Amphetamine Sensitization: Possible Implications for Humans

[Epsilon Alpha]

So one significant part of the puzzle of long term amphetamine use is sensitization, which may be a significantly separate phenomenon from "tolerance" in the traditional sense.
Its been fairly well established that some effects of amphetamine use are strengthened and persist for significant amounts of time, in my attempts to understand these changes I've found several interesting and concerning leads.

Firstly, there seems to be a distinct link between amphetamine use and bipolar disease/addiction/schizophrenia which is supported by both in vivo testing and epidemiological data.
http://www.sciencedirect.com/science...06322395004971 (increased drug liking and decreased euphoria in healthy humans with repeated administration)
http://archpsyc.ama-assn.org/cgi/con...tract/68/6/545 (similarities in frontal lobe function to those seen in schizophrenia)
http://www.sciencedirect.com/science...66432809005841 (a well written study on mood stabilizers and sensitization in rats)
http://www.springerlink.com/content/78106r6158t4618t/ (a review of the amphetamine sensitization model of schizophrenia)

http://www.sciencedirect.com/science...49763410000849
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675806/

Been working the whole weekend, so I'll post more when I'm free and rested.

[puerco911]

come on man, this already gettin me stressed out and is barely Monday!!!

[dontknow]

More proof amphetamine's are garbage! It's basically like taking Meth. Stick to Methylphenidate instead.

[Tussmann]

Methylphenidate is an amphetamine, and evidence suggests that it is inferior to things like d-amp for those with ADHD.

[dontknow]

Methylphenidate is an amphetamine, and evidence suggests that it is inferior to things like d-amp for those with ADHD.

Err? MPH is a amphetamine derivative, but that doesn't mean they're structurally the same, or have the same psychopharmacodynamics.

Amphetamines (d-amphetamine, Adderal, et al. - which is what they used in those studies) have been shown over and over again to be neurotoxic.

[kassem23]

Err? MPH is a amphetamine derivative, but that doesn't mean they're structurally the same, or have the same psychopharmacodynamics.

Amphetamines (d-amphetamine, Adderal, et al. - which is what they used in those studies) have been shown over and over again to be neurotoxic.

Err again... Methylphenidate resembles cocaine more than it resembles amphetamine. Amphetamine (alpha-methyl-PEA) is basically methylated PEA.

And there's no conclusive evidence in the neurotoxicity department, FWIW. This has been discussed over and over again.

[kassem23]

Methylphenidate is an amphetamine, and evidence suggests that it is inferior to things like d-amp for those with ADHD.

Incorrect on both accounts, unfortunately. Methylphenidate shows equal efficacy to amphetamine in studies with about ~70% efficacy rate for ADHD. There's a difference in the predominantly inattentive class which seem to respond better to amphetamine(s) than methylphenidate.

[dontknow]

Err again... Methylphenidate resembles cocaine more than it resembles amphetamine. Amphetamine (alpha-methyl-PEA) is basically methylated PEA.

And there's no conclusive evidence in the neurotoxicity department, FWIW. This has been discussed over and over again.

Err x 3... that's what i said. MPH ISN'T Amp. And MPH, AMP, cocaine, Meth, MDMA, are going to have a similar chemical structure - benzene aromatic ring bonded with amine side group, because that's the dopamine key.

And there's no evidence of AMP toxicity? There's several in vivo studies in this post alone.

The difference is that MPH is a dopamine re-uptake inhibitor, whereas AMP is a dopamine releaser... and the latter is where the problems arise.

[kassem23]

Err x 3... that's what i said. MPH ISN'T Amp. And MPH, AMP, cocaine, Meth, MDMA, are going to have a similar chemical structure - benzene aromatic ring bonded with amine side group, because that's the dopamine key.

Did I say it was amphetamine? No.

And there's no evidence of AMP toxicity? There's several in vivo studies in this post alone.

"In this post alone"...you mean thread right?

By the way...sensitization =! neurotoxicity, period.

Now, to battle your view on amphetamine and neurotoxicity I'll just refer you to this discussion as it has been thoroughly discussed in the past on this board. For instance, Ricaurte's infamous primate study (16014752) was thoroughly critique by a bunch of posters on this board, and as if I recall correctly by scientists, as well. I'll refer you to Frangible's points about this study here (post552735), and in that thread you'll find a lot of more information that I do not have time to present to you again.

Also, if you're inferring that amphetamine(s) may kill people quicker than people who are not on the drug through cardiovascular mechanisms, this article begs to differ (22161946).

The difference is that MPH is a dopamine re-uptake inhibitor, whereas AMP is a dopamine releaser... and the latter is where the problems arise.

We already know that methylphenidate is neuroprotective, so that's besides the point. The question is whether amphetamine long-term poses any significantly relevant clinical problems long-term.

[puerco911]

We already know that methylphenidate is neuroprotective, so that's besides the point. The question is whether amphetamine long-term poses any significantly relevant clinical problems long-term.

well is been used since WWII right? dont we think we would know by now??? I dont think it is....only with overdose, not the therapeutic dose....although thats dependent on the personal chemistry i suppose

[kassem23]

well is been used since WWII right? dont we think we would know by now??? I dont think it is....only with overdose, not the therapeutic dose....although thats dependent on the personal chemistry i suppose

In another thread I talked about the ethical dilemmas of the conduction of long-term studies in ADHD cohorts. You also have to take into account that the entire mechanism of action of amphetamine is not understood yet.

As for dose-dependent neurotoxicity I'd say yes, but in commonly prescribed areas of doses, I'd say it's doubtful, but cannot be ruled out completely.

[Tussmann]

Every professor I've had has classified methylphenidate into the amphetamine class, even with extensive knowledge of how their mechanisms differ. Weird :/

Anyways, regardless of what the literature indicates, the vast majority of people I know prefer Adderall and d-amp to methylphenidate products. Methylphenidate, in most cases, comes with more anxiety, and more crashes. Moreover, prescribed doses of methylphenidate seem to make a lot of users actually depressed, whereas amphetamine compounds avoid this.

[kassem23]

Every professor I've had has classified methylphenidate into the amphetamine class, even with extensive knowledge of how their mechanisms differ. Weird :/

I've seen the same kind of knowledge misappropriated in the news in Denmark and it continues to frustrate me. Clearly suggests that the authors and/or professors in the field haven't looked into nor understood the basic chemistry behind the compounds.

[Epsilon Alpha]

Well MPH is what we call a chain substituted amphetamine in my faculty, but its well known that it has a completely different mechanism of action.
But AMP sensitization seems to increase how "primed" the VTA is to reward, while decreasing NAcc sensitivity to reward.

http://jpet.aspetjournals.org/content/264/1/249.short
http://www.jneurosci.org/content/20/15/5575.short
http://www.sciencemag.org/content/310/5752/1340.short

[SNR]

On topic.. Are you suggesting that humans (incl. animals?) have a reason to sensitize to amphetamines?
What about endogenous amphetamines like molecules (Beta-phenylalanine I think..), would humans sensitze to their effects?

[Sanction]

On topic.. Are you suggesting that humans (incl. animals?) have a reason to sensitize to amphetamines?
What about endogenous amphetamines like molecules (Beta-phenylalanine I think..), would humans sensitze to their effects?

If you mean an evolutionary reason, sure... it's likely part of the system to create Pavlovian habits. In any species this would be useful for enhancing survival via feeding or fleeing behaviors.

Just because our dopaminergic systems respond to exogenous amphetamine doesn't mean they evolved to respond to amp specifically (it's just a happy coincidence AFAIK)

[Infinite1]

It appears that therapeutic doses of AMP does cause significant changes in VMAT expression similar to that seen in high dose AMP/stim usage. Although it is suspected that these changes decrease the ability to efficiently sequester DA, it is not currently known whether that is reflective of a neurotoxic state. Interestingly there appears to be changes in the expression of VMAT in those with PD.

It is also likely that through chronic usage AMP's reversal of DAT causes a reduction in DAT functioning due to internalization of DAT, this has only been indicated in doses that are above those used clinically but I suspect that this effect is on a gradient scale.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581712/

High-dose administration of psychostimulants traffics the vesicular monoamine transporter-2 (VMAT-2), as assessed by subcellular fractionation of rat striatal tissue. This study demonstrates that administration of low doses of amphetamine or methylphenidate differentially traffic VMAT-2 within nerve terminals, with effects similar to those observed after high-dose administration. Trafficking of vesicular glutamate, acetylcholine, or GABA transporters was not altered by high- or low-dose amphetamine or methylphenidate treatment. These data represent the first report that amphetamine redistributes VMAT-2 protein. In addition, these data demonstrate that the trafficking of VMAT-2 after amphetamine or methylphenidate is selective for monoaminergic neurons.

[Tussmann]

I've seen the same kind of knowledge misappropriated in the news in Denmark and it continues to frustrate me. Clearly suggests that the authors and/or professors in the field haven't looked into nor understood the basic chemistry behind the compounds.

That's exactly the thing though, my entire paper on ADHD was an in detail report on the distinct MOA of both drugs, but I still was corrected for presuming methylphenidate wasn't an amphetamine.

Here is the teacher that corrected me: http://www.rhodes.edu/psych/21801_21814.asp

And, here is some of her research:

Pond BP, Gerecke KM and Smeyne RJ (2006) Effect of long-term methylphenidate treatment on gene expression in various brain regions Society for Neuroscience, Atlanta, Georgia.

Pond, BP, Gerecke KM, Jiao Y, Smeyne M, Rong Y and Smeyne RJ (2006). Effect of long-term methylphenidate treatment on gene expression in various brain regions. ACNP.

Pond BP, Gerecke KM and Smeyne RJ (2005) Effect of long-term methylphenidate treatment in an experimental model of Parkinsonism. Society for Neuroscience, Washington DC.




I think she knows her shit...

[Niflheim]

That's exactly the thing though, my entire paper on ADHD was an in detail report on the distinct MOA of both drugs, but I still was corrected for presuming methylphenidate wasn't an amphetamine.

Here is the teacher that corrected me: http://www.rhodes.edu/psych/21801_21814.asp

And, here is some of her research:

Pond BP, Gerecke KM and Smeyne RJ (2006) Effect of long-term methylphenidate treatment on gene expression in various brain regions Society for Neuroscience, Atlanta, Georgia.d, BP, Gerecke KM, Jiao Y, Smeyne M, Rong Y and Smeyne RJ (2006). Effect of long-term methylphenidate treatment on gene expression in various brain reions. ACNP.
ond BP, Gerecke KM and Smeyne RJ (2005) Effect of long-term methylphenidate treatment in an experimental model of Parkinsonism. Society for Neuroscience, Washington DC.

ink she knows her shit...

Methylphenidate is referred to as a ring-substituted phenethylamine, which isn't exactly wrong, but still... just remember that that doesn't need to mean much. Phenelzine is a substituted phenethylamine, as is methoxyphenamine, but they share little resemblance of amphetamine, pharmacologically. Just the structure is similar.

[Dybowski]

Its a moot argument, there are enough similarities to argue for it, yet enough differences to argue against it.

Chemically most accurately MPH is a combo between a piperadine and an amphetamine.
somebody answered this better than me and I didn't bother to check for posts while int he process of posting.

Pharmaceutically, as you guys know there exists a large difference in action. Enough to make one neuroprotective and the other neurotoxic at certain doses.

These are strong substances, they are likely to mess with the fundamental neurochemistry of an individual, we know there are far reaching implications, I would love to see a multi decade study of the brains of amp/mph therapeutic users.