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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 24 of 24. This is the beginning of the thread.
Posted by Dave001 on August 27, 2005, at 20:13:03
I posted the following to sci.med almost verbatim, so some of it may
seem out of context.Link to citation:
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=abstract&list_uids=16014752>;========================================================
J Pharmacol Exp Ther. 2005 Jul 13; [Epub ahead of print]Amphetamine treatment similar to that used in the treatment of adult
ADHD damages dopaminergic nerve endings in the striatum of adult
non-human primates.Mechan-Mayne A, Yuan J, Hatzidimitriou G, Xie T, Mayne A, McCann UD,
Ricaurte GA.Johns Hopkins University.
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.PMID: 16014752
===========
A cursory scan of the 43 paper says that a reduction
of some 30-50% of dopamine neuronal markers were observed after four
weeks. The subjects received oral preparations (self-administered) of
a 3:1 ratio of the d- and l- amphetamine isomers (sounds familiar). The
doses were similar to the upper end of the range used in medicine, as
were plasma drug concentrations. Because "amphetamine" is sometimes
misappropriated to derivatives and structurally similar chemicals, I
should point out that the study did in fact involve amphetamine.Have any of you seen a decent article (preferably peer-reviewed) that
gives an estimation of a human NOAEL of amphetamine (d- or racemic), in
addition to, of course, its basis? None of the animal studies that I've
read thus far provide justification for the current prescribing
guidelines or the FDA's MRTD (whether such evidence should be necessary
to justify its medical use is another subject entirely). Postmortem
histopathological observations of former methamphetamine addicts are
wholly unimpressive.Methylphenidate doesn't appear nearly as neurotoxic as amphetamine in
animal studies (indeed, it has even prevented amphetamine-induced
neurotoxicity in some studies), so I'm interested to know why the latter
is often used in place of the former, when the difference is usually
only marginal.BTW, is Johns Hopkins known for a tendency toward bias concerning the
controversial use of these medicines?
Posted by ed_uk on August 28, 2005, at 8:29:45
In reply to Study: neurotoxicity from amphetamine in primates, posted by Dave001 on August 27, 2005, at 20:13:03
It's interesting. In many countries, amphetamines are not available on prescription, only MPH is available.
~ed
Posted by linkadge on August 28, 2005, at 15:20:28
In reply to Re: Study: neurotoxicity from amphetamine in primates » Dave001, posted by ed_uk on August 28, 2005, at 8:29:45
I fully believe it. MPH is probably neurotoxic as well.
Linkadge
Posted by utopizen on August 28, 2005, at 16:12:31
In reply to Re: Study: neurotoxicity from amphetamine in primates, posted by linkadge on August 28, 2005, at 15:20:28
Keep in mind all neurons die, and all amphetamines do is actually prolong their lifespan.
Neurotoxicity?
If you don't sleep, or eat food, of course you'll get neurotoxicity. I can guarantee these primates did not sleep, and would suspect they lost appetite as well.
Unlike nonhuman primates, humans can actually train themselves to mediate and take deep breathing exercises to respond to the agitation-provoking symptoms, the restlessness, and sleep, and eat, despite the dose of the drug
(trust me, I've had finals week, and it's an art to do deep breathing at any dose).
Also, keep in mind this: The word "neurotoxicity" is the most pathetic excuse for a medical term ever. If you ever read a "neurotoxicity" study, keep in mind doctors rarely take them seriously.
Ask your doc what "neurotoxicity" means. It's derived from neurotoxocology. Oh, what a developed science that is!
Neurotoxocology had yet to find a more precise measure to use as a "gold standard" than "LD-50": Lethal Dose 50%.
Selling Draino? Before you do, make sure you give 200 beagle pups the stuff, and keep feeding it to them until half of the population dies. Once only 100 remain, note the dose last used, and that's the LD-50. (Look at the PDR, and you'll find "LD-50" rated for every drug-- I wish I was making this up).
What a benchmark. What will they think of next, Thomas Edison?
If they're that "precise" with determining how toxic draino is, I wouldn't bet my life on studies using primates using fMRIs or other brain scan technologies that one of the premier researchers using them, Dr. George Bush at MGH (no relation) admits is extremely experimental and little is known of them.
P.S.-- This post is not in reference to any prior poster.
Posted by ed_uk on August 28, 2005, at 16:16:05
In reply to Neurotoxicity is a pretty sketchy term, posted by utopizen on August 28, 2005, at 16:12:31
>This post is not in reference to any prior poster.
Hmmm. I wasn't saying that amphetamines shouldn't be available, just that they're not available in many countries. We do have Dexedrine in the UK, I'd like to try it.
~ed
Posted by linkadge on August 28, 2005, at 16:50:15
In reply to Neurotoxicity is a pretty sketchy term, posted by utopizen on August 28, 2005, at 16:12:31
Why even wait for more conclusive evidence? Why bother to pick at the wording of the study? I think it is fully concievable that stimulants can induce dammage to the dopaminergic neurons.
Sure they do die on their own, why accelerate that rate?
From www.biopsychiatry.com
"Normally the brain's irreplaceable complement of 30-40 thousand odd dopaminergic cells tends to die off at around 13% per decade in adult life. Their death diminishes the quality and intensity of experience. It also saps what in more ontologically innocent times might have been called one's life-force. Eighty percent loss of dopamine neurons results in Parkinson's disease, often prefigured by depression."
Linkadge
Posted by Dave001 on August 28, 2005, at 21:52:00
In reply to Re: Study: neurotoxicity from amphetamine in primates, posted by linkadge on August 28, 2005, at 15:20:28
> MPH is probably neurotoxic as well.
On what basis? Neither methylphenidate (MPH) nor cocaine (which are
pharmacologically very similar) appear similar to amphetamine in animal
studies of neurotoxicity. At low doses, MPH even appears mildly
*neuroprotective*, but that's mostly from memory and I certainly
wouldn't leap to speculation about what happens in humans.
Posted by Dave001 on August 29, 2005, at 0:40:07
In reply to Neurotoxicity is a pretty sketchy term, posted by utopizen on August 28, 2005, at 16:12:31
> Keep in mind all neurons die, and all amphetamines do is actually
> prolong their lifespan.Sorry, but it's difficult to take what you're saying seriously, since
you've just demonstrated that you don't know what a neuron is.> Neurotoxicity?
Yes. Damage to dopaminergic axon terminals (i.e., not transient chemical
changes).> If you don't sleep, or eat food, of course you'll get neurotoxicity.
> I can guarantee these primates did not sleep, and would suspect they
> lost appetite as well.Diet, exercise, sleep, temperature, etc., are among the most basic
environmental factors that researchers control for. Furthermore, it is
nonsense to say that sleep deprivation or lack of food are neurotoxic in
any meaningful sense. How they influence the development of
neurotoxicity is another matter, which again, is something that is
controlled for.[...]
> Also, keep in mind this: The word "neurotoxicity" is the most
> pathetic excuse for a medical term ever. If you ever read a
> "neurotoxicity" study, keep in mind doctors rarely take them
> seriously.That isn't surprising, considering that very few doctors have expertise
in drug toxicology research; they're concerned with the practical
application of medicine. Would you really expect prescribing patterns to
change whenever some new contradictory finding from a study in mice is
published?> Ask your doc what "neurotoxicity" means. It's derived from
> neurotoxocology. Oh, what a developed science that is!What on earth does the etymology of "neurotoxicity" have to do with the
implications of this study? You seem really hung up on the term
"neurotoxicity." Substitute "brain damage" if you feel that it's more
palatable.
<snip>
Posted by Dave001 on August 29, 2005, at 2:30:32
In reply to Re: Neurotoxicity is a pretty sketchy term, posted by linkadge on August 28, 2005, at 16:50:15
> Why even wait for more conclusive evidence? Why bother to pick at the
> wording of the study? I think it is fully concievable that
> stimulants can induce dammage to the dopaminergic neurons.
>
>
> Sure they do die on their own, why accelerate that rate?I agree. At the very least, one should be aware of the potential for
damage, whether or not it _does_ occur at therapeutic doses. That
amphetamines can cause lasting damage to dopaminergic neurons in animals
has been known for a long time, but what has been inexplicably dismissed
is the need to determine the level at which humans are susceptible to
such damage, and to find a maximum dose range that provides a reasonable
margin of safety.There are obvious difficulties with conducting studies of neurotoxicity
in humans, but at least non-human primates make it much easier to
extrapolate doses. It's plausible that say, 10 mg/day in rats is
comparable with doses used in humans in clinical practice. Adjusting for
body surface area alone would account for much of the difference, and
then one must consider the much faster rate at which amphetamines are
metabolized in rats (independent from body mass/surface area variables).
Researchers have tried to account for latter variable using methods of
administration that provide a continuous release of drug via infusion or
(IIRC) implantable pellets.[...]
> called one's life-force. Eighty percent loss of dopamine neurons
> results in Parkinson's disease, often prefigured by depression."That's another problem: the symptoms of neuronal degeneration would
probably only manifest after a large amount of damage had already
resulted. The brain seems to adapt pretty well until neurons drop below
a critical level, not to mention amphetamine itself could mask some of
the deterioration. Tolerance is underappreciated.Dave
> Linkadge
Posted by ed_uk on August 29, 2005, at 3:30:14
In reply to Re: Neurotoxicity is a pretty sketchy term, posted by linkadge on August 28, 2005, at 16:50:15
Hi Link,
Do you have the link to the study on MPH and DNA damage?
~Ed
Posted by Dave001 on August 29, 2005, at 4:05:36
In reply to Re: Neurotoxicity is a pretty sketchy term, posted by Dave001 on August 29, 2005, at 2:30:32
<snip>> There are obvious difficulties with conducting studies of neurotoxicity
> in humans, but at least non-human primates make it much easier to
> extrapolate doses. It's plausible that say, 10 mg/[*kg*/]day in rats is
> comparable with doses used in humans in clinical practice. Adjusting for
> body surface area alone would account for much of the difference, and
> then one must consider the much faster rate at which amphetamines are
> metabolized in rats (independent from body mass/surface area variables).Oops. I had _meant_ to say 10 mg/kg/day. I couldn't go back to edit my
post, so please make note of the correction.
Posted by linkadge on August 29, 2005, at 8:47:53
In reply to Re: Study: neurotoxicity from amphetamine in prima, posted by Dave001 on August 28, 2005, at 21:52:00
I know that both cocaine and ritalin simialarly regulate intermediate early genes, cFos immunoreactivity etc. in animal studies. Which is supposedly indicative of a similar addiction potential. This gene expression seems to presist years after the last sustained use. This in itself is not necessarily indicative of neurotoxicity.
Some articles on cocaine's neurotoxic potential:http://cocaine.org/reward/pleasure.html
http://www.psychiatry.ufl.edu/Newsletters/Content/little.pdf----------
On methlyphenidate's neurotoxic potential.
http://www.amphetamines.com/methylphenidate/longtermdop.html
http://www.pslgroup.com/dg/2488d2.htm
Linkadge
Posted by linkadge on August 29, 2005, at 9:03:32
In reply to Re: Neurotoxicity is a pretty sketchy term, posted by Dave001 on August 29, 2005, at 2:30:32
Many researchers propose that ADD is not caused by a lack of dopamine, but probably rather a functional deficiancy (ie. somehow the receptors are not working optimally and/or underdevelopment of certain brain regions)
If this was the case than the last thing you want to do is to induce dammage to the few functional receptors that one has remaining.Let me give another example. Parkinsons is not caused by a lack of dopamine, but rather problems in dopamine reception due to neuronal loss. While amphetamines have been found to provide symptomatic improvement to the condition, they may infact worsen the course of the illness, due to their neurotoxic potential.
Linkadge
Posted by linkadge on August 29, 2005, at 9:06:05
In reply to Re: Neurotoxicity is a pretty sketchy term » linkadge, posted by ed_uk on August 29, 2005, at 3:30:14
Dammage in chromosomes in patients treated short term with methylphenidate.
http://www.medicalnewstoday.com/medicalnews.php?newsid=20433
While not direct neurotoxicity, could indirectly indicate problems.
Linkadge
Posted by ed_uk on August 29, 2005, at 9:15:45
In reply to Re: Neurotoxicity is a pretty sketchy term » ed_uk, posted by linkadge on August 29, 2005, at 9:06:05
>Dammage in chromosomes in patients treated short term with methylphenidate.
Thanks Link, it's worrying isn't it.......
~Ed
Posted by linkadge on August 29, 2005, at 10:45:50
In reply to Re: Neurotoxicity is a pretty sketchy term » linkadge, posted by ed_uk on August 29, 2005, at 9:15:45
It is worrying. If I knew that I was so hyperactive that I could never be normal without it, then it would be a different story.
I find that off meds, I have to rethink, (in painstaking detail), every little fear that I ever shrugged off. But if it it serves to bring more concrete resolution, I'll delve.
Linkadge
Posted by Dr. Bob on August 29, 2005, at 17:23:27
In reply to Re: Neurotoxicity is a pretty sketchy term, posted by Dave001 on August 29, 2005, at 0:40:07
> it's difficult to take what you're saying seriously, since
> you've just demonstrated that you don't know what a neuron is.Please don't post anything that could lead to others feeling put down.
If you or others have questions about this or about posting policies in general, or are interested in alternative ways of expressing yourself, please see the FAQ:
http://www.dr-bob.org/babble/faq.html#civil
Follow-ups regarding these issues should be redirected to Psycho-Babble Administration. They, as well as replies to the above post, should of course themselves be civil.
Thanks,
Bob
Posted by utopizen on August 29, 2005, at 19:54:20
In reply to Re: Neurotoxicity is a pretty sketchy term, posted by linkadge on August 28, 2005, at 16:50:15
> "Normally the brain's irreplaceable complement of 30-40 thousand odd dopaminergic cells tends to die off at around 13% per decade in adult life. Their death diminishes the quality and intensity of experience. It also saps what in more ontologically innocent times might have been called one's life-force. Eighty percent loss of dopamine neurons results in Parkinson's disease, often prefigured by depression."
>If neurons were some trust fund, I'd be concerned.
Fortunately, it's not that simple. Your brain has this incredibly capacity to heal. There's hope for me yet.
Depression tends to make people's IQ go plummeting at its worst. I certainly felt like I was "going stupid."
It's not true. Your brain heals. It's incredibly capable to heal.
by the way, not to point out the obvious, but it's not actually possible to "count" or partition how much of your dopamine neurons are living/dead in humans quite yet.
They're still having difficulty finding massive holes in people's brains after they suffer, well, massive brain injuries.
It's not like they can take someone who took coke everyday of their life for 40 years and figure that out from a PET scan.
Like I said, it's a good day for a radiologist to determine where the massive holes are from falling off a cliff.
Everything else is either made up or from rat trials. I'm not sure which is more reliable yet.
Posted by utopizen on August 29, 2005, at 20:12:04
In reply to Re: Neurotoxicity is a pretty sketchy term, posted by linkadge on August 29, 2005, at 9:03:32
>
> Let me give another example. Parkinsons is not caused by a lack of dopamine, but rather problems in dopamine reception due to neuronal loss. While amphetamines have been found to provide symptomatic improvement to the condition, they may infact worsen the course of the illness, due to their neurotoxic potential.
>I'm not sure if it could actually be proven that this is why Parkinson's disease is somehow worsened, since the disease itself is incredibly and rapidly degenerative as it is.
Whether you give an amphetamine or not, it's going to worsen either way. Isolating that to amphetamines is not any task I'd like to prove if my life depended on it.
A lot of things, for a lack of a more precise explanation, don't havbe a more precise expanation than we'd like to isolate them to.
That's just the way life works. Most things are a result of multiple factors-- even taking a hot shower will help to decrease inflammation caused by amphetamines. So, to what extent does this alter anything? Who cares?
If you can manage your life without amphetamines, I applaud that.
Not because of neurologists trying to pretend their rat research makes any sense-- just because it's proof you are willing to live your own life, and find it okay without needing further support.
But if you feel your life is impaired, let's not make neuronal salvation into a religion, and don't worry about it.
Seriously, I have serious doubts about the mere association being placed on the use of amphetamines and the increased risk (is that what is being suggested??) of Parkinson's.
There's enough people who eat meth in place of food each day to know this simply is not true.
Certainly not anything to lose sleep over if you're taking low doses like ADD meds are prescribed at.
I might also remind folks they've found oral Nizoral effective at Stanford for cocaine cessation in rats. So effective, they felt convinced it would work in humans.
The humans were found, in controlled trials, to increase their use of the coke.
So I don't worry about my life's future based on how rats-- the only means to research just about anything in neurology to the depths we're discussing here- bear any signifigance of merit whatsoever. It's nothing to do with you, it's just the rats. I hate rats. =)
Posted by linkadge on August 30, 2005, at 8:30:38
In reply to Re: Neurotoxicity is a pretty sketchy term, posted by utopizen on August 29, 2005, at 20:12:04
>I'm not sure if it could actually be proven that
>this is why Parkinson's disease is somehow
>worsened, since the disease itself is incredibly
>and rapidly degenerative as it is.A drug that has been proven in rats (and in humans) to selectively cause morphological changes to the dopaminergic system should be avoided in a disease where dopaminergic neurons are sparse.
>Whether you give an amphetamine or not, it's
>going to worsen either way. Isolating that to
>amphetamines is not any task I'd like to prove
>if my life depended on it.Smoking during chemotherapy for lung cancer ain't going to make things any better.
>A lot of things, for a lack of a more precise
>explanation, don't havbe a more precise
>expanation than we'd like to isolate them to.Ok sure,
>That's just the way life works. Most things are
>a result of multiple factors-- even taking a hot
>shower will help to decrease inflammation caused
>by amphetamines. So, to what extent does this
>alter anything? Who cares?I care. I try to gather the factors, and alter the ones I am capable of altering.
>If you can manage your life without
>amphetamines, I applaud that.If it is not a factor that you can change, then so be it. For my best friend, taking a stimulant is not somthing he can change. Snorting it is something he can change.
>But if you feel your life is impaired, let's not
>make neuronal salvation into a religion, and
>don't worry about it.Just because you're not paranoid, doesn't mean somebody isn't watching you.
>Seriously, I have serious doubts about the mere
>association being placed on the use of
>amphetamines and the increased risk (is that
>what is being suggested??) of Parkinson's.I wasn't saying that amphetamines caused Parkinson's. I was saying that many doctors now theorize that ADD/HD has nothing to do with a lack of dopamine, but rather an issue related to lack of functionality of the dopamine receptor (like in Parkinsons's). If this is true, than amphetamines are not the ideal treatment, as in animal models they do not appear to be friendly to the integrity of the dopamine receptor.
>There's enough people who eat meth in place of
>food each day to know this simply is not true.I won't even bother to respond to that.
>Certainly not anything to lose sleep over if
>you're taking low doses like ADD meds are
>prescribed at.You are right. Loosing sleep won't help anything.
>I might also remind folks they've found oral
>Nizoral effective at Stanford for cocaine
>cessation in rats. So effective, they felt
>convinced it would work in humans.
>The humans were found, in controlled trials, to
>increase their use of the coke.Science can make mistakes. Does that mean we tune them out completely?
>So I don't worry about my life's future based on
>how rats-- the only means to research just about
>anything in neurology to the depths we're
>discussing here- bear any signifigance of merit
>whatsoever. It's nothing to do with you, it's
>just the rats. I hate rats. =)If only that were true, the research would be easier to shrug off. You'd be surprised the number of brains of deceased drug addicts make it into scientist's labritories. Well, because unlike other human beings, those who eat meth instead of food, tend to not live very long.
Linkadge
Posted by ankh on August 31, 2005, at 20:06:38
In reply to Re: please be civil » Dave001, posted by Dr. Bob on August 29, 2005, at 17:23:27
A request -- I'm using from 5 to 35 mg of desoxyn a day. I'm in my fifties, had several concussions, and started this after having too many side effects and too little primary effect from the other stimulants prescribed for attention deficits.
How much is too much? The new manufacturer's product isn't sustained release, and feels much less effective to me.
Posted by lizabent on September 2, 2005, at 13:54:01
In reply to Re: Neurotoxicity is a pretty sketchy term » linkadge, posted by ed_uk on August 29, 2005, at 9:15:45
Hi all,
Can't help but chime in--if you have bad ADd/ADHD, your brain is already a little off...I bet the primates in the study didn't have ADD/ADHD! I take Adderall, and just hope that the little damage done by the stimulant will offset the damage done by increased cortisol and decreased neurogenesis in the dentate gyrus of the hippocampus caused by how depressed I got when I couldn't pay attention to anything.Studies like these reassure us that taking meds should really only be done inf medically necessary, since neuroscience (my field) is in the baby stages and will be for the next several hundred years...But if medically necessary, they can save your life. Who would have thought that smokers had a lower risk of Parkinson's Disease?
There are so many paradoxes in the psychopharmacology literature...Liz
Posted by linkadge on September 2, 2005, at 14:16:07
In reply to Re: Neurotoxicity is a pretty sketchy term, posted by lizabent on September 2, 2005, at 13:54:01
It is true about smoking and parkinson's. But that does not negate all the negative effects of smoking.
I am not saying that the neurotoxic effects of stimulants are the only factor that should be considered when one decides weather or not to take one.
I do believe that the effects are real, and should be a consideration.
Nobody knows the net effect of taking a stimulant. Some studies suggest an improved adulthood outcome while others point to more complications, including and increased risk of depression.
Linkadge
Posted by Dr. Bob on September 2, 2005, at 20:17:39
In reply to Re: please be civil -- Dr Bob, any info on subject, posted by ankh on August 31, 2005, at 20:06:38
This is the end of the thread.
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