What the fuck means therapeutic doses of amphetamine doesn't cause neurotoxicity???

[AlphaMethylPhenyl]

First of all, people can't pinpoint the neurotransmitter they're feeling; it just doesn't work that way.

You're going through withdrawal. I must seriously stress that you should take your medicine as prescribed.

No, of course its not. Amphetamine is actually extremely complicated, with several mechanisms and more than just dopamine/serotonin/norepinepherine involved.

 

[MrSpeedyG]

Ho-Chi-Minh, I know you can't feel a specific neurotransmitter but without getting off topic I can deffintly feel a difference between serotonergic and dopaminergic feelings especially the depression from their deficiency, they both have two different feelings ie why wellbutrin works better than SSRIs for certain people and vice versa. Serotoninergic depression feels dark and heavy and deep emotionally, dopaminergic depression feels really dry for lack of a better word and your perception changes. Anyway, completely off topic and what I just said is no doubt fuel waiting to be lit up...

I know amphetamine is much more complicated than dopamine release, was in serious comedown/withdrawal when I was writing that, what I meant was neurotoxic effects rely heavily on amphetamine causing an overabundant amount of dopamine which then oxidises creating free radicals and overwhelms the endogenous antioxidant system and that oxidative stress is the primary mechanism... What I meant was that I am having doubts that it is reliant on dopamine release and that amphetamine itself regardless of how much dopamine gets released is a culprit in neurotoxicity... As in it isnt the excess dopamine stimulation and oxidation that causes the neurotoxicity such as excess glutamate release causing excitotoxicity but maybe amphetamine directly. If anyone can see what I'm saying here...

 

[AlphaMethylPhenyl]

We never really answered this question. Only one truly pertinent study was posted on dl-amphetamine.

 

[r4nx77]

I have been a long time 'lurker', of this forum, and other forums (I have ADHD).
Well, I continue to search about amphetamines and neurotoxicity (maybe a little too much for my own good), but neurotoxicity definitely exists.
I think its my time to start pitching in to the community and sharing my knowledge, instead of just lurking.

Take a read of this:

"The most recent study we found, published on March 13, 2015, states that Dexamphetamine studies on animals have shown neurotoxic effects on the dopaminergic system. Though, little is known about such effects on the human brain. The trial concluded to say that, Dexamphetamine users were found to have significantly lower striatal DA D2/3 receptor bindings. They also observed a blunted DA release and DA functionality due to an acute dAMPH challenge, as well as blunted subjective response. Finally, in agreement with the clinical studies, it determined that recreational use of Adderall/Dexamphetamine in human subjects is associated with dopaminergic system dysfunction. The findings warrant further investigations and call for caution when using this drug recreationally and for ADHD."

Here is a link to this actual study:
http://www.ncbi.nlm.nih.gov/pubmed/25394786

There are a few other studies I have found too, that state that neurotoxicity DOES exist with ADHD medication such as Adderall and Dexedrine.
Though, through my research, I found many pages and posts from forums and websites of "protective measures" when using amphetamines.
This is the one I found to have the most useful information:
http://adderallsafety.org/what-is-neurotoxicity/

I believe the dosages they quote on this page are related to dexamphetamine (not adderall) - so dont confuse that.
A smaller dose of Dexamphetamine is equivalent to a larger dose of Adderall (so you will need to manually gain an understanding of the post and dosages).
The point that the site makes is only use a dose of what you actually need to help with your ADHD, anything more is not worth it.
If you use amphetamines for recreational use (or even for ADHD treatment), then also, please read on.

There are a lot of posts, threads, sites, and actual studies, which show that some supplements can help PREVENT or *possibly REVERSE damage caused by amphetamines.
These are called anti-oxidants, specifically those that cross the BBB. Melatonin in particular (time-release because Melatonin has a short half life, time-release will keep it in your system for longer), has proved to prevent the development of Parkinson's Disease. And many believe that it can help protect your brain while using stimulants.
There are many more supplements that can help protect your brain while using stimulants, not only supplements, but tactics of taking stimulants effectively.
I suggest you read the page I posted above, as it goes into much more detail than I ever can.
Its a long read, but definitely worth the knowledge.
I wish I knew these things from the beginning, and thats why im sharing this information now. Please be careful people, and if you MUST take stimulants, then PLEASE take preventative measures while doing so.

 

[Nagelfar]

...It seems that therapeutic doses doesn't cause dopamine neurons damage. But Illicit dosing would kill neurons. ...But wtf does that mean? Where end therapeutic doses and where start illicit doses?

The simple and rational explanation to the question is that the therapeutic dose is the one discovered to be below the threshold of a damaging dose; and thereafter deemed a "therapeutic" dose as contrasted to not.

 

[afshin]

Spoiler: long post

I have been a long time 'lurker', of this forum, and other forums (I have ADHD).
Well, I continue to search about amphetamines and neurotoxicity (maybe a little too much for my own good), but neurotoxicity definitely exists.
I think its my time to start pitching in to the community and sharing my knowledge, instead of just lurking.

Take a read of this:

"The most recent study we found, published on March 13, 2015, states that Dexamphetamine studies on animals have shown neurotoxic effects on the dopaminergic system. Though, little is known about such effects on the human brain. The trial concluded to say that, Dexamphetamine users were found to have significantly lower striatal DA D2/3 receptor bindings. They also observed a blunted DA release and DA functionality due to an acute dAMPH challenge, as well as blunted subjective response. Finally, in agreement with the clinical studies, it determined that recreational use of Adderall/Dexamphetamine in human subjects is associated with dopaminergic system dysfunction. The findings warrant further investigations and call for caution when using this drug recreationally and for ADHD."

Here is a link to this actual study:
http://www.ncbi.nlm.nih.gov/pubmed/25394786

There are a few other studies I have found too, that state that neurotoxicity DOES exist with ADHD medication such as Adderall and Dexedrine.
Though, through my research, I found many pages and posts from forums and websites of "protective measures" when using amphetamines.
This is the one I found to have the most useful information:
http://adderallsafety.org/what-is-neurotoxicity/

I believe the dosages they quote on this page are related to dexamphetamine (not adderall) - so dont confuse that.
A smaller dose of Dexamphetamine is equivalent to a larger dose of Adderall (so you will need to manually gain an understanding of the post and dosages).
The point that the site makes is only use a dose of what you actually need to help with your ADHD, anything more is not worth it.
If you use amphetamines for recreational use (or even for ADHD treatment), then also, please read on.

There are a lot of posts, threads, sites, and actual studies, which show that some supplements can help PREVENT or *possibly REVERSE damage caused by amphetamines.
These are called anti-oxidants, specifically those that cross the BBB. Melatonin in particular (time-release because Melatonin has a short half life, time-release will keep it in your system for longer), has proved to prevent the development of Parkinson's Disease. And many believe that it can help protect your brain while using stimulants.
There are many more supplements that can help protect your brain while using stimulants, not only supplements, but tactics of taking stimulants effectively.
I suggest you read the page I posted above, as it goes into much more detail than I ever can.
Its a long read, but definitely worth the knowledge.
I wish I knew these things from the beginning, and thats why im sharing this information now. Please be careful people, and if you MUST take stimulants, then PLEASE take preventative measures while doing so.

Just finished reading the study you refer to since im on dexamphetamine adhd-meds myself, and one thing i find odd is that the "recreational" dexamph users (who use dexamph an avarage of 27.8 +/- 17 times a year with an avarage amount of 800 mg +/- 1200 mg per time - and have been using it on avarage for 13.9 +/- 8.7 years with a total exposure to dexamph of 352.6 +/- 465 grams) -also use a bunch of other drugs a whole lot more than the control group.

(control-group right side)

[TABLE="width: 100%"]
[TR]
[TD="colspan: 4"]Other substances[/TD]
[/TR]
[TR]
[TD]Average tobacco use (cigarettes/month)[/TD]
[TD]261.0 (±279.8[/TD]
[TD]0[/TD]
[TD]0.01[/TD]
[/TR]
[TR]
[TD]Average alcohol use (units/month)[/TD]
[TD]103.5 (±146.6)[/TD]
[TD]104.5(±83.5)[/TD]
[TD]0.49[/TD]
[/TR]
[TR]
[TD]Average cannabis use (joints/year)[/TD]
[TD]410.3(±480.5)[/TD]
[TD]19.4(±31.8[/TD]
[TD]0.02[/TD]
[/TR]
[TR]
[TD]Average MDMA use (pills/year)[/TD]
[TD]3.8±10.6)[/TD]
[TD]0[/TD]
[TD]0.32[/TD]
[/TR]
[TR]
[TD]Average cocaine use (occasions/year)[/TD]
[TD]5.0(±5.2)[/TD]
[TD]0.1(±0.4)[/TD]
[TD]0.009[/TD]
[/TR]
[/TABLE]


The authors do talk a bit about this in the limitation-part of the study:

Second, it cannot be excluded that the observed DAergic dysfunction is due to other drugs than dAMPH since AMPH users had more experience with tobacco, cannabis and cocaine then controls. However, other than cocaine, none of these drugs is known to affect the integrity of the DAergic system. For that reason we performed post hoc analyses adjusting for cocaine use. It is therefore unlikely that the findings of the present study are caused by substances other than dAMPH.

Well i call bullshit on this, seems to me the autors are a bit quick to dismiss the fact that the (pretty heavy) use of other substances could very well be affecting the results this study shows. I mean you dont have to spend very long time using google scholar to find studies showing that cannabis, tobacco and mdma use does in fact have effects on the DAergic system...


https://www.researchgate.net/public...tobacco_addiction_A_high-resolution_PET_study

The dopamine (DA) system is known to be involved in the reward and dependence mechanisms of addiction. However, modifications in dopaminergic neurotransmission associated with long-term tobacco and cannabis use have been poorly documented in vivo. In order to assess striatal and extrastriatal dopamine transporter (DAT) availability in tobacco and cannabis addiction, three groups of male age-matched subjects were compared: 11 healthy non-smoker subjects, 14 tobacco-dependent smokers (17.6 ± 5.3 cigarettes/day for 12.1 ± 8.5 years) and 13 cannabis and tobacco smokers (CTS) (4.8 ± 5.3 cannabis joints/day for 8.7 ± 3.9 years). DAT availability was examined in positron emission tomography (HRRT) with a high resolution research tomograph after injection of [11C]PE2I, a selective DAT radioligand. Region of interest and voxel-by-voxel approaches using a simplified reference tissue model were performed for the between-group comparison of DAT availability. Measurements in the dorsal striatum from both analyses were concordant and showed a mean 20% lower DAT availability in drug users compared with controls. Whole-brain analysis also revealed lower DAT availability in the ventral striatum, the midbrain, the middle cingulate and the thalamus (ranging from −15 to −30% ). The DAT availability was slightly lower in all regions in CTS than in subjects who smoke tobacco only, but the difference does not reach a significant level. These results support the existence of a decrease in DAT availability associated with tobacco and cannabis addictions involving all dopaminergic brain circuits. These findings are consistent with the idea of a global decrease in cerebral DA activity in dependent subjects.

Cannabis also seems to have a bunch of diffrent effects on dopamine-systems in the brain, and the pepole in this study do seem to smoke quite a bit of weed compared to the control group (the avarage diffrence is almost 400 joints a year...)
http://www.nature.com/articles/natu...1ub7xBNNY78SVOOJ4CvltCUgE9RQSlEFuAUEW7_vwFw==
http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201621a.html

Overall this study seems to be pretty poorly designed, comparing a bunch of pepole who use a bunch of diffrent drugs - and with pretty hefty liftime exposures to dexamph - with a control group who seems to use a whole lot less drugs, dosent really strike me like a properly designed study.

 

[serotonin2A]

Just finished reading the study you refer to since im on dexamphetamine adhd-meds myself, and one thing i find odd is that the "recreational" dexamph users (who use dexamph an avarage of 27.8 +/- 17 times a year with an avarage amount of 800 mg +/- 1200 mg per time - and have been using it on avarage for 13.9 +/- 8.7 years with a total exposure to dexamph of 352.6 +/- 465 grams) -also use a bunch of other drugs a whole lot more than the control group.

(control-group right side)

[TABLE="width: 100%"]
[TR]
[TD="colspan: 4"]Other substances[/TD]
[/TR]
[TR]
[TD]Average tobacco use (cigarettes/month)[/TD]
[TD]261.0 (±279.8[/TD]
[TD]0[/TD]
[TD]0.01[/TD]
[/TR]
[TR]
[TD]Average alcohol use (units/month)[/TD]
[TD]103.5 (±146.6)[/TD]
[TD]104.5(±83.5)[/TD]
[TD]0.49[/TD]
[/TR]
[TR]
[TD]Average cannabis use (joints/year)[/TD]
[TD]410.3(±480.5)[/TD]
[TD]19.4(±31.8[/TD]
[TD]0.02[/TD]
[/TR]
[TR]
[TD]Average MDMA use (pills/year)[/TD]
[TD]3.8±10.6)[/TD]
[TD]0[/TD]
[TD]0.32[/TD]
[/TR]
[TR]
[TD]Average cocaine use (occasions/year)[/TD]
[TD]5.0(±5.2)[/TD]
[TD]0.1(±0.4)[/TD]
[TD]0.009[/TD]
[/TR]
[/TABLE]


The authors do talk a bit about this in the limitation-part of the study:



Well i call bullshit on this, seems to me the autors are a bit quick to dismiss the fact that the (pretty heavy) use of other substances could very well be affecting the results this study shows. I mean you dont have to spend very long time using google scholar to find studies showing that cannabis, tobacco and mdma use does in fact have effects on the DAergic system...


https://www.researchgate.net/public...tobacco_addiction_A_high-resolution_PET_study


Cannabis also seems to have a bunch of diffrent effects on dopamine-systems in the brain, and the pepole in this study do seem to smoke quite a bit of weed compared to the control group (the avarage diffrence is almost 400 joints a year...)
http://www.nature.com/articles/natu...1ub7xBNNY78SVOOJ4CvltCUgE9RQSlEFuAUEW7_vwFw==
http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201621a.html

Overall this study seems to be pretty poorly designed, comparing a bunch of pepole who use a bunch of diffrent drugs - and with pretty hefty liftime exposures to dexamph - with a control group who seems to use a whole lot less drugs, dosent really strike me like a properly designed study.

I can't imagine that it would be possible to find more than one or two people that use dextroamphetamine recreationally but no other substances -- and especially legal ones like nicotine and alcohol. The question is really whether the results would be representative of recreational amphetamine users (as opposed to people with ADHD). Furthermore, although all of the other substances impact DA, none of them besides amphetamine are suspected of being neurotoxic to DA. So it is reasonable to cautiously link the changes to amphetamine.

 

[afshin]

I can't imagine that it would be possible to find more than one or two people that use dextroamphetamine recreationally but no other substances -- and especially legal ones like nicotine and alcohol.

Well one idea would be to find a control group with more simular drug use but who dont use dexamph, should not be very hard and would make for a better comparison.

The question is really whether the results would be representative of recreational amphetamine users (as opposed to people with ADHD). Furthermore, although all of the other substances impact DA, none of them besides amphetamine are suspected of being neurotoxic to DA. So it is reasonable to cautiously link the changes to amphetamine.

You are right of course, however when i read this study last night i cant remember finding any conclusive evidence of actual neurotoxicity, all they observe is DAergic dysfunction.

i find this part interesting:

One of the explanations for the lower reward anticipation found in recreational dAMPH users may be an innate hypofunction of the DAergic system, which, in turn, may reflect increased sensitivity toward dAMPH (ab)use and or addiction. A leading theory about addiction states that reduced sensitivity for natural reinforcers underlies the development of addiction (also referred to as the reward deficiency hypothesis; Comings and Blum, 2000). According to this theory, the dAMPH group may have an innate DAergic hypofunction, which, in turn, has predisposed them to developing a penchant for stimulant use. Indeed, even after prolonged abstinence, lower D2 receptor availability in a wide variety of addicted individuals has been reported (for review see Volkow et al., 2009). In addition, lower D2 receptor availability has been linked to increased impulsivity measures (Buckholtz et al., 2010), which in itself has been put forward as a component cause for the development of addiction (for review see Hommer et al., 2011). Thus, it is possible that our findings may not relate to dAMPH use, but rather increased impulsivity due to low D2 receptor availability. However, we cannot exclude the possibility that selection bias or confounding by factors that were not included in the current study are responsible for the observed differences in this explorative study. Only a large-scale prospective study, as we previously conducted for MDMA (de Win et al., 2008), will be able to show the causal nature of our findings, and exclude that pre-existing differences (such as low D2 receptor availability) underlie our findings.

 

[serotonin2A]

Well one idea would be to find a control group with more simular drug use but who dont use dexamph, should not be very hard and would make for a better comparison.



You are right of course, however when i read this study last night i cant remember finding any conclusive evidence of actual neurotoxicity, all they observe is DAergic dysfunction.

i find this part interesting:
[/FONT][/COLOR]

Its not as easy as you think to recruit adults willing to spend there time in a scanner who don't use any intoxicating substances.

DA dysfunction induced by use of alcohol, nicotine, or cannabis shouldn't reduce dopamine release in response to amphetamine challenge.

 

[afshin]

Its not as easy as you think to recruit adults willing to spend there time in a scanner who don't use any intoxicating substances.

DA dysfunction induced by use of alcohol, nicotine, or cannabis shouldn't reduce dopamine release in response to amphetamine challenge.

Hehe yeah i guess you make a good point about recruiting pepole for studies


Also guys: seems i made a bit of a stupid (and somewhat embarrassing) mistake here... When sitting reading this study the other night i was using a bunch of ghb, and turns out i was sitting there reading the wrong study haha disregard my previous posts i will read up on the actual study refered to sober

 

[Cotcha Yankinov]

DA dysfunction induced by use of alcohol, nicotine, or cannabis shouldn't reduce dopamine release in response to amphetamine challenge.

I'm a tad confused. In some ex-MDMA users there is a lower expression of SERT, and I'm under the impression that this could just be an adaptation rather than reflect neurotoxicity. If AMPH users show a semi-persistent downregulation of DAT that isn't related to neurotoxicity, won't that have an effect on the increase in dopamine seen with a DRA? Or is the increase in dopamine with DRAs mostly dependent on the cytosolic pool, and it doesn't make a difference whether you have 5 or 10 DATs to reverse?

In the case that it is really the cytosolic pool rather than the level of DAT expression that matters, I have also read that VMAT2 may be rather dynamic, so I wonder if that may be affected by drugs of abuse and confound results as well.

I guess I'm just curious if you can use the increase in i.e. 5-HT that you see with an SRA to pick apart whether or not there is neurotoxicity in ex-MDMA users, or if we are only expecting that a typical increase of 5-HT from a releasing agent will be preserved with users of non-releasing agent drugs, and that releasing agents in particular can induce neuroplastic changes that can affect those results. I hope this makes sense...

 

[serotonin2A]

I'm a tad confused. In some ex-MDMA users there is a lower expression of SERT, and I'm under the impression that this could just be an adaptation rather than reflect neurotoxicity. If AMPH users show a semi-persistent downregulation of DAT that isn't related to neurotoxicity, won't that have an effect on the increase in dopamine seen with a DRA? Or is the increase in dopamine with DRAs mostly dependent on the cytosolic pool, and it doesn't make a difference whether you have 5 or 10 DATs to reverse?

In the case that it is really the cytosolic pool rather than the level of DAT expression that matters, I have also read that VMAT2 may be rather dynamic, so I wonder if that may be affected by drugs of abuse and confound results as well.

I guess I'm just curious if you can use the increase in i.e. 5-HT that you see with an SRA to pick apart whether or not there is neurotoxicity in ex-MDMA users, or if we are only expecting that a typical increase of 5-HT from a releasing agent will be preserved with users of non-releasing agent drugs, and that releasing agents in particular can induce neuroplastic changes that can affect those results. I hope this makes sense...

Your basic question is whether a tolerance to amphetamine due to DAT downregulation could confound this study. The answer is that it could -- but so could a lot of factors. This study is just a rough assessment showing that there is an alteration of how dopaminergic terminals function.

 

[Cotcha Yankinov]

This study is just a rough assessment showing that there is an alteration of how dopaminergic terminals function.

If amphetamine challenge studies and DAT/dopamine receptor labeling imaging studies can be confounded by tolerance/neuroplastic changes, do you have any ideas on how one would go about trying to detect neurotoxicity in vivo?

Some researchers seem to take 5-HT2A upregulation as a sign of serotonergic neurotoxicity in ex-MDMA users, and even that seems like it could be confounded by neuroplastic changes... But is there a dopamine receptor equivalent to 5-HT2A upregulation?