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Consider a contribution! It is from the excellent book Ecstasy: The Complete Guide edited by Julie Holland which contains a number of very interesting articles on the topic of MDMA, its complications, and its potential as a psychiatric medication. Erowid had a very small part in helping Matt with his literature review and its dense pages are a must-read for anyone truly dedicated to understanding the scientific complexities of this challenging psychoactive. Considering how many people use MDMA, serious acute adverse events seem rare. MDMA appears generally similar to psychostimulants such as methamphetamine with respect to the risks of acute toxicity. With trained personnel, properly screened volunteers, and established protocols for monitoring and treating adverse events, these acute risks appear modest and do not present a strong argument against carefully conducted clinical research with MDMA. On the other hand, the risks associated with possible long-term brain damage are more difficult to assess. Numerous studies in animals have shown that MDMA can produce long-lasting decreases in brain functions involving the neurotransmitter serotonin. It is unclear what these changes mean. Lasting behavioral changes in MDMA-exposed animals have been seldom detected and are fairly subtle when they are found. Though limited in scope, studies of ecstasy users present a strong probability that similar serotonergic changes occur in many humans. Studies comparing ecstasy users and nonusers support an association between modestly-lowered intelligence testing, or cognitive performance tests, and ecstasy use, but clinically significant performance decreases have not been detected. In other words, there is no increased incidence of clinical complaints or findings. The modest findings in behavioral studies of MDMA neurotoxicity have led some to dismiss concerns about MDMA neurotoxicity as politically-motivated alarmism. It is commonly pointed out that though fenfluramine and methamphetamine produce similar changes, their status as prescription medications was not affected by this finding. In 15 years of research on MDMA neurotoxicity, no published studies have investigated whether MDMA exposure can cause significant toxicity that only becomes apparent with aging. This fact must be taken into account when considering the risks and benefits of possible clinical studies. Perhaps the single most worrisome issue surrounding MDMA neurotoxicity is that there may be significant toxicity associated with serotonergic changes that is currently undetected. Although millions of people have taken millions of doses of ecstasy, controlled studies of users have not been large enough to detect any but the most common chronic adverse effects. Possible adverse effects such as an increased incidence of affective disorders, like depression, may have gone unnoticed. Because so little is known about possible long-term clinical implications of MDMA neurotoxicity, we believe it is important to minimize the risks of neurotoxicity in research volunteers. It is hoped that the information presented here may contribute to assessments of, and perhaps reductions in, the risks associated with MDMA use. This chapter will discuss 1 the nature and meaning of MDMA-induced serotonergic changes; 2 the possible mechanisms of these changes; 3 factors influencing the severity of these changes such as dose, route of administration, species and animal strain, and environment ; and 4 the time course of these changes and recovery. The latter part of this chapter will focus on the implications of long-term serotonergic changes by discussing 5 the behavioral and functional effects of MDMA-induced serotonergic changes in animals; 6 studies comparing ecstasy users to nonusers including personality, cognitive, and functional comparisons ; 7 available data from clinical studies in which MDMA was administered; and 8 potential strategies for reducing risk to human volunteers. Limitations of space unfortunately prevent a full discussion of every important paper and aspect of this complex topic. In this chapter, drug doses and dosing patterns used in research that produce these long-term serotonergic changes will be referred to as 'neurotoxic regimens. In this chapter, any changes noted at 7 or more days after drug administration will be considered 'long-term. The term 'neurotoxicity' is more difficult to define. Though no universal definition exists, most definitions are broad enough to encompass both short-term alcohol-induced headaches and the permanent nerve cell loss caused by the drug MPTP. A more useful approach to the question of whether MDMA is neurotoxic is to describe the nature and mechanisms of the long-term changes it can cause. In this way, it is evident that some neurotoxic MDMA regimens produce both changes in the serotonergic system and acute damage to the brain by free radicals, and thereby cause a loss of nerve cell axons. This suggests that MDMA neurotoxicity is a type of drug-induced damage, even though the consequences of this damage are unknown. MDMA does produce long-lasting changes to the serotonergic system at some doses. These long-term changes include decreases in brain concentrations of the neurotransmitter serotonin 5-HT and its metabolite 5-hydroxyindoleacetic acid 5-HIAA. Levels of tryptophan hydroxylase TPH , the enzyme that begins the synthesis of 5-HT within the serotonergic nerve cell are decreased. There are also decreases in the density of the serotonin reuptake transporter SERT , the protein on the membrane of serotonergic neurons that recycles released 5-HT by pulling it back into the cell. Most studies suggest that MDMA primarily causes long-term changes in serotonergic axons that have their cell bodies in an area of the brainstem called the dorsal raphe nucleus. Long-lasting decreases in these serotonergic markers suggest that either a some type of 'down regulation' has occurred, meaning the nerve cell is making and maintaining less of the markers, or b that serotonergic axons are permanently lost. The question of whether MDMA is truly neurotoxic stems from this issue. Down regulation suggests an active adaptation to drug effects, while axonal loss suggests true damage may have occurred. Determining which actually happens can be difficult. SERT density may change in response to drugs, but this has been difficult to consistently demonstrate Le Poul, ; Ramamoorthy, Similarly, 5-HT levels can be influenced by diet and other factors. By attaching a marker to the 5-HT molecule by a process called immunocytochemistry, 5-HT is stained, allowing serotonergic axons and terminals to be seen under a microscope. The initial swelling suggests some type of axonal damage, while the later decrease in stained axons suggests a loss of axons. However, some have argued that immunocytochemistry cannot determine whether or not measured differences in 5-HT are accompanied by changes in the axons themselves. Because of this limitation, it is necessary to confirm the apparent loss of axons using techniques that do not rely on serotonergic markers. Transport of materials within axons is crucial for maintaining cell structure and function. Lasting reductions in axonal transport suggest a drastic impairment of axonal functioning and, more likely, loss of axons. One can assess axonal transport by measuring the movement of compounds between brain regions that serotonergic axons should connect. For example, if injected into the cortex the outer layer of the brain the fluorescent dye Fluoro-Gold should be transported along serotonergic axons into cell bodies in the brainstem. Their results suggest that a loss of axons occurs after at least some neurotoxic regimens of MDMA and related drugs. Another method of assessing loss of nerve terminals involves measuring the vesicular monoamine transporter type II VMAT2. In other words, decreased VMAT2 would suggest that nerve terminals and axons have been lost. Therefore, at least some neurotoxic regimens of MDMA are associated with structural changes to cells. The above data consistently indicate that MDMA can cause serotonergic axons to degenerate and that this explains at least some of the MDMA-induced decrease in serotonergic markers. Further evidence of axonal degeneration comes from studies in which recovery from MDMA neurotoxicity is associated with apparent sprouting and regrowth of axons discussed in more detail below. Why, then, has MDMA neurotoxicity been controversial? One reason is that attempts to measure MDMA-induced cell damage itself yield ambiguous results. In general, neural cell damage can be detected by two techniques, using silver staining and measuring the expression of glilal fibrillary acidic protein GFAP. Furthermore, the MDMA-induced cell damage detected by silver staining appears to occur in nonserotonergic cells Commins, ; Jensen, as well as in what are likely serotonergic axons Scallet, These inconsistencies are difficult to interpret. Some believe they are evidence that MDMA-induced serotonergic changes result from down regulation of the serotonergic system rather than damage e. Others have argued that the techniques for measuring cell damage are simply insensitive to selective serotonergic damage Axt, ; Bendotti, ; Wilson, Because studies of axonal transport and VMAT2 changes have provided strong evidence of MDMA-induced axonal damage, it appears that serotonergic down regulation can no longer fully explain the long-term effects of MDMA. Structural changes to serotonergic axons must also be explained. Although we are not aware that this hypothesis has been advanced, one could argue that loss of axons represents a non-neurotoxic form of neuroplasticity, or benign change in the nerve cell in response to drugs. Non-neurotoxic though not necessarily beneficial morphological changes can occur in the CNS as the result of alterations in serotonin levels reviewed in Azmitia It appears more likely, however, that these changes are, in fact, the result of damage, specifically damage involving oxidative stress. The Role of Oxidative Stress in MDMA neurotoxicity Free radicals are highly reactive chemicals that contain one or more unpaired electrons and exist separately. Free radicals can damage neural molecules through reactions called reduction and oxidation, and thereby alter the ability of these molecules to carry out their normal cellular function. Neurotoxic regimens of MDMA increase oxidative stress in the brain. In this chapter, the term 'oxidative stress' will be used to refer to both the increase in reactive chemicals, including free radicals, and the burden they place on cellular functioning. MDMA-induced oxidative stress has been shown in two ways. First, researchers have examined the brains of MDMA-treated animals for thiobarbituric acid reacting substances Colado,a; Jayanthi, ; Sprague, b. Increases in these substances suggest that neural lipids, or fat molecules in the brain cells, have been oxidized. Second, researchers have perfused the brains of live animals with either salicylate or d-phenylalanine. These substances react with hydroxyl radicals to form 2,3-dihydroxybenzoic acid and d-tyrosine, respectively. By measuring formation of these compounds, researchers have demonstrated that neurotoxic MDMA regimens increase the amount of extracellular hydroxyl radicals of the striatum Shankaran, a; b and hippocampus Colado, b; b , two areas of the brain involved in movement, and memory, respectively. There is strong evidence that oxidative stress is involved in the mechanisms of MDMA neurotoxicity. The free radical scavenger N-tert-butyl-alpha-phenylnitrone decreases both MDMA-induced hydroxyl formation and MDMA neurotoxicity in rats; this latter effect, however, may be partially due to an attenuation of MDMA-induced high body temperature, or hyperthermia Che, ; Colado, ; ; Yeh At the same time, these genetically modified mice are protected from the acute inactivation of antioxidant enzymes and free radical changes seen in normal mice after a neurotoxic MDMA regimen Jayanthi, In summary, MDMA neurotoxicity involves an initial period of oxidative damage, where an increase in free radicals damages neural lipids. This damage seems to be part of the sequence of events producing serotonergic neurotoxicity since treatments that decrease MDMA-induced oxidative stress also decrease the long-term serotonergic changes Aguirre, While MDMA can cause loss of axons, some serotonergic down regulation cannot be ruled out. Research on methamphetamine-induced dopaminergic neurotoxicity has led some to conclude that long-term dopaminergic changes can occur without significant axonal loss Harvey, ; Wilson, Whether this is also the case with MDMA is unknown. For now, it seems reasonable to consider long-term serotonergic alterations after MDMA exposure as indicating that some degree of damage has occurred, while remembering that one is also measuring the response of the serotonergic system to acute drug effects and loss of axons. Proposed Sources of Oxidative Stress Several possible sources of neurotoxic oxidative stress have been proposed. Second, both MDMA and dopamine can be metabolized to highly reactive quinone-like molecules. Quinones are molecules which are often very reactive, can form free radicals, and are thus potentially damaging to neural molecules. There is not yet conclusive evidence to implicate any of these possible causes and some combination of mechanisms is possible. The possible roles of energy exhaustion or impairment, MDMA metabolites, and dopamine metabolites are discussed below. It has also been proposed that 5-HT metabolites, increased intracellular calcium, nitric oxide, or glutamate may contribute to MDMA neurotoxicity. However, current evidence provides little support for these theories and their discussion will be omitted in the interest of brevity. Cellular energy exhaustion or impairment may cause MDMA neurotoxicity. Normal activity of the neuron cause a certain degree of oxidative stress. A sustained increase in neuronal activity would therefore be expected to increase oxidative stress. More importantly, increased neuronal activity is accompanied by increased energy consumption that could eventually lead to a depletion of neuronal energy sources. This can impair the energy-requiring mechanisms that maintain and repair neurons. Furthermore, the most important source of cellular energy, mitochondria, can be impaired by oxidative stress Crompton, Mitochondria produce adenosine triphosphate ATP , the source of energy for most cellular processes. Insufficient ATP will lead to cell damage or death. Whether energy exhaustion or impairment actually plays a role in MDMA neurotoxicity is not yet clear. MDMA does increase activity of the enzyme glycogen phosphorylase Poblete and Azmitia , which suggests that MDMA could decrease glial stores of glycogen, an important source of energy in the brain. MDMA-induced alterations in mitochondria functioning have been reported Burrows, , but it is not yet clear if these alterations are sufficient to impair mitochondria and damage cells. Since later times were not examined, it remains possible that ATP is decreased at later time points. However, it is difficult to investigate this possible role. Hypothetically, a given metabolite may only be toxic in the presence of MDMA, when the metabolite has high concentrations in the brain for several hours, or when certain acute effects of MDMA have already occurred. In such situations, administering the toxic metabolite on its own would not necessarily lead to toxicity. Thus, it is hard to interpret the many studies in which an MDMA metabolite was administered and no evidence of neurotoxicity was found Elayan, ; Johnson, ; McCann, b; Steele, ; Zhao, The MDMA metabolite, alpha-methyl dopamine, may contribute to neurotoxicity as its metabolites that can deplete 5-HT miller et al The oxidation of dopamine can form hydrogen peroxide which, in turn, may produce hydroxyl radicals. A quinone-like dopamine metabolite may also be formed with potential to generate further free radicals Cadet and Brannock ; Graham, Among many other potential toxic effects on cells, dopamine oxidation products have been shown to impair mitochondrial functioning Berman and Hastings There is currently little direct evidence to support a role for dopamine metabolites in MDMA neurotoxicity. Some dopaminergic drugs alter MDMA neurotoxicity, but it is not clear that this is due to increasing or decreasing dopamine release. Many dopaminergic drugs are now thought to affect MDMA neurotoxicity through nonspecific mechanisms such as altering body temperature Colado, a; Malberg, or scavenging free radicals Sprague and Nichols a; b; Sprague, Most MDMA neurotoxicity studies have used multiple dose regimens. These studies show that 'binge' use of MDMA carries greater risk of neurotoxicity than single doses. Multiple dose neurotoxic regimens appear able to produce more profound and possibly more lasting serotonergic changes than single MDMA administration Battaglia, The results of multiple dose studies are difficult to compare across species since the same interval between doses can have very different effects in two species with different clearance rates of MDMA. The effect of the route of MDMA administration in altering long-term serotonergic changes has been investigated. In the rat, subcutaneous injection and oral administration of MDMA produce comparable 5-HT depletions in the hippocampus Finnegan, Studies with nonhuman primates have yielded less consistent results. In the squirrel monkey, Ricaurte a found that repeated oral administration of MDMA resulted in only one-half to two-thirds as much 5-HT depletion as the equivalent subcutaneous dose. In the rhesus monkey, in contrast, Kleven reported that repeated oral administration of MDMA produced twice the decrease in hippocampal SERT activity as was produced by repeated subcutaneous injection. These apparent differences between nonhuman primate species increase the difficulty of assessing the risk of oral MDMA administration in humans. Different species differ in sensitivity to MDMA neurotoxicity. These apparent strain differences may also be influenced by differences in ambient temperature and animal housing Dafters, ; Gordon, In comparison to rats, nonhuman primates seem to be more sensitive to MDMA neurotoxicity, suffering more damage at lower doses Ali, ; Fischer, ; Insel, ; Ricaurte, ; Ricaurte, a; but see also De Souza, , for slightly different results. Many MDMA neurotoxicity studies have used squirrel monkeys as subjects. The threshold dose for producing long-term 5-HT depletions in squirrel monkeys is somewhere between 2. Two weeks after a single 5. In contrast, no long-term serotonergic changes occurred after 2. Determining the threshold dose for 5-HT depletions in this species is difficult since all published studies using rhesus monkeys have employed multiple dose neurotoxic regimens. In one study, 1. Similarly repeated doses of 2. In another experiment, Insel found that 2. In a study that raises interesting questions about possible tolerance to MDMA neurotoxicity, Frederick investigated the long-term effects of escalating doses of MDMA. Intramuscular MDMA 0. One month after the final dose-response determination and 21 months after the initial escalating dose regimen, animals were sacrificed. Few significant serotonergic effects were found. Thus, data on rhesus monkeys are complex and perhaps all that can be said with certainty is that the threshold dose for long-term 5-HT depletions appears to be above 1. Research on MDMA neurotoxicity has sometimes been criticized for the repeated high dose regimens that are commonly used. It is true that many of the neurotoxic regimens are not designed to be clinically relevant but were intended to maximize the serotonergic neurotoxicity of MDMA in order to better understand its mechanisms and consequences. However, comparing dose on the basis on body weight can be misleading. In general, smaller species excrete drugs more quickly and form metabolites in greater amounts than larger species. This is due to many factors including the proportionally larger livers and kidneys and faster blood circulation times in smaller mammals Lin ; Mordenti, As a result of such factors, the time it takes to lower the plasma levels of MDMA by half is about 1. This suggests that small species may require higher doses to achieve drug exposures comparable to those seen in larger species. These considerations at least partially justify the apparently high doses commonly used in rodent toxicity studies. Unfortunately, higher doses tend to alter the character of the drug exposure. While they lengthen the time smaller animals are exposed to the drug, they also tend the produce higher peak blood concentrations of drug and greater acute effects than occur in larger species at lower doses. A number of techniques have been developed for estimating equivalent drug doses in different species Ings ; Lin ; Mahmood ; Mordenti, One of the most commonly used techniques, allometric interspecies scaling, involves administering a drug to different species and measuring resulting blood concentrations of drug. These measurements are then used to determine the relationships between species weight, drug exposure, and dose. Drug exposure in humans can then be estimated from these relationships. In these estimates, equivalent drug exposures are assumed to produce equivalent drug effects, including neurotoxicity. Recently, Ricaurte estimated that as little as 1. Estimates of this sort are useful for emphasizing that the MDMA dose required to produce neurotoxicity in humans may be within the range of commonly administered doses, despite the seemingly higher doses used in rodent studies. However, such estimates require making assumptions about the mechanisms of neurotoxicity. For example, it is necessary to assume that the different species experience comparable drug effects when blood concentrations of drug are the same. This may not be true of neurotoxicity. Several other possible reasons for species differences in MDMA neurotoxicity have already been given. In addition, species may differ in the brain concentration of drug produced by a given blood concentration. It is not known if this is the case with MDMA, although it does seem to be true for fenfluramine Campbell Furthermore, if MDMA neurotoxicity is caused by a toxic metabolite, as some have suggested, then the more extensive metabolism of MDMA expected in smaller animals will lead to increased neurotoxicity. Formation of specific drug metabolites in different species is difficult to predict and few data are available on MDMA. Research on species differences in fenfluramine metabolism have led some to conclude that no nonhuman species provides a good model of possible human fenfluramine neurotoxicity Caccia, ; Marchant, Because current data suggest that both MDMA and metabolite exposure may mediate neurotoxicity, more data are needed from more species before interspecies dose conversions can be made with any confidence. As a result, small increases in dose can lead to large increases in drug exposure. When dose was increased from mg to mg, drug exposure almost doubled in human volunteers, as measured by area under the curve of MDMA plasma concentration verses time de la Torre, However, formation of some metabolites remained approximately constant. These complex dose-dependent pharmacokinetics in humans further increase the difficulty of estimating dose conversions between species. Nonetheless, these human studies with MDMA do suggest that doses above mg may be associated with unexpectedly increased drug exposure and therefore risks of toxicity. Extent of Neurotoxicity in Rats is Influenced by Environment, Especially Ambient Temperature new: Influence of Environment, especially Ambient Temperature, on Neurotoxicity in Rats and Mice Several studies have explored the relationships between environmental temperature, animal core temperature, and neurotoxicity. In rats, MDMA can dose-dependently impair temperature regulation Broening, ; Colado, ; Dafters ; ; Gordon, , perhaps through alterations in the functioning of the hypothalamus and thermoregulatory behaviors. Resulting changes in animal temperature can alter neurotoxicity; hyperthermia increases and hypothermia decreases serotonergic depletions. Thus, the degree of hyperthermia has been found to correlate with both long-term 5-HT depletions in adult rats Broening, ; Colado, ; ; Malberg, and long-term dopamine depletions in mice Miller, In addition to the ambient temperature, the degree of hyperthermia is influenced by the thermal conductivity of animal housing and hydration status Dafters, ; Gordon, The mechanisms by which temperature affects MDMA neurotoxicity are unclear. MDMA-induced neurotransmitter release may be temperature sensitive Sabol, , although studies examining the temperature dependence of methamphetamine-induced dopamine release have reported conflicting findings Bowyer, ; LaVoie, It may also be that increased temperature nonspecifically increases the rate of chemical reactions and contributes to oxidative stress, as this does occur in the neurotoxicity which is seen with decreased blood supply Globus, Prolonged hyperthermia has been shown to decrease the number or function of mitochondria in some brain regions, suggesting decreased energy stores Burrows, However, hyperthermia on its own does not selectively damage the serotonergic system. Despite the apparent relationship between hyperthermia and MDMA neurotoxicity, it would be a simplification to think that avoiding hyperthermia ensures that humans who have taken MDMA will not undergo long-term serotonergic changes. The link between temperature and neurotoxicity has been primarily investigated in rodents but has not been investigated in primates. Hypothermia does protect against methamphetamine-induced dopaminergic neurotoxicity in rodents Ali et al. However, the influence of temperature on neurotoxicity remains to be conclusively demonstrated in primates. Time Course of Changes and Extent of Recovery High doses of MDMA have a two-phase effect on serotonergic functioning, first causing acute decreases, then partial recovery, then chronic decreases. Approximately 6 hours later, levels begin to return to normal, but this recovery is not sustained. About 24 hours after dosing, 5-HT levels begin a second, sustained decrease and remain significantly lower than baseline 2 weeks later. This sustained decrease is thought to be associated with axonal damage. The intracellular enzyme TPH follows a similar time course, with decreased activity occurring within 15 minutes of drug administration. The recovery of TPH activity appears to involve regeneration of enzyme that was inactivated by oxidation rather than synthesis of new enzyme. SERT functioning is also altered. Schmidt reported that 2. Of note, Kish did find striatal 5-HT depletions in a chronic ecstasy user who died shortly after ecstasy ingestion. This suggests that at least some of the doses administered by humans are sufficient to produce 5-HT depletions. The above description focuses on serotonergic changes because these are used to measure toxicity. Many other acute neurochemical changes occur after MDMA exposure. For example, dopamine is released Stone, and dopamine transporter reuptake activity is decreased within 1 hr of high dose MDMA Fleckenstein, ; Metzger, MDMA can also acutely increase dopamine synthesis Nash, As noted previously, mice are selectively vulnerable to MDMA-induced dopaminergic neurotoxicity Logan, ; Miller,; Stone, a. In some studies, long-term alterations in dopaminergic functioning have been seen in other species e. More interestingly, fluoxetine remains almost fully protective if given 3 or 4 hours after MDMA. By 4 hours, most of the MDMA-induced release of 5-HT and DA has already occurred Gough, ; Hiramatsu, and increases in extracellular free radicals Colado, b; Shankaran, a and lipid peroxidation the alteration of fat molecules by free radicals Colado, a can be measured. Nevertheless, the administration of fluoxetine at this point decreases subsequent extracellular oxidative stress Shankaran, a and long-term 5-HT depletions Schmidt, ; Shankaran, a. Fluoxetine will still be partially protective if given 6 hours after MDMA but has no protective effect 12 hours after administration Schmidt, This shows that neurotoxic MDMA regimens initiate a series of events that become increasingly damaging between 3 and 12 hours after drug administration in rats. Slow recovery of serotonergic functioning can be seen following a neurotoxic dose of MDMA. The extent of recovery is different in different species. In rats, there is extensive recovery of indicators of serotonergic functioning 1 year after drug exposure Battaglia, ; Lew, ; Sabol, ; Scanzello, , although there is significant variation in recovery between individual animals Fischer, In primates, some recovery of serotonergic function occurs but is less extensive than in the rat. Altered serotonergic axon density was still detectable 7 years after MDMA exposure in one study of squirrel monkeys Hatzidimitriou, Therefore, despite some recovery, MDMA-induced serotonergic changes are likely permanent in this primate species. This apparent species difference may be partially related to the more severe initial serotonergic damage usually seen in primates compared to rats, but also likely indicates a species difference in regrowth of serotonergic axons. These studies are summarized in Table I and are, perhaps, impressive for the limited nature of their behavioral findings. It is clear that neurotoxic MDMA exposure can both alter neurochemical functioning and the response of animals to subsequent drug exposures. However, so far only two published studies suggest that MDMA-exposed animals have behavioral alterations or functional impairments at seven or more days after last MDMA exposure. Dafters demonstrated that MDMA-exposed animals have a lasting thermoregulatory impairment. Fourteen weeks after exposure to a neurotoxic MDMA or placebo regimen, rats were placed in a warm environment. MDMA-exposed rats had significantly larger increases in core temperature than control rats. It has been known for many years that individuals who experience heat stroke have increased susceptibility to subsequent episodes for some time Shapiro, and it appears possible that the same phenomenon is being detected here. Another study has suggested that neurotoxic MDMA exposure may cause cognitive impairment in rats. Marston detected drug-free alterations in performance of a delayed memory task. In contrast, Ricaurte and Robinson were unable to demonstrate any long-term effect of MDMA neurotoxicity on spatial navigation memory tasks in rats. The cautious interpretation of behavioral animal studies of MDMA neurotoxicity is that we should not expect gross behavioral effects of MDMA neurotoxicity in humans, even when extensive serotonergic changes have occurred. It should also be remembered that we poorly understand the role of 5-HT in the brain reviewed in Lucki, and that this makes it more difficult to detect 5-HT-related changes. Findings from studies of ecstasy users may allow more focused and hypothesis-driven studies of animals. Escalating doses of 0. Right shift in MDMA dose-response curve for time estimation, short-term memory, color and position discrimination, and motivation tasks at post 21 mo. None, although researchers note that 2 of 8 MDMA-exposed rats failed to acquire lever pressing with 20 sec reinforcement delays during the 8 hr session. Significant pretreatment x treatment x crossing times interaction, suggesting altered S-MDMA -induced behavioral activation at post 21 days. Drug-free locomotion at 21 days; RUinduced behavioral activation at 21 days. Increased conditioned place preference response to cocaine in MDMA group at 2 post wks. Increased motor stimulant effects of 5. Loss of rate-dependence of response of nigrostriatal cells to either quipazine or apomorphine at post 1 wk. Basal activity of nigrostriatal DA neurons; Quipazine-induced inhibition of nigrostriatal DA cell firing for all cells at post 1 wk. Spontaneous behavior, body temperature, and skilled paw reach 'staircase task'. Increased cocaine-induced dopamine release in nucleus accumbens in MDMA group at 2 wks after neurotoxic regimen. Increased morphine-induced antinociception assessed by tail flick test at post 2 wks. Decreased inhibitory effects of DA and SKF on glutamate-evoked firing in nucleus accumbens cells at post days. Inhibitory effects of GABA on glutamate-evoked firing in nucleus accumbens cells at post days. Increased d,l-Fenfluramine-stimulated prolactin release at post 2 and 4 months. Increased d,l-Fenfluramine-stimulated prolactin release at post 4 and 8 months. Saline-stimulated ACTH and prolactin release at post 2 weeks; d,l-Fenfluramine-stimulated prolactin release at post 12 months. Performance in a spatial memory task using a T-maze and scopolamine-induced changes in performance on this task. Increased time to find hidden platfrom in first trial of spatial navigation task at post 2 days. Spatial navigation task after 1st trial, skilled reaching task, place navigation learning-set task, foraging task, with or without atropine pretreatment. Decreased d-fenfluramine-stimulated 5-HT release in frontal cortex at post 2 wks. Cerebral glucose utilization in neocortex, raphe nuclei, and some hippocampal areas at post 14 days. Auditory startle, emergence from darkened chamber, complex maze navigation, response to hot plate, FI 90 operant behavioral task at post 2 to 4 weeks.. Decreased in McCann et al. Increased in Reneman et al. Decreased neuroendocrine response to serotonergic drugs, in 3 of 5 studies. Increased at 2 months, normal at 12 months in rats Poland et al. Decreased in Gerra et al. Altered in Reneman et al. Increased in some hipppocampal areas 2 wks Sharkey et al. Archived by Erowid with permission of Author.

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