MDMA/neurotoxicity misconceptions (long)

[zorn]

Hello all. I've been lurking on the Bluelight forums for a while, and finally got around to posting. I've noticed a couple common misconceptions floating around about MDMA neurotoxicity... so here's some info I've collected. Feel free to correct me if I've got something wrong. Apologies in advance if I sound like an know-it-all jerk.

1) MDMA Neurotoxicity is caused by dopamine uptake into serotonergic axons
Yes, I know this is what the Dancesafe slideshow says. It may very well be part of the story, but it's not the only plausible mechanism, and the debate is not settled. This "integrated hypothesis" was first proposed in 1998 by Sprague et al, in
http://www.erowid.org/chemicals/mdma/articles/pdf/1998_sprague_1.pdf
There's considerable evidence in support of the role of dopamine (DA) in neurotoxicity; namely that lesions of domiminergic cells or destruction of DA blocks neurotoxicity, while DA precurosors enhance it. However, there a few problems with this. First, some of the most extensive damage occurs in the hippocampus, a region which is only scarcely innervated by DA neurons. Second, MDMA must be administered systemically for neurotoxicity to occur. Injections of MDMA directly into the brain (i.c.v.) at neurotoxic concentrations consistently fail to produce any damage. See
http://www.erowid.org/chemicals/mdma/articles/pdf/2001_bai_1.pdf http://www.erowid.org/chemicals/mdma/articles/pdf/1998_shankaran_1.pdf http://www.erowid.org/chemicals/mdma/articles/pdf/1999_shankaran_2.pdf http://www.erowid.org/chemicals/mdma/articles/pdf/1999_shankaran_3.pdf
This tends to suggest that the damage is caused by metabolites of MDMA itself, several of which are known to be neurotoxic to SE neurons, since such metabolites would only be produced in significant concentrations during systemic administration. However efforts to locate said metabolite have so far been unsuccessful.
Other theories I've seen in the literature include the culprit being neurotoxic metabolites of SE itself, and the "energy-starvation" of SE neurons. However they seem to be less favored now.
A comprehensive theory of what exactly happens will have to take all of these factors into account. There are a number of possibilities -- perhaps systemic MDMA in necessary to stimulate sufficient DA release to cause damage; or perhaps DA is necessary for the formation of the damaging MDMA metabolite, or perhaps both mechanism are at work in different regions of the brain.
What does seem certain is that oxidative metabolites of *something* cause the damage. Sprague's paper above lists a number of lines of evidence pointing towards this, and there have been papers reporting that both vitamin C and alpha-lipoic acid (both antioxidants or "free radical" scavengers) block neurotoxicity. See
http://www.erowid.org/chemicals/mdma/articles/pdf/2001_shankaran_1.pdf http://www.erowid.org/chemicals/mdma/articles/pdf/1999_aguirre_1.pdf
It's not that important, but I was somewhat surprised when I started looking at the journals and found that the DA hypothesis wasn't set in stone... thought some here might be interested.
2) Prozac and other SSRI's can be taken up to 6 hours after MDMA and still fully protect against neurotoxity
This is what one might naively expect from the abstract of the original paper describing post-MDMA SSRI protection (below). However, the authors actually claimed that there was not "significant at P5-HTP takes hours typically, but 5-HTP->serotonin takes minutes or less. So 5-HTP pills will take the usual ~hour to "kick in."
Hope someone finds this interesting/useful. If you care about MDMA research info, I suggest Erowid/MAPS's new database at http://www.erowid.org/chemicals/mdma/articles ; they have a very complete collection, and you can read the fulltexts without having to be at a university with journal subscriptions.
Care,
zorn

 

[CrackerWheat]

This should be in a FAQ ;-)

 

[MattBomb]

all those articles, thats WAAAYYYY too much to read m8, if u cut it down substantially i might be able to understand it better.
so basically ur sayin neurotoxity is caused by oxidative metabolites of *something*? as well as the dophamine part??

 

[babydoc_vic]

Nice work zorn. Indeed, there remains a great deal we don't understand on this issue, and you have done a great job of summarising it.
I want to know how we should translate the doses of vitamin c and alpha lipoic acid used in the studies by Shankaran et al, and Aguirre et al respectively. The rats were given 100mg per kg in each study, so what does that mean for humans? (I suck at maths!)
I agree this should be developed for the FAQ section.

 

[FrolicAtNight]

Excellent report Zorn! Although I was aware of most DA and SE brain mechanics you're synopsis was very useful. Keep up the good work!

 

[zorn]

Thanks, all. I put together most of this info a while back during random reading and discussions with friends... thought y'all might like to see it.
mattbomb-
Heh, just trying to provide references. The basic idea is that the body breaks something down into free radicals, which get pulled up into serotonin neurons and wreak their havoc there. That something that gets broken down could be MDMA, serotonin, or dopamine(DA). There's more damage with more DA, and no damage with no DA, which suggests that DA is what gets broken down. But when MDMA is put straight to the brain and not broken down by the body, there isn't any damage, which suggests MDMA is what gets broken down. There's probably some complicated crap going on that will explain this.
-zorn

 

[zorn]

babydoc--
Extrapolating from the doses of vit C / ALA is difficult, since these studies always use obscene amounts to show an effect. Using the standard formula, rat (200g) dosages are about ~6 times smaller than human (70kg) dosages, giving about 17mg/kg or 1.2g in a 150lb human. That's a large amount of either ALA or vit C.
However, neither study used single doses. The rats were given vit C 5 times and MDMA(10mg/kg) 4 times over 12 hours in one study, and ALA 4 times and MDMA (20mg/kg) once over two days in the other. The half-life of ALA in humans is only about half an hour, so I don't know why they bothered giving it for two days. Maybe it's longer in rats.
Pharmacokinetic considerations also enter into play. The C/ALA above was injected; people are unlikely (I hope) to shoot up their vitamins. The oral bioavailability of ALA is something like 33%, while that of vitamin C drops with dose and has high individual variance, but is less than 50% for oral doses over a gram. Making that correction we get 3.6g ALA and 2-6g of vitamin C. This is an unsafe amount of ALA and a lot of C. Some (crazy) people take 4 or more grams of vitamin C daily with no problem; others get uncomfortable side effects with more than a gram. Just for reference, the US RDA for C is 0.06 grams.
So the rat doses used in these studies correspond to ridiculous amounts of ALA or vitamin C, especially considering the rats were given the dose four or five times in a short period of time. If this is close to the minimum effectively protective dose, it's not good; you can't get such plasma concentrations safely. I'd guess, though, that lower doses would work. Plus the body has some natural antioxidant capacity which would do proportionally more of the "work" with a lower amount of MDMA. Hopefully someone will do a study on this dose-effect relationship soon.
To get to the point: if I had to guess a good human neuroprotective regimin, I would recommend taking the largest safe amounts of ALA and vitamin C. That seems to be less than a gram of ALA, preferably in time-release form, before taking any MDMA. Vitamin C is cheap and safe, so however much is comfortable... offhand 2g a few hours before, 2g with, and 2g a few hours after MDMA seems good enough. If this doesn't give you any side effects (stomache, diarrhea, etc) sober, should be fine.
From the above I imagine you can see how many guesses and assumptions I had to make just to get a rough estimate of a human neuroprotective dose. And humans and rats are very different creatures, so any number of those guesses could very easily be wrong. We won't know for sure until someone does a study on oral antioxidants blocking neurotoxicity in humans. It's very feasible, but somehow I'm guessing that's one study NIDA isn't gonna be in a rush to fund...
--zorn

 

[Drug Dustbin]

"In monkeys (and rats), a one-time oral dose of 5mg/kg (monkey) has been found to be neurotoxic, causing a long-term 20% reduction of SE levels in the thalamus and hypothalamus."
This study doesn't permit any conclusions as to a possible neurotoxicity. Ricaurte measured only 5-HT and 5-HIAA levels. It has been shown that MDMA-induced decrease in 5-HT and 5-HIAA leves can occur independently of changes in 5-HT uptake sites (Insel et al. 1989). Thus reductions in 5-HT and 5-HIAA alone can not be considered as a reliable indicator of neurodegeneration.
"Of course extrapolation is difficult, but it makes me doubt there is a "free" period... I'd guess you start accumulating damage right after the MDMA starts working."
The axon terminal has some protective reductive capabilities against reactive oxidizing species, thus if the damage is due to oxidative stress, I could imagine that there would be some treshold level .
"5mg/kg is a lot, but it isn't that simple. There is a standard mg/kg scaling formula that goes as weight_ratio^0.7 used for interspecies scaling. Incidentally, the formula correctly predicts the neurotoxic dose in monkeys from mice and vice versa. Using that, we find that the equivalent one-time neurotoxic dose in humans is 1.4-1.7 mg/kg, or about 100 mg for a 150lb person. As you probably know, that's the amount of MDMA usually in a pill."
Vollenweider et al. critisized the scaling methods used by Ricaurte. See:
Vollenweider FX, Jones RT, Baggott MJ.
Caveat emptor: editors beware.
Neuropsychopharmacology. 2001 Apr;24(4):461-3.
"5-HTP is actually metabolized to serotonin very quickly. The natural step of tryptophan->5-HTP takes hours typically, but 5-HTP->serotonin takes minutes or less. So 5-HTP pills will take the usual ~hour to "kick in.""
The half-life of 5-HTP is about 5 hours.
Magnussen I, Nielsen-Kudsk F.
Pharmacokinetics of intravenously administered L-5-hydroxytryptophan in man.
Acta Pharmacol Toxicol (Copenh). 1979 Apr;44(4):308-14.
Westenberg HG, Gerritsen TW, Meijer BA, van Praag HM.
Kinetics of l-5-hydroxytryptophan in healthy subjects.
Psychiatry Res. 1982 Dec;7(3):373-85.
[This message has been edited by Drug Dustbin (edited 13 November 2001).]

 

[Vorticity]

While we're on the topic, I have a question. We have all heard that for people who take Prozac for depression, it takes a few weeks for the levels of Prozac to build up in your brain and you start feeling "better." Similarly, you have to stop taking Prozac for at least a week in order to roll.
So, if it takes this long for Prozac and similar drugs to buld up in your brain, how can taking Prozac the same night as rolling possibly help prevent neurotoxicity. I know the mechanisms for increasing serotonin levels and preventing neurotoxicity are different, but how can you can enough in your brain to actually do anything with one dose?

 

[Vorticity]

Drug Dustbibn - if you have the time, can you elaborate on the criticisms of Ricuarte's scaling methods?

 

[fairnymph]

Vorticity -- In regards to your prozac question -- as you noted yourself, the mechanisms for relieving depression (which do take a while to start working) are different from those mechanisms that reduce neurotoxicity.
Look at it this way; there is a DIRECT effect of SSRIs, and this is what (theoretically) reduces MDMA neurotoxicity. Then there is an indirect effect of SSRIs -- the SSRIs cause changes that cause other changes -- and it is the indirect effects that relieves depression. Taking an SSRI once doesn't make the direct effect any less effective -- it only makes the indirect effect nonexistant or negligible.
Also, in the studies done on neurotxicity with prozac, the rats were only given the prozac on one day, and still they had the findings that they did.

 

[djremix]

great post, outlining all the issues we think about, but hate to admit

just a quickie, will taking an anti oxidant formulae(incl. ala,q10,vit a,c etc etc) before and during the roll diminish its effects?
i currently take it when i start feeling the comedown, along with 5-htp and bang that up 45 minutes later with a 20mg prozac.
now i think 200mg with 20mg prozac wont cause anything bad, warning about 5-htp and prozac are only relevant for people on daily prozac doses right?
------------------
If you think life is really good, wait till you hear the REMIX!

 

[day_for_night]

many people on this board do also acknowledge the metabolite theory, myself included. personally, i beleive it to be the more significant of the two neurotoxic effects. this is why we always recomend people to take alpha lipoic acid after they take MDMA, significantly reducing the effects of the metabolites on serotonin receptors.

 

[zorn]

dustbin--
You make some good points, thanks for responding.
"This study doesn't permit any conclusions as to a possible neurotoxicity. Ricaurte measured only 5-HT and 5-HIAA levels. It has been shown that MDMA-induced decrease in 5-HT and 5-HIAA leves can occur independently of changes in 5-HT uptake sites (Insel et al. 1989). Thus reductions in 5-HT and 5-HIAA alone can not be considered as a reliable indicator of neurodegeneration."
Insel's JPET paper did find a dose range of MDMA that would lower long-term 5HT/5HIAA levels without noticable , and I saw it in some others as well. Vollenweider's group in Zurich seems to think this makes 5-HTP and 5-HIAA binding an unreliable measure of neurotoxicity, whereas Ricaurte&McCann's (aww, they're married, how cute) group at Hopkins thinks otherwise. Now a long-term, dose-dependent drop in brain serotonin levels seems pretty sketchy to me. Additionally studies (including Schmidt's)have shown that post-MDMA SSRI administration blocks this drop. So the long-term 5-HTP/5-HIAA drop is a dose-dependent effect with the same timecourse as neurotoxicity, and is independent of the subjective effects. Now it's still possible that this drop in 5-HTP not a sign of anything "bad," but I doubt it, especially since 5-HTP/5-HIAA levels are generally a good marker of serotonin function. Perhaps there is damage to the axons which lowers their ability to produce and export serotonin, but does not destroy the terminals. I also question if 5-HTP levels might simply be a more sensitive measure than SSRI receptor binding.
"The axon terminal has some protective reductive capabilities against reactive oxidizing species, thus if the damage is due to oxidative stress, I could imagine that there would be some treshold level."
Yes; the axon's protective capabilities derive from the presence of natural noncritical antioxidant species which "sacrifice" themselves for the greater good of the organism. These will provide a buffer against damage from oxidizing radicals until they are depleted, but they will not necessarily fully block damage. One would indeed expect there to be a threshold level of the oxidizing agent, below which damage would be insignificant. Whether there is also a nontrivial threshold time below which significant damage will not accumulate, with an eventually damaging dose of the oxiding radicals, is less clear. It depends on a number of factors including the concentrations, affinities, and kinetics of the protective and damaging species. There could well be such a period; or damage could start accumulating near-immediately.
My reason for believing there is not a safety window comes from a look at Schmidt et al's data. The error levels make it impossible to draw conclusions with certainty, but the data suggests a linear dropoff. Offhand, 5HT levels of 3h vs 0h are off by 2sigma, and 3h vs control by 1sigma. This gives a probability of 84-93% that there is some 5HT depletion at 3h, depending how you do the analysis. This isn't enough to make a definite conclusion, but in the absence of other evidence, the smart money is on 3h not being safe.
I hadn't read Vollenweider et al's response... they make some interesting points; sadly, knowing very little pharmacology, I can't comment on the debate. Hopefully studies of the neurotoxic dose of MDMA in other species will as suggested confirm or deny the validity of this "allometric" scaling. I was happy though not surprised to hear that their study found no change in 5-HT transporter density after administering 1.7mg/kg to their human subjects. I would be very interested in whether CSF 5-HT or 5-HIAA levels were at all lowered in these subjects.
Let me say that I'm not claiming it's clear that single doses of ~100mg MDMA are neurotoxic in humans. In fact I tend to doubt it; McCann et al's 1998 study found only an average 25% drop in serotonin levels in people with an average of 228 uses, 3.9 pills/use.
"The half-life of 5-HTP is about 5 hours."
There's a couple problems here. First, the study you referenced was discussing the kinetics of simultaneous carbidopa and 5-HTP. Carbidopa is an inhibitor of peripheral decarboxylase, which takes 5-HTP to 5-HT, as well as l-dopa to dopamine. (It does not pass the BBB, so is often used with l-dopa during therapy for Parkinsonian, to prevent the l-dopa from getting metabolized outside the brain. You could similarly use it with 5-HTP to increase the mental effects.) As 95% or something the body's serotonin is outside the brain, it slows the pharmacokinetics somewhat. Without carbidopa, the half-life is something like 2 hours. Similarly the rate constant decarboxylation of 5-HTP->5-HT in the brain is 0.007/min, eg a half-life of 99 min. See Acta Pharmacol Toxicol (Copenh) 1978 Jul;43(1):36-42 or J Neural Transm Gen Sect 1992;88(1):1-10.
In any case, there is a difference between the half-life and rate of 5HT production. Since brain 5-HT is such a small portion of total body 5-HT, even rapid synthesis of brain 5-HT may not effect the overall pharmacokinetics. The main concern is how quickly brain 5-HT stores are replenished by reasonable doses of 5-HTP. With first-order kinetics, the t=0 production rate will be ln(2)*dose/halflife.
There may also be homeostatic mechanisms at work which would increase the rate of 5-HTP brain uptake or 5-HT synthesis during 5-HT depletion. Annoyingly, I can't find decent info online on 5-HTP pharmacokinetics. This paper below looks promising: JPET 1976 Jun;197(3):545-55. Maybe I'll go check it out in (gasp) print.
If this isn't convincing, take a look at the MDMA papers involving 5-HTP: Sprague et al found pretreatment with 50mg/kg ip 5-HT 30 min before 20mg/kg ip MDMA fully blocked neurotoxicity; Gudelsky et al found it massively boosted both MDMA-induced serotonin and dopamine levels. This is a lot in human terms, but you get the point... and the ratio of MDMA vs. 5-HTP is not unlike that in people.
http://www.erowid.org/chemicals/mdma/articles/pdf/1996_gudelsky_1.pdf http://www.erowid.org/chemicals/mdma/articles/pdf/1994_sprague_1.pdf
Final rant: Someone should really be pursuing studies on the blockade of MDMA-induced neurotoxicity in humans, and pushing for the dissemination of information about this! I am SO aggravated by the US government's apparent belief in harm maximization.

 

[zorn]

djremix --
Vit C or ALA don't really do a whole lot besides be antioxidants, so they shouldn't do anything to your roll... I'd be shocked if they did. Not sure about Prozac/5-HTP safety, maybe someone else knows.
day_for_night --
Yup, I didn't mean that many bluelighters didn't also believe above stuff... just that I often saw people state the converses as facts, which they aren't.
Care,
zorn

 

[Drug Dustbin]

"Perhaps there is damage to the axons which lowers their ability to produce and export serotonin, but does not destroy the terminals."
May be that the tryptophan hydroxylase is inactivated by oxidation with lower dosages than the actual axon terminal damage happens.
"There's a couple problems here. First, the study you referenced was discussing the kinetics of simultaneous carbidopa and 5-HTP."
This was totally my error. I misquoted my own notes. The half-life of 5-HTP without peripheral decarboxylase inhibitor is about 2 hours, as you noted.
For the rest of your article I suggest the following articles:
Reibring L, Agren H, Hartvig P, Tedroff J, Lundqvist H, Bjurling P, Kihlberg T, Langstrom B.
Uptake and utilization of [beta-11C]5-hydroxytryptophan in human brain studied by positron emission tomography.
Psychiatry Res. 45(4):215-25, 1992.
Agren H, Reibring L, Hartvig P, Tedroff J, Bjurling P, Hornfeldt K, Andersson Y, Lundqvist H, Langstrom B.
Low brain uptake of L-[11C]5-hydroxytryptophan in major depression: a positron emission tomography study on patients and healthy volunteers.
Acta Psychiatr Scand. 83(6):449-55, 1991.
And about the synthesis rate of serotonin (the whole way, not only 5-HTP->5-HT conversion):
Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, de Montigny C, Blier P, Diksic M.
Differences between males and females in rates of serotonin synthesis in human brain.
Proc Natl Acad Sci U S A. 94(10):5308-13, 1997.
"If this isn't convincing, take a look at the MDMA papers involving 5-HTP: Sprague et al found pretreatment with 50mg/kg ip 5-HT 30 min before 20mg/kg ip MDMA fully blocked neurotoxicity; Gudelsky et al found it massively boosted both MDMA-induced serotonin and dopamine levels. This is a lot in human terms, but you get the point... and the ratio of MDMA vs. 5-HTP is not unlike that in people".
I think the interesting question here is that the results of Gudelsky et al. suggest that preloading with 5-HTP would increase the effects of MDMA, but the clinical evidence (which I have read here in Bluelight) suggest that this is not necessarily the case.

 

[Vorticity]

In both those papers, something else was always added in with the 5-htp. In Gudelsky it was carbidopa (what is that anyway?) and in Sprague it was "RO 4-4602". Are these substances which help the 5-htp get into the brain, or not be destroyed along the way?
And could this be why 5-htp doesn't have a profound effect in humans?

 

[zorn]

Yeah, those are peripheral decarboxylase inhibitors; I should have mentioned that.
dustbin you mention the clinical evidence -- do you mean you have seen actual clinical trials on the effect of 5-HTP w/MDMA in humans, or just anecdotal reports? The reports I have seen differ widely, with many people swearing 5-HTP has an effect that "can't be placebo," many saying it was totally ineffective, and some saying it reduced the effects of E. Individual variation or placebo effects might account for these differences; my point is that 5-HTP->5-HT synthesis is not so slow that preloading would necessarily have no effect.
"May be that the tryptophan hydroxylase is inactivated by oxidation with lower dosages than the actual axon terminal damage happens."
In a cruel twist of fate, TPH's structure happens to make it especially vulnerable to oxidation, so it may indeed be one of the first things to go. The important question is then the turnover rate of TPH in the brain when it's been depleted. If it's more than a couple weeks, temporary TPH-depletion could explain the lowered 5-HT/5-HIAA levels, and we have a bigger margin of safety. If it's only a few days to a week, which I suspect, this explanation is outta luck. It'd be surprising if Ricaurte et al missed this, but who knows? Unfortunately I don't know TPH's turnover rate and couldn't find anything in a cursory Medline search. Anyone else know?
The bigger question here is whether waiting two weeks after MDMA administration is enough to eliminate any transient effects. Waiting longer would be better in this case, but then the strange recovery patterns Ricaurte et al observed (over-innervation in some areas, under-innervation in others) might confound measurements of toxicity.
Have you gotten a chance to look at those Reibring, Agren, Hartvig et al papers? The abstracts look interesting, but I don't have access to Psychiatry Res, and certainly not to Acta Psychiatr Scand, unless I pay to order copies. Couldn't really see the relevance to the current discussion though.
Finally the PNAS paper, while very interesting stuff, seems to have limited relevance here as well. It did contain a godsend: "Using the postmortem concentrations of serotonin reported by Young et al. (34) for the putamen (466 ng/g) and temporal cortex (11 ng/g), and the present data for the rates of serotonin synthesis, the time required to synthesize an amount of serotonin equal to the tissue content is 31 and 48 min for the putamen of males and females, respectively, and 0.8 and 1.3 min, respectively for the temporal cortex." Those numbers are of course dependent upon sufficient concentrations of l-tryptophan; they jump to 310 & 192 / 8 & 52 minutes for male & female cortex and putamen respectively after tryptophan depeletion.
So as I suggested above, reasonable levels of 5-HTP should allow the brain to quickly replenish its serotonin stores; in fact more quickly than above, as they were using radiolabelled tryptophan to measure the full synthesis time. Since the half-life of 5-HTP is about 2 hours, one would presumably want to take this compound very close to the time one ingested MDMA if using it to try and keep up 5HT levels. Of course this says nothing about whether 5HTP boosting 5HT release or the subjective response from MDMA.
Also this suggests to me that the depression of serotonin levels for several days post-MDMA, probably linked to the post-MDMA depression many people experience, requires additional explanation besides MDMA-induced depletion of serotonin stores, since these stores, with an adequate diet, should be replenished within hours. Two possibilities come to mind. The long half-life of MDMA may mean that it is keeping 5HT levels relatively low long after the roll has ended. Or the destruction of TPH discussed above may lead to a short term inability to fully synthesize serotonin. This agrees with the reported ability of 5-HTP postloading to eliminate the post-MDMA depression, since 5-HTP->5-HT does not require TPH.
Thanks to drug_dustbin and everyone else for adding to this discussion... it's making me learn a fair bit. Care,
zorn
[This message has been edited by zorn (edited 16 November 2001).]

 

[FrolicAtNight]

Great thread guys! Since we're talking pre-loading/post-loading, do you have any research and/or experience with SNRI's like Effexor?
Is it better to use a Re-uptake specific SSRI or take advantage of an SNRI (i.e. Effexor-venlafaxine hydrochloride) broader re-uptake capabilities- serotonin and norepinephrine. Any comments would be more than helpful.
Hope you're having a great day!

 

[zorn]

Frolic-
I don't know of any reason an SNRI would really be useful. MDMA stimulates some NE release, but it's not known to be neurotoxic at NE synapses. So SNRIs vs SSRIs shouldn't make too much of a difference, given that your SNRI is sufficiently effective at blocking SE reuptake transporters. I'd err on the safe side and use SSRIs which have been shown effective in animals, eg fluoxetine, paroxetine, citalopram, etc.
-zorn
[This message has been edited by zorn (edited 16 November 2001).]