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The Complete Guide to Toxicity and Risks of Ecstacy

The Complete Guide to Toxicity and Risks of Ecstacy

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Published by: MagikFungus on Sep 20, 2012
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10/29/2014

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Does MDMA Cause Brain Damage?
 
by Matthew Baggott, BA, and John Mendelson, MD
 from Ecstasy: The Complete Guide ed. Julie Holland Spring 2001This article, written in early 2001, is the best currently available overview of MDMAneurotoxicity. 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. Mattew Baggott's article on neurotoxicity waswritten as he was finishing his truly epic MDMA literature review published by MAPS as part of  their work to explore MDMA as a potential therapeutic agent. Erowid had a very small part inhelping Matt with his literature review and its dense 376 pages are a must-read for anyone trulydedicated to understanding the scientific complexities of this challenging psychoactive.This summary of the neurotoxicity issue for Dr Holland's book, however, is much moreaccessible and should be understandable by anyone with college-level reading skills and interest.1.
 
 
 
 
 
 
 
 
Introduction
 The acute toxic effects of MDMA are well documented by hundreds of case reports of adverse
 
events in illicit users. Considering how many people use MDMA, serious acute adverse eventsseem rare. MDMA appears generally similar to psychostimulants such as methamphetamine withrespect to the risks of acute toxicity. With trained personnel, properly screened volunteers, andestablished protocols for monitoring and treating adverse events, these acute risks appear modestand 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 difficultto assess. Numerous studies in animals have shown that MDMA can produce long-lastingdecreases in brain functions involving the neurotransmitter serotonin. It is unclear what thesechanges mean. Lasting behavioral changes in MDMA-exposed animals have been seldomdetected and are fairly subtle when they are found. Though limited in scope, studies of ecstasyusers present a strong probability that similar serotonergic changes occur in many humans.Studies comparing ecstasy users and nonusers support an association between modestly-loweredintelligence testing, or cognitive performance tests, and ecstasy use, but clinically significantperformance 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 dismissconcerns about MDMA neurotoxicity as politically-motivated alarmism. It is commonly pointedout that though fenfluramine and methamphetamine produce similar changes, their status asprescription medications was not affected by this finding. However, it is reasonable to note thatthe truly long-term effects of MDMA exposure are unknown. In 15 years of research on MDMAneurotoxicity, no published studies have investigated whether MDMA exposure can causesignificant toxicity that only becomes apparent with aging. This fact must be taken into accountwhen considering the risks and benefits of possible clinical studies. Perhaps the single mostworrisome issue surrounding MDMA neurotoxicity is that there may be significant toxicityassociated with serotonergic changes that is currently undetected. Although millions of peoplehave taken millions of doses of ecstasy, controlled studies of users have not been large enough todetect any but the most common chronic adverse effects. Possible adverse effects such as anincreased incidence of affective disorders, like depression, may have gone unnoticed.Because so little is known about possible long-term clinical implications of MDMAneurotoxicity, we believe it is important to minimize the risks of neurotoxicity in researchvolunteers. It is hoped that the information presented here may contribute to assessments of, andperhaps reductions in, the risks associated with MDMA use. This chapter will discuss (1) thenature 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 thesechanges and recovery. The latter part of this chapter will focus on the implications of long-termserotonergic changes by discussing (5) the behavioral and functional effects of MDMA-inducedserotonergic changes in animals; (6) studies comparing ecstasy users to nonusers (includingpersonality, cognitive, and functional comparisons); (7) available data from clinical studies inwhich MDMA was administered; and (8) potential strategies for reducing risk to humanvolunteers.Limitations of space unfortunately prevent a full discussion of every important paper and aspect
 
of this complex topic. For a broader sense of the range of views on MDMA neurotoxicity, thereader is therefore advised to consult other review articles (Boot, 2000; Burgess, 2000; Green,1995; Hegadoren, 1999; McKenna , 1990; Morgan 2000; O'Callaghan, 2001; Seiden, 1996;Sprague, 1998; Steele, 1994), and the issue of Neuropsychobiology (Vol. 42, 2000) dedicated toMDMA neurotoxicity.
MDMA Can Induce Long-term Serotonergic Changes
 Before discussing MDMA-induced changes and their meaning, it is necessary to define a fewterms. 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." Neurotoxic regimensoften consist of four to eight injections of MDMA given over the course of one to four days;however, a single injection of MDMA can also produce these changes. In this chapter, anychanges noted at 7 or more days after drug administration will be considered "long-term." Manystudies examining the brains of animals at longer time periods (often at 2, 4, or 8 weeks) haveestablished that the MDMA-induced changes at 7 days are primarily long-term in nature.The term "neurotoxicity" is more difficult to define. Though no universal definition exists, mostdefinitions are broad enough to encompass both short-term alcohol-induced headaches and thepermanent 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 changesit can cause. In this way, it is evident that some neurotoxic MDMA regimens produce bothchanges in the serotonergic system and acute damage to the brain by free radicals, and therebycause 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. Theselong-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 aredecreased. 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 itback into the cell. Most studies suggest that MDMA primarily causes long-term changes inserotonergic axons that have their cell bodies in an area of the brainstem called the dorsal raphenucleus.Long-lasting decreases in these serotonergic markers suggest that either (a) some type of "downregulation" 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 trulyneurotoxic 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 happenscan be difficult. SERT density may change in response to drugs, but this has been difficult toconsistently demonstrate (Le Poul, 2000; Ramamoorthy, 1998). Similarly, 5-HT levels can beinfluenced by diet and other factors. Because MDMA has been shown to rapidly inactivate theenzyme TPH, decreased 5-HT levels would be expected until TPH activity returns to normal.

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