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Methylphenidate neurotoxic?

methylphenidate mph neurotoxic

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#1 NeuroNootropic

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Posted 14 January 2013 - 10:51 PM


I've always read on these forums that MPH is neuroprotective, but then I stumbled upon this study:

[reference='http://www.plosone.o...ology/Principal Findings

Through the use of stereological counting methods, we observed a significant reduction (~20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri​dine(MPTP). Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigra (SN) were observed with both acute and chronic dosing of 10 mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum, although these were seen only at an acute dose of 10 mg/kg and not following chronic dosing.

Conclusion

Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences.[/reference]

I was just about to start taking MPH too. Can someone more knowledgeable than me please comment on these findings?

#2 jillin

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Posted 15 January 2013 - 02:38 AM

http://www.plosone.o...al.pone.0033693

From figure 1-J, 1mg/kg MPH + no MPTP shows only a slight decrease when compared against control + MPTP; however, this is still worrying as MPTP induces the typical Parkinsonian symptopathology. As for the 10mg/kg groups, it doesn't surprise me that the data shows marked dopaminergic neurodegeneration, as 10mg/kg is an absurdly high dosage. With that said, thank you for bringing this article to light, it was an interesting read, and it made me very thankful for only needing 5mg per day of MPH to treat my ADHD (down from the usual 20mg per day) -- thanks to Cerebrolysin.

http://www.ncbi.nlm....les/PMC2701286/

In this article, they talk about the proposed neuroprotective mechanism of MPH.. in the case of METH-induced toxicity.

Edited by jillin, 15 January 2013 - 02:50 AM.


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#3 gray.bot

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Posted 15 January 2013 - 03:36 AM

Yet another reason to be taking Selegiline for anti-aging...

I haven't had a chance to take methylphenidate with selegiline, but I'm sure the mix would be radical :)

Because anything else that increases dopamine (whether releasing it, preventing reuptake, or resensitizing receptors) seems to be wickedly enhanced by selegiline.

Next stop, cerebrolysin with selegiline experiments!

(that's the one you inject in your butt right?) :P

#4 NeuroNootropic

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Posted 15 January 2013 - 04:07 AM

http://www.plosone.o...al.pone.0033693

From figure 1-J, 1mg/kg MPH + no MPTP shows only a slight decrease when compared against control + MPTP; however, this is still worrying as MPTP induces the typical Parkinsonian symptopathology. As for the 10mg/kg groups, it doesn't surprise me that the data shows marked dopaminergic neurodegeneration, as 10mg/kg is an absurdly high dosage. With that said, thank you for bringing this article to light, it was an interesting read, and it made me very thankful for only needing 5mg per day of MPH to treat my ADHD (down from the usual 20mg per day) -- thanks to Cerebrolysin.

http://www.ncbi.nlm....les/PMC2701286/

In this article, they talk about the proposed neuroprotective mechanism of MPH.. in the case of METH-induced toxicity.


My psychiatrist prescribed me 30 mg of Biphentin (extended release MPH). Would this dose cause neurotoxicity according to the study?

#5 jillin

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Posted 15 January 2013 - 04:47 AM

So your MPH dosage is roughly half of what the study deemed to be the base line "chronic" dosage. I can't tell you that chronic use of such a dosage can be neurotoxic as it is not within my scope of practice/knowledge yet, I am just a graduate student. However, from my previous post, the data from this study still warrants concern, as the control + MPTP group showed more dopaminergic neurons than the 1mg/kg MPH w/o MPTP. MPTP is a very potent, fast acting, and highly selective dopaminergic neurotoxin -- it is a fearsome substance; we are talking about artificially inducing late stage (4-5) Parkinsonian symptopathology. So, with that knowledge and using it to compare with the 1mg/kg MPH w/o MPTP group, it is very worrisome that the highly potent and dangerous neurotoxin, MPTP, still manages to have more dopaminergic cells than the 1mg/kg MPH alone group. Also a word of warning, I only did a quick skim of the article and of the figures -- I could have missed something vital. I am at the library and looking through longecity on my tablet during my study breaks, so take what I say with a grain of salt.

#6 NeuroNootropic

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Posted 15 January 2013 - 07:15 AM

The study has to be flawed then. This is the first time I've heard a NDRI can kill dopamine cells. If this is true then amphetamines are less neurotoxic than methylphenidate.

Edit: So apparently the mice they used are resistant to MPTP neuron loss which is why it didn't affect them much. MPTP itself is not neurotoxic, but is metabolized into MPP+ in the brain by MAO-B so the mice they used are probably deficient in MAO-B. They used the Swiss-Webster strain in case anyone is interested.

Someone also voiced their concern over this study and the authors responded to it: http://www.plosone.org/annotation/listThread.action?root=53905

Still, a 20% reduction in dopaminergic neurons in the Substantia nigra from therapeutic MPH doses is significant and worrying. The authors stated that the plasma levels of mice treated intraperitoneal injection with MPH were comparable to that of a human taking a therapeutic dose of MPH.

As far as I'm concerned, the Substantia nigra does not regrow or regenerate dopaminergic neurons, correct? Isn't this the reason why Parkinson's get's worse and not better regardless of what treatment the patient is getting? However, this study suggests that Rasagiline regenerates SN neurons:

The anti-Parkinson drug rasagiline (Azilect), an irreversible and selective monoamine oxidase (MAO)-B inhibitor, was shown to possess neuroprotective activities, involving multiple survival pathways among them the up-regulation of protein kinase C (PKC)alpha, PKCepsilon, the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w and the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF). More recently, employing conventional neurochemical techniques, as well as transcriptomic and proteomic screening tools, combined with a biology-based clustering method, it was shown that rasagiline also possesses neurorescue/neurogenesis activity in mice midbrain dopaminergic neurons when given chronically, post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This action was attributed to the activation of cell signaling mediators associated with neurotrophic factors responsive-tyrosine kinase receptor (Trk) pathway, including ShcC, SOS, AF6, Rin1, and Ras and the increase in the Trk-downstream effecter phosphatidylinositol 3 kinase (PI3K) protein and its substrate, Akt/PKB. It is interesting to determine whether a similar effect is seen in Parkinsonian patients after long-term treatment with rasagiline, which may have implications as a possible disease modifying agent.

→ source (external link)


I'm just not sure anymore. Is it worth it to take MPH?

Edited by NeuroNootropic, 15 January 2013 - 08:09 AM.

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#7 NeuroNootropic

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Posted 15 January 2013 - 08:49 AM

I found a discussion on this over at the addforums: http://www.addforums...ad.php?t=122014

They think that mice and human dosages are equivalent, i.e. 1 mg/kg for a mouse is the same as 1 mg/kg for a human. I guess they don't know the doses are supposed to be converted. So 1 mg/kg for a mouse would be 1 * 0.081 = 0.081 mg/kg for a human and 10 mg/kg for a mouse would be 0.81 mg/kg for a human.

#8 jillin

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Posted 16 January 2013 - 02:14 AM

Your wording is a bit confusing but I think you understand the concept of converting mg/kg dosages for mice and for humans. However, I will just explain it briefly: the average lab mouse weighs roughly 20 grams; 20g = 0.02kg; 1mg * 0.02kg = 0.02mg dosage for said mouse. For humans, we take the calculated animal (20gram) dosage of 0.02mg * Km factor (the surface area to weight ratio) ratio between model animal and human; so the human equivalent dosage for said 1mg/kg animal dosage is: 0.02mg * [(km for animal, 3 for a mouse of weight 20grams)/(km for an adult human, 37 for an adult of weight 60kg)]. One would then get a human equivalent dosage of 0.0812mg/kg -- which then goes to be extrapolated with respective human weight of interest for pertinent dosage. Also, I apologize as I have not been able to read your first post due to Uni responsibilities -- however, I will do so on the weekend and tell you what I think about it. With that said, I don't think you should worry about taking MPH for your ADHD due to fears of possibly developing Parkinsons down the road. If it puts you at ease, throughout my academic career, both undergraduate in Neuroscience, and graduate, I have not read a study about chronic MPH use showing a correlation in an increase chance of developing Parkinsons. However, off the top of my head, I can recall reading about 6-7 studies correlating chronic amphetamine usage with an increase chance of developing Parkinsons; in one study, the risk chance was ~16%, if my memory serves me right.

I found a discussion on this over at the addforums: http://www.addforums...ad.php?t=122014

They think that mice and human dosages are equivalent, i.e. 1 mg/kg for a mouse is the same as 1 mg/kg for a human. I guess they don't know the doses are supposed to be converted. So 1 mg/kg for a mouse would be 1 * 0.081 = 0.081 mg/kg for a human and 10 mg/kg for a mouse would be 0.81 mg/kg for a human.


Edited by jillin, 16 January 2013 - 02:50 AM.


#9 jillin

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Posted 16 January 2013 - 03:41 AM

Apologies, 0.0812 is the km factor of the mice over humans, so 0.0812 * 0.02mg (chronic dosage for 20gram mouse) = human equivalent dosage, which would be 0.0016mg/kg. Also, MPTP is neurotoxic in my book, regardless of its initial inert structural chemistry. If one were to deem something to be a non-neurotoxin based solely on their initial inert properties, I could then say MDMA or certain long-chained hydrocarbons (i.e. hexane, heptane, etc etc) to be non-neurotoxins also; however this is not the case. If a substance, be it, in its initial structural chemical makeup, or in its metabolite constitutions, result in neurotoxicity -- it's a neurotoxin.

Edited by jillin, 16 January 2013 - 03:58 AM.


#10 InquilineKea

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Posted 09 March 2014 - 06:42 AM

Hmm.. there's also these two papers:

http://www.ncbi.nlm....pubmed/22968482
http://www.sciencedi...006899306000606

Some more reading:
http://www.reddit.co..._neurotoxicity/
http://www.definitiv...read.php?t=1157

I'm not totally sure what to believe right now. Though I would not be too concerned yet, as there is evidence in both directions.

Edited by InquilineKea, 09 March 2014 - 06:49 AM.

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#11 Saffron

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Posted 09 March 2014 - 11:50 AM

Releasers are worse then reuptake inhinhitors, so of MPH is toxic this is a sad finding.

My favorite anti-oxidant for the brain is Lipoic Acid or R-Lipoic Acid. People should not take irreversible MAO-B inhibitors. They should use a reversible one & at a dose thats below 50% inhibition. With irreversibles you would have to take it like once every 4 days and at a dose below 50% inhibition.

#12 lammas2

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Posted 09 March 2014 - 06:32 PM

People should not take irreversible MAO-B inhibitors. They should use a reversible one & at a dose thats below 50% inhibition. With irreversibles you would have to take it like once every 4 days and at a dose below 50% inhibition.

Why?
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#13 Nobility

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Posted 09 March 2014 - 08:48 PM


Methylphenidate is good. but at the same time, well in my opinion; there will be much better/safer/etc version of something just like




Methylphenidate in the future???

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#14 xks201

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Posted 11 March 2014 - 06:14 AM

I would surmise that genetics have a lot to do with how neurotoxic it is. If you already have a problem with dopamine metabolism, which adderall and ritalin have been proven in some cases to correct - perhaps it is not so toxic. If you do not have these mutations then it is possible it is quite toxic.





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