
Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice - hoggle
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0033693
======
refurb
A quick read of the abstract indicates that loss of neurons only occurred in
mice at the higher dose (10 mg/kg).

Typical doses of Ritalin in kids (6+ years old) is 5-10 mg per day in two
doses.[1] 6 year old weigh about 20 kg (50th percentile) so each dose is ~0.25
mg/kg (5/20). Even if you double the dose, it's 0.50 mg/kg, below the 1 mg/kg
where the study saw no neuron loss.

To get to 10 mg/kg, kids would have to take 200 mg in a single dose. I'm
pretty sure the side effects would be utterly intolerable even at half of that
dose.

It's probably worth following up, but I wouldn't be worried about this
finding.

[1] [http://www.mayoclinic.org/drugs-
supplements/methylphenidate-...](http://www.mayoclinic.org/drugs-
supplements/methylphenidate-oral-route/proper-use/drg-20068297)

~~~
fasteo
You cannot directly convert mouse to human doses. For this, you need to
calculate HED[1] (Human Equivalent Dosage). Using your numbers:

HED (mg/kg) = Animal Dose (mg/kg) x [Animal Km / Human Km]

We use 3 for mice and 25 for human (child)

HED = 10 x ( 3 / 25) = 1,2 mg/kg

In a 20kg kid we have a dose of 24 mg, which is only slightly higher than a
normal dose.

[1]
[http://www.fasebj.org/content/22/3/659.full.pdf](http://www.fasebj.org/content/22/3/659.full.pdf)

~~~
refurb
That's a fair comment. One can't assume that an equal dose per kg will
translate reliabily from an animal to a human.

My only reply is that the BSA method of dose conversation has issues of it's
own (referred to in your paper) with regards to drug metabolism.

Also, the focus of the paper is on dose translations from animal to human
studies. One would obviously want to be conservative in that regard.

~~~
fasteo
You are right. Drug metabolism is key here; that´s why I am not too worried
about the results of this study.

I have a child (24kg) with - properly diagnosed - severe ADHD on 20mg daily
and the benefits clearly outweigh the potential risks; as with everything in
life, nothing has zero risk.

~~~
sabarn01
Adult here who has taken Methylphenidate for 28 years. I would strongly
suggest that weekends and holidays are also days off the medication.

~~~
zxcvvcxz
Out of curiosity why do you recommend this?

~~~
sabarn01
As every one else said, but I will add a couple of notes.

ADD is part of who I am its just not very compatible with current work
environments. I don't like to feel drugged all the time and I know that i'm ok
with out being medicated.

I have developed sufficient coping skills as an adult to enable me to choose
when I need to be medicated and when I don't.

~~~
hoggle
I just wanted to thank you for still answering on this thread. Your sharing of
your experiences is very much welcome, I've only been on Ritalin for over a
month and already feel exactly as you describe it. Still, I'm asking myself if
you couldn't also harm your wiring by having this on/off thing going on (I'm
currently on 30mg Ritalin LA which presumably is a rather high dosage). I've
always been more interested into computers so this brain thing is kind of new
to me - a blacker kind of box than it already is so to say :)

~~~
sabarn01
I would have been kicked out of school with out ritalin so there wasn't much
option when I started taking it at 9. You have to judge for yourself as an
adult if the costs out weight the risks.

------
may
I think this is the money quote -- noting that these effects are noted on
neurotypcial, and not on ADHD brains and therefore may or may not be
generalizable:

These results can only be interpreted in the context on normal brain structure
and function, and thus would have direct implications for the
illicit/neurocognitive use of MPH. Since the underlying anatomy and
biochemistry of ADHD has not been definitively characterized, our findings may
or may not be generalizable to the vast majority of humans who are properly
diagnosed with ADHD and are prescribed methylphenidate. Nevertheless, this
work supports studies [51], [57], [58], [59] that demonstrate that drugs shown
to increase the levels of dopamine in the synaptic cleft can contribute to
degenerative changes in the basal ganglia.

~~~
jessaustin
_...the underlying anatomy and biochemistry of ADHD has not been definitively
characterized..._

That's an understatement. The same could be said of any "disorder" or
"syndrome" the study of which is motivated primarily by commerce in
pharmaceuticals. If humanity survives long enough, future medicine will see
"ADHD" as lying mostly within normal human psychological variety. Our clumsy
efforts at treatment will be seen as prescribing 6" shoe risers to everyone,
whether they're 5'1" or 6'3".

~~~
Houshalter
That sounds sort of dismissive to people who have ADHD. It is a real condition
with real effects on people's lives, who get very real benefits from
medication. It is not like prescribing 6" shoes to everyone. Of course the
type of medication and dosage is adjusted to the patient.

------
bayesianhorse
So this article seems to point to a neurodegenerative effect of
Methylphenidate. I would caution against drawing conclusions from this study
as of yet. MP has been used for decades and there does not seem to be a
clinically evident effect of this sort.

In order to derive clinical recommendations (like "stop taking ritalin") the
potential damage has to be higher than that of all the "side effects" of ADHD,
for example violence, depression and social problems. Which currently does not
seem to be the case...

~~~
xkcd-sucks
Traditional Parkinson's symptoms (problems w/ voluntary movement) only show up
after 80-90% of dopaminergic neurons are gone. That's a whole lot of dead
cells.

Symptoms of pre-Parkinsonian dopaminergic neuron loss are (anhedonia,
depression, psychiatric weirdness without movement disorder) are just
beginning to be described, and it's very likely that stimulant use will be
shown to cause pre-Parkinsonian symptoms in human populations _once we know
what to look for, and after somebody decides to spend tons of time and money
investigating it._

Maybe the appropriate clinical recommendation is to exercise caution with DAT
ligands, and to use them as minimally as possible?

~~~
bayesianhorse
So the mice showed 80% loss after what? One or two years of chronic use? How
come people have taken this for twenty years and more and we didn't notice the
Parkinson epidemic?

~~~
xkcd-sucks
The mice showed a ~20% loss at high dose.

At the low dose, the mice showed no significant loss _but were vulnerable to a
sub-threshold dose of a toxin_ and toxin+MPH mice showed a ~20% loss.

This is in figure 1, and in the discussion. Exactly what behavioral effects
result from a 20% loss of DA neurons is still an open question.

So, the clinical implication is that people on methylphenidate might be
vulnerable to things (rotenone, heavy metals, etc) which aren't toxic to
"normal" people.

------
narrator
Methinks excess dopamine in the brain can get metabolized directly by MAO into
DOPAL which, if ALDH2 is busy, can cause superoxide formation and cell death.

"Both the accumulation of DOPAL and the enhancement of rotenone-induced
toxicity were abrogated by inhibiting the formation of DOPAL with the MAO
inhibitor, clorgyline. These observations suggest that the MAO-catalyzed
formation of DOPAL and its accumulation by various mechanisms may be important
processes that aggravate the neurotoxicity associated with mitochondrial
dysfunction."

[http://pharmrev.aspetjournals.org/content/59/2/125.full](http://pharmrev.aspetjournals.org/content/59/2/125.full)

So this is why MAO inhibitors are neuroprotective. They prevent this reaction.

------
Snackchez
Are there any similar types of research being done for Modafinil? I've
recently been prescribed a "therapeutic" dose of Ritalin (I reacted severely
to the lowest regular dose of Concerta) but have not started taking it. I'm
wondering if this is as bad as it sounds as my technical reading comprehension
skills are not that astute.

I was using modafinil before with some success. The only problem was that my
sleep patterns were all over the map and getting regular good sleep was
becoming difficult.

~~~
mietek
I'm also interested in long-term studies on modafinil. Please let me know if
you find any.

As for the sleep patterns, I've found sporadic use of melatonin to be quite
helpful:

[http://www.gwern.net/Melatonin](http://www.gwern.net/Melatonin)

------
hoggle
For anybody returning to this thread, here are some other discussions around
this study I found on the web (thank you duckduckgo :)

[http://www.longecity.org/forum/topic/61161-methylphenidate-n...](http://www.longecity.org/forum/topic/61161-methylphenidate-
neurotoxic/)

[http://www.reddit.com/r/Nootropics/comments/1yd5bf/methylphe...](http://www.reddit.com/r/Nootropics/comments/1yd5bf/methylphenidate_neurotoxicity/)

[http://www.plosone.org/annotation/listThread.action?root=539...](http://www.plosone.org/annotation/listThread.action?root=53905)

[https://www.quora.com/What-are-the-long-term-effects-of-
Adde...](https://www.quora.com/What-are-the-long-term-effects-of-Adderall-
Dexedrine-or-Ritalin-use)

\---

And some studies suggesting other adverse neurodegenerative effects of MPH as
well:

"Methylphenidate treatment induces oxidative stress in young rat brain"

[http://www.sciencedirect.com/science/article/pii/S0006899306...](http://www.sciencedirect.com/science/article/pii/S0006899306000606)

"Methylphenidate induces lipid and protein damage in prefrontal cortex, but
not in cerebellum, striatum and hippocampus of juvenile rats."

[http://www.ncbi.nlm.nih.gov/pubmed/22968482](http://www.ncbi.nlm.nih.gov/pubmed/22968482)

------
asciimo
This is anecdotal, but rodents I know never have a hard time focusing or
providing requisite attention. I think that ADHD is over-diagnosed in this
population. OCD, on the other hand, is prevalent, but actually beneficial for
the rodent lifestyle IMHO.

~~~
tunap
Perhaps if you had finished with "sedentary lifestyle" or "consumption
lifestyle" you wouldn't have been modded down so far? What do I know, I'm just
another un-diagnosed aberrant.

~~~
Houshalter
I think he means the rats they did the study on.

------
apstls
I wonder if Adderall, Vyvanse, and other ADD medications are chemically
similar enough to Methylphenidate that they would exhibit a similar effect.

~~~
Houshalter
Brand names are Concerta, Methylin, Ritalin, Equasym XL. I believe Adderall
and other ADHD medications are similar in. I thought it was even in the title,
but possibly the mods changed it. Watch it lose traction because no one knows
what "Methylphenidate" means.

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droopyEyelids
Flagged for exaggerated headline, only demonstrated in mice now, which react
differently to many stimulants.

~~~
vixin
Maybe I've missed something but where is the exaggeration in the headline
'Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice '? You mean it
doesn't and they're wrong?

~~~
eatitraw
It could be that HN mods altered the headline by the time you saw it.

------
paulwithap
Does this come as a surprise to anyone?

