Neurotoxicity of recreational substances (loooong)

[II Gyan II]

It's been long mentioned in the media that some substances like methamphetamines and MDMA are neurotoxic (dopamine and serotonin neurons resp.). With Ecstasy (MDMA), there is some controversy over the extent of such toxicity. With meth, it seems well-established. Ricaurte, probably the world's pre-eminent researcher on Ecstasy, says "Everyone in the field has accepted [MDMA] is a neurotoxin. I think those [dissenting] arguments have to be put in perspective.".

However, I came across a link to this interesting article. The author spews some rhetoric initially. Later on, however, he writes

The widely publicised claim that Ecstasy causes neurodegeneration or brain damage (which might result in long term problems such as depression or even Parkinson's Disease) is based on animal experiments, most of them carried out by Ricaurte(3) and McCann(4). Since counting damaged neurons is impractical, they used indirect methods which are disputed by other experts, in particular O'Callaghan of the US Environmental Protection Agency.
O'Callaghan was given a $750,000 commission to find the most accurate method for assaying neurotoxicity in humans(5). He came up with a procedure called Reactive Gliosis which shows that Methamphetamine, Ecstasy and fenfluramine are not neurotoxic. His findings pleased the French drug company Servier who wanted to market fenfluramine in the USA, and this year the US Food and Drug Administration called both O'Callaghan and Ricaurte as expert witnesses to decide whether fenfluramine was safe. Ricaurte's research shows that both Ecstasy and fenfluramine are identically neurotoxic and therefore fenfluramine should not be released. But the expert committee took O'Callaghan's view and decided to grant unlimited use on the grounds that the benefits of fenfluramine outweigh the possible risks... It is a slimming pill.

O'Callaghan's view was again strengthened in June this year* by the finding that, contrary to studies using Ricaurte's means of assay, chronic methamphetamine users' brains were not damaged when examined after they had died.

*1996.

For the two claims

1) Assay of neurotoxicity, he cites "Assessing Neurotoxicity of Drugs of Abuse(PDF) by J O'Callaghan, NIDA monograph 1993". The relevant article in this monograph is on pg 188. A scan reveals

...the authors and colleagues wanted to utilize an endpoint that would reveal damage anywhere in the CNS following exposure to any type of neurotoxicant. This endpoint needed to be a sensitive indicator of neural damage as well as one that could be readily quantified. Gliosis, a condition otherwise known as astrogliosis or reactive gliosis, satisfies all these requirements...

[snip]

Various substituted amphetamines (e.g., amphetamine, methamphetamine, methylenedioxyamphetamine, methylenedioxymethamphetamine [MDMA], fenfluramine, parachloroamphetamine) are considered to be neurotoxic because they produce long-term (several days to several months) decrements in indicators of brain dopaminergic and serotonergic function

[snip]

our findings suggest that the transient methamphetamine-induced decrease of striatal dopamine in the rat is not an adequate predictor of underlying damage to
nigrostriatal neurons.**

[snip]

However, even when the methamphetamine dosage was increased to as much as 150 mg/kg, twice daily for 2 days, we failed to see marked increases in GFAP at time points ranging from 2 to 9 days postdosing***

[snip]

Multiple high-dose regimens of MDMA result in evidence of terminal degeneration based on reduced silver degeneration stains (Commins et al. 1987). Most of these data have been obtained from studies in the rat because serotonergic neurons apparently are not affected by MDMA in the mouse

[snip]

Thus, the fact that MDMA-dosing regimens that cause long-lasting decreases in 5-HT do not result in astrogliosis (figure 5) suggests that such regimens may lead to down-regulation of serotonin biosynthesis without causing nerve terminal or axonal degeneration.

[snip]

Based on the results of studies of a large variety of prototype neurotoxicants, the authors feel confident that assays of GFAP represent a sensitive means for detecting and quantifying neural damage.

[snip]

What then are we to make of our data for the effects of amphetamines in the rat? The simple conclusion is that high dosages of these compounds are required to cause neural damage in this species. Long-lasting effects of substituted amphetamines on a number of constituents of serotonergic and dopaminergic neurons have been described over the years (Gibb et al. 1990). However, one implication of these data is that these effects, when observed in the rat, may not reflect amphetamine-induced damage to serotonergic or dopaminergic pathways. These arguments are not meant to imply that most amphetamine derivatives are not detrimental to dopaminergic and serotonergic function. The long-lasting amphetamine-induced deficits in the biochemical machinery associated with these transmitter systems are suggestive, minimally, of a long-term deficit in function. Such effects can be considered adverse or “neurotoxic” to the affected pathways. Our findings emphasize the need to establish the dosage requirements for such effects in relation to the dosage requirements needed to cause neural damage.

**They do find neurotoxicity in mice, however.
***indicating lack of neurotixicity


2) Meth possibly not neurotoxic, "Striatal Dopamine Nerve Terminal markers in Human Chronic Methamphetamine Users by JM Wilson et al, Nature Medicine 2: 699-703 (1996)". The linked abstract of this cite says, "...levels of DOPA decarboxylase and the vesicular monoamine transporter, known to be reduced in Parkinson's disease, were normal. This suggests that chronic exposure to methamphetamine does not cause permanent degeneration of striatal dopamine nerve terminals at the doses used by the young subjects in our study..."

Has it been proven one way or the other, since then? Can someone provide the straight dop(amine)?

[kinoons]

<Mods -- Sorry if this oversteps the bounds of copywrited material, I'm a little unsure about it. I got it off a website I have access through via my university. If you are not part of the uni you can't get in.>

Title: Cognitive performance and serotonergic function in users of ecstasy.

Authors: Verkes RJ, Gijsman HJ, Pieters MS, Schoemaker RC, de Visser S, Kuijpers M, Pennings EJ, de Bruin D, Van de Wijngaart G, Van Gerven JM, Cohen AF

Source: Psychopharmacology

Date of publication: 2001 Jan 1
Volume 153
Issue 2
Pages 196-202

Abstract RATIONALE: (+/-) 3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy") has been shown to cause long term damage to serotonergic cerebral neurons in animals. The neurotoxic effects in humans are less clear and little is known about the functional consequences, although some studies suggest memory impairment. Given the widespread use of MDMA, our lack of knowledge raises concerns. OBJECTIVE: We investigated, in humans, the relation between past use of ecstasy and cognitive performance as well as serotonergic function. Methods: Two groups of 21 males with moderate and heavy recreational use of MDMA, respectively, and a control group of 20 males without use of MDMA were compared. All were from the same subculture. Reaction time, direct recall, and recognition were assessed. Serotonergic function was measured by the neuro-endocrine response to a placebo-controlled, crossover challenge with dexfenfluramine. RESULTS: Ecstasy users showed a broad pattern of statistically significant, but clinically small, impairment of memory and prolonged reaction times. Heavy users were affected stronger than moderate users. Release of cortisol but not of prolactin after dexfenfluramine administration was significantly reduced in both groups of ecstasy users compared with the controls. Analyses of covariance showed that likely confounding variables including recent exposure to ecstasy, psychosocial profiles and use of other drugs did not explain the differences found between the groups. CONCLUSIONS: These results provide further evidence that use of ecstasy may be associated with impairment of memory and of serotonergic function. These findings are compatible with neurotoxicity of ecstasy as shown in animals.




If you want the full text you'll need to purchase the issue

[II Gyan II]

Originally Posted by kinoons

3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy") has been shown to cause long term damage to serotonergic cerebral neurons in animals
...
RESULTS: Ecstasy users showed a broad pattern of statistically significant, but clinically small, impairment of memory and prolonged reaction times.

This doesn't address the issue, for the following reasons

1)Impairment of cognitive functions is not the issue. Neural damage is. I take that to mean physical damage. In the O'Callaghan quotes, in the last snippet, the author uses neurotoxic in quotes to indicate that deficit in function isn't what he considers neurotoxicity to be. In short, I'm talking about definite conclusions on physical degeneration.

2)The initial quote above, "ecstasy has been shown to cause" is exactly what's in question. Are there any further studies on MDMA neurotoxicity based on gliosis, as opposed to earlier/other methods? The broad question being, what's the current consensus on the authoritative process to assess neurotoxicity?

[casdave]

One of the problems here is that Ecstasy is commonly mixed with other drugs, as part of the tablet itself or mixed in by the user, I know that cocaine sometimes is used alongside ecstasy.

Commonly a small amount of Heroin(at least in the UK) is in the tablet, I believe that the MDMA in ectstasy is not all that pure either, with other related compounds involved as the processing is not particularly rigorous.

I also notice that there is no metion of dose/bodymass so it makes me wonder how great in scale was the amount that lab animals were given.

'Moderate' in terms of drug use is meaningless, what is moderate to one person may be a huge dose, or miniscule depending upon the observer.

There is no mention of longer terms effects, does MDMA cause permanent damage or not ?

Testing those who are currently using the drug only shows the short term effect, what about those who have used it but no longer do so?

Many substances are neurotoxic, but sometimes their effects are neither long lasting, noor permanent, other neurotoxin damage is cumulative but this is true of plenty of prescribed drugs, and industrial chemicals.

The most disturbing thing though in these studies, is that the authers seems to have already had an agenda, they have not kept an open mind and they have not asked the questions that any pharmaceutical reasearcher would undoubtedly have done.

I do not wish to come across as a defender of drug taking, but this study is not helpful, I just don't see a great deal of therapeutic value for overdosers, nor real evidence of damage, just a great deal of speculation on a very narrow and badly specified pattern of drug use.

[II Gyan II]

Originally Posted by casdave

Many substances are neurotoxic, but sometimes their effects are neither long lasting, noor permanent, other neurotoxin damage is cumulative but this is true of plenty of prescribed drugs, and industrial chemicals.

Probably, but the key focus in my OP is how to detect any neurotoxicity accurately.

[Monkeypants]

Ricaurte was disgraced anyway. Did you guys see the Peter jennings special?

http://www.citypaper.com/2003-12-10/mobs.html

[casdave]

Nope, never saw it.

Given all the flaws I noticed, and with an non-medical background, it seems surprising to me that other experts in the field did not come up with a more thorough debunking somewhat sooner, but then there would probably be research grants in jeopardy for dissenters.

My concern is that if there is real damage, beyond and above levels of say alchohol, or even just plain prescription drugs, this widely publicised study will taint the credibility of any findings of reputable scientists in the eyes of those who actually take the drug.

This scepticism is already extent among the sub 18 years olds about the hazards of general drug use, and by the time they are ready to believe the risks of heroin etc, it is too late for many.

We seem to have a nasty form of puritanicalism in our culture, if we enjoy something it must be harmful, even if we cannot prove it, take this against a more rational approach which would be to look objectively at the evidence and then make decisions based upon it.

No wonder there are so many 'new age' idiots hugging trees, listening to crystals, because rubbish studies like this are hardly any better.

Even an ignoramous such as I knows that standard procedure for testing effects of drugs, or pretty much any such chemical experiement is to first accurately determine the type of compound used, its strength and purity.

[kinoons]

Originally Posted by II Gyan II

This doesn't address the issue, for the following reasons

1)Impairment of cognitive functions is not the issue. Neural damage is. I take that to mean physical damage. In the O'Callaghan quotes, in the last snippet, the author uses neurotoxic in quotes to indicate that deficit in function isn't what he considers neurotoxicity to be. In short, I'm talking about definite conclusions on physical degeneration.

2)The initial quote above, "ecstasy has been shown to cause" is exactly what's in question. Are there any further studies on MDMA neurotoxicity based on gliosis, as opposed to earlier/other methods? The broad question being, what's the current consensus on the authoritative process to assess neurotoxicity?

Your first statement would be correct if the persons in the studies were under the influence of the drug at the time of the study. Since the study is of those who had previously taken ecstasy, the imparement that is spoken of can, and should be, related to possible neural damage. (assuming the persons had not taken other drugs that could also have been linked to possible neural damage. I didn't see that listed in the study. I'm assuming a good study would have excluded those patients)

As for the current concensus, that article was from 2001 -- I'll look to see if I can find any more recent.

[II Gyan II]

Originally Posted by kinoons

the imparement that is spoken of can, and should be, related to possible neural damage.

Nope. The connectionist model of neural activity would imply that deficits could be related to malregulation of certain activity in certain structures, as opposed to outright physical degeneration.

[kinoons]

While I will admit to only reading the first link I've found (its late, I have to work in the AM) It would appear that the connectionism model is just that -- Its an idea on how some people think the brain might work as a neural net. It has not been proven as an absolute (not that anyone has proven how the brain works as an absolute). I think it would be a little presumptive to say simply because one model states that deficites could (not are, not are not, just could) be related to other possibilites that those deficites are not caused by death or damage to nervous tissue. Try telling those who have had a CVA that their deficites are not being caused by the death of the tissue involved. You'll either be famous if you can prove it and make them better, or you'll be laughed out of the clinic.

If you have further information on neural nets beyond what I've seen I'd love to see it.

http://plato.stanford.edu/entries/connectionism/

[kinoons]

here are a few other articles you might like to track down on the subject. Again these are abstracts (or snipets there from) that pertain to the subject. In fear of copywrite laws I won't post the entire articles.

"Long-term neuropsychiatric consequences of "ecstasy" (MDMA): a review."
Harvard Review of Psychiatry
Montoya AG - Harv Rev Psychiatry - 01-JUL-2002; 10(4): 212-20

" <snip> Together, the studies reviewed provide substantial evidence that MDMA causes neuronal damage in animals and humans. Additional research is necessary to determine whether the MDMA-induced destruction of serotonergic neurons can have long-term and possibly permanent neuropsychiatric consequences in humans."

"Reduced N-acetylaspartate levels in the frontal cortex of 3,4-methylenedioxymethamphetamine (Ecstasy) users: preliminary results."
American Journal of Neuroradiology
Reneman L - AJNR Am J Neuroradiol - 01-FEB-2002; 23(2): 231-7


CONCLUSION: Reduced NAA/Cr and NAA/Cho ratios at (1)H MR spectroscopy provide evidence for neuronal abnormality in the frontal cortex of MDMA users; these are correlated with the degree of MDMA exposure. These data suggest that MDMA may be a neurotoxin in humans, as it is in animals.

This article does not make any claims in the abstract, good or bad, but seems like it may be intersting.

Methylenedioxymethamphetamine (MDMA, Ecstasy) neurotoxicity: cellular and molecular mechanisms.
Lyles J - Brain Res Brain Res Rev - 01-MAY-2003; 42(2): 155-68
Brain Research Reviews

[II Gyan II]

Originally Posted by kinoons

I think it would be a little presumptive to say simply because one model states that deficites could (not are, not are not, just could) be related to other possibilites that those deficites are not caused by death or damage to nervous tissue.

As opposed to being non-presumptive to say that impairment "should be" related to beural damage??

[II Gyan II]

"Long-term neuropsychiatric consequences of "ecstasy" (MDMA): a review."
Harvard Review of Psychiatry
Montoya AG - Harv Rev Psychiatry - 01-JUL-2002; 10(4): 212-20

" <snip> Together, the studies reviewed provide substantial evidence that MDMA causes neuronal damage in animals and humans. Additional research is necessary to determine whether the MDMA-induced destruction of serotonergic neurons can have long-term and possibly permanent neuropsychiatric consequences in humans."

Here's the paper (PDF)

The reviewed evidence for neurotoxicity:

Numerous animal studies have yielded clear evidence of potent MDMA-induced neurotoxic effects specific to central serotonergic systems. (17)

17 == Ricaurte G, Bryan G, Strauss L, Seiden L, Shuster C. Hallucinogenic amphetamine selectively destroys brain serotonin nerveterminals. Science 1985;229:986–8.

These studies have involved several species, including rats and a variety of primates. (18)

18 == Ricaurte GA, Martello AL, Katz JL, Martello MB. Lasting effects of (±)3,4-methylenedioxymethamphetamine (MDMA) on serotonergic neurons in nonhuman primates: neurochemical observations. J Pharmacol Exp Ther 1992;261:616–22.

The applicability of these findings to human subjects has been contested vigorously, largely because the dosage used in animal experiments is perceived to be much higher than that taken by humans. (19)

19 == Ricaurte GA, Yuan J, McCann UD. (±)3,4-Methylenedioxymethamphetamine (‘ecstasy’)–induced serotonin neurotoxicity: studies in animals. Neuropsychobiology 2000;42:5–10.

The lowest MDMA dose reported to elicit longterm structural damage in serotonergic neurons of nonhuman primates is 10 mg/kg subcutaneously daily for 4
days. (20)

20 == Gouzoulis-Mayfrank E, Daumann J, Tuchtenhagen F, Pelz S, Becker S, Kunert HJ, et al. Impaired cognitive performance in drug free users of recreational ecstasy (MDMA). J Neurol Neurosurg Psychiatry 2000;68:719–25. Scroll Below.

According to principles of interspecies scaling, this is equivalent to 1.4 mg/kg in humans, (19)

19 == See above.


I checked up 20, which cites 8 papers as "evidence" of MDMA neurotoxicity. 3 of those have Ricaurte as author, the rest mainly Battaglia. Battaglia measures levels of select markers (notably 5-HT and 5-HIAA) as indicators for neurotoxicity. But this is exactly what's in question. From my first post, O'Callaghan snippet: Thus, the fact that MDMA-dosing regimens that cause long-lasting decreases in 5-HT do not result in astrogliosis (figure 5) suggests that such regimens may lead to down-regulation of serotonin biosynthesis without causing nerve terminal or axonal degeneration.

The key questions as of now are

1a)What are the various methods in which MDMA neurotoxicity is measured?
1b)What is the confidence attached to these various methods?

I used recreational drugs as illustrations because that's where this research is controversial. But my general question still remains: what is the current consensus on the authoritative method to assess neurotoxicity?

[II Gyan II]

The final paper

Methylenedioxymethamphetamine (MDMA, Ecstasy) neurotoxicity: cellular and molecular mechanisms.
Lyles J - Brain Res Brain Res Rev - 01-MAY-2003; 42(2): 155-68
Brain Research Reviews

is here (PDF). For neurotoxicity in primates, it references Ricaurte barring one paper. All summary that I have so far read, references reductions in same select markers.

Oh, in (20) above, the specific claim for "longterm longterm structural damage in serotonergic neurons of nonhuman primates" is supported by a cite of a Ricaurte paper (Lasting effects of MDMA on central serotonergic neurons in nonhuman primates: neurochemical observations. J Pharmacol Exp Ther 1992;261:616–22.)

Virtually all MDMA neuroresearch has been conducted by about 4-5 key players; Ricaurte, McCann, Battaglia, CJ Schmidt. They have all used mostly similar methods to assess damage. What's in question are these methods!

[II Gyan II]

A counterpoint:

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.
...
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.

Full paper (pdf).

[II Gyan II]

Anyone?

[II Gyan II]

No neurobio researchers/grad students here?