FrolicAtNight
Bluelighter
Thanks for the post Zorn. Aside from the SNRI and SSRI info, can you give any useful information on a post-loading routine to prevent neurotoxicity- following MDMA. Thanks!
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H&R Moderators: VerbalTruist
MDMA/neurotoxicity misconceptions (long)
- Thread starter zorn
- Start date
fairnymph
Ex-Bluelighter
^^^
High doses of ALA (alpha lipoic acid) or other antioxidants (I take multiple doses of 600 mg, when dropping, when coming down, and the next morning), as well as 5-htp, which you may already know about (I take 200 mg when dropping, then 300 mg when I come down, 200 mg again in the morning when I wake up).
Frolic -- see my response also in the Effexor and e thread.
High doses of ALA (alpha lipoic acid) or other antioxidants (I take multiple doses of 600 mg, when dropping, when coming down, and the next morning), as well as 5-htp, which you may already know about (I take 200 mg when dropping, then 300 mg when I come down, 200 mg again in the morning when I wake up).
Frolic -- see my response also in the Effexor and e thread.
Drug Dustbin
Bluelighter
"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?"
I meant anecdotal reports read from here Bluelight.
"Unfortunately I don't know TPH's turnover rate and couldn't find anything in a cursory Medline search".
This article might answer some of your questions:
Schmidt CJ, Taylor VL.
Depression of Rat Brain Tryptophan Hydroxylase Activity Following
the Acute Administration of Methylenedioxymethamphetamine.
Biochemical Pharmacology 36(23):4095-4102, 1987.
"Have you gotten a chance to look at those Reibring, Agren, Hartvig et al papers?"
Yes. I usually have in my bookshelve the papers I refer to. Just mentioned them beacause you seemed to be interested about the regulation of 5-HTP utilization.
"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".
I agree. Have you noted that even in rats treated with neurotoxic dosages of MDMA, the levels of serotonin are in about control levels after 24 hours of MDMA administration (and then they begin to lower again)?
[This message has been edited by Drug Dustbin (edited 16 November 2001).]
I meant anecdotal reports read from here Bluelight.
"Unfortunately I don't know TPH's turnover rate and couldn't find anything in a cursory Medline search".
This article might answer some of your questions:
Schmidt CJ, Taylor VL.
Depression of Rat Brain Tryptophan Hydroxylase Activity Following
the Acute Administration of Methylenedioxymethamphetamine.
Biochemical Pharmacology 36(23):4095-4102, 1987.
"Have you gotten a chance to look at those Reibring, Agren, Hartvig et al papers?"
Yes. I usually have in my bookshelve the papers I refer to. Just mentioned them beacause you seemed to be interested about the regulation of 5-HTP utilization.
"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".
I agree. Have you noted that even in rats treated with neurotoxic dosages of MDMA, the levels of serotonin are in about control levels after 24 hours of MDMA administration (and then they begin to lower again)?
[This message has been edited by Drug Dustbin (edited 16 November 2001).]
Zorn, you may be interested is reading this (long)...it's a FDA report on the drug Pondimin (a serotonin agonist)...there is quite a bit of discussion on serotonin neurotoxicity (the identical neurotoxicity seen in MDMA use)...
http://fdagov.google.com/fdagov?client=fdagov&q=cache%3Ahttp%3A%2F%2Fwww%2Efda%2Egov%2Fohrms%2Fdockets%2Fac%2F95%2F3132t1%2Epdf+pondimin%20and%20neurotoxicity
http://fdagov.google.com/fdagov?client=fdagov&q=cache%3Ahttp%3A%2F%2Fwww%2Efda%2Egov%2Fohrms%2Fdockets%2Fac%2F95%2F3132t1%2Epdf+pondimin%20and%20neurotoxicity
zorn
Bluelighter
djboi --
Thanks, that's kinda cool. I had heard about Ricaurte testifying against the use of fenfluoramine, but hadn't ever seen an actual transcript. Makes you think about the kind of risk judgments authorities make wrt clinically acceptable drugs that may increase someone's lifespan and unacceptable drugs which may make them happier than normal.
Frolic--
Based on everything I've read, I would suggest a regimin similar to fairnymph's. 800mg sustained-release ALA / 1g vitamin C with or before dropping. Another 1mg vitamin C and 40mg fluoxetine (or equivalent) when the comedown begins to hit. Another 1g vit C / 800mg ALA early the next morning. 5-HTP isn't IMO as important; if you want to do it 200-300mg seems to be the largest amount that ppl will tolerate and so a good bet would be that while dropping, during comedown, and next morning.
In practice I prefer not to mess with 5-HTP and its possible effect on a roll, and ALA can be a pain to get and expensive. I would suggest 2g vit C with the E, 1mg vit C + 40mg citalopram with the beginning of the comedown, and 1.5g vit C the next morning. This would cover me with two probable neurotoxicity blockers acting through different mechanisms. The antioxidant holds the fort down until I'm convinced the SSRI won't mess up my roll and the whole reason I'm risking neurotoxicity in the first place.
Lol, going to a desert party on the night of the most spectacular Leonid shower in years.... I am so excited.
Care,
Zorn
[This message has been edited by babydoc_vic (edited 18 November 2001).]
Thanks, that's kinda cool. I had heard about Ricaurte testifying against the use of fenfluoramine, but hadn't ever seen an actual transcript. Makes you think about the kind of risk judgments authorities make wrt clinically acceptable drugs that may increase someone's lifespan and unacceptable drugs which may make them happier than normal.
Frolic--
Based on everything I've read, I would suggest a regimin similar to fairnymph's. 800mg sustained-release ALA / 1g vitamin C with or before dropping. Another 1mg vitamin C and 40mg fluoxetine (or equivalent) when the comedown begins to hit. Another 1g vit C / 800mg ALA early the next morning. 5-HTP isn't IMO as important; if you want to do it 200-300mg seems to be the largest amount that ppl will tolerate and so a good bet would be that while dropping, during comedown, and next morning.
In practice I prefer not to mess with 5-HTP and its possible effect on a roll, and ALA can be a pain to get and expensive. I would suggest 2g vit C with the E, 1mg vit C + 40mg citalopram with the beginning of the comedown, and 1.5g vit C the next morning. This would cover me with two probable neurotoxicity blockers acting through different mechanisms. The antioxidant holds the fort down until I'm convinced the SSRI won't mess up my roll and the whole reason I'm risking neurotoxicity in the first place.
Lol, going to a desert party on the night of the most spectacular Leonid shower in years.... I am so excited.
Care,
Zorn
[This message has been edited by babydoc_vic (edited 18 November 2001).]
zorn
Bluelighter
dustbin--
Thanks for pointing out that article, I should have thought to look for articles on MDMA and TPH... silly me. Haven't had a chance to look at the paper yet, but the article below cites it claiming TPH levels are depressed "up to two weeks" after a single 10mg/kg MDMA injection; guessing this means at two weeks TPH levels are back to normal. So they probably wouldn't be responsible for lowered 5-HT levels. I am getting quite curious about this long-term 5-HT drop with no corresponding loss of receptor density... want to know what the hell is going on.
Stone DM, Hanson GR, Gibb JW. J Neurochem, 1989; 53(2):572-81
Yes, I had noticed the rebound in serotonin levels, seems kinda odd. It could be a result of temporary continued serotonin release/recycling by the dying axons, or perhaps the result of the a slow marshalling of 5-HTP or serotonin stockpiles. Neither guess seems particularly compelling though.
Care,
Zorn
Thanks for pointing out that article, I should have thought to look for articles on MDMA and TPH... silly me. Haven't had a chance to look at the paper yet, but the article below cites it claiming TPH levels are depressed "up to two weeks" after a single 10mg/kg MDMA injection; guessing this means at two weeks TPH levels are back to normal. So they probably wouldn't be responsible for lowered 5-HT levels. I am getting quite curious about this long-term 5-HT drop with no corresponding loss of receptor density... want to know what the hell is going on.
Stone DM, Hanson GR, Gibb JW. J Neurochem, 1989; 53(2):572-81
Yes, I had noticed the rebound in serotonin levels, seems kinda odd. It could be a result of temporary continued serotonin release/recycling by the dying axons, or perhaps the result of the a slow marshalling of 5-HTP or serotonin stockpiles. Neither guess seems particularly compelling though.
Care,
Zorn
FrolicAtNight
Bluelighter
Zorn- great comments, awesome research, and insightful comments. At times I thought I was reading an open forum for a neurobiochemist convention. I graduated magna cum laude with a BS in chemistry and there were several sections that I had to pull out some books to brush up. Hats off! Have a great weekend!
so i guess the next step is to make a 6 hour sustained release capsule with 600mg ALA, 1g vit c, 2G piracetam, 150mg Co enz Q10, 200mg ibeduron(sp? supposed to be 10 times more powerfull than Q10), 300mg 5-htp.
and pop that along with your E.
and i thought everyone recommended 20mg prozac not 40mg??
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If you think life is really good, wait till you hear the REMIX!
and pop that along with your E.
and i thought everyone recommended 20mg prozac not 40mg??
------------------
If you think life is really good, wait till you hear the REMIX!
fairnymph
Ex-Bluelighter
20 mg Prozac should do it....
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You can be rich and still be a fucking moron loser who smokes crack all the time. -- Kyk
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You can be rich and still be a fucking moron loser who smokes crack all the time. -- Kyk
zorn
Bluelighter
Well, more SSRI's (at any reasonable level) won't hurt, so I figure it's best to err on the side of caution until research has definitively established an effective dose in humans. In fact, thinking about it again, the usual 20mg seems like it should be horribly ineffictive; 40mg would be as well. Uh-oh. This seems important enough for its own thread, so see http://www2.bluelight.ru/ubb/Forum15/HTML/003312.html , which I just typed up.
Care,
Zorn
Care,
Zorn
"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
I dont understand this. Are u saying the MDMA gets broken down by the body/liver etc and the metabolites go BACK INTO the brain and cause their damage?
If serotonin levels aren't the sole cause what about the effect on the receptors and the downregulation argument?
Is that more likely to be the cause of short term related MDMA probs.
-zorn
I dont understand this. Are u saying the MDMA gets broken down by the body/liver etc and the metabolites go BACK INTO the brain and cause their damage?
If serotonin levels aren't the sole cause what about the effect on the receptors and the downregulation argument?
Is that more likely to be the cause of short term related MDMA probs.
good work zorn.
the one interesting point i can see that the post is missing and would be nice to be added if its gunna become a FAQ post is a link or 2 about how neurotoxicity and hepatotoxicity are comepletely temperature dependant.
SirLSD
the one interesting point i can see that the post is missing and would be nice to be added if its gunna become a FAQ post is a link or 2 about how neurotoxicity and hepatotoxicity are comepletely temperature dependant.
SirLSD
zorn
Bluelighter
Biscuit--
Yes, that appears to be what happens. These metabolites then cause damage to the serotonergic axons and their serotonin receptors... probably in some dopamine- and temperature- dependent way. Interestingly, the same sort of systemic metabolism is necessary for methamphetamine neurotoxicity.
Short-term post-MDMA problems are likely a result of acute depletion of serotonin, damage to the serotonin-making enzyme TPH, or damage to the axons that (at least partially) heals quickly.
SirLSD--
Good point. The neurotoxicity of MDMA is very, very sensitive to the body's core temperature. Depressing this temperature just a couple degrees blocks all neurotoxicity, and raising it a few degrees greatly exacerbates the damage. A large number of agents protect against MDMA-induced neurotoxicity in animals by reducing the core temperature (sometime only when adminstered concurrently with MDMA), among them ketanserin, alpha-methyl-p-tyrosine, dantrolene, haloperidol (Haldol), and diazepam (Valium). High/low ambient temperatures have the same effect of increasing/decreasing both neurotoxicity and hepatotoxicity (liver damage). It should be noted that MDMA seems to acutely weaken the body's thermoregulation system, making one's body temperature naturally closer to the environmental temperature.
This should underline the importance of staying cool while taking MDMA. This can be difficult, as raves are often warm and dancing heats one up. Frequent breaks from dancing in a cool area and drinking plenty of cold fluids are both very good ideas.
http://www.erowid.org/chemicals/mdma/articles/pdf/1996_malberg_1.pdf (neurotoxicity) http://www.erowid.org/chemicals/mdma/articles/pdf/2001_carvalho_1.pdf (hepatotoxicity) http://www.erowid.org/chemicals/mdma/articles/pdf/1995_che_1.pdf (TPH damage)
A further cause for worry is that MDMA neurotoxicity appears to damage the body's natural thermoregulation ability. So some damage could lead to an inability to regulate temperature, which would cause the body's core temp to be higher in a warm enviroment (eg a rave), which would aggravate neurotoxicity even further... a vicious cycle. Furthermore, people who have damaged their serotonergic systems with too much MDMA use are probably at much higher risk for acute adverse reactions -- overheating, collapse, etc.
If you've done a lot of MDMA or have noticed corresponding memory or mood problems, the advice about staying cool goes double... be very careful.
http://www.erowid.org/chemicals/mdma/articles/pdf/1998_dafters_1.pdf http://www.erowid.org/chemicals/mdma/articles/pdf/2001_mechan_1.pdf
If the mods/administrators actually want to make this part of a FAQ, I'd be happy to clean it up and reorganize it, as it's sort of a long rambling discussion now.
Care,
Zorn
[This message has been edited by zorn (edited 21 November 2001).]
Yes, that appears to be what happens. These metabolites then cause damage to the serotonergic axons and their serotonin receptors... probably in some dopamine- and temperature- dependent way. Interestingly, the same sort of systemic metabolism is necessary for methamphetamine neurotoxicity.
Short-term post-MDMA problems are likely a result of acute depletion of serotonin, damage to the serotonin-making enzyme TPH, or damage to the axons that (at least partially) heals quickly.
SirLSD--
Good point. The neurotoxicity of MDMA is very, very sensitive to the body's core temperature. Depressing this temperature just a couple degrees blocks all neurotoxicity, and raising it a few degrees greatly exacerbates the damage. A large number of agents protect against MDMA-induced neurotoxicity in animals by reducing the core temperature (sometime only when adminstered concurrently with MDMA), among them ketanserin, alpha-methyl-p-tyrosine, dantrolene, haloperidol (Haldol), and diazepam (Valium). High/low ambient temperatures have the same effect of increasing/decreasing both neurotoxicity and hepatotoxicity (liver damage). It should be noted that MDMA seems to acutely weaken the body's thermoregulation system, making one's body temperature naturally closer to the environmental temperature.
This should underline the importance of staying cool while taking MDMA. This can be difficult, as raves are often warm and dancing heats one up. Frequent breaks from dancing in a cool area and drinking plenty of cold fluids are both very good ideas.
http://www.erowid.org/chemicals/mdma/articles/pdf/1996_malberg_1.pdf (neurotoxicity) http://www.erowid.org/chemicals/mdma/articles/pdf/2001_carvalho_1.pdf (hepatotoxicity) http://www.erowid.org/chemicals/mdma/articles/pdf/1995_che_1.pdf (TPH damage)
A further cause for worry is that MDMA neurotoxicity appears to damage the body's natural thermoregulation ability. So some damage could lead to an inability to regulate temperature, which would cause the body's core temp to be higher in a warm enviroment (eg a rave), which would aggravate neurotoxicity even further... a vicious cycle. Furthermore, people who have damaged their serotonergic systems with too much MDMA use are probably at much higher risk for acute adverse reactions -- overheating, collapse, etc.
If you've done a lot of MDMA or have noticed corresponding memory or mood problems, the advice about staying cool goes double... be very careful.
http://www.erowid.org/chemicals/mdma/articles/pdf/1998_dafters_1.pdf http://www.erowid.org/chemicals/mdma/articles/pdf/2001_mechan_1.pdf
If the mods/administrators actually want to make this part of a FAQ, I'd be happy to clean it up and reorganize it, as it's sort of a long rambling discussion now.
Care,
Zorn
[This message has been edited by zorn (edited 21 November 2001).]
Excellent thread. Well done on your comprehensive research, Zorn.
Often overlooked are the potential of the brain-specific antioxidant herbs, such as Ginkgo Biloba. Quality extracts of ginkgo (24% ginkgo flavonglycosides and 6% terpenoids) have pronounced antioxidant function in the brain, and act to improve neuron function and blood flow to the central nervous system.
Perhaps more significant, is the study of ginkgo and its application in aging. As we age, there is a corresponding reduction in the number of serotonin receptor sites, making the elderly more susceptible to depression, insomnia and sleep disturbances.
A 1994 study indicated that ginkgo extract can counteract the age-dependent reductions of serotonin binding sites in the human brain. The precise mechanism was not determined, yet it is believed ginkgo counteracts two major causes of the reduced number of serotonin receptor sites:
1. Impaired receptor synthesis.
2. Changes in cerebral neuronal membranes
or receptors as a result of free-radical
damage.
Ginkgo is known to both increase protein synthesis, and is a potent antioxidant with an affinity for the brain. A combination of these actions may account for the overall effect.
Whilst this study addressed age-related serotonin problems, it may very well have implications in MDMA use, and the possible changes in serotonin receptors. If you choose to use a ginkgo extract as part of your antioxidant regimen, make sure it is a standardized, high quality one.
For reference:
F. Huguet et al., "Decreased Cerebral 5-HT1a Receptors During Aging: Reversal by Ginkgo Biloba Extract (Egb 761)," J Pharm Pharmacol 46 (1994): 316-8.
Often overlooked are the potential of the brain-specific antioxidant herbs, such as Ginkgo Biloba. Quality extracts of ginkgo (24% ginkgo flavonglycosides and 6% terpenoids) have pronounced antioxidant function in the brain, and act to improve neuron function and blood flow to the central nervous system.
Perhaps more significant, is the study of ginkgo and its application in aging. As we age, there is a corresponding reduction in the number of serotonin receptor sites, making the elderly more susceptible to depression, insomnia and sleep disturbances.
A 1994 study indicated that ginkgo extract can counteract the age-dependent reductions of serotonin binding sites in the human brain. The precise mechanism was not determined, yet it is believed ginkgo counteracts two major causes of the reduced number of serotonin receptor sites:
1. Impaired receptor synthesis.
2. Changes in cerebral neuronal membranes
or receptors as a result of free-radical
damage.
Ginkgo is known to both increase protein synthesis, and is a potent antioxidant with an affinity for the brain. A combination of these actions may account for the overall effect.
Whilst this study addressed age-related serotonin problems, it may very well have implications in MDMA use, and the possible changes in serotonin receptors. If you choose to use a ginkgo extract as part of your antioxidant regimen, make sure it is a standardized, high quality one.
For reference:
F. Huguet et al., "Decreased Cerebral 5-HT1a Receptors During Aging: Reversal by Ginkgo Biloba Extract (Egb 761)," J Pharm Pharmacol 46 (1994): 316-8.
heres something i noticed personally.
after mdma, if i take piracetam the following few days i notice its effects and they get more and more subtle as the days go by.
but afterwards i stop noticing any effects.like now if i take piracetam the effects are almost non noticible(havent done e in 3 weeks yaaay!)
any correlation u think?
------------------
If you think life is really good, wait till you hear the REMIX!
after mdma, if i take piracetam the following few days i notice its effects and they get more and more subtle as the days go by.
but afterwards i stop noticing any effects.like now if i take piracetam the effects are almost non noticible(havent done e in 3 weeks yaaay!)
any correlation u think?
------------------
If you think life is really good, wait till you hear the REMIX!
B
babydoc_vic
Guest
Hyperthermia is also related to MDMA induced nephropathy (kidney damage). This is a great article - MDMA - Does It Play a Causal Role in Nephropathy? by Podraza
zorn - do you know where to find that study by Farfel and Seidel that talks about diazepam reducing temp and toxicity? Out of those drugs listed, I think it would be the best to use with e to reduce temp - dantrolene is not exactly readily prescribed (unless you have MS or cerebral palsy), haloperidol is likely to cause extra-pyramidal side effects.
[ 16 June 2002: Message edited by: babydoc_vic ]
zorn - do you know where to find that study by Farfel and Seidel that talks about diazepam reducing temp and toxicity? Out of those drugs listed, I think it would be the best to use with e to reduce temp - dantrolene is not exactly readily prescribed (unless you have MS or cerebral palsy), haloperidol is likely to cause extra-pyramidal side effects.
[ 16 June 2002: Message edited by: babydoc_vic ]
Drug Dustbin
Bluelighter
"A further cause for worry is that MDMA neurotoxicity appears to damage the body's natural thermoregulation ability. So some damage could lead to an inability to regulate temperature, which would cause the body's core temp to be higher in a warm enviroment (eg a rave), which would aggravate neurotoxicity even further..."
I think this has been shown only in rodents. Also sleep deprivation causes thermoregulatory changes in rodents.
I think this has been shown only in rodents. Also sleep deprivation causes thermoregulatory changes in rodents.
enzyme inhibition?
So if it is now known that MDMA decomposition to HHMA (and then to its quinone) is the main route to neurotoxicity, and that decomposition to HHMA is via the liver enzymes CYP2D6, CYP1A2, CYP2B6, and CYP3A4:
http://www.erowid.org/references/refs_view.php?A=ShowDocPartFrame&ID=6440&DocPartID=5981
can we assume that inhibiting those enzymes will reduce MDMA neurotoxicity? CYP2D6 could be inhibited by pre-loading with quinidine sulfate for example.
So if it is now known that MDMA decomposition to HHMA (and then to its quinone) is the main route to neurotoxicity, and that decomposition to HHMA is via the liver enzymes CYP2D6, CYP1A2, CYP2B6, and CYP3A4:
http://www.erowid.org/references/refs_view.php?A=ShowDocPartFrame&ID=6440&DocPartID=5981
can we assume that inhibiting those enzymes will reduce MDMA neurotoxicity? CYP2D6 could be inhibited by pre-loading with quinidine sulfate for example.
qwe
Bluelight Crew
i'm wondering how this thread is in healthy living, when there was no healthy living in '01?