Amphetamine Neurotoxicity in Low (ADHD) Doses or The Bitch is Back: Ricaurte Returns

[Riemann Zeta]

New article: Mechan-Mayne A, Yuan J, Hatzidimitriou G, Xie T, Mayne A, McCann UD, Ricaurte GA (2005). Amphetamine treatment similar to that used in the treatment of adult ADHD damages dopaminergic nerve endings in the striatum of adult non-human primates. JPET XX: ADV. PRINT.

Abstract:

Pharmacotherapy with amphetamine is effective in the management of attention-deficit/ hyperactivity disorder (ADHD), now recognized in adults, as well as in children and adolescents. Here we demonstrate that amphetamine treatment, similar to that used clinically for adult ADHD, damages dopaminergic nerve endings in the striatum of adult non-human primates. Furthermore, plasma concentrations of amphetamine associated with dopaminergic neurotoxicity in non-human primates are on the order of those reported in young patients receiving amphetamine for the management of ADHD. These findings may have implications for the pathophysiology and treatment of ADHD. Further preclinical and clinical studies are needed to evaluate the dopaminergic neurotoxic potential of therapeutic doses of amphetamine, in children as well as adults.

http://www.ncbi.nlm.nih.gov/entrez/...d&dopt=Abstract&list_uids=16014752&query_hl=1

Or Directly at:

http://jpet.aspetjournals.org/cgi/reprint/jpet.105.087916v1

Upon cursory inspection, there is nothing wrong methodologically in this paper. The only strong contention that I have is whether or not reductions in striatal DAT and DA/DOPAC concentrations actually represent profound dopaminergic neurotoxicity. Ricaurte, et al certainly equate these molecular parameters with permanent dopaminergic nerve terminal damage, but that has not yet been adequately shown. Also, a perhaps weaker argument against these findings is the question of whether or not the baboon and human dopaminergic systems and mechanisms of preventing dopaminergic oxidative toxicity are isomorphic.

 

[Delta9]

After his bogus MDMA studies, Ricaurte could publish a study claiming that the Earth is round and I still wouldn't believe it.

But it does make sense that receiving therapeutic doses of amphetamines would cause temporary changes to your brain (isn't that the point?), but I think it's more important to find out how long lasting these changes are.

It seems like these researches like to throw around words like "damage" and "neurotoxicity" a little too much. If they used words like "temporary alteration" or "potential changes" in brain activity, the results of studies like this could be put into a more proper perspective.

 

[BilZ0r]

Yes, there is strong evidence that transporter density is not a legitamate measure of neurotoxicity...[1].

It would seem to be that "neurotoxicity" symptomatology in increasing doses goes 5-HT depletion then SERT removal then GFAP increase then raw neurological lesion, where a true lesion has begun somewhere between GFAP activation and SERT removal.

Still, it is surprising that this is the only study I am awear of looking at low dose amphetamine treatment, at the level of ADHD prescription, I think that would be a much better way to spend NIH funding.

 

[Delta9]

Still, it is surprising that this is the only study I am awear of looking at low dose amphetamine treatment, at the level of ADHD prescription, I think that would be a much better way to spend NIH funding.

I agree. Haven't amphetamines been used medicinally at low doses for decades? You would think there would be more studies about their long-term effects on the brain.

 

[Riemann Zeta]

One question that remains insofar as I know unanswered is why amphetamines (especially (S)-amphetamine and (S)-MDMA) do not cause damage to brain adrenergic systems. The consistent focus of amphetaminergic neurotoxicity studies is damage to serotonergic (and to a slightly lesser extent, dopaminergic) neurons. Obviously, amphetamines release NA--in fact, most amphetamines cause preferential release of NA in comparison to DA and 5-HT. Thus, neurotransmitter release via reversal transport through the reuptake transporter is not, in and of itself, cytotoxic. Another theory of amphetaminergic neurotoxicity posits that oxidative stress caused by metabolism of the massive amount of cytosolic and extracellular DA is responsible for the cytotoxic effect. Don't adrenergic neurons also take up DA via the NAT protein? Why then, is there no sign of adrenergic toxicity.

 

[Twacked Out]

someone tried to explain this to me a few years ago and I dont know one way or the other but she explained that it is because of the lack of a reuptake for NA(which I dont know if thats true or not) and went on to explain that most neurotransmitter damage with serotonin and dopamine is done at the reuptake, she was a good source but I dont know how current her info on the subject was as she is 20 years out of medical school, so that may be totally untrue and something that was believed "back then", but anyway its something to think about

 

[BilZ0r]

No one knows what causes neurotoxcity. What is interesting in my mind is that meth and MDMA are both neurotoxic, even though they have quite a number of chemical differenence... They need to make like a an animal that has certain metabolic enzymes knocked out in specific neurons... that should answer some questions.

 

[OpieBopie]

F*#k, I am already damaged!

 

[nuke]

Still, it is surprising that this is the only study I am awear of looking at low dose amphetamine treatment, at the level of ADHD prescription, I think that would be a much better way to spend NIH funding.

In fact it's a terrible way to make money. Pharmaceutical companies make enormous profits every year from the sales of amphetamines for ADHD/ADD, off-label usage, and to the military. This, specifically, is why there is tons of research on meth and MDMA and nearly none of amphetamine.

No one knows what causes neurotoxcity. What is interesting in my mind is that meth and MDMA are both neurotoxic, even though they have quite a number of chemical differenence... They need to make like a an animal that has certain metabolic enzymes knocked out in specific neurons... that should answer some questions.

I'm not even sure that'd do it, as it seems all amphetamines are neurotoxic so far if they a.) cause an elevation in temperature, b.) inhibit the reuptake of DA/NE to some extent, and c.) inhibit the reuptake of SER to some extent. Keep in mind you don't see neurotoxicity in rats until you get to huge IV doses of amphetamine, but that amphetamine does have a small affinity for serotonin neurons. However, AET has a completely different struture, all these properties, and seems to cause similar deficits to MDMA.. I think it may be something inherent with the metabolism of DA, NE, and/or SER in elevated temperatures, but maybe not.

 

[panic_the_digital]

I wouldn't necessarily trust him, but wasn't the problem with his MDMA neuotoxicity studies that he "accidentally" used meth instead of MDMA?

 

[nuke]

I wouldn't necessarily trust him, but wasn't the problem with his MDMA neuotoxicity studies that he "accidentally" used meth instead of MDMA?

Yeah, it'll remain a big blotch on his reputation forever...

Ricaurte has authored over 100+ peer reviewed studies however, to his credit, and even has clinical experience, something a many medical researchers do not. He was one of the foremost researchers in substituted-amphetamine induced neurotoxicity.

 

[Riemann Zeta]

Wow, my old thread has returned from the dead. Well, it has been two years and I have not seen a follow-up study from his lab or a similar finding from another lab. Thus far, this seems to have remained a single finding from an ethically questionable researcher.

 

[fastandbulbous]

I'm not even sure that'd do it, as it seems all amphetamines are neurotoxic so far if they a.) cause an elevation in temperature, b.) inhibit the reuptake of DA/NE to some extent, and c.) inhibit the reuptake of SER to some extent. Keep in mind you don't see neurotoxicity in rats until you get to huge IV doses of amphetamine, but that amphetamine does have a small affinity for serotonin neurons. However, AET has a completely different struture, all these properties, and seems to cause similar deficits to MDMA.. I think it may be something inherent with the metabolism of DA, NE, and/or SER in elevated temperatures, but maybe not.

Seems that it's all about serotonin. Catecholamines might increase the core body temp, but it takes serotonin to reset what the core temp should be - with that sort of hyperthermia, neurotoxicity just runs wild (if the 'thermostat' in the hypothalamus is reset by excess serotonin, that means the body reaches neurotoxic temps before all out cooling (vasodilation, sweating etc) is brought into play. That would explain why meth is so neurotoxic in comparison tp plain amphetamine - the serotonin reuptake that meth blocks impacts on the hypothalamus; amphetamine being not very effective at the SERT.

 

[Pimp Lazy]

I wouldn't necessarily trust him, but wasn't the problem with his MDMA neuotoxicity studies that he "accidentally" used meth instead of MDMA?

He was supplied by a DEA contracted chemical supply house. The drugs did not come into his hands directly. It could've been a poorly executed move on the part of drug-abolitionists or genius manipulation by the pro-drug forces… whoever and wherever they are . However, the fact remains that he should've tested his standards as well as the principle component the "MDMA" or meth in actuality. There are many possibilities.

 

[Reminisant B]

The double bluff theory

His career might already have been scarred by the MDMA / Meth mix up so doing a study which appears to go against pharm companies + government plans makes him look better.

Proponents of the ANTI-MDMA cause can now start citing his articles because his intentions show neutrality / scientific thinking.

Pharm companies selling amphetamines who risk being sued over neurotoxicity (with the help of expensive lawyers) can still however convince a judge that his science is bad citing the MDMA/Meth mix up.

I.e For the media, the science community in general his work can slowly be accepted as valid. Individual law suits by persons claiming damages from the pharm companies -> the METH/MDMA bad science argument can still be very effective in pursuading otherwise - possibly even highly effective at blurring the situation. I mean if you were a pharm company and were able to choose who published the eventual bad news that amphetamine in low doses can be toxic (hypothetically speaking) whose name would you prefer on the paper?


Ok so the above is a bit stretched I know but I wouldn't be surprised if their is some kind of hidden agenda, although who knows, maybe he's just trying to do his job right as a scientist.

 

[Crimethink]

I don't know the mechanism offhand for Amp. serotonergic damage but I think I can explain why amphetamine selectively damages striatal dopamine terminal but not noradrenergic.

While it is true that dopamine is taken up through the norepineprine transporter the degree to which this occurs is regionally dependent upon NET concentration and affinity such that according to the following paper NET DA transport is only signifigant in fronto-cortical areas.

http://www.jneurosci.org/cgi/content/abstract/22/2/389

As an aside I wonder if the disposition of NE transported dopamine is different in some way.

In any case the majority of neurtoxicity occurs in intracellular compartments according to the prevailing evidence. MAO-B inhibition provides little protection, whereas nomifensine a DA transporter inhibitor blocks the majority of neurotoxicity. Both DA-quinone and hydroxyl radicals play a role as measured by 5-cysteinyl-DA and salicylic acid formation of dihydroxybenzoic acid.

http://www.ncbi.nlm.nih.gov/entrez/...ve&db=PubMed&list_uids=10994696&dopt=Abstract

I think finding effective means of quenching amphetamine induced oxidative stress, DA & 5HT neurotoxicity is vitally important

Humans ordinarily lose ~4-14% of their nigral dopamine producing cells per decade as a matter of 'normal aging.' This IMO contributes to the typical hallmarks of old age such as: shuffling gait, reduced drive, becoming 'stuck in ones ways,' failure to swing arms while walking etc. These are all subclinical manifestations of Parkinson's, a disease which appears when 75%+ of dopamine producing cells are lost.

I think it is important for anyone using amphetamine in signifigant doses for a period of time to implement some strategy to negate this. Not only that but it's a good part of any life-extension program if you want to be old and still have energy(even if you don't use Amp). I've noticed more old-age smokers (when adjusted for health) don't fit the typical sub clinical parkinsons picture...they have a bit more 'spark.'

 

[vecktor]

Will people give Ricaurte a break,
he made a mistake, everyone does. He owed up to the mistake, and though I cannot remember the exact details but I think the mistake was highlighted by his own team rather than some third party. I don't remember him tryng to hide it, but I imagine he is rather pissed off that everything he now does is dismissed because of one mistake.
I think he has done a lot of interesting research and has a lot to say that we can learn from, like most it needs to be weighed up and balanced before it is extraopolated, but nevertheless, his work has great value but like some other researchers he tends to stretch the conclusions a little far, making unproven assumptions but this does lead to intersting discussions.

If anyone has any real evidence that he is running some kind of secret agenda and his work is tainted by it, let the world see it.

In an ideal world researh into amphetamine neurotoxicity would be carried out by independent scientists paid by an independent funding source, sadly we don't live in that world.

 

[phase_dancer]

I personally think his work deserves to be scrutinized, particularly as results of other studies by his team have also been questioned. Stretching conclusions or making unproven assumptions is bad and misleading science - nothing more.

This article was originally published in the New York Times: 2nd Dec, 2003.

Research on Ecstasy Is Clouded by Errors

I also once saw another list of errors and mistakes connected to some of Ricaurte's ealier work, but i'm damned if I can find it.

 

[Adrenochrome]

I'm pretty sure I've read that dextroamphetamine neurotoxicity is acchived at much higher concentrationswhen the environment is cold. conversly dextroamphetamine neurotoxicity is achieved at much lower concentrations when the environment is very hot and when rats are deprived of water (ie Dehydrated)

 

[Broshious]

I'm pretty sure I've read that dextroamphetamine neurotoxicity is acchived at much higher concentrationswhen the environment is cold. conversly dextroamphetamine neurotoxicity is achieved at much lower concentrations when the environment is very hot and when rats are deprived of water (ie Dehydrated)

This is true of MDMA as well. Temperature is very very important ( for reasons I don't understand ) in neurotoxicity.