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).