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[ Appendix 4 sec. 4 ] [ Index ] [ Appendix 4 sec 6 ]

Appendix 4: Bibliography Pharmacology

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. 100 mg/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.