Is MDMA Neurotoxic In Humans?

methyl_ethyl · Riedel De Haen

Is MDMA (‘Ecstasy’) Neurotoxic in Humans?
An Overview of Evidence and of
Methodological Problems in Research
H. Valerie Curran
Neuropsychobiology 2000;42:34–41
full text .zip
PMID: 10867554

Abstract:

Evidence from research with a range of animal species, from rodents to non-human primates, has shown that MDMA (+/-3, 4-methylenedioxymethamphetamine) is neurotoxic. This article explores the evidence that MDMA may be neurotoxic in humans by briefly overviewing three types of research: (1) neurobiological, (2) psychological/somatic and (3) psychiatric. The first type of evidence derives from neuropharmacological and neuroendocrine studies, the second type focuses on psychological function and somatic symptoms in MDMA users, and the third involves studies of psychiatric cases in people who have taken MDMA. Evidence from these types of studies is indirect and differs in the degree to which any causative links are implied between observed effects, MDMA use and human neurotoxicity. These issues are critically discussed within the context of the wide-ranging methodological problems in human research with MDMA

methyl_ethyl · Riedel De Haen

Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA ("ecstasy").
Ricaurte GA, Yuan J, Hatzidimitriou G, Cord BJ, McCann UD.
Science. 2002 Sep 27;297(5590):2260-3.
PMID:12351788
Ricarte Scandal.zip

Abstract:

The prevailing view is that the popular recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, or "ecstasy") is a selective serotonin neurotoxin in animals and possibly in humans. Nonhuman primates exposed to several sequential doses of MDMA, a regimen modeled after one used by humans, developed severe brain dopaminergic neurotoxicity, in addition to less pronounced serotonergic neurotoxicity. MDMA neurotoxicity was associated with increased vulnerability to motor dysfunction secondary to dopamine depletion. These results have implications for mechanisms of MDMA neurotoxicity and suggest that recreational MDMA users may unwittingly be putting themselves at risk, either as young adults or later in life, for developing neuropsychiatric disorders related to brain dopamine and/or serotonin deficiency.

nyarlothotep · Mon Feb 21, 2005 10:10 pm

Retraction: "Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of methylenedioxymethamphetamine (MDMA)" (Science. 2002;297:2260-2263.)
September 5, 2003
Science
We write to retract our report "Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of methylenedioxymethamphetamine (MDMA)" (1) following our recent discovery that the drug used to treat all but one animal in that report came from a bottle that contained d-methedrine instead of the intended drug, racemic MDMA. Notably, d-methedrine would be expected to produce the same pattern of combined dopaminergic/serotonergic neurotoxicity (2) as that seen in the animals reported in our paper (1).

http://www.maps.org/media/science9.5.03.html

methyl_ethyl · Riedel De Haen

Retraction
Science, Vol 301, Issue 5639, 1479 , 12 September 2003
Retraction

EDIT: Ya beat me to it Nyarlothotep I'll leave the link to the original journal article in Science however...

much_love

methyl_ethyl

nyarlothotep · Mon Feb 21, 2005 10:35 pm

Original Article
Neuropsychopharmacology (2004) 29, 1270-1281, advance online publication, 24 March 2004;
doi:10.1038/sj.npp.1300442

Behavioral and Neurochemical Consequences of Long-Term Intravenous Self-Administration of MDMA and Its Enantiomers by Rhesus Monkeys

William E Fantegrossi1,2, William L Woolverton3, Michael Kilbourn2, Phillip Sherman2, Jie Yuan4, George Hatzidimitriou4, George A Ricaurte4, James H Woods1 and Gail Winger1
1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA
2Cyclotron/PET Facility, Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA
3Department of Psychiatry, University of Mississippi Medical Center, Jackson, MS, USA
4Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

Correspondence: Dr WE Fantegrossi, Department of Pharmacology, University of Michigan Medical School, 1150 West Medical Center Drive, Ann Arbor, M1 48101-0632, USA. Tel: +1 734 615 7755; Fax: +1 734 764 7118; E-mail: billfan@umich.edu

Received: 29 August 2003
Revised: 6 February 2004
Accepted: 10 February 2004
ABSTRACT

The effects of self-administered 3,4-methylenedioxymethamphetamine (MDMA) on behavior and neurochemistry have not been previously studied in laboratory primates. We investigated the capacity of MDMA and its enantiomers to maintain contingent responding over an extended duration, whether any decrements in the reinforcing effects of these compounds would be observed over time, whether such decrements would be MDMA-selective, and whether any neurochemical correlates could be identified. Animals were previously trained to self-administer cocaine, then exposed to periodic substitutions of various doses of racemic MDMA and its enantiomers; full dose-effect curves were generated for each MDMA compound repeatedly over the duration of the study. After approximately 18 months of MDMA self-administration, drug exposure was halted and after at least 2 months drug abstinence, animals were scanned using positron emission tomography (PET) with the vesicular monoamine transporter (VMAT) ligand dihydrotetrabenazine (DTBZ). Shortly thereafter, animals were euthanized, brains were dissected, and samples were assayed for brain monoamines and their metabolites using high-performance liquid chromatography (HPLC), and for VMAT using DTBZ binding. The reinforcing effects of racemic and R(-)-MDMA were reduced over a long series (months) of individual self-administration access periods; the reinforcing effects of S(+)-MDMA were more resistant to this effect, but were attenuated for one animal. The reinforcing effects of cocaine were not altered by chronic MDMA self-administration, nor was the VMAT binding potential as assessed by PET. Further, there were no measurable decrements in serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) or VMAT in any brain regions assayed. The reinforcing effects of MDMA are selectively attenuated by chronic MDMA self-administration, although this behavioral change appears to occur in the absence of any frank neurochemical correlates of toxicity.

http://www.maps.org/w3pb/new/2004/2004_fantegrossi_20541_1.pdf

Review article:
http://www.maps.org/sys/w3pb.pl?mode=show&type=review&r_id=1

Edit: Doubled up on the .pdf link......review link now correct.

methyl_ethyl · Riedel De Haen

‘Is MDMA a Human Neurotoxin?’: Diverse Views from the Discussants
J.J.D.Turner A.C.Parrott
Neuropsychobiology 2000;42:42–48
full text .zip
PMID: 10867555

Abstract:

Every discussant at the Novartis symposium was invited to submit a 250-word abstract, giving their views upon the question: 'Is MDMA a human neurotoxin?'. These abstracts are presented here. They illustrate a wide range of viewpoints and opinions, as might be expected from experts in such diverse fields: animal neuroscience, human cognitive testing, police pathology laboratory, psychotherapeutic institute and psychiatric hospital. Some abstracts emphasized the methodological weaknesses of the human empirical data: the uncertain nature of 'Ecstasy' tablets, the reliance on self-report data, and the contributory factors of heat, dancing/exertion, poor diet and other illicit drugs. These factors may lead to psychobiological changes, which could be misinterpreted as neural damage. The absence of gliosis in animal models was also noted, which led to suggestions that there might be alternative interpretations for the neural changes which have been observed in rats and monkeys. Others noted the absence of neural/behavioural change following a single Ecstasy tablet, or commented upon the therapeutic benefits of MDMA in a quiet supportive environment. Nevertheless, novel studies from England, Germany, Italy, the Netherlands, Scotland and Wales confirmed and extended the range of cognitive, behavioural, EEG and neurological deficits, displayed by drug-free Ecstasy users. Moreover, these deficits often remained when other illicit drug use was statistically controlled. In conclusion: If MDMA neurotoxicity in humans is a myth, then it is a myth with a heavy serotonergic component. Copyright 2000 S. Karger AG, Basel

methyl_ethyl · Riedel De Haen

MDMA (3,4-Methylenedioxymethamphetamine) or ecstasy: the neuropsychobiological implications of taking it at dances and raves.
Parrott AC.
Neuropsychobiology. 2004;50(4):329-35.
full text .zip

Abstract:

MDMA (3,4-methylenedioxymethamphetamine) or 'ecstasy' is a ring-substituted amphetamine derivative, which is widely used as a recreational drug, most particularly at dances and raves. Around 80-95% of dancers/ravers report using ecstasy/MDMA, compared to 5-15% of young people in general. This paper will consider the possible contribution of stimulatory environmental conditions to the neuropsychobiological effects of MDMA. Animal research shows that heat and crowding potentiate the acute effects of MDMA. Social interaction and intravenous drug self-administration in laboratory rats are significantly enhanced when MDMA is given under hot ambient temperatures. Loud noise and physical activity can also contribute to the general overarousal. Furthermore, MDMA impairs homeostatic thermal control in rats, leading them to overheat in hot environments. The human implications of these findings are that the hot, noisy and overcrowded conditions at raves may be providing the ideal environment to heighten the acute drug response. In recreational users, the acute medical dangers of MDMA comprise a constellation of hyperthermia-related abreactions, which generally only occur when it has been taken in hot and crowded environments. MDMA is well established as a serotonergic neurotoxin in laboratory animals, but heat and overcrowding increase the degree of distal axon terminal loss. If this also occurs in humans, then the stimulatory environments of clubs and raves may heighten the likelihood of adverse neuropsychological sequelae in recreational ecstasy users. Consistent with this prediction, the extent of self-reported dancing/exercise when on MDMA has recently been shown to be associated with significantly more psychobiological problems afterwards.

methyl_ethyl · Riedel De Haen

Loud noise enhances nigrostriatal dopamine toxicity induced by MDMA in mice.
Gesi M, Ferrucci M, Giusiani M, Lenzi P, Lazzeri G, Alessandri MG, Salvadorini A, Fulceri F, Pellegrini A, Fornai F, Paparelli A
Microsc Res Tech. 2004 Jul 1;64(4):297-303.
full text .zip

Abstract:

The neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has been intensely investigated due to the widespread abuse of this drug and its neurotoxic effects. In mice, MDMA neurotoxicity has been demonstrated for striatal dopamine (DA) terminals. However, the current literature has reported great variability in the effects induced by MDMA; this is partially due to changes in environmental conditions. For instance, elevated temperature and a crowded noisy environment markedly increase the neurotoxic effects induced by MDMA. The environmental factor loud noise is often present during ecstasy intake; however, only a few studies have analysed the consequence of a concomitant exposure to loud noise and ecstasy intake. In the present experimental work, we investigated whether nigrostriatal DA toxicity occurring after MDMA administration was potentiated in the presence of loud noise (100 dBA). We administered MDMA to C57/Black mice using a "binging" pattern for two durations of white noise exposure. We found a marked enhancement of MDMA toxicity (7.5 mg/Kg x4, 2 hours apart, i.p.) in the presence of white noise exposure lasting for at least 6 hours. The striatal damage was assessed by assaying DA levels as well as the loss of tyrosine hydroxylase (TH) and the increase in striatal glial fibrillary acidic protein (GFAP) immunohistochemistry. Since loud noise often accompanies ecstasy intake, the present findings call for more in-depth studies aimed at disclosing the fine mechanisms underlying this enhancement. 2004 Wiley-Liss, Inc.

methyl_ethyl · Riedel De Haen

(+)3,4-Methylenedioxymethamphetamine
(‘Ecstasy’)-Induced Serotonin Neurotoxicity:
Clinical Studies
Una D. McCanna Victoria Eligulashvili George A. Ricaurte
Neuropsychobiology 2000;42:11–16
full text.zip
PMID:10867551

Abstract:

(+/-)3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy') is a brain serotonergic neurotoxin in experimental animals, including nonhuman primates. It is also an increasingly popular recreational drug of abuse, and doses of MDMA that are used recreationally overlap with those that produce serotonin (5-HT) neurotoxicity in animals. Studies in human MDMA users probing for evidence of brain serotonergic neurotoxicity indicate that some MDMA users may incur MDMA-related 5-HT neural injury and, possibly, functional sequelae. In particular, MDMA users have selective decrements in cerebrospinal fluid 5-hydroxyindoleacetic acid and brain 5-HT transporters, similar to nonhuman primates with documented MDMA-induced neurotoxicity. Functional abnormalities seen in MDMA users that may be related to 5- HT injury include cognitive deficits, altered sleep architecture, altered neuroendocrine function, altered behavioral responses to 5-HT selective drugs, and increased impulsivity. Additional studies in animals, as well as longitudinal and epidemiological studies in MDMA users, are required to confirm and extend the present data, and to determine whether MDMA users are at increased risk for developing neuropsychiatric illness as they age.

the alchemist · Fri Jul 01, 2005 8:07 am

How serious and magnified is this MDMA neurotoxicity? Administration of pure MDMA of about once a month (sometimes ~2-3 times a month!) at ~ 170 mg to a 175 lb person produces a hangover but full recovery is always gained 2 days after the experience (recovery is based on observed cognitive 'problem solving' skills and athletic endurance). Alcohol hangover recoveries take longer in conducted experiments. The studied MDMA user leads a healthy and active lifestyle and has been using MDMA off and on for about 10 years. This user is still under 30. The studied patient feels more centered and peaceful now than he did 10 years ago. If this is neuropsychiatric illness, bring it on...

How often did Shura use his stepchild?

methyl_ethyl · Riedel De Haen

I think your experiences are much like all of ours. When I was "performing" some seriously abusive MDMA binge studies, I thought I would never be able to appreciate anything ever again without the use of MDMA.

It seems most of us "bounce back" from such abuse ahead of where we started. I feel that I am a perfect example of this phenom. MDMA abuse opened "doors" that were never visible to me before my usage of the drug.

I think many of the drugs that we experiment with, open doors that we would have blindly walked passed if it were not for our experimentation.

Just today I was driving a friend around town just after he ingested ~2.5mL of 1,4butanediol, I noted that he constantly made remarks pertaining to the fact that he lived in this town his whole life yet never payed any attention to what the buildings, the architecture, the beauty of the town as whole had to offer. The same can be said for any drug, each drug can open a dimension of clarity that is otherwise not attainable due to various factors/roadblocks.

If this is neuropsychiatric illness, bring it on.

It's on..... my point exactly...... Ricuarte, Parrot, they have an agenda IMO, I assume they are pressured to publish data that will work in the favour of the WOD. IMO they have tarnished their reputations with publications that are biased, agenda driven, not to mention the false claims that are made as a result of Ricuarte's well known "mix up". It is sad to say but, even though Ricuarte's statements on MDMA were retracted, (we all know what I am speaking of) many recent journal articles still site his findings, which IMO should not be legal.

just_my_thoughts,

m_e

the alchemist · Mon Jul 11, 2005 6:46 am

Spiritual experiences on 1,4-BDO? Razz

I am not a pharmacologist (although it is a hobby), but could whatever positive mental changes produced by MDMA experiences be reflected as a dissappearance of serotonin axons? Although MDMA is fun, it can easily become a replacement for boredom. That is the only downside that I feel.

MDA produces true blown depression the day after a heafty dose. I have witnessed a loved one straight up cry before going in for work the next day. All day I also wanted to cry and felt so down. This does not happen with any MDMA experiences under 200 mg IMO. Maybe any depression associated with heavy MDMA use would come from the metabolite, MDA?

It is very sad that people still quote that garbage study. I am not up on the literature so it is quite a shock to hear this.

the alchemist

Pastor John Hagee · Mon Jul 11, 2005 7:04 am

Well, I'm no pharmacologist either, but if you ask me it seems obvious that it has some serotonergic, let us say, side-effects, in higher doses don't you think?

the alchemist · Tue Jul 12, 2005 10:25 pm

I know this is a little off-topic but...

My yoga instructor just got back from a week-long meditation retreat. Before she left, she was joking about how she was hoping to find enlightenment. Smile

When she was finished at the end of the week, she found that she had 8 voicemail messages on her cell phone. When she went to check her messages, she completely forgot how to operate her cell phone. Would this not be considered cognitive "damage" by today's standards?

methyl_ethyl · Riedel De Haen

Evidence for a role of energy dysregulation in the MDMA-induced
depletion of brain 5-HT
Altaf S. Darvesh, Gary A. Gudelsky
Article in Press (To be published in a future issue of "Brain Research")
full text.pdf
doi:10.1016/j.brainres.2005.07.009

Abstract:

Although the exact mechanism involved in the long-term depletion of brain serotonin (5-HT) produced by substituted amphetamines is not completely known, evidence suggests that oxidative and/or bioenergetic stress may contribute to 3,4-methylenedioxymethamphetamine (MDMA)-induced 5-HT toxicity. In the present study, the effect of supplementing energy substrates was examined on the long-term depletion of striatal 5-HT and dopamine produced by the local perfusion of MDMA (100 μM) and malonate (100 mM) and the depletion of striatal and hippocampal 5-HT concentrations produced by the systemic administration of MDMA (10 mg/kg i.p. ×4). The effect of systemic administration of MDMA on ATP levels in the striatum and hippocampus also was examined. Reverse dialysis of MDMA and malonate directly into the striatum resulted in a 55–70% reduction in striatal concentrations of 5-HT and dopamine, and these reductions were significantly attenuated when MDMA and malonate were co-perfused with nicotinamide (1 mM). Perfusion of nicotinamide or ubiquinone (100 μM) also attenuated the depletion of 5-HT in the striatum and hippocampus produced by the systemic administration of MDMA. Finally, the systemic administration of MDMA produced a 30% decrease in the concentration of ATP in the striatum and hippocampus. These results support the conclusion that MDMA produces a dysregulation of energy metabolism which contributes to the mechanism of MDMA-induced 5-HT neurotoxicity.

Keywords: MDMA; Nicotinamide; Ubiquinone; Serotonin; Neurotoxicity

Neuroscience classification codes: Disorders of the nervous system; Neurotoxicity

regards,

m_e