Rambling background details here

I started on methylphenidate and it was great. Then, it gradually diminished in effectiveness, and right now the dose either is too little or too much; to get the mental benefits of what I once had, I feel nauseous, jittery, and my pulse/blood pressure are relatively high. (ironically, I'm not even taking that much of it)

So I was considering asking my doctor about trying dexedrine or Adderall in the hopes the side effects would lessen while keeping the beneficial effects. However I have read some things about long-term amphetamine neurotoxicity in low doses that kind of worries me, but none of the studies are really comprehensive.

So my question is: is anyone here, or does anyone know, people who have been on amphetamines for a long period of time? Was there any manifestation of the neurotoxicity as some recent studies suggest? What's the long term outcome of this treatment?

Thanks.

Sometimes anxiety issues can kick up with stimulent medication. I'd suggest you discuss this with your doctor.

Take care,
Scattered

i developed a rapid tolerance to ritalin and adderall whereas with dexedrine I do not so it may be a particular med issue...

On a sidenote, the doctor is out on vacation so I've gone through about a week of methylphenidate withdrawal. In "Brain Age" for the Nintendo DS, my math scores went up and memory/head count scores went down. Go figure.

@ Frangible.

Can you list the studies you read about neurotoxity? What exactly did it/they say?
Katy

I replied to your PM, but here's the study as well. The link isn't working for some reason but the PMID is 1601475.


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 nonhuman primates. Furthermore, plasma concentrations of amphetamine associated with dopaminergic neurotoxicity in nonhuman 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.
I emailled one of the authors and his response was something inherant to amphetamine was producing the neurotoxicity rather than oxidative stress.

I started a trial of 20mg Adderall XR today, I'm glad my psychiatrist is willing to work with me. So far I like it much better than Concerta/Methylphenidate... it's much "smoother" and less jarring, if that makes sense? Hard to describe.

I've been on dex for over 10 years and have no problems. :)

What should I expect if I do get neurotoxicity?

Not sure :) Whenever I see a study on ex methamphetamine users all the symptoms sound like they had ADD in the first place. Good to hear you are doing well though, 10 years is pretty solid.

What exactly is damaged. If amphetamine caused damage to the actual dopamine transport sites, then this could actually be a beneficial change.

From the above study:

damages dopaminergic nerve endings in the striatum of adult nonhuman primates.

Any new developments on this?

Are there any measures that can be taken reduce amphetamine induced neurotoxicity?

Neurotoxicity is so often missused now days...

Amphetamine will never be neurotoxic at the dosages used for adhd. You DON'T have any damage to your dopamine system. You may have problems with your medication, if it's caused by adaptation to its physiological effects, or an actual adjustment to the medication itself, I don't know.

Neurotoxicity is usualy seen (as far as stimulant abuse goes that is) with methamphetamine abuse. There has never been any such cases at normal dosages used for treatment of ADHD in a otherwise healthy person.

Take a look around the web for yourself. There are many claims (usualy made by people selling a product) that it does occur, but for some reason, in actual studies, its never been found anywhere. (aside from lab rats being given some insane dosage.)

Do you have a citation for that study? Who conducted it? Where was it published? What was the protocol used? What behavioral changes were noticed as a result of the neurotoxicity? What were the actual doses used?

Also, "dopaminergic nerve endings in the striatum" is actually not very specific. Presynaptic or postsynaptic nerve endings? What specific damage was done? Did it kill the cell, or did it just result in damage to proteins/receptors/ion channels/protein kinases in the cell or cell membrane?

Also, what percentage of the nonhuman primates experienced this damage? What was the extent of the damage? How much did it vary from individual to individual? For that matter, how many individual primates were studied?

This is why you need to provide a citation for that study. Either a link to the pubmed/medline stub, or the title, authors, journal, and publication date. Without that information, all I see is a vague and fairly useless paragraph.

We have a policy on this board, especially in the science forum and the medication forums, to always provide citations, especially when you quote a study directly. If this is a legitimate study, then it should be fairly easy for me to look it up and verify it if you provide a citation.

Just reread your post and saw the PMID$....but you must have the wrong number, because PMID 1601475 is:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed

Incidence of hypoglycaemia in children with severe Plasmodium falciparum malaria around Rourkela, Orissa state.



I do not believe that this is the study to which you refer. Care to try again?

I think this is the one you're looking at:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16014752&query_hl=2&itool=pubmed_docsum

Amphetamine treatment similar to that used in the treatment of adult attention-deficit/hyperactivity disorder damages dopaminergic nerve endings in the striatum of adult nonhuman primates.



Ricaurte GA (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Ricaurte+GA%22%5BAuthor%5D),
Mechan AO (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Mechan+AO%22%5BAuthor%5D),
Yuan J (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Yuan+J%22%5BAuthor%5D),
Hatzidimitriou G (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Hatzidimitriou+G%22%5BAuthor%5D),
Xie T (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Xie+T%22%5BAuthor%5D),
Mayne AH (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Mayne+AH%22%5BAuthor%5D),
McCann UD (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22McCann+UD%22%5BAuthor%5D).
First, I should mention that nobody trusts any study done by Ricaurte involving giving drugs to primates. He performed a study on MDMA in primates which had to be publicly retracted after it surfaced that he had given them massive doses of the wrong drug (methamphetamine) because of a "mislabelled bottle."

That being said...here's part of the conclusion section of the study:


Although the present preclinical observations may have clinicalimplications, it would be premature to extrapolate them to humansreceiving amphetamine treatment for ADHD for several reasons.First, the dopaminergic neurotoxicity may only occur in thecontext of doses of amphetamine that result in plasma concentrationscomparable with those found in these experiments; lower dosageregimens that engender lower plasma amphetamine concentrationsmay not be associated with toxic effects on central dopaminergicneurons. Second, the mechanisms of amphetamine-induced dopaminergicneurotoxicity are not known, and theoretically, could be operantin nonhuman primates (and rodents) but not in humans. Third,aspects of amphetamine metabolism in nonhuman primates may differfrom those in humans, and such differences could potentiallyresult in neurotoxicity in nonhuman primates but not in humans.Fourth, the relative sensitivity of brain dopaminergic neuronsto amphetamine toxicity in nonhuman primates and humans is unknown.Fifth, it is possible that the effects observed in normal primateswith amphetamine may not be observed in ADHD patients becausesuch patients presumably have abnormal neurotransmitter function,and such abnormalities may influence the expression of amphetamineneurotoxicity. Finally, it is important to note that amphetamineneurotoxicity data from the present studies were obtained inadult nonhuman primates; as such, although they may have implicationsfor adults receiving amphetamine for the treatment of ADHD,their implications for children are less clear, because studiesassessing the influence of age on the ontogeny of amphetamineneurotoxicity suggest younger animals are less susceptible tothe neurotoxic effects of amphetamine (Cappon et al., 1997http://jpet.aspetjournals.org/icons/fig-down.gif (http://jpet.aspetjournals.org/cgi/content/full/315/1/91#REF5);Miller et al., 2000http://jpet.aspetjournals.org/icons/fig-down.gif (http://jpet.aspetjournals.org/cgi/content/full/315/1/91#REF24)). Future studies in young adolescent primatesare needed.

It is reasonable to wonder why, if clinically relevant dosesof amphetamine produce toxic effects on brain dopaminergic neuronsin nonhuman primates, evidence of dopaminergic neurotoxicityhas not been revealed in clinical or neuroimaging studies ofpatients with ADHD. With regard to clinical studies, it is importantto recognize that parkinsonism may not become manifest untilcentral dopaminergic function is reduced by approximately 80to 90% (Koller et al., 1991http://jpet.aspetjournals.org/icons/fig-down.gif (http://jpet.aspetjournals.org/cgi/content/full/315/1/91#REF16)), a degree of dopamine reductionthat is approximately 2-fold greater than that observed in thecurrent study. Abnormalities in cognitive function, anotherpotential functional consequence of dopaminergic loss (Robbins,2003http://jpet.aspetjournals.org/icons/fig-down.gif (http://jpet.aspetjournals.org/cgi/content/full/315/1/91#REF29)), may be difficult to distinguish from the underlying symptomsof ADHD for which amphetamine is being prescribed. Indeed, giventhe fact that abnormalities in dopaminergic neural functionare believed, in part, to underlie symptoms of ADHD (Fone andNutt, 2005http://jpet.aspetjournals.org/icons/fig-down.gif (http://jpet.aspetjournals.org/cgi/content/full/315/1/91#REF10)), any indication of abnormal dopaminergic functionin amphetamine-treated patients might be attributed to underlyingdisease, rather than amphetamine neurotoxicity. With respectto neuroimaging studies, it is important to recognize that mostsubjects with ADHD who have been included in PET/SPECT studiesof the DAT have been medication-naive individuals (Krause etal., 2000http://jpet.aspetjournals.org/icons/fig-down.gif (http://jpet.aspetjournals.org/cgi/content/full/315/1/91#REF17), 2003http://jpet.aspetjournals.org/icons/fig-down.gif (http://jpet.aspetjournals.org/cgi/content/full/315/1/91#REF19); Jucaite et al., 2005http://jpet.aspetjournals.org/icons/fig-down.gif (http://jpet.aspetjournals.org/cgi/content/full/315/1/91#REF14)) and that in those isolatedinstances in which ADHD patients treated with stimulants havebeen included, those treated with amphetamine (rather than methylphenidate)were either excluded from the analysis (Krause et al., 2003http://jpet.aspetjournals.org/icons/fig-down.gif (http://jpet.aspetjournals.org/cgi/content/full/315/1/91#REF19))or were not analyzed separately (Dougherty et al., 1999http://jpet.aspetjournals.org/icons/fig-down.gif (http://jpet.aspetjournals.org/cgi/content/full/315/1/91#REF8); Krauseet al., 2002http://jpet.aspetjournals.org/icons/fig-down.gif (http://jpet.aspetjournals.org/cgi/content/full/315/1/91#REF18)). Notably, results of these imaging studies havenot been entirely consistent, with both increases (Doughertyet al., 1999http://jpet.aspetjournals.org/icons/fig-down.gif (http://jpet.aspetjournals.org/cgi/content/full/315/1/91#REF8); Krause et al., 2000http://jpet.aspetjournals.org/icons/fig-down.gif (http://jpet.aspetjournals.org/cgi/content/full/315/1/91#REF17)) and no change (van Dyck etal., 2002http://jpet.aspetjournals.org/icons/fig-down.gif (http://jpet.aspetjournals.org/cgi/content/full/315/1/91#REF34)) in DAT density reported in the striatum of ADHD patients.Thus, for a variety of reasons, the absence of previous clearclinical or PET/SPECT data showing evidence of DAT changes consistentwith dopaminergic neurotoxicity in patients with ADHD previouslytreated with amphetamine should not be construed as evidencethat it does not occur.One other thing that should be mentioned...ADHD individuals have been observed to have an abnormally high density of striatal DAT (dopamine transport) sites in the striatum. Thus a reduction in striatal DAT density would not actually be a bad thing for individuals with ADHD, if it were to occur.

Also, this study occurred over the course of only 4 weeks. If serious damage were apparent in four weeks of use, why do we not see external evidence of neurotoxicity in humans who have been taking similar doses for years? I have a sneaking suspicion that something else may be going on here.