Introduction

The purpose of this document is to provide an update on the current status of research on the putative neurotoxicity of MDMA, covering the period from mid-1990 to the present. Research on MDMA neurotoxicity predating that period has been previously summarized in a review article, "Neurochemistry and neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)" by D. J. McKenna and S. J. Peroutka, (Journal of Neurochemistry Vol. 54 (1), pp. 14-22).

Since the publication of that review, MDMA has become increasingly utilized within the neurosciences as a valuable research tool for investigating the mechanisms and sequelae of serotonergic neurotoxicity, along with other neurotoxic amphetamine derivatives such as fenfluramine and parachloroamphetamine (PCA). While the various animal models used in the study of MDMA neurotoxicity are now well-established, the question of the potential risks for human users of MDMA, being harder to measure and quantify, remain unresolved. The recent research findings can be summarized under various categories, as is done below.

Blockade of neurotoxicity by 5-HT2 receptor antagonists

Schmidt, et. al. 1990 reported that the 5-HT2 receptor antagonists MDL 11,939 and ritanserin administered within one hour after MDMA can block the reduction in 5-HT and tryptophan hydroxylase activity detectable within one week after multiple doses of MDMA. The regionally nonspecific blockade was suggested to be due to serotonergic modulation of dopamine synthesis. The 5-HT2 antagonists apparently interfered with MDMA-stimulated dopamine synthesis, reducing the intracellular pool of dopamine (DA) and leading to a reduction of sustained DA release. These conclusions were supported by the finding that administration of L-DOPA with MDMA reversed the protective effects of the 5-HT2 antagonists (Schmidt , et al. 1991)

Release Studies

Differential release of 5-HT/DA - correlation with neurotoxicity

McKenna, et al. 1991 investigated the effects of MDMA and a number of it structural congeners on the differential release of [3H]5-HT and [3H]DA from synaptosomal preparations. They reported that the release of [3H]5-HT induced by MDMA is partially blocked by 10-6 M fluoxetine. The (+) enantiomers of both MDA and MDMA are more potent than the (-) enantiomers as releasers of both [3H]5-HT and [3H]DA. Eleven analogues, differing from MDA with respect to the nature and number of ring and/or side chain substituents, also show some activity in the release experiments, and are more potent as releasers of [3H]5-HT than of [3H]DA. The hallucinogen DOM does not cause significant release of either [3H]monoamine. Possible long-term serotonergic neurotoxicity was assessed by quantifying the density of 5-HT uptake sites in rats treated with multiple doses of selected analogues using [3H]paroxetine to label 5-HT uptake sites. In the neurotoxicity study of the compounds investigated, only (+)MDA caused a significant loss of 5-HT uptake sites in comparison to saline-treated controls.

Release of norepinephrine by MDMA

In a related study, Fitzgerald and Reid (1990) investigated the effect of MDMA on release of [3H]norepinephrine, [3H]DA, and [3H]5-HT from rat brain slices. MDMA enhanced the stimulation-induced efflux of [3H]norepinephrine, but not of the other two [3H]-monoamines, from brain slices. This was the first demonstration of a direct stimulation of [3H]norepinephrine release by MDMA.

Studies using 5-HT uptake inhibitors

Previous investigators have shown that administration of 5-HT uptake inhibitors such as fluoxetine up to 3 hours post-MDMA can abolish or attenuate the long-term serotonergic changes indicative of neurotoxicity. Similarly, receptor binding studies and autoradiography with tritiated uptake inhibitors has been used to demonstrate a reduction in the density of 5-HT uptake sites in MDMA-treated animals, and this is one of several parameters indicative of neurotoxicity. Several recent studies have been extensions of this work with 5-HT uptake inhibitors.

Use of 6-nitro-quipazine to measure reduction in 5HT binding sites and blockade of neurotoxicity

Hashimoto , et al. 1990 used a new 5-HT selective uptake inhibitor, 6-nitro-quipazine, to block serotonergic neurotoxicity following administration of MDMA. These investigators also used [3H]6-NO-quipazine as a selective radioligand to demonstrate reduced density of uptake sites in MDMA treated rats. Essentially this work duplicates previous findings using fluoxetine and [3H]paroxetine using a new ligand for the uptake site.

Effect on [3H]paroxetine binding in frontal cortex and blood platelets

Nash , et al. 1991 used [3H]paroxetine to measure the density of uptake sites in brains and platelets of MDMA-treated rats. Rats administered multiple doses of MDMA showed the expected reductions in brain uptake sites 7 days after treatment, but there was no corresponding reduction in blood platelet sites, indicating that platelets cannot be used as a peripheral marker for MDMA neurotoxicity. These workers also observed that pretreatment with the 5-HT 2/1C antagonist ketanserin reduced the reduction of brain uptake sites after a single dose of MDMA.

In vivo autoradiography with [3H]paroxetine

The in vitro utility of [3H]paroxetine to determine the loss of 5-HT uptake sites in MDMA-treated animals has been previously established. Scheffel and Ricaurte (1990) extended this technique to the in vivo level using [3H]paroxetine. They administered the radioligand to rats via tail vein injection and measured specific binding four hours later. They reported that the specific binding paralleled the known distribution of 5-HT uptake sites. Animals treated with either the serotonin neurotoxin 5,7-DHT or MDMA showed a markedly reduced density of 5-HT uptake sites. These results indicated that paroxetine or one of its derivatives could potentially be used as a ligand for PET (Positron Emission Tomography) to study serotonergic neurons following neurotoxic injury.

Structure/activity, & behavioral studies

Two recent studies have focused on changes in behavioral parameters and structure/activity.

Effect of neurotoxicity on discrimination and CCP

Schecter (1991) investigated the effect of MDMA neurotoxicity on behavior in the drug discrimination and conditioned place preference assays. Rats were trained to distinguish MDMA from vehicle in the drug discrimination assay. The drug was also observed to produce conditioned place preference (CCP) as 1.5 mg/kg doses increased the time the animals spent in the chamber associated with MDMA. Subsequent administration of neurotoxic doses of MDMA were shown to significantly attenuate the animal's response to MDMA in the drug discrimination paradigm, but showed no effect in the CCP assay.

Effect of alpha-methyl epinine in neurotoxicity

Alpha-methyl epinine is one of the major microsomal metabolites of MDMA. Steele , et al. 1991 investigated the possible involvement of this compound in the serotonergic neurotoxicity attributed to MDMA. Brain microsomal fractions from mice and rats both produced similar amounts of the metabolite on incubation with MDMA. Rat liver microsomes produced a significantly greater amount of alpha-methyl epinine than did mouse liver microsomes. There was no evidence of stereoselectivity for the reaction, in contrast to the neurotoxicity, which is attributable primarily to the S(+) isomer of MDMA. Intracerebroventricular injection of alpha-methyl epinine resulted in no significant decline in biogenic amines or their metabolites one week later, indicating that this metabolite alone is not responsible for neurotoxicity.

Neurotransmitter/neuroendocrine effects

A number of recent studies have focused on changes in neurotransmitter and neuroendocrine systems as possible physiological markers for neurotoxicity induced by MDMA.

Changes in neurotensin and dynorphin A systems

For example, Johnson , et al. 1991 demonstrated that levels of neurotensin-like immunoreactivity (NTLI) and dynorphin-like immunoreactivity (DLI) was significantly increased 18 hours after a single administration of MDMA. Co-administration of SCH 23390, a D1 selective antagonist, or MK-801, a noncompetitive NMDA antagonist, blocked the MDMA-induced changes in immunoreactivity, but the dopamine D2 antagonist sulpiride failed to block the effects. These findings suggest that the MDMA-induced changes in NTLI and DLI involve both the dopaminergic and glutaminergic systems.

Diminished hormonal responses in MDMA-treated animals

Poland (1990) investigated the effects of MDMA pretreatment on 5-HT- coupled neuroendocrine response, specifically prolactin and corticotropin. MDMA-treated rats subsequently administered the 5-HT1a agonist 8-hydroxy-DPAT displayed a blunted corticotropin response and an enhanced prolactin response. These results suggested that neurochemical changes produced by MDMA are associated with functional alterations as manifested by 5-HT-coupled neuroendocrine response.

Changes in fos-proteins

Dragunow , et al. 1991 reported that injections of MDMA resulted in an accumulation of c-fos protein and fos-related antigens in the caudate-putamen, nucleus accumbens, and olfactory tubercle within 2 hr after injection. Fos levels returned to baseline within 24 hours, but fos-related antigens persisted for at least another 24 hours. The NMDA antagonist MK-801 inhibited fos and fos-related antigen induction after MDMA, but the 5-HT uptake inhibitor fluoxetine had no effect.

Anatomic studies of MDMA neurotoxicity

Molliver , et al. 1990 published a review paper summarizing this group's extensive work on the neuroanatomical correlates of MDMA neurotoxicity. The results reported there are essentially similar to those previously reported, viz., that unequivocal signs of axon degeneration are seen in fine 5-HT axons (but not beaded axons or raphe cell bodies) within 48 hours after MDMA administration. Within six to eight months, there is persistent serotonergic reinnervation of frontal cortex along a fronto-occipital gradient in a manner simulating perinatal development of 5-HT innervation. Although the sprouting axons are anatomically similar to the damaged axons, it remains unknown whether a normal pattern of innervation is re-established.

Prenatal exposure to MDMA

An important consideration for the human users of MDMA concerns possible adverse effects on the fetus. Relatively few studies have addressed this issue, however, a recent paper by St. Omar, et al. 1991 has done so. Groups of pregnant rats were administered varying doses of MDMA on alternate gestational days 16-18. Gestational duration, litter size, neonatal birth weights and physical appearance at birth were unaffected by MDMA treatment. Pregnancy weight gain was significantly reduced by MDMA. Progeny growth, maturational parameters, surface righting reflex, swimming performance, forelimb grip strength, milk induced behavior, passive avoidance behavior, figure 8 maze activity, and the density of 5-HT uptake sites, 5-HT, and 5-HIAA levels were unaffected by MDMA treatment. Olfactory discrimination was enhanced in both male and female progeny, and negative geotaxis was delayed in female pups. In the dams, MDMA caused significant reductions in 5-HT and 5-HIAA levels in discrete brain areas. It was concluded that prenatal exposure to MDMA causes only subtle behavioral changes in developing rats, while the dams are at risk for the characteristic spectra of serotonergic changes.

Primate neurotoxicity no-effect level

Ricaurte (personal communication,1992) and associates at Johns Hopkins University recently completed the data analysis portion of a primate study which for the first time has identified a no-effect level for MDMA neurotoxicity. The study involved six primates, three controls and three experimental animals who received an oral administration of 2.5 mg/kg of MDMA once every two weeks for four months (8x). Eight brain regions were examined for 5-HT and 5-HIAA content. There were no significant differences between experimental and control animals in any of the brain regions studied. Since a previous study by Ricaurte (1988a) has shown that a single oral dose of 5.0 mg/kg causes neurotoxicity only in the thalamus and hypothalamus, this study demonstrates that the primate no-effect level lies somewhere between 2.5 and 5.0 mg /kg.

Human study of response of MDMA users to DMT

Strassman (personal communication,1992) recently completed an FDA-approved human study in which the physiological and psychological responses of eleven subjects to various i.v. doses of DMT were studied. Physiological measures included ss-endorphin, ACTH, prolactin, corticol, growth hormone, baseline and maximum rise temperature and pupil diameter responses. Psychological measures included the Profile of Mood States (POMS) and the Hallucinogenic Rating Scale (HRS) developed specifically for this experiment. Subjects were divided into two groups, "MDMA Positive" and "MDMA Negative". The "MDMA Positive" group included six subjects who had taken MDMA five or more times. Not including one of those had taken MDMA 75-100 times, the average exposure for the "MDMA Positive" group was about 10x. The "MDMA Negative" group included the remaining five subjects had taken MDMA never or only once, with an average exposure of less than 1x. Analysis of the physiological measurements revealed no significant differences between the groups in ss-endorphin, ACTH, prolactin, corticol, growth hormone, baseline and maximum rise temperature responses, across all four doses of DMT and placebo. The standard analytic tool was ANOVA with repeated measures. The only significant difference between the "MDMA Positive" and "MDMA Negative" groups was that the maximum change in pupil diameter relative to baseline was less in the positives than the negatives, across all doses of drug/placebo. Dr. Strassman noted "If one believes that 5-HT2 receptors in the eye mediate the effect of DMT on pupil size, then this is oppostive what one would expect; i.e. if "denervation hypersensitivity" occurred, one would expect more robust pupil dilation. The pupil data was the least complete (people were reluctant to open their eyes during the period of DMT intoxication), thus ANOVA without repeated measurements was used as a less than ideal tool." Analysis of the psychological data showed no significant differences in the POMS given both before and after the injections of DMT. Regarding the HRS, no differences were noted in responses for any of the 6 factors between the "MDMA Positive" and "MDMA Negative" groups across all doses of DMT/placebo; neither were there any interaction effects.

Risk assessment for neurotoxicity

Gaylor and Slikker (1990) discuss various approaches to the assessment of neurotoxicity using MDMA as an illustrative example. Conventionally, allowable dose (exposure) levels are established by dividing a no observed adverse effect level (NOAEL) by uncertainty factors that account for interspecies and intraspecies differences for experimental results extrapolated from animals to humans. The procedure makes no use of estimates of risk as a function of dose nor does it acknowledge any risk at the NOAEL. The approach presented in this paper is as follows: in the absence of a definition of an adverse effect, an abnormal level for a measure of toxicity can be established which occurs only in a small fraction of a population which is not exposed to the substance under investigation. Risk is defined as the proportion of a population whose levels of a measure of toxicity equal or exceeds the abnormal level of the measure under study. This procedure is more versatile than the NOAEL/uncertainty factor approach since it provides estimates of risk as a function of dose of a potential neurotoxic substance.

Based on the known data on MDMA's neurotoxicity in animal models, one can also formulate a risk assessment based on comparable doses in humans and animals. Previous investigators have demonstrated differential species sensitivity to the neurotoxic effects of MDMA (cf. McKenna & Peroutka, 1990). For instance rats given up to 4 x 10 mg/kg doses of MDMA do not show significant evidence of neurotoxicity when measured by ablation of the serotonin uptake site; when reduction in brain 5-HT levels are the parameter used, only two 10 mg/kg doses are sufficient to cause significant neurotoxicity. The risk of neurotoxicity is also a function of the number of doses as well as the size of the dose. Rats show evidence of neurotoxicity after 8 x 5 mg/kg doses administered consecutively over 4 days; mice are relatively insensitive to MDMA, and do not show evidence of neurotoxicity after 8 x 30 mg/kg. Primates are apparently more sensitive to MDMA than rodents. For example, Ricaurte and co-workers (1988b) measured 60% lower levels of 5-HIAA in CSF of squirrel monkeys after 8 x 5 mg/kg; brain levels of 5-HT in these animals were 94% lower than controls; rats administered an equivalent dose displayed only a 40% reduction in brain 5-HT. These investigators also reported that 8 x 5 mg/kg doses administered p.o. were approximately 1/3 as effective in producing neurotoxicity as equivalent doses administered subcutaneously. In subsequent studies (Ricaurte, personal communication) these investigators found in squirrel monkeys that the oral administration of 2.5 mg/kg every two weeks for four months (8x) produced no evidence of reduced brain 5-HT or 5-HIAA levels in any of the eight brain regions studied. Given that there are rather marked differences in sensitivity even among closely related species (cf. rats vs mice), the relevance of these figures for human users of MDMA is difficult to assess. A typical psychotherapeutic or "recreational" dose of MDMA is on the order of 100 - 160 mg p.o.; for a 75 kg adult this amounts to 1.3 - 2.1 mg/kg. The latter figure is approximately 1/2 of the lowest doses which manifest any indication of neurotoxicity in primates. The proposed dose regimen in the IND protocol submitted by Grob, et al (1992) is that subjects will receive oral doses of MDMA between 1.25 and 2.0 mg/kg; supplemental doses may be administered, but the combined oral dose will not exceed 2.3 mg/kg, a combined dose below the lower bound primate no-effect level of 2.5 mg/kg. Subjects will receive four treatment sessions, separated by intervals of two to four weeks. Based on the results of the most relevant animal model, i.e., repeated oral administration of low doses in the primate, it is unlikely that the dose regimen proposed in the IND protocol would cause significant long-term serotonergic neurotoxicity. This assessment is, however, only a reasonable extrapolation based on the available animal data.

The only other data available to provide a relevant benchmark are the studies of human users of MDMA reported by Peroutka et al (1987), Ricaurte et al (1990), Price et al (1989) and Strassman (personal communication,1992). Peroutka found no difference in CSF 5-HIAA levels between a small group of MDMA users and literature controls. In Ricaurte's study, 5-HIAA, HVA, and MHPG was measured in CSF of 33 subjects previously exposed to MDMA, and compared with levels of these metabolites in a control sample of patients undergoing myelography for low back pain. In the MDMA using population, significantly lower (26%, p < 0.05) levels of 5-HIAA but not the other metabolites were found. Price found a non-significantly lower prolactin response to l-tryptophan in nine MDMA subjects (preselected for their low 5-HIAA levels in Ricaurte's study) than in controls. Strassman found no significant differences between "MDMA Positive" and "MDMA Negative" subjects in ss-endorphin, ACTH, prolactin, corticol, growth hormone, baseline and maximium rise temperature responses to the i.v. administration of DMT.

Though the studies of Peroutka (1987) and Strassman (personal communication,1992) reveal no evidence of MDMA neurotoxicity, the studies of Ricaurte et al (1990) and Price et al (1989) may be indicative of some degree of serotonergic neurotoxicity in the MDMA population. However, this interpretation needs to be qualified in several respects as the patient population in those studies differs in several important respects from that of the proposed IND protocol. Several factors should be considered. For one thing, virtually all of the patients in the studies of Ricaurte et al. (1990) and Price et al (1989) were polydrug users, having a history of exposure to marijuana, hallucinogens, and other ring substituted amphetamines and stimulants such as cocaine and possibly methamphetamine. The effect of polydrug exposure on CSF serotonin levels has not been assessed but may be significant. Another factor is the wide range of doses the subjects received from self-experiments. While the average dose was 0.98 to 2.6 mg/kg, the daily dose ranged from 150 to 700 mg; in addition, while the mean frequency of use was 3.4 x 1.8 weeks between doses, a significant number (13 of 33 subjects) reported brief periods (5 to 7 days) of daily use. Hence, both the range of administered doses and the frequency differs markedly from the projected dose regime for the IND. Even given the wide range of acute doses and frequency of exposure, Ricaurte et al (1990) found no correlation between these parameters and CSF 5-HIAA levels and the difference in prolactin response found by Price et al (1989) was not significant and the subjects were not representative of the MDMA users in Ricaurte's study. Serious caution should be exercised in extrapolating these data to the proposed study. The frequency and acute exposure to MDMA in the proposed study is quite moderate by comparison and lies below the no-effect level in primates.

The risk of neurotoxicity experienced by the end-stage cancer patients is important only in so far as it is related to any resultant functional consequences. At the current time, no significant functional consequences have been reported in primates with substantial serotonergic deficiencies. In addition, there are hundreds of thousands of people who have been exposed to amounts of MDMA or fenfluramine greatly in excess of the doses that will be administered in this experiment and they seemingly do not suffer from minor or serious functional consequences related to possible serotonergic neurotoxicity.

Because of the uncertainty of MDMA neurotoxicity, the end-stage cancer patients will receive lumbar punctures (to obtain CSF for 5-HIAA determination), tryptophan challenge tests (to measure prolactin secretion), and neuropsychological tests given two weeks prior to the initial experimental session and two weeks following the final session. The amounts of MDMA used in this experiment should not place the subjects at risk of serious functional consequences while the inclusion of physiological and neuropsychological measures for neurotoxicity should be sufficient to detect any substantial indications of serotonergic deficiency if such effects do occur.

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