mainly of psychosomatic patients involving problems such as allergies, eczema, sexual dysfunction, troublesome urination, cardiac irregularities, and cancer. There were some positive changes reported, and in some cases there were no improvements. No details are presented.

Watson, L. and Beck, J. New Age Seekers: MDMA Use as an Adjunct to Spiritual Pursuit. J. Psychoactive Drugs 23 261-270 (1991).

In an analysis of a sociological investigation into the lay use of MDMA, the quality of MDMA experiences with a sub-set of "New Age" oriented users. As there appears to be a wide variety of motivations for MDMA use, care must be paid to the social context in evaluating drug-using behaviour.

Widmer, S. Ins Herz der Dinge Lauschen, vom Erwachen der Liebe. Nachtschatten Verlag, Solothurn, Switzerland, 1989.

This reference book of just over 300 pages, is a thorough collection of ideas, comments, and illustrations, of the use of MDMA and/or LSD in psychotherapy. It is in German.

Wolfson, P.E. Meetings at the Edge with Adam: A Man for All Seasons. J. Psychoactive Drugs 18 329-333 (1986).

An extensive discussion is presented listing the potential virtues and hazards of MDMA use in the psychotherapeutic setting. The roles of drugs currently used, and those of MDMA-like action that might some day be available, are reviewed. A case report of the use of MDMA in a family problem situation is presented in considerable detail.

Allen, R.P., McCann, U.D. and Ricaurte, G.A. Persistant Effects of (+/-)3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") on Human Sleep. Sleep, 16 560-564 (1993).

A number of MDMA users were studied as to sleep performance. They showed a significant decrease in sleep time (19 minutes) and non-REM sleep (23.2 minutes). The authors conclude that the recreational use of MDMA may induce lasting CNS serotonergic damage.

Ames, D. and Wirshing, W.C. Ecstasy, the Serotonin Syndrome, and Neuroleptic Malignant Syndrome - A Possible Link. J. Am. Med. Assoc. 269 869 (1993).

A short review of both the "serotonin syndrome" and the "neuroleptic malignant syndrome" are presented, and compared to the portrait presented with MDMA overdose. A path of medical intervention is suggested based on the neurotransmitter disturbances associated with these syndromes.

Barrett, P.J. 'Ecstasy' misuse - Overdose or Normal Dose? Anaesthesia 48 83 (1993).

The personal experiences of this physician is that there is no straightforward relationship the dose of 'ecstasy' used, and the complications that might follow this exposure. Dehydration is common, but this follows the energy expenditure in the drug use scene. Supportive therapy should be continued, but its efficacy must be continuously evaluated.

Campkin, N.T.A. and Davies, U.M. Treatment of 'Ecstasy' Overdose with Dandrolene. Anaesthesia, 48 82-83 (1993).

An exploration is presented for the first reported use of Dandrolene in the treatment of MDMA overdose. Its value in treatment is discussed, and remains uncertain. Nonetheless the recreational use of MDMA appears to remain a potentially lethal pastime.

Cregg, M.T. and Tracey, J.A. Ecstasy Abuse in Ireland, Irish Med. J. 86 118-20 (1993).

An epidemiological study of MDMA use in Ireland is presented, based upon reports to the National Poisons Information Centre in Dublin. Most of those described were male (80%) and largely in the 16-20 year old group. The symptoms presented are described as being relatively mild.

Davis, W.M. and Borne, R.F. Pharmacologic Investigation of Compounds Related to 3,4-Methylenedioxyamphetamine (MDA). Substance and Alcohol Actions/Misuse, 5 105-110 (1984).

Acute toxicity studies on MDMA and several homologues, in mice, showed LD-50's of about 100 mg/Kg (i.p.) (for MDMA). In aggregate, the lethality was increased several-fold.

de Man, R.A., Wilson, J.H. and Tjen, H.S. Acute Liver Failure Caused by Methylenedioxymethamphetamine ("Ecstasy"). Nederlands Tijdschrift voor Geneeskunde. 137 727-9 (1993).

An eighteen year old female who had regularly taken 1-2 tablets of MDMA every weekend, developed acute liver failure. She recovered following two months of hospitalization. It is claimed that this is the 10th published case of hepatotoxicity following MDMA use.

Friedman, R. Ecstasy, the Serotonin Syndrome, and Neuroleptic Malignant Syndrome - A Possible Link. Reply. J. Am. Med. Assoc. 269 869-870 (1993).

A plan for the treatment of MDMA toxicity is presented, based on the similarity of its symptoms with the "serotonin syndrome."

Frith, C.H. 28-Day Oral Toxicity of Methylenedioxymethamphetamine Hydrochloride (MDMA) in Rats. Project Report, Toxicology Pathology Associates, Little Rock, Arkansas (1986)

A controlled toxicological study on some 100 rats with chronically administered MDMA (dosages up to 100 mg/Kg) showed several behavioural signs (hyperactivity, excitability, piloerection. exophthalmus, and salivation). Neither gross nor microscopic pathology was evident at necropsy.

Frith, C.H., 28-Day Oral Toxicity of Methylenedioxymethamphetamine Hydrochloride (MDMA) in Dogs. Project Report, Toxicology Pathology Associates, Little Rock, Arkansas (1986)

A controlled toxicological study of some 24 dogs with chronically administered MDMA (dosages up to 15 mg/Kg) showed several behavioural signs including circling, depression, dilated pupils, hyperactivity, rapid breathing, and salivation. On necropsy, there were examples of reduced testicular size, including microscopically noted atrophy. Prostatic hyperplasia was present in two high dose males.

Frith, C.H., Chang, L.W., Lattin, D.L., Walls, R.C., Hamm, J. and Doblin, R. Toxicity of Methylenedioxy-methamphetamine (MDMA) in the Dog and the Rat. Fundamental and Applied Tox. 9 110-119 (1987).

Toxicity studies were performed on dogs and rats and signs are described. No histopathological lesions within the CNS were observed in either species, although unusual clinical observations were recorded.

Goad, P.T. Acute and Subacute Oral Toxicity Study of Methylenedioxymeth-amphetamine in Rats. Project Report, Intox Laboratories, Redfield, Arkansas, (1985).

Subacute toxicity studies on rats in graded doses (25 mg/Kg/day in 25 mg increments to 300 mg) were conducted. In acute studies, the LD-50 is given as 325 mg/Kg, some six times the reported i.p. LD-50. No histological evidence of brain damage was observed.

Gledhill, J.A., Moore, D.F., Bell, D. and Henry, J.A. Subarachnoid Haemorrage Associated with MDMA Abuse. J. Neurol. Neurosur. Psychiat. 56 1036-1037 (1993).

Shortly following the consumption of MDMA, a 25 year old woman presented with severe headache and vomiting. A CT scan showed subarachnoid haemorrhaging which was successfully controlled. There had apparently been a preexisting "berry" aneurysm which may have ruptured with the surge of blood pressure from the drug. She had been a regular MDMA user for two or three years before this incident.

Hardman, H.F., Haavik, C.O. and Seevers, M.H. Relationship of the Structure of Mescaline and Seven Analogs to Toxicity and Behaviour in Five Species of Laboratory Animals. Tox. and Appl. Pharmacology 25 299-309 (1973).

This report describes several studies supported by the Army Chemical Centre during the period 1953-1954, and declassified in 1969. MDMA was one of eight compounds (including also mescaline, DMPEA, MDPEA, MDA, DMA, TMA and alpha-ethyl-MDPEA) studied in five animals (mouse, rat, guinea pig, dog, and monkey).

The toxicology study showed MDMA to be one of the more toxic of the drugs studied, in most animals second only to MDA. The average LD-50's given were 97, 49 and 98 mg/Kg (for the mouse, rat and guinea pig, resp. - following i.p. administration), and 16 and 26 mg/Kg (for the dog and monkey, i.v. administration).

Behavioural studies in dog and monkey were made over the dosage ranges of 5-50 and 10-75 mg/Kg respectively. These levels evoked a broad range of motor activity, autonomic activity and CNS activity in both animals (the dog more than the monkey) but the ranges studied included the lethal dose levels. Interestingly the monkey showed behaviour interpreted as hallucinations for MDMA, whereas mescaline (an acknowledged hallucinogenic compound) produced no such behaviour at doses more than two times higher (200 mg/Kg i.v.). Structure-activity relationships are discussed.

Anon: Analog, Australian Forensic Drug Analysis Bulletin 12 14 (1990).

Two deaths associated with a plane crash, were analysed. There was MDMA present (blood, 1.4 and 1.7 mg/L; liver, 1.5 and 6.9 mg/kg; stomach, 0.24 and 0.55 mg; urine, 48 amd 44 mg/L). And also present was ethanol (blood, 0.165 and 0.145 g/100 mL) as well as the qualitative presence of cannabinoids (in both).

Barrett, P.J. Ecstasy and Dandrolene. British Med. J. 305 1225 (1992).

An argument is made against the administration of Dandrolene in instances of hyperthermia following ecstasy intoxication. This is a muscle relaxant which may reduce thermogenesis associated with muscular activity. Rehydration seems the wiser course and supportive measures may be sufficient treatment.

Benazzi, F., and Mazzoli, M. Psychiatric Illness Associated with "Ecstasy". Lancet 338 1520 (1991).

A case of severe depression following MDMA exposure is reported. The syndrome included loss of energy, weight, and interest in all activities, decreased appetite, psychomotor retardation, hypersomnia, diminished ability to concentrate, and suicidal ideation.

Brown, C.R., McKinney, H., Osterloh, J.D., Shulgin, A.T., Jacob III P. and Olson, K.R. Severe Adverse Reaction to 3,4-Methylenedioxymethamphetamine (MDMA). Vet. Hum. Toxicol. 28 490 (1986).

A 32 year old female presumably ingested a "standard" dose, and became comatose, but survived. Serum level was reported to be 7 micrograms/mL.

Brown, C. and Osterloh, J. Multiple Severe Complications from Recreational Ingestion of MDMA (Ecstasy). J. Am. Med. Soc. 258 780-781 (1987).

A considerable body of clinical detail and selected laboratory finding is present in an apparent MDMA toxicity situation involving a 32 year old female. Serum levels of 7 mg/mL and urine levels of 410 and 816 mg/mL were reported (the latter upon admission and on the second day). An immunoenzyme assay for MDMA (using a system designed for amphetamine) reacted with MDMA at 25 mg/mL at the amphetamine cut-off point of 300 nanograms/mL. The observed complications were similar to those observed in amphetamine overdoses, and might possibly be due to an idiosyncratic reaction, an allergic reaction, or to malignant hyperthermia.

Campkin, N.T.A. and Davies, U.M. Another Death from Ecstasy. J. Royal Soc. of Med. 85 61 (1992).

A young male was admitted both unconscious and convulsing following the consumption of three ecstasy tablets. Despite heroic treatment, he died some five hours later. Serum MDMA levels were measured (1.26 mg/L) although no MDA was detected. The diagnosis included disseminated intravascular coagulation with prolonged clotting times, hypofibrinogenaemia, elevated fibrin degradation products and thrombocytopaenia.

Chadwick, I.S., Linsley, A., Freemont, A.J. and Doran, B. Ecstasy, 3,4-Methylenedioxymethamphetamine (MDMA), a Fatality Associated With Agulopathy and Hyperthermia. J. Royal Soc. Med. 84 371 (1991).

A fatality associated with MDMA is reported. Blood and gut levels are given. Extensive morbid post mortem details are also outlined.

Davis, W.M., Hatoum, H.T. and Waters, I.W. Toxicity of MDA (3,4-Methylenedioxyamphetamine) Considered for Relevancy to Hazards of MDMA (Ecstasy) Abuse. Alcohol and Drug Abuse, 7 123-134 (1987).

The toxicological literature is reviewed, and it is suggested that the toxicological data obtained from MDA be extrapolated to MDMA. A comparison of these two drug is presented.

de Silva, R.N. and Harries, D.P. Misuse of Ecstasy. British Med. J. 305 309 (1992).

This is the reinstatement of four observed cases of intracerebral haemorrhage following exposure to ecstasy or amphetamine. The original article appeared in the Scottish Med. Journal, authored by Harries and de Silva..

Dowling, G.P. Human Deaths and Toxic Reactions Attributed to MDMA and MDEA. The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Kluwer, New York. (1990) Ed: S.J. Peroutka.

A thorough review is presented of the case records of the reported deaths associated with MDMA use. It was concluded that such deaths are exceedingly rare, especially when considering the widespread use of this drug.

Dowling, G.P., McDonough III, E.T. and Bost, R.O. 'Eve' and 'Ecstasy' A Report of Five Deaths Associated with the Use of MDEA and MDMA. J. Am. Med. Assoc. 257 1615-1617 (1987)

Five deaths occurred in the Dallas area which have involved either MDMA or MDE. One death was stated to be due to MDMA. Two of the others had had preexisting heart conditions, one had asthma, and one was electrocuted, apparently from having climbed and fallen from a power pole. In these latter cases, MDMA was not felt to have been the primary cause of death. It is suggested that a preexisting cardiac disease may predispose an individual to sudden death with MDMA. It was only with the asthma death that there was given a body level (blood) of MDMA, and it was 1.1 mg/mL.

Ellis, P. and Schimmel, P. Ecstasy Abuse. New Zealand Medical Journal 102 358 (1989).

A severely disturbed young woman was seen as a patient. She made frequent references to "Ecstasy." A urine analysis showed no evidence for the presence of MDMA, although there was observed a high level of phenothiazines. She was admitted to the psychiatric word and started on antipsychotic medication. After three days there, she committed suicide. The authors conclude, "We are concerned that clinicians should be aware of the potentially serious medical and psychiatric consequences of the use of [MDMA] in sensitive individuals or in overdose."

Ellis, S.J. Complications of "Ecstasy" Misuse. Lancet 340 726 (1992).

A criticism is levelled at the medical letters published, and especially the media coverage, concerning the association of ecstasy use and human trauma. The terms used, are judgmental and scaremongering. The danger associated with MDMA use is clouded by the reports being out of context. In the absence of correlary information such as alcohol consumption, or even an estimate of MDMA use.

Fahal, I.H., Sallomi, D.F., Yaqoob, M. and Bell, G.M. Acute Renal Failure after Ecstasy. British Med. J. 305 29 (1992).

A nearly lethal case of acute renal failure is reported six hours following the alleged ingestion of three "ecstasy" tablets at a rave. It is felt that the use of the drug may have contributed to the trauma.

Gorard, D.A., Davies, S.E. and Clark, M.L. Misuse of Ecstasy. British Med. J. 305 309 (1992).

A case of jaundice is reported in a young student who had been using ecstasy recreationally over a period of several months. The symptoms cleared and there were no complications.

Harries, D.P. and de Silva, R.N. 'Ecstasy' and Intracerebral Haemorrhage. Scottish Med J. 37; 150-152 (1992).

Four cases of intracerebral haemorrhage are reported, following exposure to amphetamine ecstasy, or mixtures thereof.

Hayner, G.N. and McKinney, H. MDMA The Dark Side of Ecstasy. J. Psychoactive Drugs 18 341-347 (1986).

The emergency treatment of two toxic episodes involving MDMA are described. One case, a 34 year old male, had a complex drug history involving mainly opiates, but the timing of the crisis suggested that MDMA injection was responsible. The other case, involving a 33 year old female, has been discussed in detail (see Brown et al., above). A listing of the side-effects that may be experienced in cases of MDMA toxicity is also presented.

Henry, J. A. Ecstasy and the Dance of Death. British. Med. J. 305 5-6 (1992).

The positives and negatives of the drug Ecstasy (MDMA) are weighed. On the positive side, the psychotherapeutic potentials in fields as divergent and marriage guidance, alcoholism, and enhancement of perception in elderly people, have been explored, although they have been found to be without benefit. On the negative side, the adverse effects can include convulsions, collapse, hyperpyrexia, disseminated intravascular coagulation, rhabdomyolysis, acute renal failure, weight loss, exhaustion jaundice, "flashbacks,", irritability, paranoia, depression, or psychosis. The long term effects will take time to document in detail.

Henry, J.A., Jeffreys, K.J. and Dawling, S. Toxicity and Deaths from 3,4-Methylenedioxymethamphetamine ("Ecstasy"). Lancet 340 384-387 (1992).

A report of the seven or so deaths within the United Kingdom, associated with the use of MDMA, is presented. The clinical data in these deaths, as well as in other, non-fatal, legal situations, are brought together, and discussed. Most of the lethal events involved hyperthermia, whether from the effects of the drug itself, or from circumstances associated with its use.

Hughes, J.C., McCabe, M. and Evans, R.J. Intracranial Haemorrhage Associated with Ingestion of 'Ecstasy.' Arch. Emerg. Med. 10 372-374 (1993).

The summary of this report emphasizes the importance of a drug analysis in emergency medicine. The drug in this case was found to be amphetamine, not MDMA. Some mention should have been made also about the importance of not constructing a totally misleading title. Ecstasy was not involved.

Keenan, E., Gervin, M., Dorman, A. and O'Connor, J.J. Psychosis and Recreational Use of MDMA ("Ecstasy"). Irish J. Psychological Med. 10 162-163 (1993).

A patient presented with bizarre behavior, paranoid delusions and intermittant auditory hallucinations. He gave a history of taking MDMA weekly for a period of some five months. During his recovery period (with chlorpromazine) over the following few months, he has stopped the use of MDMA, and finds that the occasional use of cannabis does not worsen his symptoms.

Krystal, J.H., Price, L.H., Opsahl, C., Ricaurte, G.A. and Heninger, G.R. Chronic 3,4-Methylenedioxymethamphetamine (MDMA) Use: Effects on Mood and Neuropsychological Function? Am. J. Drug Alcohol Abuse 18 331-341 (1992).

A group of self-acknowledged past MDMA users, participants in a tryptophan challenge test, were evaluated for a number of possible neuropsychological deficits in a battery of tests. There were no indications of deficit, although some mild memory impairment was suggested. This was felt to be inconsequential (the volunteers that just recently flown some distances to participate in the tests, and the only documented drug common to all subjects was the intentionally administered tryptophan. The conclusions, nonetheless, are framed to raise concerns about the possible detrimental effects of MDMA use.

Larner, A.J. Complications of "Ecstasy" Misuse. Lancet 340 726 (1992).

An extensive discussion is presented on the mechanism of thermogenesis caused by the use of MDMA. There may indeed be a genetic predisposition to such forms of hyperthermia. Intervention with Dandrolene, although it itself is not centrally active, may be justified.

Lee, J.W.Y. Catatonic Stupor After Ecstasy. Brit. Med. J. 308 717-18 (1994).

The author has re-evaluated the diagnosis of two patients reported to have suffered catatonia as a consequence of having taken MDMA (Maxwell et al., Brit. Med. J. 307 1399 (1993). He feels from the symptoms presented, that one was stuporous and suffered mutism, and the other, who also did not speak, had simply presented with a "wild-eyed" look. The text-book criteria for a catonia diagnosis are reviewed.

McCann, U.D. and Ricaurte, G.A. Lasting Neuropsychiatric Sequelae of (+/-) Methylenedioxymethamphetamine ("Ecstasy") in Recreational Users. J. Clin. Psychopharm. 11 302-305 (1991).

The prolonged responses of two patients, who had allegedly ingested large quantities of MDMA, are described. It is suggested that there may be lasting adverse functional consequences in vulnerable persons following large dose exposure.

McGuire, P. and Fahy, T. Chronic Paranoid Psychosis after Misuse of MDMA ("Ecstasy"). British Med. J. 302 697 (1991).

Two cases are reported of chronic paranoid psychosis that followed alleged long-term self-administration of large quantities of MDMA. Other drugs had also been involved, and no toxicological evidence could confirm the drug history. Intervention treatment (Haloperidol, Sulpiride) resulted in some improvement.

O'Neill, D. and Dart, J.K. Methylenedioxyamphetamine (Ecstasy) Associated Keratopathy. Eye 7 805-806 (1993).

Three instances of othrwise unexplained corneal epitheliopath are described following the alledged taking of "Ecstasy." Although no documetation of drug exposure is mentioned, the drug has been assumed to be methylenedioxymethamphetamine (MDMA), rather than the methylenedioxyamphetamine (MDA) mentioned in the title and the text.

Pallanti, S., and Mazzi, D. MDMA (Ecstasy) Precipitation of Panic Disorder. Biol. Psychiatry 32 91-95 (1992).

The authors describe three patients whose panic disorder began during recreational use of MDMA (Ecstasy) and was subsequently complicated by agoraphobic avoidance that continued autonomously after cessation of the drug. Their panic disorder responded well to serotoninergic antidepressant drugs, although there was no psychotherapy done to work through the cause of the panic.

Peroutka, S.J., Pascoe, N. and Faull, K.F. Monoamine Metabolites in the Cerebrospinal Fluid of Recreational Users of 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"). Res. Commun. Subst. Abuse 8 125-138 (1987).

Lumbar punctures from five MDMA users with various histories were assayed (some weeks following the last exposure) for the levels of metabolites from the three major neurotransmitters serotonin, dopamine, and norepinephrine. All assays fell within normal limits.

Price, L.H., Ricaurte, G.A., Krystal, J.H. and Heninger, G.R. Neuroendocrine and Mood Responses to Intravenous L-Tryptophan in 3,4-Methylenedioxymethamphetamine (MDMA) Users. Arch. Gen. Psychiat. 46, 20-22 (1989).

Nine self-acknowledged MDMA users were used as test subjects for the determination of the ability of tryptophan to increase the serum prolactin level. This response can be used as a measure of serotonin integrity There was a statistically insignificant lessening of PRL concentrations in the MDMA users.

Reynolds, P.C., Personal Communication, 1986.

A 35-years old male, who claimed to have taken MDMA, Valium, and LSD (and who died shortly after admission) had the following body levels (in mg/mL):

Blood Urine Bile Gastric (total) MDMA 1.46 13.7 1.98 414 mg. MDA .03 (present)

Neither diazepam nor nordiazepam were found.

Ricaurte, G.A. Studies of MDMA-Induced Neurotoxicity in Nonhuman Primates: A Basis for Evaluating Long-Term Effects in Humans. NIDA Research Monograph Series #94 306-322 (1989).

Dose-related serotonin depletion in experimental animals is tabulated. A comparison of primate results to those reported from rats, has allowed an extrapolation to the human MDMA-user. The conclusion drawn that, as there have been no clear indicators of problems with MDMA users, if there is damage in man it may be very subtle in nature, possibly lying outside of our present techniques for detecting it, and possibly being very slow in onset, as compared to the rapid consequences seen from the MPTP trauma in the dopaminergic system.

Rittoo, D.B. and Rittoo, D. Complications of "Ecstasy" Misuse. Lancet 340 725 (1992).

A cautionary note is sounded about the misinterpretation of the origins of hyperthermia as a complication in the course of anesthesia, when in fact it might be the result of prior MDMA ingestion. A serum level for MDMA is suggested as a protective manoeuvre.

Rittoo, D., Rittoo, D.B. and Rittoo, D. Misuse of Ecstasy. British Med. J. 305 309-310 (1992).

Three teenagers were observed with chest pains following the use of ecstasy and alcohol, and several hours of dancing. All electrocardiograms and radiographs were normal, and there were no complications.

Rohrig, T.P. and Prouty, R.W. Tissue Distribution of Methylenedioxymethamphetamine. J. Anal. Tox. 16 52-53 (1992).

Two cases of death involving methylenedioxymethamphetamine (MDMA) are reported; one case is a fatal acute overdose and the other is a drug-related death. The tissue distribution of MDMA is reported in both cases.

Russell, B., Schwartz, R.H. and Dawling, S. Accidental Ingestion of 'Ecstasy' (3,4-Methylenedioxymethylamphetamine). Archiv. Dis. Childhood 67 1114-1115 (1992).

A case is reported of a 13 month old boy who ingested one capsule of Ecstasy. Neurological and cardiovascular side effects predominated, which responded well to treatment with a Chlormethiazole infusion.

Sawyer, J. and Stephens, W.P. Misuse of Ecstasy. British Med. J. 305 310 (1992).

Two cases of "fits" are reported in young patients who had consumed Ecstasy. There were no complications or sequelae.

Schifano, F. Chronic Atypical Psychosis Associated with MDMA ("Ecstasy") Abuse. Lancet 338 1335 (1991).

A psychotic state is described in a patient who had been using MDMA on occasion over the course of four years. Other drugs (cannabis, alcohol, benzodiazepines, cocaine) were also used, sporadically. Neuroleptic therapy did not appear to improve his mental state.

Screaton, G.R., Cairns, H.S., Sarner, M., Singer, M., Thrasher, A. and Cohen, S.L. Hyperpyrexia and Rhabdomyolysis after MDMA ("Ecstasy") Abuse. Lancet 339 677-678 (1992).

Three cases are described that alledgedly involved the use of MDMA and came to medical attention because of extreme hyperthermia. Disseminated intravascular coagulation (DIC) apparently followed as a consequence of the hyperpyrexia. Rapid cooling of the patient is recommended in such cases.

Shearman, J.D., Chapman, R.W.G., Satsangi, J., Ryley, N.G. and Weatherhead, S. Misuse of Ecstasy. British Med. J. 305 309 (1992).

A woman experienced acute jaundice on two occasions, in from one to two weeks following the use of ecstasy, suggesting an idiosyncratic response to the drug.

Shulgin, A.T. and Jacob III, P. 1-(3,4-Methylenedioxyphenyl)-3-aminobutane: A Potential Toxicological Problem. J. Toxicol. - Clin. Tox. 19 109-110 (1982).

An alert is written for the toxicological community that through the ambiguity of the term "piperonylacetone," two different chemical precursors for both MDA and MDMA have been publicly advertised and made available. Efforts to synthesize MDMA might, through misrepresentation, yield a largely unexplored homologue.

Smilkstein, M.J., Smolinske, S.C., Kulig, K.W. and Rumack, B.H. MAO Inhibitor/MDMA Interaction: Agony after Ecstasy. Vet. Hum. Toxicol. 28 490 (1986).

An abstract of a report of a 50 year old male who injected alleged MDMA while on a fixed regimen of the monoamine oxidase inhibitor phenelzine. He developed severe hypertension, diaphoresis, an altered mental status, and marked hypertonicity. With supportive care he recovered fully in some 6 hours. Caution is expressed in possible interrelations between MDMA and MAO inhibitors.

Smilkstein, M.J., Smolinske, S.C. and Rumack, B.H. A Case of MAO Inhibitor/MDMA Interaction: Agony after Ecstasy. Clin. Toxicol. 25 149-159 (1987).

This is the actual published paper that appeared as an abstract under similar authorship and similar title above. There are considerable clinical details concerning the emergency room intervention.

Stone, R.J. Response to the paper of Singarah and Laviec. Anaesthesia 48 83 (1993).

Tests are suggested that might assay the hyperthermia aspects of MDMA intoxication. Perhaps those who succumb to acute toxicity may be expressing responses that are genetic mediated.

Suarez, R.V. and Riemersma, R. "Esctasy" and Sudden Cardiac Death. Amer. J. Forensic Med. Pathol. 9 339-341 (1988).

An apparently natural death involving cardiac problems has been found to be related to MDMA use. The drug levels are given for blood and urine, but none of the metabolite MDA was identified as being present.

Tehan, B. Ecstasy and Dantrolene. Brit. Med. J. 306 146 (1993).

An argument is advanced supporting the clinical intervention with Dantrolene in MDMA toxicity cases. This is supported by the successful outcome of a problem associated with MDE where body temperature responded quickly to the use of this agent.

Verebey, K., Alrazi, J. and Jaffe, J.H. The Complications of "Ecstasy" (MDMA). J. Am. Med. Assoc. 259 1649-1650 (1988). Osterloh, J. and Brown, C., In Reply. ibid. 259 1650 (1988).

The body levels of MDMA and MDA following a single human trial of 50 mg are given. The peak plasma level seen (105.6 ng/Ml at 2 hrs.) decreased to 5.1 ng/Ml at 24 hrs. MDA occurred in plasma at lower levels, and both compounds appeared in urine. This suggests that the toxic incident reported by Brown and Osterloh may have followed a considerable overdose.

Whitaker-Azmitia, P.M. and Aronson, T.A. "Ecstasy" (MDMA)-Induced Panic. Am. J. Psychiat. 146 119 (1989).

Three cases are reported of transient panic attacks in individuals following the ingestion of alleged MDMA.

Williams, H., Meagher, D. and Galligan, P. M.D.M.A. ("Ecstasy"); a Case of Possible Drug-induced Psychosis. Irish J. Med. Sci. 162 43-44 (1993).

A disturbed and aggressive patient was seen at the time of a police arrest, some 48 hours following the consumption of a half-tab of alledged MDMA His medical history included a skull fracture two months earlier, and his mother had a history of psychotic depression and paranoid delusions. His urine analysis showed only cannabis and benzodiazepines, the latter medically administered. His bizarre behavior and mental disorientation was treated with Haloperidol, Diazepam, Carbamazepine, and finally with a total of 600 mg Clopenthixol which allowed an eventual resolution of his psychosis and disorientation.

Winstock, A.R. Chronic Paranoid Psychosis after Misuse of MDMA. British Med. J. 302 1150-1151 (1991).

A brief survey of the frequency and nature of use of MDMA is presented. A check list of reported symptoms is given, and the suggestion is offered that as it might induce psychosis more research is needed.

Wodarz, N. and B=F6ning, J. "Ecstasy" - Induziertes Psychotisches Depersonalisationssyndrom. Nervenarzt 64 478-80 (1993).

Following the consumption of two tablets of MDMA, a 21-year old patient exhibited a psychotic depersonalisation disorder with suicidal tendencies. With medication, the symtoms disappered over the course of six months. "Flash-backs" occurred repeatedly.

Woods, J.D. and Henry, J.A. Hyperpyrexia Induced by 3,4-Methylenedioxyamphetamine ("Eve") Lancet 340 305 (1992).

A 30 year old man was admitted in convulsions, two hours after having taken six tablets of ecstasy. He recovered and was dismissed 72 hours later. Serum analysis showed the presence of 1.51 mg/L MDA and 0.2 g/L ethanol. The urine level of MDA was 48.6 mg/l but an analysis for MDMA showed only 0.5 mg/l as being present. Errors in synthesis were suspected. The original ingestion of MDMA is unlikely as MDA is only a minor metabolite of it.

Anon: Verfahren zur Darstellung von Alkyloxyaryl-, Dialkyloxyaryl- und Alkylendioxyarylaminopropanen bzw. deren am Stickstoff monoalkylierten Derivaten. German Patent, 274,350; Filed December 24, 1912, issued May 16, 1914. Assigned to E. Merck in Darmstadt.

A chemical process is described for the conversion of several allyl- and propenyl-aromatic compounds to the corresponding beta-or alpha-bromopropanes. These, in turn, react with ammonia or primary amines to produce the corresponding primary 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 is mentioned.

Anon: Formyl Derivatives of Secondary Bases. German Patent 334,555, assigned to E. Merck. 1920. CA 17:1804a (1923).

A chemical conversion of MDMA to its formyl derivative, and the properties of the latter, are described. No pharmacology is mentioned.

Biniecki, S. and Krajewski, E. Preparation of DL-1-(3,4-Methylenedioxy)-2-(methylamino)propane and DL-1-(3,4-dimethoxyphenyl)- 2-(methylamino)propane. Acta Polon. Pharm. 17 421-425 (1960). CA 55:14350e (1961).

A chemical procedure is given for the conversion of safrole to the beta-bromopropane with HBr, and its subsequent conversion with alcoholic methylamine to MDMA. 4-Allylveratrole was similarly converted to 3,4-dimethoxy-N-methyl- amphetamine.

Bohn, M., Bohn, G. and Blaschke, G. Synthesis Markers in Illegally Manufactured 3,4-Methylenedioxyamphetamine and 3,4-Methylenedioxymethamphetamine. Int. J. Legal Med. 106 19-23 (1993).

Some twelve impurities have been described and identified in samples of illicitly prepared MDMA and MDA. Their role as markers for the synthetic routes used, or for connercting different lots of the drugs, is discussed.

Braun, U., Shulgin, A.T. and Braun, G. Centrally Active N- Substituted Analogs of 3,4-Methylenedioxyphenylisopropylamine (3,4-Methylenedioxyamphetamine), J. Pharm. Sci. 69 192-195 (1980).

Twenty two homologues and analogs of MDA were synthesized and their physical properties presented. Twelve of them 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 mg orally; MDE somewhat less potent with a dosage requirement of 140-200 mg orally; and MDOH, which was similar to MDMA in potency. Some animal pharmacology is reviewed, and a comparison between MDMA and MDA (toxicology, CNS pharmacology, and human effectiveness) is tabulated.

Cerveny, L., Kozel, J. and Marhoul, A. Synthesis of Heliotropin. Perfumer and Flavorist 14 13-18 (1989).

Piperonal is a most desirable precursor to piperony methyl ketone (PMK) which can, in turn, be converted directly to either MDA or MDMA. This is a synthetic procedure for the preparation of piperonal (heliotropin) from the precursor catechol (pyrocatechol).

Fujisawa, T. and Deguchi, Y. Concerning the Commercial Utilization of Safrole. J. Pharm. Soc. Japan 74 975 (1954). CA 49:10958i (1955).

The conversion of safrole to piperonylacetone is described, using formic acid and hydrogen peroxide, in acetone. The yield is satisfactory, and this is probably the most direct and efficient conversion of a natural product to an immediate precursor to MDMA.

Hashimoto, K., Hirai, K. and Goromaru, T. Synthesis of Racemic, S(+)- and R(-)-N-[methyl-3H] 3,4-Methylenedioxymethamphetamine. J. Labelled Cpds. and Radiopharmaceut. 28 465-469 (1990).

Tritium-labelled MDMA was synthesized from MDA by reaction with radioactive methyl iodide in a 60% yield. The optical isomers were separated on a chiral HPLC column.

Janesko, J.L. and Dal Cason, T.A. Seizure of a Clandestine Laboratory: The N-Alkyl MDA Analogs. Paper presented at the 39th Annual Meeting of the American Academy of Forensic Sciences, San Diego, CA Feb. 16-21 (1987). See Microgram 20 52 (1987).

Several clandestine laboratories have been seized, revealing the illicit preparation of not only MDMA, but the N-ethyl (MDE), the N-propyl (MDPR), the N-isopropyl (MDIP) and the N,N-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 homologues were found, prepared by catalytic hydrogenation.

Nakai, M. and Enomiya, T. Process for Producing Phenylacetones. U.S. Patent #4,638,094, dated January 20, 1987.

A high yield procedure is described, for the conversion of an allylbenzene to the corresponding phenylacetone. Specifically, the MDMA precursor 3,4-methylenedioxyphenylacetone is prepared in a 95% yield from safrole and butyl nitrite, in the presence of palladium bromide.

Nichols, D.E. Synthesis of 3,4-Methylenedioxymethamphetamine Hydrochloride. FDA Master File on MDMA. 1986.

A detailed synthesis of MDMA from piperonylacetone is presented, including all the spectroscopic and physical detail, bibliographies and CVs as required to define a drug product for medical needs.

Shulgin, A.T. and Jacob III, P. Potential Misrepresentation of 3,4-Methylenedioxyamphetamine (MDA). A Toxicological Warning. J. Anal. Tox. 6 71-75 (1982).

The commercial availability and overt misrepresentation of 3,4-methylenedioxybenzylacetone as 3,4-methylenedioxyphenylacetone might well suggest that an unsuspecting attempt to synthesize MDMA may yield a new and unexplored base, 1-(3,4-methylenedioxyphenyl)-3-(methylamino)butane. This compound was synthesized, and characterized in comparison to MDMA. The analogous relationship between MDA and its comparable homologue, 1-(3,4-methylenedioxyphenyl)-3-aminobutane, was also explored.

Yourspigs, U.P. The Complete Book of Ecstasy. Synthesis Books, Birmingham, Alabama. 1992.

This is an underground press book describing, quite adequately, the equipment and the synthetic prosesses needed for the synthesis of MDMA, starting with safrole or Oil of Sassafras. The preparation of MDEA (EVE) is also offered.

Anon: Analytical Profiles of Substituted 3,4-Methylenedioxyamphetamines: Designer Drugs Related to MDA. Published by CND Analytical, Auburn, Alabama. 109 p. (1988).

An atlas of spectra, chromatographic behaviour, outlines of chemical preparations, and a brief history of MDA, and over a score of its homologues, is presented. Spectra of the usual synthetic precursors are also given. MDMA is represented with its UV, IR (both salt and base), MS, and HPLC characteristics.

Andrey, R.E. and Moffat, A.C. Gas-Liquid Chromatographic Retention Indices of 1318 Substances of Toxicological Interest on SE-30 or OV-1 Stationary Phase. J. Chromatog. 220 195-252 (1981).

The GC characteristics of many abuse drugs are presented in a review format. MDMA is included without experimental detail.

Bailey, K., By, A.W., Legault, D. and Verner, D. Identification of the N-Methylated Analogs of the Hallucinogenic Amphetamines and Some Isomers. J.A.O.A.C. 58 62-69 (1975).

MDMA and four analogous methamphetamine derivatives (corresponding to 2-, 3-, and 4-methoxyamphetamine (MA) and 3-methoxy-4,5-methylenedioxyamphetamine (MMDA)) were synthesized and spectroscopically characterized. The synthesis was from the corresponding phenylacetone through the Leuckart reaction with N-methylformamide. The reported m.p. (of the hydrochloride salt) is 147-8 degrees C. The U.V., NMR, IR and mass spectral data are presented. Rf values (five systems) and GC retention times (four systems) are also given.

Churchill, K.T. Identification of 3,4-Methylenedioxymethamphetamine. Microgram 18 123-132 (1985).

An analytical profile, through spectrographic tools such as UV, TLC, GC, NMR, MS, is presented for a sample of MDMA seized in Georgia. Comparisons with MDA are presented.

Clark, C.R., Noggle, F.T. and De Ruiter, J. Liquid Chromatographic and Mass Spectal Analysis of N,N-disubstituted 3,4-Methylenedioxyamphetamines. J. Liq. Chrom. 13 263- 274 (1990).

The preparation of the N-methyl-N-ethyl, the N-methyl-N-propyl, and the N-methyl-N-isopropyl homologues of MDMA is described, but no physical properties are given. The route involves the reductive methylation of the appropriate preformed N-alkyl MDA homologues. Chromatographic properties, and some mass spectroscopic data, are presented.

Clark, C.R., DeRuiter, J. and Noggle, F.T. GC-MS Identification of Amine-Solvent Condensation Products Formed During Analysis of Drugs of Abuse. J. Chrom. Sci. 30 399-404 (1992).

It is reported that during the GC-MS analysis of methanol solutions of primary amines such as MDA, amphetamine and phenethylamine, there is the formation of a small amount of the Schiff base product between the amine and formaldehyde. This product co-elutes, and is not the tetrahydroisoquinoline. Methanol solutions of MDMA result in detectable methylation, with the formation of N,N-dimethyl-MDA.

Clark, C.R., Valaer, A.K., DeRuiter, J. and Noggle, F.T. Synthesis, Stability and Analytical Profiles of 3,4-Methylenedioxyamphetamines: Derivatives of "Ecstasy"(MDMA). J. Alabama Acad. Sci. 64 34-48 (1993).

A number of the known homologues of MDMA were prepared to study their properties for eventual analytical purposes. The tools used were GCMS and HPLC using a reversed phase system.

Cody, J.T and Schwartzhoff, R. Fluorescence Polarizatrion Immunoassay Detection of Amphetamine, Methamphetamine, and Illicit Amphetamine Analogues. J. Anal. Toxicol. 17 26-30 (1993).

The Abbott Diagnostic Amphetamine/Methamphetamine II and Amphetamine Class Reagents were evaluated on the Abbott TDx for cross-reactivity to amphetamine and methamphetamine sterioisomers, several of their metabolites, and various illicit drugs. MDA, MDMA, MDE, as well as 4-hydroxymethamphetamine showed a cross-reactivity that would allow this procedure to be used as a screening tool.

Cody, J.T. Cross-Reactivity of Amphetamine Analogues with Roche Abuscreen Radioimmunoassay Reagents, J. Anal. Tox. 14 50-53 (1990).

Some 15 variously substituted amphetamine and phenethylamine derivatives, with and without N-substituents, were screened at various concentrations using the Roche Abuscreen Radioimmunoassay for amphetamines. Using amphetamine as a standard, only MDA was found to cross-react. All other compounds were negative, even at the highest concentrations. These included MDMA, MDE, MDOH, N,N-dimethyl-MDA, 2-MA, 4-hydroxyamphetamine, 2,5-DMA, TMA, methamphetamine, DOM, DOET, DOB, 2C-B and mescaline.

Cody, J.T. Detection of D,L-Amphetamine, D,L-Methamphetamine, and Illicit Amphetamine Analogs Using Diagnostic Products Corporation's Amphetamine and Methamphetamine Radioimmunoassay. J. Anal. Tox. 14 321-324 (1990).

The commercial radioimmune assay procedures for amphetamine and methamphetamine were evaluated for a number of illicit drugs with the amphetamine backbone. MDA and MDMA gave substantial cross reactivity with both kits, but most of the others (DOM, mescaline, DOET. 2C-B, DOB, TMA) did not.

Dal Cason, T. The Characterization of Some 3,4-Methylenedioxyphenylisopropylamine (MDA) Analogs. J. Forensic Sci. 34 28-961 (1989).

The synthesis and complete spectroscopic identification of several N-alkylated homologues of MDA are presented. The compounds include MDA (and its acetyl derivative), MDMA, MDE, MDPR, MDIP, MDOH (and its acetyl derivative), MDDM, and the acetyl derivative of the oxime of MDP-2-P. Included are melting points, as well as GCMS, NMR, IR and HPLC details.

DeRuiter, J., Clark, C.R. and Noggle Jr., F.T. Liquid Chromatographic and Mass Spectral Analysis of 1-(3,4-Methylenedioxyphenyl)-1-propanamines: Regioisomers of the 3,4- Methylenedioxyamphetamines. J. Chrom. Sci., 28 129-132 (1990).

The chromatographic and spectroscopic properties, but not the synthetic details, are given for a series of alpha-ethyl benzylamines isomeric with MDA. The N-H, methyl, dimethyl, ethyl, propyl and isopropyl homologues are discussed.

Eichmeier, L.S. and Caplis, M.E. The Forensic Chemist; An "Analytic Detective." Anal. Chem. 47 841A-844A (1975).

An analytical anecdote is presented showing the logical procedure used to distinguish MDMA from closely related drugs such as MDA in a seized sample. MDMA was acknowledged to be similar to MDA but, whereas MDA is a controlled substance, MDMA is exempt (sic) from Federal control.

Fitzgerald, R.L., Blamke, R.V., Glennon, R.A., Yousif, M.Y., Rosecrans, J.A. and Poklis, A. Determination of 3,4-Methylenedioxyamphetamine and 3,4-Methylenedioxymethamphetamine Enantiomers in Whole Blood. J. Chrom. 490 59-69 (1989).

Extracts of whole blood containing added MDA or MDMA were derivatized with N-trifluoroacetyl-L-prolyl chloride. The resulting diastereoisomers were separated by GC, allowing a sensitivity of analysis in the nanogram range.

Gan, B.K., Baugh, D., Liu, R.H. and Walia, A.S. Simultaneous Analysis of Amphetamine, Methamphetamine, and 3,4-Methylenedioxymethamphetamine (MDMA) in Urine Samples by Solid-phase Extraction, Derivatization, and Gas Chromatography/Mass Spectrometry. J. For. Sci. 36 1331 (1991).

A method is described in which the extracts of urine are derivatized with trifluoroacetic anhydride. Deuterated amphetamine and methamphetamine were used as internal standards.

Gough, T.A. and Baker, P.B. Identifiction of Major Drugs of Abuse Using Chromatography. J. Chromatog. Sci. 20 289-329 (1982).

An extensive review of the analytical identification of many abuse drugs is abstracted. MDMA is mentioned as one of these. There is no new experimental information presented.

Gupta, R.C. and Lundberg, G.D. Application of Gas Chromatography to Street Drug Analysis. Clin. Tox. 11 437-442 (1977).

A gas chromatography screening procedure is described, in which the retention times of over 100 drugs are compared to those of methapyriline or codeine. MDMA is amongst them.

Hansson, R.C. Clandestine Laboratories. Production of MDMA 3,4-Methylenedioxymethamphetamine. Analog. 9 1-10 (1987).

A compilation of forensic information pertaining to MDMA is presented, including spectra (UV, MS, IR), synthetic approaches, and observations from clandestine laboratory operations (seen in Australia).

Hearn, W.L., Hime, G. and Andollo, W. Recognizing Ecstasy: Adam and Eve, the MDA Derivatives - Analytical Profiles. Abstracts of the CAT/SOFT Meetings, Oct. 29 - Nov. 1, 1986, Reno/Lake Tahoe, Nevada, USA.

A study is reported comparing MDA, MDMA and MDE in the EMIT immunoanalytical assay system that is designed for amphetamine. Even though they are all of decreased reactivity, there is cross-reactivity and they may be picked up as positives. Using the bottom limit cut-off of 300 nanograms/mL for amphetamine there would be a response from as little as 10-15 mg/mL of MDMA. This is a value that might be encountered in the early stages of MDMA use.

Helmlin, H., and Brenneisen, R. Determination of Psychotropic Phenylalkylamine Derivatives in Biological Matrices by High-Performance Liquid Chromatography with Photodiode-Array Detection. J. Chromatog. 593 87-94 (1992)

An HPCL analysis procedure was described for the analysis of MDMA and MDA in human urine. Six hours following the administration of a 1.7 mg/kg dosage to several patients, urine concentrations ranged from 1.48 to 5.05 ug/ml. The major metabolite, MDA, showed concentrations ranging from 0.07 to 0.90 ug/ml. A separate study of the cactus Trichocereus patchanol showed a mescaline content of from 1.09 to 23.75 ug/ml

Helmlin, H-J. and Brenneisen, R. Determination of Psychotropic Phenylalkylamine Derivatives in Biological Matrices by High-performance Liquid Chromatography with Photodiode-array Detection. J. Chrom. 593 87-94 (1992).

An HPLC analytical scheme has been developed for the characterization and potential quantitative measurement of some fifteen phenethylamine drugs of forensic interest. Of specific clinical interest was the urine analyses of several patients following the administration of 1.7 mg/Kg of MDMA. These values, from samples collected about six hours following drug administration, showed a range of 1.48 - 5.05 ug/mL for MDMA, and 0.07 - 0.90 ug/mL for the metabolite, MDA.

Helmlin, H. -J., Bracher, K., Salamone, S.J. and Brenneisen, R., Analysis of 3,4-Methylenedioxymethamphetamine (MDMA) and its Metabolites in Human Plasma and Urine by HPLC-DAD, GC-MS and Abuscreen-Online. Abstracts from CAT/SOFT Joint Meeting, October 10-16, 1993, Phoenix, Arizona.

Urine and plasma samples were taken from a number of patients being administered 1.5 mg/Kg MDMA for psychotherapy research purposes. Maximum plasma levels (300 ng/mL) were seen at 140 minutes. The main urinary metabolites were 4-hydroxy-3-methoxymethamphetamine and 3,4-dihydroxymethamphetamine, both excreted in conjugated form. The two N-demethylated homologues of these compounds were present as minor metabolites. The cross-reactivity of the Abuscreen immunoassay for both the metabolites (including MDA, another metabolite) and the parent drug were determined.

Holsten, D.W. and Schieser, D.W. Controls over the Manufacture of MDMA. J. Psychoactive Drugs 18 371-2 (1986).

A strong argument is made for attending to the quality of manufacture, and the basic concepts of ethical principles in the exploring of drugs that have not been evaluated against the usual pharmaceutical standards. Government interference in such studies becomes necessary, to safeguard the public.

Julian, E.A. Microcrystalline Identification of Drugs of Abuse: The Psychedelic Amphetamine. J. Forensic Sciences 35 821-830 (1990).

The diliturate salts (5-nitrobarbituric acid salts) of several psychedelic amphetamines have been made and observed. The amines were PA, MDA MMDA (1, not 2 as implied), DOM, DOB, TMA, Mescaline, MDMA and MDEA. Photographs of the crystals are shown.

Kunsman, G.W., Manno, J.E., Cockerham, K.R. and Manno, B.R. Application of the Syva EMIT and Abbott TDx Amphetamine Immuniassays to the Detection of 3,4-Methylenedioxmethamphetamine (MDMA) and 3,4-Methylenedioxyethamphetamine (MDEA) in Urine. J. Anal. Tox. 14 149-153 (1990).

Two popular immunological drug assays, designed for the determination of amphetamine, have been applied to urines that had been spiked with varying amounts of MDMA and MDE. The EMIT assay was insensitive except at the highest level, but there was considerable cross-reactivity with the fluorescent polarization assay.

Lim, H.K., Su, Z. and Foltz, R.L. Stereoselective Disposition: Enantioselective Quantitation of 3,4-(Methylenedioxy)Methamphetamine and Three of its Metabolites by Gas Chromatography/Electron Capture Negative Ion Chemical Ionization Mass Spectrometry. Biol. Mass Spect. 22 403-11 (1993).

A sensitive assay for MDMA and three of its metabolites has been developed. It recognizes the optical activity of the chiral centers, and has been used to determine the degree of asymmetric metabolism of racemic MDMA in both rats and mice.

Lim, H.K., Zeng, S., Chei, D.M. and Flotz, R.L. Comparitive Investigation of Disposition of 3,4-(Methylenedioxy)methamphetamine (MDMA) in the Rat and the Mouse by a Capillary Gas Chromatography-Mass Spectrometry Assay Based on Perfluorotributylamine-enhanced Ammonia Positive Ion Chemical Ionization . J. Pharmaceut. Biomed. Anal. 10 657-665 (1992). An assay is described that allows a quantitative measure of MDMA and three

of its primary metabolites, methylenedioxamphetamine, 4-hydroxy-3-methoxymethamphetamine and 4-hydroxy-3-methoxyamphetamine. The latter two metabolites were excreted mainly as the glucuronide and sulfate conjugates. The metabolic patterns of the rat and the mouse are compared.

Michel, R.E., Rege, A.B. and George, W.J. High-Pressure Liquid Chromatography / Electrochemical Detection Method for Monitoring MDA and MDMA in Whole Blood and Other Biological Tissues. J. Neurosci. Methods 50 61-66 (1993).

An method is described for the analysis of MDMA and MDA in biological samples. It claims a high sensitivity and a short turn-around time. MDE is used as an internal standard. Spiked blood samples, rather than actual clinical specimens, were used.

Noggle, F.T., Clark, C.R. and DeRuiter, J. Liquid Chromatographic and Spectral Methods for the Differentiation of 3,4-Methylenedioxymethamphetamine (MDMA) from Regioisomeric Phenethylamines. J. Liq. Chromatog. 14 913-1928 (1991).

Three isomers of MDMA, with the changes restricted to the alpha-carbon and the nitrogen substituents, have been synthesized. These are the two phenethylamines N-ethyl and N,N-dimethyl-3,4-methylenedioxyphenethylamine, and 1-(3,4-methylenedioxyphenyl-2-aminobutane (BDB). Although their mass spectra are quite similar, they can be distinguished from one-another by HPLC.

Noggle, F.T., Clark, C.R. and DeRuiter, J. Liquid Chromatorgraphic and Mass Spectral Analysis of 1-(3,4-Methylenedioxyphenyl)-3-Butanamines, Homologues of 3,4-Methylenedioxyamphetamines. J. Chrom. Sci. 27 240-243 (1989).

The HPLC and GC properties of several homologues of MDA and MDMA are reported employing the homologous ketone 3,4-methylenedioxyphenyl-3-butanone are studied. These include the primary amine, and the N-methyl, ethyl, dimethyl, (n)-propyl and (i)-propyl homologues. The N-hydroxy was made, but its possible thermal instability was not discussed.

Noggle Jr., F.T., Clark, C.R. and DeRuiter, J. Identification of Safrole and Bromosafrole in Samples from the Clandestine Synthesis of MDMA from Sassafras Oil. Microgram 24 7-13 (1991).

An analysis of seized samples from an illicit MDMA laboratory showed one to be sassafras oil that contained safrole by GCMS. The other appeared to be the result of the addition of hydrobromic acid to safrole to produce two "bromosafroles." Addition of methylamine to this material produced some MDMA.

Noggle Jr., F.T., Clark, C.R. and DeRuiter, J. Gas Chromatographic and Mass Spectrometric Analysis of Samples from a Clandestine Laboratory Involved in the Synthesis of Ecstasy from Sassafras Oil. J. Chrom. Sci. 29 168-173 (1991).

Samples from a clandestine laboratory gave, on GC-MS analysis, evidence for the intended synthesis of MDMA from the oil of sassafras. The natural component safrole gave, with the addition of HBr, the 2-bromopropane intermediate which, on treatment with methylamine, gave MDMA.

Noggle Jr., F.T., DeRuiter, J. and Long, M.J. Spectrophotometric and Liquid Chromatographic Identification of 3,4-Methylenedioxyphenylisopropylamine and its N-Methyl and N-Ethyl Homologues are presented. J. A. O. A. C. 69 681-686 (1986).

A synthesis of MDEA (the N-ethyl homolog of MDA) is reported, and the infra-red spectra of the free bases, the hydrochloride salts, and the phenylisothiocyanate adducts are recorded, as is the HPLC retention behaviour for both the bases and these derivatives.

Noggle Jr., F.T., Clark, C.R., Andurkar, S. and DeRuiter, J. Methods for the Analysis of 1-(3,4-Methylenedioxyphenyl)-2-Butanamine and N-Methyl-1-(3,4-Methylenedioxyphenyl)-2- Propanamine (MDMA). J. Chrom. Sci. 29 103-106 (1991).

The infra-red and mass spectra, and the GC and HPLC retention times, of these two known compounds, are given.

Noggle Jr., F.T., Clark, C.R., Bouhadir, K.H. and DeRuiter, J. Liquid Chromatographic and Mass Spectral Analysis of 1-(3,4-Methylenedioxyphenyl)-3-propanamines: Regioisomers of MDMA. J. Chrom. Sci. 29 78-82 (1991).

A series of N-substituted homologues of methylenedioxyphenyl-(n)-propylamine was prepared, and described by chromatographic and spectroscopic means. No melting points or other synthetic analytical detail was given.

Noggle, F.T., Clark, C.R., Pitts-Monk, P. and De Ruiter, J. Liquid Chromatographic and Mass Spectral Analysis of 1-(3,4-Dimethoxyphenyl)-2-propanamines: Analogs of MDMA. J. Chrom. Sci. 29 253-257 (1991).

A number of 3,4-dimethoxy counterparts of MDMA and its homologues have been prepared and analysed by HPLC. Described are 3,4-dimethoxyamphetamine, the N-methyl, the N- ethyl, and the N,N-dimethyl homologues.

Noggle Jr., R.T., Clark, C.R., Valaer, A.K. and DeRuiter, J. Liquid Chromatographic and Mass Spectral Analysis of N-Substituted Analogues of 3,4-Methylenedioxyamphetamine. J. Chromatog. Sci. 26 410 (1988).

Several spectral properties, and the HPLC separation characteristics of MDMA and several of its homologues and analogues (MDE, MDPR, DMMA and MDOH) are described.

Noggle Jr., F.T., DeRuiter, J., McMillian, C.L. and Clark, C.R. Liquid Chromatographic Analysis of some N-Alkyl-3,4-Methylenedioxyamphetamines. J. Liq. Chromatog. 10 2497-2504 (1987).

The HPLC separation characteristics of MDA, MDMA, MDE and MDDM (N,N-dimethyl-MDA) are reported on a reversed phase column.

Noggle Jr., F.T., Clark, C. R. and DeRuiter, J. Gas Chromatographic and Mass Spectrometric Analysis of N-Methyl-1-aryl-2-propanamines Synthesized from the Substituted Allylbenzenes Present in Sassafras Oil. J. Chrom. Sci. 20 267-271 (1991).

The several allylaromatic essential oils in Sassafras have been studied in the regeospecific addition of HBr to form the beta-bromopropane. The bromine atom was subsequently displace with methylamine to form the corresponding methamphetamine. Safrole gives rise to MDMA.

O'Brian, B.A., Bonicamp, J.M. and Jones, D.W., Differentiation of Amphetamine and its Major Hallucinogen Derivatives using Thinlayer Chromatography. J. Anal. Tox. 6 143-147 (1982).

Two thin-layer chromatographic systems, and several procedures for detection, are described for MDMA and 18 analogues. The retention times and the visualization colour changes are compared and described. Detection limits in urine were determined from artificially spiked samples. The reference sample of MDMA was synthesized from MDA by methylation with methyl iodide, and separation from the co-generated dimethyl and trimethylammonium homologues by liquid- liquid extraction and preparative TLC.

Poklis, A., Fitzgerald, R.L., Hall, K.V. and Saady, J.J. Emit-d.a.u. Monoclonal Amphetamine / Methamphetamine Assay. II. Detection of Methylenedioxyamphetamine (MDA) and Methylenedioxymethamphetamine (MDMA). For. Sci. Intern. 59 63-70 (1993)

MDA and MDMA have been found to be cross-reactive in both the monoclonal and the polyclonal immunological EMIT assay. The former was much more sensitive, presumably sufficiently so for the detection of these drugs in urine following clinical intoxication.

Ramos, J.M., Johnson, S. and Poklis, A. MDMA and MDA Cross Reactivity Observed with Abbott TDx Amphetamine/Methamphetamine Reagents. Clin. Chem. 34 991 (1988).

A study of the cross-reactivity of MDMA and MDA with the Abbott TDx fluorescent polarization immuno assay showed that these two drugs gave positive tests for amphetamine and methamphetamine at levels that were clinically relevant. This expands the utility of this screening procedure, but also demands additional care in the interpretation of positive results that are obtained clinically.

Renton, R.J., Cowie, J.S. and Oon, M.C. A Study of the Precursors, Intermediates and Reaction By-Products on the Synthesis of 3,4-Methylenedioxymethylamphetamine and its Application to Forensic Drug Analysis. Foren. Sci. Intern. 60 189-202 (1993).

MDMA was prepared by three separate synthetic routes, and the trace byproducts and impurities were identified and presented in a way that probable synthetic method could be deduced for legal purposes.

Ruangyuttikarn, W. and Moody, D.E. Comparison of Three Commercial Amphetamine Immunoassays for Detection of Methamphetamine, Methylenedioxyamphetamine, Methylenedioxymethamphetmaine, and Methylenedioxyethylamphetamine. J. Anal. Toxicol. 12 229-233 (1988).

Three commercial immunoassays for the detection of amphetamine in urine (Abuscreen, a radioimmune assay, RIA; EMIT, a homogeneous enzyme immuno assay procedure; and TDx, a fluorescent polarization immuno assay, FPIA) have been assayed for their responses to methamphetamine, MDA, MDMA, and MDE. Some cross-reactivity to amphetamine is seen with all compounds, but the response is extremely variable depending upon the assay employed.

Ruybal, R. Microcrystalline Test for MDMA. Microgram 19 79-80 (1986).

MDMA gives a sensitive microcrystalline test with gold chloride. The crystal form is similar to that of methamphetamine.

Shaw, M.A. and Peel, H.W. Thin-layer Chromatography of 3,4-methylenedioxyamphetamine, 3,4-Methylenedioxymethamphetamine and other Phenethylamine Derivatives. J. Chromatog. 104 201-204 (1975).

A broad study is presented on the TLC analyses of many phenethylamines. The compound specifically named in the title, 3,4-methylenedioxymethamphetamine (MDMA), was a misprint that was subsequently corrected to the intended compound, MMDA. MDMA was not a part of this study.

Simpson, B.J., Simpson, T.P. and Lui, R.H. Microcrystalline Differentiation of 3,4-Methylenedioxyamphetamine and Related Compounds. J. Forensic Sciences 36 908 (1991).

Crystal gold salts can distinguish between MDA, mescaline, and DOET, whereas MDMA and MDE form crystals similar to one another and are not easily distinguished. DOM and N-hydroxy-MDA compounds were soluble in the gold chloride reagents and formed no crystals.

Sutherland, G.J. 3,4-Methylenedioxymethamphetamine (MDMA) A Basis for Quantitation by UV Spectrophotometry. Analog 10 1-3 (1988).

Due to the absence of reference samples of MDMA (in Australia) a seized sample has been evaluated and provides a basis for quantitation employing UV.

Tedeschi, L., Frison, G., Castagna, F., Giorgetti, R. and Ferrara, S.D. Simultaneous Identification of Amphetamine and its Derivatives in Urine Using HPLC-UV. Intern. J. Legal Med. 105 265-9 (1993).

Four compounds are rapidly extracted from urine, derivatized with sodium 1,2-naphthaquinone-4-sulfonate, and separated from one-another by HPLC on an ion-pair reversed phase system, using a detector at 480 nm. The compounds were amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA).

Verweij, A. Clandestine Manufacture of 3,4-Methylenedioxymethylamphetamine (MDMA) by low pressure Reductive Amination. A Mass Sectrometric Study of some Reaction Mixtures. Forensic Science International, 45 91-96 (1990)

An analysis by GCMD has been made of the contaminants present in illicitly synthesized MDMA. Most of them are ascribed to impurities in the starting piperonyl acetone (piperonal, safrole, isosafrole) or in the starting methylamine (ammonia, dimethylamine, methylethylamine).

Verweij, A.M. Contamination of Illegal Amphetamine. Hydrastatinine as a Contaminant in 3,4-(Methylenedioxy)methylamphetamine. Arch. Krim. 188 54-7 (1991). The presence of hydrastatinine has been reported in the analysis of

illicitly prepared MDMA. This extraordinary chemistry might involve the generation of a phenylacetaldehyde as an intermediate in the oxidation processes involving the conversion of the starting material, safrole. Structural identification depended on the comparisons of mass spectra.

Verweij, A.M.A. and Sprong, A.G.A. A Note About some Impurities in Commercially Available Piperonylmethylketone. Microgram 26 209-213 (1993).

An extensive collection of compounds, structures and IR spectra of impurities in commercial piperonylmethylketone (a precursor to MDMA) is carefully reproduced, to allow a determination to be made of the method of synthesis. The actual source of the precursor ketone that was studied here, however, was apparently not known, so no immediate application of this origin fingerprinting is obvious.

Yamauchi, T. The Analysis of Stimulant-analogue Compounds (3,4-Methylenedioxymethamphetamine Hydrochloride). Kagaku Keisatsu Kenkyusho Hokoku, Hokagaku Hen. 39 23 (1986).

People from abroad have provided samples of drugs that had been heretofore unidentified in Japan. An analytical profile of one such drug, MDMA, is provided employing most modern spectroscopic tools.

Abbott, A. and Concar, D. A Trip into the Unknown. New Scientist, August 29, 1992, pp. 30-34.

An overview is presented on the history of MDMA and the difficulty in determining if there is human risk paralleling the known neurotoxic effects in experimental primates. A picture is given of its extensive use in the popular party structure known popularly as "raves," and it has become the third most widest used drug in England, surpassed only by marijuana and amphetamine.

Abramson, D.M. Ecstasy: The New Drug Underground. New Age, October, 1985, pp 35-40.

This article addresses the questions that are raised by the conflict of governmental banning of drugs that are of potential value in psychotherapy, and the therapist's determination to continue exploring their use.

Adamson, S. "Through the Gateway of the Heart: Accounts of Experiences with MDMA and other Empathogenic Substances." Four Trees Publications, San Francisco. Foreword by R. Metzner. 1985.

This book is a collection of some fifty personal accounts, largely involving MDMA. Some are from the notes of therapists, involving clinical usage, and others are personal accounts from self-exploration.

Adelaars, A. Ecstasy: De opkomst van een Bewustzijnsveranderend Middel. Published by In De Knipscheer, Amsterdam, 1991. ISBN 90 6265 342 1. 136 pp (Dutch).

This small paperback volume presents a brief history of psychedelic drugs, then the history of MDMA both in Holland and in the broader scene. The topics range from therapy to popular use.

Adler, J. Getting High on 'Ecstasy.' Newsweek, April 15, 1985, p. 96.

This is a short, apparently factual, overview of both the chemical and the "street" use of MDMA. It is generally sympathetic to its medical potential.

Anon: Several reports from the Brain/Mind Bulletin:

(1) MDMA: Compound raises medical and legal issues. Brain/Mind Bulletin, 10, #8, April 15, 1985.

The title article is presented, and nearly the entire issue is given over to a thorough coverage of the medical and scientific aspects of MDMA.

(2) Psychiatrists, drug-abuse specialists testify in L.A. at first MDMA hearing. Brain/Mind Bulletin, 10, #12 July 8, 1985.

A news report on the first round of hearings in Los Angeles, concerning the scheduling of MDMA. An overview of the testimony is presented.

(3) Judge proposes more lenient schedule for MDMA. Brain/Mind Bulletin, 11, #11 June 16, 1986.

Administrative Law Judge Francis Young recommended, at the conclusions of the MDMA hearings, that the DEA put the drug into Schedule III, partly to ease research with the compound, and partly due to the absence of demonstrated abuse of the drug.

(4) MDMA: Federal court decides that DEA used improper criteria. Brain/Mind Bulletin, 13, #2 November, 1987.

A report is given as to the First Court of Appeals in Boston, ruling that the DEA had not sufficiently considered the arguments concerning the current medical use of MDMA.

Anon: DEA Proposal to Ban New Psychedelic Protested. Substance Abuse Report, December, 1984. pp 4-5.

The several letters that were addressed to the DEA in response to its announcement in the Federal Register to consider the scheduling of MDMA, are here abstracted and commented upon.

Anon: Ecstasy: 21st Century Entheogen. Private Tract, 28 pages.

This is an elaborate thesis that is directed totally to the promotion of the use of MDMA. There is a presumed question and answer section, that is designed for the cautiously curious.

Anon: MDMA. NIDA Capsules. Issued by the Press Office of the National Institute on Drug Abuse, Rockville, Maryland. July 1985.

A two-page precis describing the health problems encountered with MDMA use, its relationship to the neurotransmitters, and the moves being made at the Justice Department to combat "designer drugs" such as MDMA in the future.

Anon: Designer Drugs: A New Concern for the Drug Abuse Community. NIDA Notes, December, 1985, pp. 2-3.

A discussion of "designer drugs" is arranged in four groups: variations on fentanyl, on meperidine, on PCP, and on amphetamine and methamphetamine. MDMA fits this last group. The research directions of NIDA are discussed.

Anon. Esctasy of the Eighties. Frontline, August 24-September 6, 1985 (page 83-85).

A review article on the emergence of MDMA, published in one of India's major national magazines. No new information, and no suggestion that there is any use in India.

Anon. The Hyping of Ecstasy. The Illustrated London News, October, 1988 pp. 29-32.

A developing fad is described in London, called "Acid House" which involves loud rock music, violent dancing, and the use of MDMA. It is being largely ignored by the authorities.

Anon: Mind-bending Drug Could Leave Brains Permanently Warped. New Scientist, 21 January (1989) p. 30.

A short summary of the AAAS meeting in San Francisco. Peroutka is quoted as saying the consumers of MDMA should abandon its use altogether. If they continue, he said, they risk damage to their nervous systems that may take decades to manifest itself. It could emerge initially as depression or disturbance to sleep. This is the first hint as to the specific form of the down-the-road damage that is being promoted as a cost of using MDMA.

Anon: "Ice" and "Ecstasy" Two Dangerous Psychotropic Drugs. International Criminal Police Review. 45 1-24 (1990).

A brief review of the dangers and health hazards of two designer drugs is presented; vis., methamphetamine and MDMA. International controls of the easily available chemical precursors should be instituted. The author is the ICPO-Interpol General Secretariat.

Anon: Deal mit Cadillac (September 4, 1989); Ecstasy und Cadillac (November 12, 1989). Der Spiegel.

Two of several news articles appearing in Germany, presenting the scandal surrounding the chemical firm Imhausen-Chemie. It had been producing, and selling, large quantities of a precursor to MDMA (piperonylacetone, which they called PMK) as well of literally millions of tablets of the final product itself (which they called "Ecstasy," "XTC," "Adam" or "Cadillac."). The magnitude of operation was tons of drug, and millions of tablets. And, of course, the money volume was many millions of Deutsche Marks.

Bakalar, J.B. and Grinspoon, L. Testing Psychotherapies and Drug Therapies: The Case of Psychedelic Drugs. The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Kluwer, New York. (1990) Ed: S.J. Peroutka.

The problems associated with the social and medical acceptance of drugs as a valid component of the psychotherapeutic process are outlined and discussed. MDMA is used as a specific point of illustration.

Barbour, J. Cracking Down: What You Must Know About Dangerous Drugs. The Associated Press. 1986.

This is a 63 page illustrated essay, aimed at stopping drug use and abuse by scaring the reader. Unfortunately, the information is not completely accurate. MDMA is spun together with other designer drugs as things that destroy the brain.

Barendregt, C. Dutch Conference on MDMA. The International Journal on Drug Policy 1 Issue #6 (1990?).

This is a summation of the January 23, 1990 conference in Amsterdam, sponsored by the Dutch Institute on Alcohol and Drugs. With the passing of legislation against MDMA in November 1988, the criminal aspect of the use of this drug has quite logically increased. Dutch drug law (of 1976) distinguishes two categories of drug; those with an unacceptable risk (Group 1, containing such drugs as cocaine and heroin) and those with less risk (Group 2, containing only marijuana and hash). Newly marketed, and illegalized, drugs such as MDMA can only be defined as Group 1 as Group 2 is closed to any new substances. It was concluded that the risks of MDMA use are to be found in its legal status, rather than in its pharmacological properties.

Barnes, D.M. New Data Intensifies the Agony over Ecstasy. Science 239 864-866 (1988).

A review and commentary is presented of the Winter Conference on Brain Research, 23-30 January, 1988, in which there was a section on MDMA. A distillation of the comments made yields the feeling that more clinical work is needed to define the value, and that there would not likely be any further clinical work done. There are extensive quotations from some of the authors of recent animal studies on serotonin toxicity.

Barnett, R. DEA: RSVP re MDMA. Editorial from KCBS, July 29, 1985.

With the possibility of therapeutic value seen in some psychiatric cases, KCBS felt that the action of the DEA (making MDMA illegal) short-circuited the hearings process, and was premature. A request is made to allow research on the effects and potentials of this drug to continue.

Baum, R.M. New Variety of Street Drugs Poses Growing Problem. Chemical and Engineering News, September 9, 1985. pp. 7-16.

A completely professional article discussing the challenges presented to law enforcement officials, legislators and scientists, by the invention of analogues of illegal drugs by underground chemists. MDMA is held out as being quite apart from the fentanyl and meperidine examples, and is analysed at some length.

Beck, J. MDMA: The Popularization and Resulting Implications of a Recently Controlled Psychoactive Substance. Contemporary Drug Problems Spring, 1986. pp 23-63.

A historical analysis is made of the relationship between drug illegalization and social issues. MDMA is used as a specific example, and a considerable body of first hand observations of its use is also presented.

Beck, J. and Morgan, P.A. Designer Drug Confusion: A Focus on MDMA. J. Drug Education 16 267-282 (1986).

This article discusses the competing definitions and issues surrounding the various designer drugs, but is primarily devoted to an examination of MDMA. A rationale is offered as to why interest in MDMA will continue to grow.

Beck, J. and Rosenbaum, M. "Pursuit of Ecstasy: The MDMA Experience." State University of New York Press, New York. 239 pp. (1994).

This book is the first complete analysis of the clinical value of MDMA, and it brings together into one place the previously scattered reports of the drug's use in therapy. The information that is compiled here, was originally the raw material for a report to the National Institute of Drug Abuse (NIDA), as the presentation of a summary of a contract awarded the authors to study MDMA. The final report was never published by NIDA, and so this book serves as a supurb vehicle for making these findings available as public information.

Beebe D.K. and Walley, E. Update on Street Drugs in Mississippi. Journal of the Mississippi State Medical Association, 1989 Dec,

Drug abuse is on the rise in Mississippi. Treatment centers across the state report significant increases in substance abuse cases. Consequently, family physicians must have the most current, accurate information available and the skills with which to treat either an acute crisis or the chronic problems related to drug abuse. The authors present an overview of the clinical presentations and management of some of the most widely used designer drugs: crack, ecstasy and PCP.

Beebe, D.K. and Walley, E. Update on Street Drugs in Mississippi. Journ. Miss. State Med Ass. 30 387-390 (1989).

A discussion of the drug abuse problem in Mississppi is presented. MDMA is listed with a check list of the medical compilation that can follow use.

Beebe, D.K. and Walley, E. Substance Abuse: The Designer Drugs. AFP May 1991, p. 1689.

A brief overview of the "Designer Drug" is presented, using mescaline, the synthetic opiods, the aryehexylamines, and methaquelone as prototypes.

Bost, R.O. 3,4-Methylenedioxymethamphetamine (MDMA) and Other Amphetamine Derivatives. J. Forensic Sci. 33 576-587 (1988).

A series of amphetamine derivatives are discussed as "Designer Drugs" with structures slightly modified from explicitly named illegal drugs. A number of emergency cases are presented, which are documented with MDA, MDMA and MDE involvement. A number of analytical procedures are demonstrated.

Buchanan, J. Ecstasy in the Emergency Department. Clinical Toxicology Update, 7 1-4 (1985).

A review of the history and the pharmacology of the psychoactive amphetamines is given. The overall recommendation for the emergency room is to expect an overdosed patient to present with signs similar to those with an amphetamine overdose, and to expect to treat primarily signs of anxiety and hypertension. The attending physician can expect the patient to be unaware of the actual toxin he has taken, and careful laboratory work will be needed to identify the chemical in body fluids and drug samples.

Callaway, E. The Biology of Information Processing. J. Psychoactive Drugs 18 315-318 (1986).

A review is presented of the difficulties that are classically part of the communication of information, and the roles of the many psychologists and physicians who have addressed the problem. The study of neurotransmitters, and thus drugs that involve these brain chemicals, is part of the eventual understanding. The role of non-classic "unsleepy drugs" (stimulants) such as MDMA are speculated upon as potential tools in this study.

Chaudhuri, A. Cause and E-ffect. Time Out, August 5-12 (1992).

A review of the background of MDMA and the increasing medical concern in England regarding its popularity in the rave scene. Arguments are advanced for its removal from Category A of English law, allowing its potential in therapy to be explored.

Chesher, G., Some Views on Ecstasy. Modern Medicine of Australia April 1990 pp. 76-85.

A brief and quite accurate review is given as to the background, therapeutic interest, legal history, and neurotoxicity of MDMA.

Climko, R.P., Roehrich, H., Sweeney, D.R. and Al-Razi, J. Ecstasy: A Review of MDMA and MDA. Int'l Journal of Psychiatry in Medicine. 16 359-372 (1986-87).

A review of the pharmacology and toxicity of MDA is presented, with some additional data for MDMA. A balanced presentation with 75 references.

Cohen, S. They Call It Ecstasy. Drug Abuse & Alcoholism Newsletter, Vista Hill Foundation. 14 # 6. September, 1985.

A basically negative overview of the prospects of MDMA in therapy. There is wistful note with the "we've been through all this before" feeling. LSD had hope, LSD failed, and this too shall fail.

Conner, M. and Sherlock, K. Attitudes and Ecstasy Use. Paper presented at the European Association of Experimental Social Psychology, 15-20 September, 1993, Lisbon.

An anonymous questionaire was distributed amongst young people (in England) who had varying degrees of experience with MDMA. Over half the sample had tried the drug, and a substantial minority used it regularly. The results are discussed in terms of the design of literature that could be directed at changing this use pattern.

Corliss, J. Agonizing over Ecstasy. Santa Cruz Sentinel, Friday March 24, 1989.

An update on the controversy surrounding the use of MDMA, geared for popular consumption. Emphasis is on serotonin and damage, if not now, maybe somewhere down the road.

Deluca, N. Closed Doors/Closed Minds. KCBS Editorial. July 10, 1986.

An opinion is expressed, that the easy answer to MDMA given by the federal government, illegalization by placement into Schedule I, was the wrong answer. It appears that MDMA warrants a closer look by therapists, and the DEA should not simply lock the drug away where it cannot be investigated.

Doblin, R. Murmurs in the Heart of the Beast: MDMA and the DEA, HHS, NIDA, NIMH, ADAMHA, FBI and the WHO. Privately printed. August 8, 1984.

This is a collection of many of the letters exchanged between the DEA and the FDA, that led to the decision to place MDMA in the listings of scheduled drugs. Also included are the DAWN (medical emergency) reports, and letters written in response to the proposed scheduling.

Doblin, R. The Media Does MDMA. Privately printed, August 5, 1985 -July 2, 1987.

This is a collection of articles, newspaper accounts, writings from many sources, that touch upon MDMA. It is arranged as a collage.

Doblin, R. A Proposal for Orphan Pharmaceuticals, Inc. A Division of Neurobiological Technologies, Inc. August 4, 1987.

A review of the history of MDMA and the arguments for its legitimate commercial consideration are presented. The NTI Board of Directors did not accept this proposal.

Doblin, R. Risk Assessment: The FDA and MDMA Research. PM&E (Psychedelic Monographs and Essays) 4 98 (1989).

A brief review of the current status of the neurological toxicity studies, and an analysis of their extrapolation to human subjects.

Doblin, R. (1) MDMA: Risk Assessment and the FDA. April 14, 1989. (2) Regulation or Prohibition? MDMA Research in Switzerland and the United States. May 26, 1989. (3) Multidisciplinary Association for Psychedelic Studies, Summer, 1989.

These are three privately published tracts. The first reviews the present research status of MDMA, and presents an overview of the clinical experiments under way in Switzerland. The second essay lists the names and addresses of the Swiss researchers. The third entry is a continuing newsletter publication with articles and announcements concerning developments in the area of psychedelic research. News on MDMA is of the highest priority.

Dowling, C.G. The Trouble with Ecstasy. Life Magazine, August, 1985, pp. 88-94.

A pictorial article timed to coincide with the first of the hearings concerning the eventual fate of MDMA, and with the effective placement of it under emergency legal control.

Edwards, G. Blasted with Ennui. British Med. J. 298 136 (1989).

A highly critical opinion is shared with the readers concerning yet another drugs being promoted as an adjunct to psychotherapy, given a appealing name, and as has happened before, eventually discovered to be highly damaging.

Ehrlich, B. Understanding Ecstasy: The MDM Story. Privately Printed Book Manuscript. About 70 pages. 1986.

This is a partial draft of a book, privately printed and circulated, covering the history and paramedical use of MDMA.

Ehrnstein, L.B., Reflections on Drug Enforcement and Drug Use. Psychedelic Monographs and Essays, 2 17-24 (1987).

An instructive and favorable review of the history and the possible usefulness of MDMA is presented. There are suggestions offered as to how the inexperienced subject might approach MDMA for personal development.

Eisner, B. ECSTASY, The MDMA Story. Ronin Press, Berkeley 1989. 228 pages.

This book is a complete review of much of the background and history of the origin and entry of MDMA into the culture. It was in this book that an earlier edition of this bibliographic summary appeared

Farrell, M. Ecstasy and the Oxygen of Publicity. Brit. J. Addiction 84 943 (1989).

A short and appropriate review of how the furious and righteous publicity given the use of MDMA in Britain, fuelled its popularity.

Fitzgerald, J. MDMA and Harm. Intern. J. Drug Policy 2 #4 Jan-Feb. (1991).

An overview of the history of MDMA use is presented, to allow the formation of opinion as to the properness of its legalization. It is concluded that no change in the legal status is warranted.

Fitzgerald, J. MDMA and Harm. Intern. J. Drug Policy 2 22-24 (1993)

An analysis of the MDMA problem, vis-a-vis Australian law, is presented. There balance of the literature presentation of harm regarding the drug leans towards its being relatively safe. However, there is no evidence that the community is harmed or suffering in any way by its being maintained in an illegal status. Thus it should remain illegal.

Gallagher, W. The Looming Menace of Designer Drugs. Discover 7 24 (1986).

A long and gloomy article on the growing problems of uncontrolled analogues of heroin. There is a heavy emphasis on the medical professional's use and involvement in drug abuse. A one page side-box gives a view of MDMA, with balance between therapeutic potential and the risks of using unevaluated and unapproved new drugs.

Garfinkel, S.L. The Price of Ecstasy. New Age Journal, May 1989, p. 22.

This is a brief review of the current legal/clinical status of MDMA, with a note-worthy quote from the FDA spokeswoman Susan Cruzan. "It is irrelevant to talk about clinical trials of a drug that has no legitimate medical use."

Gertz, K.R. "HugDrug" Alert: The Agony of Ecstasy. Harper's Bazaar, November 1985, p. 48.

A popular article is offered, with a balanced discussion of the case for, and the case against, the use of MDMA.

Gibb, J.W., Johnson, M. and Hanson, G.R. Neurochemical Basis of Neurotoxicity, NeuroToxicity 11 317-322 (1990).

The properties of 6-hydroxydopamine and 5,7-dihydroxytryptamine are reviewed, in a presentation of the dopaminergic and serotonergic systems. The principle drugs of discussion are methamphetamine and MDMA.

Gibb, J.W., Johnson, M., Stone, D. and Hanson. G.R. MDMA: Historical Perspectives. Ann. N.Y. Acad. Sci. 600 601-612 (1990).

A review of a number of neurotoxicological aspects of MDMA is presented.

Gibb, J.W., Stone, D., Johnson, M. and Hanson, G.R. Neurochemical Effects of MDMA. The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Kluwer, New York. (1990) Ed: S.J. Peroutka.

An extensive review of the neurotoxicological properties of MDMA is presented. The data suggest that although MDMA perturbs both the dopaminergic and serotoninergic systems of experimental animals, it is only the serotoninergic system that is persistently altered.

Glennon, R. A. Discriminative Stimulus Properties of Phenylisopropylamine Derivatives. Drug and Alcohol Dependence 17 119-134 (1986).

A broad review of many substituted phenylisopropylamines and their responses in discriminative studies in animals trained to discriminate amphetamine (or, separately, DOM) from saline. MDMA produced no DOM-appropriate response (DOM is an hallucinogen) but did cross react with amphetamine (a stimulant).

Gold, M.S. Ecstasy, Etc. Alcoholism and Addiction Sept-Oct. 1985. p. 11.

Criticism of the popular use of untested drugs such as MDMA is presented. It is argued that all new "wonder euphorogenics" should be considered extremely dangerous until proven safe and effective for a specific condition by the FDA and the medical research community.

Goldstein, R. The Facts about 'Ecstasy' A Talk with Andrew Weil. The Village Voice, February 7, 1989, p. 31.

This is an overview of the present status of MDMA, followed by a careful and balanced interview with Andrew Weil on its clinical use and hazards.

Grant, A. and Wagner, J. Case Book: The Batman. Ecstasy. Detective Comics No. 594, published by DC Comics, Inc. 1988.

A magnificently lurid illustrated story of how the use of Ecstasy drove a sound business man and currency trader to total madness, voices in the head, urge to blow up the principals in the New York drug trade. He was the final victim. Drugs kill.

Grinspoon, L. and Bakalar, J.B. What is MDMA? Harvard Medical School Mental Health Letter 2 8 (1985).

A brief presentation of the cogent facts that define MDMA.

Grinspoon, L. and Bakalar, J.B. A Potential Psychotherapeutic Drug? The Psychiatric Times, January, 1986. pp 4-5, 18.

A review of the development of the use of drugs in psychotherapy, and a discussion of the role that a drug like MDMA might play in this medical area.

Grinspoon, L. and Bakalar, J.B. Can Drugs be Used to Enhance the Psychotherapeutic Process? Amer. J. Psychotherap. 40 393-404 (1986).

There is evidence that the psychotherapeutic process can be enhanced by the use of drugs that invite self-disclosure and self-exploration. Such drugs might help to fortify the therapeutic alliance and in other ways. One drug that may prove promising for this purpose is the psychedelic amphetamine MDMA.

Hagerty, C. "Designer Drug" Enforcement Act Seeks to Attack Problem at Source. American Pharmacy NS25 10-11(1985).

An extensive argument is presented for the passage of the "Designer Drug" Enforcement Act, to effectively attack the sources of new drugs.

Harris, L. S. The Stimulants and Hallucinogens under Consideration: A Brief Overview of their Chemistry and Pharmacology. Drug and Alcohol Dependence, 17 107-118 (1986).

A literature review is made of a number of drugs that are under consideration for international control. MDMA is briefly mentioned, and described as being in man more of a stimulant than a hallucinogen.

Hershkovits, D. Esctasy: The Truth About MDMA. High Times November, 1985. p. 33.

An interview was held with Richard Seymour, author of the book MDMA. Many good and reasonable questions, answered directly and accurately.

Hollister, L.E. Clinical Aspects of Use of Phenylalkylamine and Indolealkylamine Hallucinogens. Psychopharmacology Bulletin 22 977-979 (1986).

A generally negative evaluation of the use of hallucinogens (such as MDA, MDMA, LSD) based largely on the potential of neurotoxicity and the absence of clinical verification of value. Most of the value must be gleaned from studies of twenty years ago, and the absence of recent research is ascribed to unusually high toxicity or to the lack of interest. The legal difficulties are not addressed.

Johnson, T. Trafic d'Extase. Actuel #137. November (1990) p. 107 et seq.

This is an in-depth but reasonably current overview of the drug ecstasy and its role in the drug scene in Amsterdam, where it is apparently being synthesized for the entire continent. Comments from the as well detractors as the promoters are gathered together, with a final word on its potential legalization.

Jones, R. Why the Thought Police Banned Ecstasy. Simply Living, 2 #10. p. 91-95.

A review of the United States controversy concerning MDMA as seen through Australian eyes. There are implications of considerable use in Australia.

Kirsch, M.M. "Designer Drugs" CompCare Publications, Minneapolis. 1986.

This book is organized into chapters that treat each of some half-dozen drugs that have been created or modified so as to circumvent explicit legal restrictions, or have recently emerged into popularity. One chapter, entitled "Ecstasy", spins together the popular lore concerning MDMA with quotations from various writers and lecturers and several anonymous users.

Klein, J. The New Drug They Call 'Ecstasy', New York (magazine), May 20, 1985, pp 38-43.

This is a popular article that brings together quotations that express the broad range of attitudes held by both the proponents and the opponents of the current clinical employment of MDMA. Some historical background is presented, as well as an articulate description of the effect the drug produces.

Korf, D., Blanken, P. and Nabben, T. Een Nieuwe Wonderpil? Verspreiding, effecten en risico's van ecstasygebruik in Amsterdam. A book in Dutch of over 150 pages. (1991)

The origins, distribution, availability, and use of Ecstasy in The Netherlands is discussed. Since 1988, MDMA has been covered under the Opium Act, but there is little active police intervention. There appears to be extensive misrepresentation of this drug with frequent substitution of some amphetamine-like substitute. The street price remains very high.

Laverty, R. and Logan, B.J. Ecstasy Abuse. New Zealand Med. J. 102 451 (1989).

A request is extended to practitioners for information concerning possible MDMA exposure with their patients. If possible, a sample of the drug involved in any referral could be given for analysis, which would allow an accurate estimate to be made of the magnitude of this particular drug problem in New Zealand.

Leavy, J. Ecstasy: The Lure and the Peril. The Washington Post June 1, 1985. Zagoria, S. More "Peril" than "Lure." ibid. July 3, 1985,

A well researched and careful article reviewing all aspects of the MDMA palavar. The reply by Mr. Zagoria expressed the thought that Ms. Leavy's presentation was too enticing, with lure outweighing peril.

Leverant, R. MDMA Reconsidered. J. Psychoactive Drugs 18 373-379 (1986).

A summation of thoughts and impressions gathered at the Oakland, California Conference on MDMA (May, 1986). The theme presented is the need of open-mindedness in the area of personal and well as clinical freedom of research, and MDMA was used as a focal point.

Lyttle, T. and Montagne, M. Drugs, Music, and Ideology: A Social Pharmacological Interpretation of the Acid House Movement. Intern. J. Addict. 27 1159-1177 (1992).

The development of the "Acid House" phenomenon from it's origin in 1988 in England, is reviewed with particular emphasis placed on the role played by music and drugs in the changing of statesof consciousness.

Mandi, J. Ecstasy. The Face #38, November, 1991. Three page article.

A rather balanced and reasonable article about some reasons for, and some difficulties associated with, the excessive use of MDMA.

McConnell,H. MDMA. The Journal. July 1, 1986 pp. 11-12.

A thorough review of the Oakland, California MDMA conference is presented, in considerable detail and with excellent balance.

McDonnell, E. One World, One Party. S.F. Weekly, January 29, 1992 pp 12-13.

A view of the rave scene in San Francisco, with the emphasis on MDMA (but with LSD and mushrooms also contributing) and smart drinks (vitamins, minerals, and little alcohol). and lights and music and colour. All is very expensive, and very much in style. Psychedelic drug use is taken for granted.

McGuire, P. and Fahy, T. Flashbacks following MDMA. Brit. J. Psychiatry. 160 276 (1992).

A retrospective analysis of an earlier report concerning MDMA use has uncovered the fact that flashbacks had occurred. An apology is extended for the polypharmacy that was implied in that report; cannabis was present but there was no evidence for the presence of MDMA. Apparently an analysis for MDMA use was not asked for and so it was not reported as being present. More frequent urine screenings should help to implicate MDMA with medical problems, in light of the current widespread use of the drug.

McKenna, D.J. and Peroutka, S.J. The Neurochemistry and Neurotoxicity of 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"), J. Neurochem. 54 14-22 (1990).

A thoroughly documented review of the present state of knowledge of the effects of MDMA on animal systems.

McKenna, D.J. and Peroutka, S.J. Serotonin Neurotoxins: Focus on MDMA (3,4-Methylenedioxymethamphetamine, "Ecstasy"). In: Serotonin Receptor Subtypes: Basic and Clinical Aspects, Editor, Peroutka, Wiley-Liss, New York. pp.125-146 (1991).

In a volume on serotonin receptors (part of a receptor biochemistry and methodology series) the "halogenated amphetamine" receptor subtype is characterized in an extensive review essay of MDMA and the neurotoxicity that is ascribed to it.

McNeil, L. A Woodstock of Their Own. Details, Decemeber 1991 pp. 26-38.

This is a candid expose of one explicit rave weekend in Los Angeles. The picture shows that the entire structure is build about the drug MDMA which is an essential component of the event.

Molliver, M.E., Berger, U.V., Mamounas, L.A., Molliver, D.C., O'Hearn, E. and Wilson, M.A. Neurotoxocity of MDMA and Related Compounds: Anatomical Studies. Ann. N. Y. Acad. Sci 600 640-664 (1990).

A review and discussion is presented from a recent symposium of serotonin neuropharmacology. Comparisons of MDMA, MDA, p-chloroamphetamine and fenfluramine are made.

Nasmyth, P. The Agony and the Ecstasy. The Face, October, 1986 p. 52.

A popularized article from England on the properties and the uses of MDMA. It strongly suggests that the drug is already deeply instilled in British culture.

Nasmyth, P. Laing on Ecstasy. International J.Drug Policy. 1 14-15 (1989).

A brief profile of the late controversial psychiatrist R.D.Laing, and his views of the potential of the drug MDMA in a therapy role.

Newmeyer, J.A. Some Considerations on the Prevalence of MDMA Use. J. Psychoactive Drugs 18 361-362 (1986).

An epidemiology survey of MDMA use (as of 1986) from the usual information sources (Drug Abuse Warning Network, DAWN; the Community Epidemiology Work Group, CEWG; police department reports, medical examiner or coroner's office reports) gives little indications that there is a medical problem associated with its use. Epidemiologically, it can not be considered at the present time a problem. It may well be that the material currently enjoys controlled, careful use by a number of cognoscenti (as did LSD in the early 1960's) and perhaps in future years a larger number of less sophisticated individuals will be drawn into its usage, and will find ways to evince adverse reactions, police involvement, and other unpleasant consequences.

Newmeyer, J.A. X at the Crossroads. J. Psycho. Drugs 25 341-342 (1993).

A short essay addresses the question of the eventual responses of the public to MDMA. Arguments are presented that support its gaining de facto tolerance (achieving a status akin to that of marijuana) but other observations that could lead to a hostile LSD-like rejection. He believes that the next two years will be decisive.

Nichols, D.E. MDMA Represents a New Type of Pharmacologic Agent and Cannot be Considered to be either a Hallucinogenic Agent or an Amphetamine-type Stimulant.

This is an unpublished essay submitted both to the DEA and to the WHO group, through the offices of Richard Cotton. It presents a point by point analysis from both in vitro and in vivo studies of the pharmacological properties of MDMA and its isomers, with MDA (a structurally related hallucinogenic compound) and other amphetamines. He concludes that its actions represent a new classification of pharmacology, and clinical research with it in psychotherapy would argue against placing it in Schedule I.

Nichols, D.E. Differences Between the Mechanism of Action of MDMA, MBDB, and the Classic Hallucinogens. Identification of a New Therapeutic Class: Entactogens. J. Psychoactive Drugs 18 305-313 (1986).

This article presents a review of the extensive neurological and pharmacological evidence that supports the stand that MDMA and MBDB should be classified neither as hallucinogens (psychedelic drugs) nor as simple stimulants. An argument is made for a novel classification, entactogens.

Nichols, D.E. and Oberlender, R. Structure-Activity Relationships of MDMA and Related Compounds: A New Class of Psychoactive Drugs. Ann. N. Y. Acad. Sci. 600 613-625 (1990).

A review of the pharmacological and behavioral properties of MDMA and MBDB suggests that they represent members of a new class of psychopharmacological agents. A extensive discussion is also included.

Nichols, D.E. and Oberlender, R. Structure-Activity Relationships of MDMA-Like Substances, NIDA Research Monograph Series #94 pp. 1-29 (1989).

A critical review of the structures and activities of compounds related to MDMA is presented, with particular attention directed to a somewhat less neurotoxic homolog MBDB. A considerable discussion is attached, with questions, comments, and answers, from the actual conference.

Nichols, D.E. and Oberlender, R. Structure-Activity Relationships of MDMA and Related Compounds: A New Class of Psychoactive Agents? The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Kluwer, New York. (1990) Ed: S.J. Peroutka.

An extensive analysis has be made of the structures of drugs that resemble MDMA, and the nature of their action. An argument is presented for the acceptance of a pharmacological classification of Entactogens as being distinct from the Hallucinogens, or psychedelic drugs.

O'Rourke, P.J. Tune In. Turn On. Go To The Office Late on Monday. Rolling Stone, December 19, 1985 p. 109.

The MDMA popularity craze is presented in a humorous retrospective of the drug attitudes of the 1960's.

Peroutka, S.J. Incidence of Recreational Use of 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") on an Undergraduate Campus. New England J. Med. 317 1542-1543 (1987).

A random, and anonymous, poll of undergraduates at Stanford University (California) showed that some 39% of all students were experienced with MDMA (mean number of uses was 5.4, and dosage range was 60-250 mg). To date, he finds no evidence to suggest that MDMA is neurotoxic in humans.

Peroutka, S.J. 'Ecstasy': A Human Neurotoxin? Arch. Gen. Psychiat. 46 191 (1989).

A letter to the editor presents three anecdotal observations in connection with the recreational use of MDMA. (1) Frequent use decreases the favorable responses. (2) Chronic use changes the nature of the response, and (3) the material appears not to be addictive. It has been concluded that there may well be a long-term and potentially irreversible effect of MDMA on the human brain. Recreational use should be avoided.

Randall, T. Ecstasy-Fuelled 'Rave" Parties Become Dances of Death for English Youths. J. Am. Med. Soc. 268 1505-1506 (1992).

A news report and medical perspective on the problems being reported as associated with the use of ecstasy (MDMA) in the British rave scene. A brief history of ecstasy is provided.

Randall, T. 'Rave' Scene, Ecstasy Use, Leap Atlantic. J. Am. Med. Soc. 268 1506 (1992).

A brief history of the 'rave' scene in Britain is presented. The recent appearance of the phenomenon in the United States, and elsewhere around the world, is discussed.

Rattray, M. Ecstasy: Towards an Understanding of the Biochemical Basis of the Action of MDMA. Essays in Biochemistry 26 77-87 (1991).

A review of the history, pharmacoloy and neurochemistry of MDMA is presented. Much of the presented information is factual, some of it is speculative, and several points are simply wrong.

Riedlinger, T.J. and Riedlinger, J.E. Psychedelic and Entactogenic Drugs in the Treatment of Depression. J. Psycho. Drugs 26 41-55 (1994).

Both the virtues of, and the problems associated with, the incorporation of psychedelic drugs into psychotherapy are discussed.

Renfroe, C.L. MDMA on the Street: Analysis Anonymous. J. Psychoactive Drugs 18 363-369 (1986).

In the twelve years (up to 1983) that PharmChem conducted its Analysis Anonymous service, they evaluated over 20,000 samples of street drugs. MDMA and MDA had been classified together (in some 610 examples) and of these 72 had been alleged to be MDMA. In the years 1984-1985, a cooperating reference laboratory (S.P., Miami, Florida) reported an additional 29 alleged MDMA samples. Of these 101 samples, over half proved to be, indeed, MDMA, and half of the remaining contained MDMA. This is considered a remarkably high validity rate. The origins, descriptions, and costs are discussed.

Riedlinger, J.E. The Scheduling of MDMA: A Pharmacist's Perspective. J. Psychoactive Drugs 17 167-171 (1985).

A critical viewpoint is taken of the scheduling procedures employed with MDMA. This paper is adapted from the original letter of protest sent to the DEA, and from the written testimony presented at the hearings.

Riedlinger, T. and Riedlinger, J. The 'Seven Deadly Sins' of Media Hype in Light of the MDMA Controversy. PM&E (Psychedelic Monographs and Essays). 4 22 (1989).

This is a carefully written criticism of the uneven ways in which the popular press weighs and presents controversial issues such as the story concerning MDMA.

Rippchen, R. MDMA Die Neue Sympathiedroge. Der Grune Zweig 103, Medieneexperimente D-6941 Luhrbach, West Germany (1986).

A book of some 47 pages, giving an immense body of information on MDMA (in German) including translations of articles by Greer. Also included is information on other drugs such as MDE and 2C-B.

Roberts, M. Drug Abuse. MDMA: "Madness, not Ecstasy" Crosstalk section, Psychology Today. June, 1986.

An update of an earlier article (Psychology Today, May, 1985) which emphasizes the neurological findings, and the concept of unregulated drug synthesis. Congressional action prohibiting the manufacture and distribution of similar drugs is urged.

Roberts, T.B. The MDMA Question. Section on Social Concerns. AHP Perspective. May, 1986. p. 12.

This is a soul-searching review asking the questions as to where we must acknowledge the line between the need of drug use in therapy, and tolerating drug use in society. Provisions must be made, of course, for both.

Robins, C. The Ecstatic Cybernetic Amino Acid Test. San Francisco Examiner Image, February 16, 1992 p. 6 et seq.

A trip with the author is made through an evening, of a San Francisco rave. The noise, the excessive focus on drugs, smart drinks, energy, dance, music, cyberpunk this and virtual reality that; all make a statement of rebellion. It may all die out, but the concept is truly international in scope, and might soon require the older generation to take it seriously.

Rosenbaum, M. and Doblin, R. Why MDMA Should Not Have Been Made Illegal, Unpublished Essay, 1990.

A brief history and analysis of the illegalization of MDMA is presented.

Saunders, N. "E for Ecstasy" Saunders, London (1993) 318 pp.

A thorough review of the medical, social and legal history of MDMA is presented, in a well documented analysis of this highly controversial drug, at the height of its popularity. The rave scene is described, as is the beginning acceptance of MDMA as a valuble therapeutic tool. An annotated bibliography, by Alexander Shulgin, is attached.

Saunders, N. MDMA - The View from England. MAPS 4 22-24 (1993).

A review is presented of the present position of MDMA in England. A critical discussion of the medical reports, the legal status, and the problems of misrepresentation which are inevitable when the streets are the only source for purchase. Speculations as to future developments are encouraging.

Schuckit, M.A. MDMA (Ecstasy): An Old Drug with New Tricks. Drug Abuse and Alcoholism Newsletter 23 #2 April, 1994.

A review is presented of the history, social use and dangers of MDMA use. The intended audience is the practicing physician.

Sawyer, M. Ecstasy. Select, July 1992 pp 56-61.

A strongly written review covering all sides of the rave scene in England, and the damage that is being done by the strenuous laws against ecstasy. Emphasis is placed on the fraud that is rampant in the misrepresentation of the identities of the drugs that are being sold as MDMA.

Schulman, R. The Losing War Against "Designer Drugs." Business Week, June 24, 1985 pp. 101-104.

An overview of the MDMA controversy. A preview is presented, of the pharmaceutical industry's response (OK to ban it, but not with the haste that might have a chilling effect on the development of new pharmaceuticals) and local law enforcement enthusiasm (Florida has granted the State Attorney General the power to place a drug on the Controlled Drug List in as little as 24 hours).

Sedgwick, B., Lo, P. and Yee, M. Screening and Confirmation of 3,4-Methylenedioxymethamphetamine (MDMA) in Urine: Evaluation of 1000 Specimens. Abstracts of the CAT/SOFT Meetings, Oct. 29 -Nov. 1, 1986, Reno/Lake Tahoe, Nevada.

A sequence of 1000 "at risk" samples were screened for the presence of methamphetamine (MA) and/or MDMA (not distinguishable in the initial analysis). Of 133 presumptive positive tests, none proved to be positive for MDMA.

Seymour, R.B. "MDMA" Haight-Ashbury Publications, San Francisco. 1986

This is a volume devoted entirely to the single drug MDMA. Nine chapters discuss its origins, facts that apply to it, its bright side and dark side, in a carefully balanced presentation. It was made available for the Oakland, California symposium, MDMA: A Multidisciplinary Conference, May 17-18, 1986.

Seymour, R.B. Ecstasy on Trial. High Times, November, 1986. p. 33.

A retrospective review article of the controversies stirred up by the publicity that followed the government hearings and the illegalization of MDMA.

Seymour, R.B., Wesson, D.R. and Smith, D.E. Editor's Introduction. J. Psychoactive Drugs. 18 287 (1986).

An introduction is made to an entire issue of the Journal dedicated to the several papers presented at a two-day conference on the topic of MDMA. This was held May 17-18, 1986, at the Health Education Centre of the Merritt

Peralta Medical Centre, in Oakland, California. Shafer, J. MDMA: Psychedelic Drug Faces Regulation. Psychology Today, May, 1985. pp. 68-69.

This is a short overview presenting the clinical and legal views of a number of psychiatrists, administrators and researchers.

Shulgin, A.T. Twenty Years on an Ever-changing Quest, Psychedelic Reflections, Eds. L. Grinspoon and J.B. Bakalar, Human Science Press, New York (1983). pp. 205-212.

This is an essay on the philosophy of research associated with psychedelic drugs. MDMA is described briefly, with some of its history, pharmacology, and therapeutic potential.

Shulgin, A.T. What is MDMA? PharmChem Newsletter 14 3-11 (1985).

A hypothetical interview is presented, distilling the questions fielded from many reporters, and the substance of the answers given to these questions.

Shulgin, A.T. The Background and Chemistry of MDMA. J. Psychoactive Drugs 18 291-304 (1986).

This review gathers together the physical properties of MDMA, and the published information as to toxicity and pharmacology, as of the date of the Oakland, California conference (May, 1986).

Shulgin, A.T. History of MDMA, The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Kluwer, New York. (1990) Ed: S.J. Peroutka.

A review, with 158 references, is presented that outlines the current (mid-1989) literature on then published literature on MDMA.

Siegel, R.K. Chemical Ecstasies. Omni, August 1985. p. 29.

This short essay advises caution in the immediate acceptance of drugs that are enthusiastically promoted but which have not been thoroughly researched.

Smith, D.E. and Seymour, R.B. Abuse Folio: MDMA. High Times, May, 1986. p. 30.

There is a continuing series of drug information sheets, one being published in each issue of High Times. This contribution is a neutral, factual presentation of the nature and use, and of the hazards and liabilities associated with the drug MDMA.

Smith, D.E., Wesson, D.R. and Buffum, J. MDMA: "Ecstasy" as an Adjunct to Psychotherapy and a Street Drug of Abuse. California Society for the Treatment of Alcoholism and Other Drug Dependencies News 12 (September) 1985 pp 1-3. A letter to the Editors in response: Holsten, D.W. and Schieser, D.W. Controls over the Manufacture of MDMA. The original authors' reply: ibid. 12 (December) 1985 pp 14-15.

A brief review of the therapeutic virtues and abuse risks that are associated with MDMA, and the chilling effect that illegalization of drugs has had on medical research. The authors were reminded in rebuttal (Holsten and Schieser) that the exploratory use of new drugs outside of the controls that apply to the pharmaceutical industry carry real risks as to safety and quality of product.

Solowij, N. and Lee, N. Survey of Ecstasy [MDMA] Users in Sydney. Drug and Alcohol Directorate NSW Health Department, 1991 (Sydney). CEIDA, PMB No. 6, P.O. Rozelle NSW 2039 (Australia).

An extensive survey is presented of many Ecstasy users in Sydney. It has been found that the principle use of the drug has been directed towards fun, at social gatherings, and the primary effects have been the expression of a positive mood state. A secondary effect has been that of stimulation with an expression of energy and activation. Reports describe the properties of insight and of perceptual/sensual enhancement.

Solowij, N., Hall, W. and Lee, N. Recreational MDMA Use in Sydney: A Profile of "Ecstasy" Users and their Experiences with the Drug. Brit. J. Addictions 87 1161-1172 (1992).

An anonymous survey of MDMA users involved with the social "rave" scene showed a consensus of the users' having experienced positive mood states, and feelings of closeness with others. The stimulant effects were secondary. The usual statements of caution are attached.

Sternbach, G.L. and Varon, J. Designer Drugs. Postgraduate Medicine 91 169-176 (1992).

A review is presented of several synthetic variations of known illegal drugs. The major emphasis is on the opiates (modification of demerol, i.e., MPPP and MPTP) and on the mescaline-methamphetamine analogues (namely, MDA, MDMA and MDEA).

Straus, H. From Crack to Ecstasy; Basement Chemists can Duplicate almost any Over-the-border Drug. American Health, June, 1987 pp. 50-54.

A brief review of the concept of special formulations or syntheses of drugs for the extra-medical market. MDMA is brought in as a minor example.

Szabo, P. MDMA Restrictions too Hasty? The Journal, July/August 1989, p. 4.

A brief news report describes a study reported to the American Psychiatric Association meeting (San Francisco, 1989) involving some 20 psychiatrists who were familiar with MDMA. The opinion of Dr. Liester (University of California at Irvine) sums up the consensus. There is a need for clinical research with this promising drug, and this is not likely in view of the Government's current restrictions.

Taylor, J.M. MDMA Frequently Asked Questions List. Internet (Usenet) Newsgroup alt.drugs, January 5, 1994

This is a review of the known facts relating to MDMA. It is balanced and fair, but it maintains the chemical errors from the ChemicalAbstracts in its synthetic portion, that hydrogen peroxide is used in place of water in the final hydrolysis. Considering its very wide public distribution, this distillation of facts is of excellent quality and must be respected as a fine public service.

Toufexis, A. A Crackdown on Ecstasy. Time Magazine. June 10, 1985. p. 64.

A news report on the placing of MDMA into emergency Schedule I status. The complement to Newsweek's positive article of about the same time.

Turkington, C. Brain Damage Found with Designer Drugs. Amer. Psychological Assn. Monitor March, 1986.

A negative review of the neurotransmitter research. This is probably the source of the oft-quoted "fact" that these drugs are the first demonstration of a neurotransmitter being modified to a neurotoxin.

von Hoyer, E. The Agony of Ecstasy; A Consumer's Guide. Dated April 20, 1988, and identified with "WRT 404 / S. Hubbard"

The is a short essay covering the use of, the action of, and the history of MDMA. It is replete with incorrect information, and has little other value.

Weigle, C. and Rippchen, R., MDMA: Die Psychoaktive Substanz fur Therapie, Ritual und Rekreation. Der Grune Zweig 103, Germany. Printed in Austria about 1991. 88 pages.

A collection of essays on MDMA, some originally in German, some translated, covering the entire spectrum of clinical and social aspects of the drug.

Whitaker-Azmitia, P.M. Depression to Ecstasy. The New Biologist, 1 145-148 (1989).

This is a review of a conference on the neuropharmacology of serotonin, sponsored by the New York Academy of Sciences, on July 10-13, 1989. The final session was devoted to MDMA and, involving its potential neurotoxicity, was one of the more controversial ones. It is stated that dramatic evidence was presented at the conference that a serious level of damage had occurred to the serotonin neurons of human MDMA users.

Wolfson, P.E. Letter to Richard Cotton, Dewey, Ballantine, Bushby, Palmer & Wood, Washington, D.C.

A report is made of the effective use of MDMA in conjunction with psychotherapy, in the treatment of both depressed and schizophrenic patients. The apparent anti-manic and anti-paranoia action of MDMA allowed the opening of discourse and allowed intervention with more conventional therapy. It is suggested that there is a promising potential for its use in certain psychotic situations, and a telling argument is made against its legal classification in Schedules I or II.

Woolverton, W.L. A Review of the Effects of Repeated Administration of Selected Phenethylamines. Drug and Alcohol Dependence 17 143-150 (1986)

A review from the literature of the chronic toxicological findings regarding a number of compounds that are being proposed for international control. One reference to MDMA is cited, the Fed. Proc. note (Virus, et al. 45 1066 (1986) which has been published (see Commins, et al., 1987, section 8 above).

Wright, W.R. XTC, Analyte of the Month, 10 3 (1989). Published by the American Association for Clinical Chemistry.

A brief and factual review of MDMA, with a little history and some comments on the validity of immunological assays for MDMA using amphetamine assays.

Zizzo, P. MDMA - Aspects of it's Psychopharmacology. Unpublished essay written for Psych. 119, University of California at Davis, Spring 1989.

This 10 page essay briefly reviews the background and history of the therapeutic work done with MDMA.

Burger, A. "Drugs and People" University Press of Virginia, Charlottesville, 1986. p. 65. This quotation, from the chapter on neurohormones, will be the sole example given of the irresponsible misinformation that can be published by experts in the field.

[in reference to designer drugs] "Others are synthetic compounds tried out by addicts in the hope that they might give them a new mental high. The most dangerous of these materials are 3-methylfentanyl and MDMA, a relative of methamphetamine. Both produce dangerous damage to the general health of the users and cause heroin-like addiction at unbelievably low doses."

Glennon, R.A., Rosecrans, J.A. and Young, R. Drug-induced Discrimination: A Description of the Paradigm and a Review of its Specific Application to the Study of Hallucinogenic Agents. Medical Research Reviews 3 289-340 (1983).

"Racemic - MDA produces (conditioned response) effects similar to those of DOM, however, administration of its N-methyl derivative, racemic MDMA, to the DOM-trained animals, resulted in disruption of behaviour."

Nichols, D.E. and Glennon, R.A. Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens, in Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives Ed. B.L. Jacobs, Raven Press, New York. (1984)

"N-Alkylation of the phenethylamines abolishes or greatly attenuates biological activity. Two noteworthy exceptions are the (N-methyl and N-ethyl) 3,4-methylenedioxy substituted compounds. These retain potency nearly comparable to the parent MDA, but present a different qualitative picture. Their duration of action is reduced to about 1-1/2 to 2 hours and they produce only minor disruption of normal sensory processing. They apparently amplify empathy and would seem to be ideal candidates as adjuncts to psychotherapy."

Shulgin, A.T. Psychotomimetic Drugs: Structure-Activity Relationships. Handbook of Psychopharmacology Volume 11; Stimulants, Eds. L.L.Iversen, S.D. Iversen and S.H. Snyder, Plenum Press, New York. p. 292. (1978)

"MDMA has a higher threshold level than does MDA but otherwise it is very similar in potency. Within the effective dose range (100-150 mg orally) the effects are first noted very quickly, usually within one-half hour following administration. With most subjects the plateau of effects is reported to occur within another one-half hour to one hour. The intoxication symptoms are largely dissipated in an additional two hours, except for a mild residual sympathomimetic stimulation, which can persist for several additional hours. There are few physical indicators of intoxication, and psychological sequelae are virtually nonexistent. Qualitatively, the drug appears to evoke an easily controlled altered state of consciousness with emotional and sensual overtones very reminiscent of low levels of MDA."

Shulgin, A.T. Hallucinogens. Burger's Medicinal Chemistry, 4th Edition, Part III, Ed. M.E. Wolff, Wiley and Son, New York. p 1120. (1981)

"This affective interaction (a state of sensory amplification and enhancement without appreciable sympathomimetic stimulation, an easy communication between subject and observer) is even more clearly evident in the N-methyl homolog of MDA (i.e., MDMA) which is substantially free of perceptual distortion at effective dosages (75-150 mg)."

Shulgin, A.T., Chemistry of Psychotomimetics, Psychotropic Agents Part III, Alcohol and Psychotomimetics; Psychotropic Effects of Central Acting Drugs, Eds. F. Hoffmeister and G. Stille, Springer-Verlag, Berlin. p 14. (1982)

"Several of these substituted amphetamine analogs have been studied as their N-methyl homologues (in analogy with the relationship between amphetamine and methamphetamine). Although most show a striking drop in potency, MDMA (the N-methyl homologue of MDA) retains full activity."

Stafford, P. Psychedelics Encyclopedia, Revised Edition, J.P. Tarcher, Inc., Los Angeles, CA p 289. (1983)

"Synthesis of MDMA, active in the doses of the 75-100 mg range and shorter and milder in its effects than MDA, was not reported in the scientific literature until 1960. It has since been established that MDMA was one of the "Experimental Agents" tested at Edgewood Chemical Warfare Service, where it was labelled EA-1475. (MDA was labelled EA-1299)."

Weil, A. and Rosen, W. Chocolate to Morphine; Understanding Mind-active Drugs, Houghton Mifflin Company, Boston, 1983. p 108

"A newer drug, MDM (methylenedioxymethylamphetamine, also known as MDMA, Adam, and "XTC"), gives the same general effect (as MDA) but lasts four to six hours instead of ten to twelve. Because of the shorter duration of action, it seems gentler on the body with less day-after fatigue."