New study! Released Mar.30th, Ecstasy "brain-toxicity" no longer detectable! 02-04-2004 17:54 (#1803307) Hot on the heels of the wonderful ABC Special, "Ecstasy Rising", a new study gets published! Please Read! Behavioral and Neurochemical Consequences of Long-Term Intravenous Self-Administration of MDMA and Its Enantiomers by Rhesus Monkeys. Neuropsychopharmacology 2004 Feb 16,Published Online first ( ) [allinfo] Fantegrossi WE, Woolverton WL, Kilbourn M, Sherman P, Yuan J, Hatzidimitriou G, Ricaurte GA, Woods JH, Winger G Review author Ilsa Jerome Review date Tue Mar 30 16:14:10 2004 Last updated Tue Mar 30 18:15:44 2004 Review Study Questions Toxic Effects of MDMA in Monkeys New findings suggest that when use patterns are more similar to humans, brain toxicity no longer detectable It appears that MDMA may be far less toxic than previous research may have led people to believe. Rhesus monkeys that regularly pressed levers to receive i.v. injections of MDMA for eighteen months had little to no signs of harm to brain serotonin or dopamine neurons. However, they did work less hard for MDMA over the course of the study, even while they continued to work for cocaine injections. The researchers measured harm to the brain in several ways, including measuring levels of a protein associated with neurons and measuring brain levels of serotonin and dopamine, and none of these methods detected signs of obvious neurotoxicity. These findings also suggest that apparent tolerance to the effects of MDMA (seen here as reduced interest in taking more of it) does not occur as a result of damage to serotonin or dopamine neurons. The seven monkeys in this study were all experienced with the basics of drug-self administration procedures, wherein pressing a lever a certain number of times is rewarded with a drug injection. Four of the monkeys had a chance to get MDMA injections, and three were never given the opportunity to receive MDMA. Monkeys had the chance to self-administer drugs during two hour-long sessions each day, one in the morning and one in the afternoon, and the sessions took place in a comfortably warm room (22 degrees C, or about 72 degrees F). In this study, the monkeys first learned to self-administer cocaine. Then, every third to fourth session, they would receive racemic MDMA, or one of its enantiomers (forms), R-(-)-MDMA or S-(+)-MDMA) instead of cocaine, in doses ranging from 0.003 to 3 mg/kg per injection. Every now and then, the monkeys were given saline instead of any drug, to make sure they were pressing levers for the drugs, and not for some other reason. On average, the monkeys self-administered between 2 and 4 mg/kg MDMA during a session, though in some cases a monkey might self-administer up to 15 mg/kg MDMA, or one of its forms. As time passed, monkeys in this study did not work as hard to get MDMA, even though they did not stop working to receive cocaine when it was available. By the end of the study, they self-administered less MDMA than at the start of the study. This suggests that like some Ecstasy users, the monkeys may have been growing tolerant to the desirable subjective effects of MDMA (the effects that kept them pressing the lever for more). Monkeys grew tolerant to the effects of racemic MDMA and to the R-(-) form of the drug over time, but findings supporting tolerance to S-(+)-MDMA were less certain. This is because one of the monkeys self-administered less S-(+)-MDMA over time, but another monkey self-administered more of it over time. Two months after monkeys in the MDMA group received their last dose of the drug, six of the seven monkeys (three in the MDMA group and three controls) underwent PET scans with a radioactively labeled drug called DTBZ. This compound is used to measure VMAT, a protein associated with axon terminals, with reduction in DTBZ binding considered a sign of neurodegeneration. Seven to ten days after undergoing the PET scan, MDMA and control monkeys were killed by pentobarbital overdose, and brains were removed and divided, and studied with separate measures. The researchers measured levels of the neurotransmitters serotonin (5-HT) and dopamine, and their respective metabolites 5-HIAA and DOPAC in many brain areas, including frontal, temporal, parietal and occipital areas, hypothalamus and hippocampus. Researchers used more radioactive DTBZ to measure VMAT in a brain area called the striatum. If the researchers found differences in PET scans between the MDMA and control monkeys, or lower rates of DTBZ binding in striatal areas, or if they found lower levels of brain serotonin or dopamine, then they would consider these findings signs that MDMA had harmed the brain (neurotoxicity). Even though monkeys reduced their intake of MDMA over time, PET scans showed no differences in binding for radioactively labeled DTBZ, a sign that MDMA self-administering and control monkeys still had the same amounts of VMAT in their brains, and that no harm had come to serotonin or dopamine axons. When striatal tissue was examined in more detail with DTBZ, the researchers still found no differences between slices from monkeys with access to MDMA and controls. Furthermore, the two groups of monkeys did not have significantly different levels of brain serotonin, dopamine, or metabolites for these two neurotransmitters in any of the areas studied. Though there were decreases in serotonin in frontal, parietal and temporal cortex, these decreases were not statistically significant, were below levels seen in other studies in non-human primates, and did not affect the hippocampus, a brain area implicated in learning and memory. Taken together, these findings suggest that these monkeys, like some regular Ecstasy users, "lost interest in" MDMA after prolonged access to it, but that this apparent tolerance to MDMA effects did not arise from harm to serotonin or dopamine neurons. Eighteen months of approximately 120 to 139 separate exposures to doses of MDMA similar to those used by human Ecstasy users produced tolerance to drug effects, but did not produce serotonin or dopamine toxicity, since markers for this toxicity were absent or nearly absent. There are a number of methodological problems with this study. For instance, the sample size in this study is very small, and all measures of neurotoxicity were made at least two months after the last dose of MDMA. However, other studies reporting signs of serotonin neurotoxicity in non-human primates have used equally small or smaller sample sizes, and one study found signs of neurotoxicity seven years after the last dose of MDMA (Hatzidimitriou et al. 1999). It is true that the monkeys that self-administered MDMA were also trained to self-administer the psychostimulant methamphetamine, while control monkeys never had the opportunity to take this drug, opening up the possibility that methamphetamine might have produced effects of its own, or altered MDMA effects. But exposure to methamphetamine occurred after monkeys learned to take MDMA, and one of the monkeys was removed from the study before any exposure to methamphetamine had begun, so results from this animal would not be affected by exposure to methamphetamine. So, why didn't the monkeys in this study show any signs of damage to serotonin or dopamine axons after they took an average of 2 to 4 mg/kg MDMA on 120 to 139 separate occasions, even though other studies have found signs of damaged serotonin neurons after repeated doses of MDMA (see for example Hatzidimitriou et al. 1999; Taffe et al. 2002; Winsauer et al. 2002). One important difference between this study and previous research is that doses of MDMA the monkeys self-administered were lower and less frequent than in studies that found serotonin neurotoxicity. Doses of MDMA were generally higher than those self-administered by the monkeys in this study. Researchers used higher doses because according to an "interspecies scaling" model of drug metabolism, these doses were supposed to produce the same levels of MDMA seen in humans taking lower doses. Critics of this model have argued that interspecies scaling may not be the best model for computing doses of MDMA in other animals intended to match doses in humans (Vollenweider et al. 2001). A recent study also performed in rhesus monkeys lends support to this criticism (Bowyer et al. 2003). In this study, researchers examined the amount of the S-(+) form of MDMA seen in a monkey's bloodstream after a 10 mg/kg injection of MDMA. They found that this dose, commonly used in studies of MDMA toxicity, produced ten times the MDMA levels seen in the range of doses given to humans in research studies (Bowyer et al. 2003), suggesting that MDMA doses used in earlier studies were not equivalent to most doses taken by most Ecstasy users. Non-human primates in previous studies also received MDMA several times a day rather than only once a day, and MDMA was administered over at least two consecutive days rather than every three to four days. This means that non-human primates in earlier studies also received MDMA more often than they did in this study. It still may be the case that more frequent or higher doses of MDMA could harm brain serotonin neurons, but not at the doses self-administered in this study. Since Ecstasy users rarely report use more often than once a week, it seems that most Ecstasy users operate on schedules of use closer to those experienced by the monkeys in this study than to dose regimens used in earlier studies, so this study may be a better approximation of human Ecstasy use in terms of frequency as well as in terms of drug dose. Another major difference between this study and studies that have found signs of harm to brain serotonin neurons is that MDMA was self-administered in this study, and not given to subjects by the researchers. This is referred to as "contingent" administration, in contrast to "noncontigent" administration, and the authors note that studies with other substances suggest that drug effects, even effects on brain chemistry, can depend on whether non-human animal subjects self-administer the substance, or are given it independent of their actions. To date, no research has studied differences in effects of contingent and noncontingent administration of MDMA, but this study raises the possibility that such differences exist. It may be the case that MDMA is only harmful to serotonin cells when it is given noncontingently, but that such effects are greatly reduced when doses are self-administered. If the findings uncovered by Fantegrossi and colleagues can be generalized to humans, then it appears that anecdotal reports of tolerance to MDMA, or its "loss of magic" over time cannot be treated as indicators of harm to the brain. It is not clear what lies behind reduced rates of MDMA self-administration. It is possible that MDMA changes the number or level of activity of specific serotonin receptors, perhaps as a result of repeated stimulation of affected receptors. If the "loss of magic" in humans is analogous to reduced self-administration in rhesus monkeys, then the cause or causes of long-term tolerance to MDMA effects cannot be harm to serotonin or dopamine neurons. Findings reported in this study also suggest that regular ingestion of MDMA may not harm serotonin axons. If this is the case, then taking a few doses of 125 mg (approximately 1.8 mg/kg) MDMA at three to five-week intervals seems especially unlikely to pose any risks of harm to these neurons. Reference Fantegrossi WE, Woolverton WL, Kilbourn M, Sherman P, Yuan J, Hatzidimitriou G, Ricaurte GA, Woods JH, Winger G. (2004) Behavioral and Neurochemical Consequences of Long-Term Intravenous Self-Administration of MDMA and Its Enantiomers by Rhesus Monkeys. Neuropsychopharmacology. 2004 Feb 16 [Epub ahead of print] Full Text in PDF Format Further Reading Bowyer JF, Young JF, Slikker W, Itzak Y, Mayorga AJ, Newport GD, Ali SF, Frederick DL, Paule MG (2003) Plasma levels of parent compound and metabolites after doses of either d-fenfluramine or d-3,4-methylenedioxymethamphetamine (MDMA) that produce long-term serotonergic alterations. Neurotoxicology 24: 379-390. Hatzidimitriou G, McCann UD, Ricaurte GA (1999) Altered serotonin innervation patterns in the forebrain of monkeys treated with (+/-)3,4-methylenedioxymethamphetamine seven years previously: factors influencing abnormal recovery. J Neurosci. 1999;19,12:5096-107. Taffe MA, Davis SA, Yuan J, Schroeder R, Hatzidimitriou G, Parsons LH, Ricaurte GA, Gold LH (2002) Cognitive performance of MDMA-treated rhesus monkeys: sensitivity to serotonergic challenge. Neuropsychopharmacology 27; 993-1005. Vollenweider FX, Jones RT, Baggott MJ. (2001) Caveat Emptor: Editors Beware (reply) Neuropsychopharmacology 24; 461-463. Winsauer PJ, McCann UD, Yuan J, Delatte MS, Stevenson MW, Ricaurte GA, Moerschbaecher JM (2002) Effects of fenfluramine, m-CPP and triazolam on repeated-acquisition in squirrel monkeys before and after neurotoxic MDMA administration. Psychopharmacology (Berl) 159: 388-396 More test should be done ,,,,but the future looks promising .
