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Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice

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Re: Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice

#21

Post by chimeracoder »

neurotech1 wrote: post #18
refurb wrote: post #6

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 t…

Exactly. Dosage relative to weight matters when drawing conclusions. Its easy to read articles/papers like the OP link and be alarmed, but the three biggest risk factors with Ritalin (and similar drugs) is that the dose is appropriate for weight, the dosage is scheduled properly and sleep. If the dosage schedule is above the half life of the medication, and blood level is still high at +12 hours later then neurons wi…

> This is also why recreational crystal meth [1] is very bad for the brain. Crystal meth overloads the neurons and definitely not equivalent to Rx Ritalin as intelligently prescribed.

"Crystal meth" isn't equivalent to Ritalin (methylphenidate), but it is equivalent to Desoxyn (brand name for methamphetamine), and more or less equivalent to Adderall (d-amphetamine, with a bit of l-amphetamine).

All three drugs are prescribed for a variety of conditions and, in appropriate doses, are safe[0]. The main difference between Desoxyn and Adderall is that the extra methyl group attached to the amphetamine makes it cross the blood-brain barrier more easily, which means that the equivalent doses are smaller (by weight). The metabolic processes and the effects on the brain are virtually identical, though, so it's misleading to draw a line between them and label one as "good" and the other "bad".

The real reason that people think of crystal meth as "bad" is because it's taken in far higher doses recreationally than would ever be prescribed medically, and because it's smoked (not that this is inherently bad, but changing the means of ingestion changes the onset, duration of effects, etc.[1])

[0] At least, to the extent that we can say that any pharmaceutical is "safe"

[1] This is why nicotine gum is frustrating to many smokers, because it takes much longer to absorb.

Re: Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice

#22

Post by bayesianhorse »

xkcd-sucks wrote: post #9
bayesianhorse wrote: post #3

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…

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 h…

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?

Re: Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice

#23

Post by bayesianhorse »

theonewolf wrote: post #8
bayesianhorse wrote: post #3

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…

This type of degenerative side effect though might especially express itself later in life: making you much more likely to develop say dementia earlier than a normal human. It's not like it would be an immediate side effect. Often brain damage chronically over time is not immediately visible.

That effect should have been shown by now. I don't know of any studies specifically looking at this, but various global agencies require post-approval studies and monitoring which should have picked up on this.

It's not like this drug is prescribed rarely or introduced very recently...

Re: Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice

#24

Post by refurb »

fasteo wrote: post #19
refurb wrote: post #6

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 t…

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

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.

Re: Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice

#25

Post by refurb »

schrodingersCat wrote: post #16
refurb wrote: post #6

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 t…

There may be pharmacokinetic reasons for using these higher doses in mice. The rate at which drugs absorb through the blood brain barrier, are metabolized by the liver, and are eliminated by the kidneys are all factors one must consider. Not to mention the does response for MPD in mice may in fact be different. The goal of this study was not to simulate therapeutic dosing of MPD, but of chronic (short term, high dose…

I agree. I would love to see what plasma concentrations were achieved in the mice at each dose and compare that to what is typically seen in humans.

Re: Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice

#26

Post by schrodingersCat »

fasteo wrote: post #19
refurb wrote: post #6

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 t…

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

Thank you for posting this. I do not personally work with animals, but I knew there must be a way to convert doses between mice and humans given how often my colleagues test drugs on rats and mice.

Re: Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice

#27

Post by fasteo »

refurb wrote: post #24
fasteo wrote: post #19

Earlier quoted context omitted.

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

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.

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.

Re: Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice

#28

Post by 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

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

Re: Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice

#29

Post by jessaustin »

may wrote: post #15

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 charac…

...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".

Re: Methylphenidate Exposure Induces Dopamine Neuron Loss in Mice

#30

Post by ryan-c »

refurb wrote: post #6

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 t…

I was on about 60mg/day (across three doses) when I was 8 or 9. Not sure how typical that kind of dosing is.
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