How is amphetamine neurotoxic? What does it do to you?

[Seppi]

Imagine your brain as a billion little engines. Now rev a group of the engines to 10,000 rpm and what happens? They explode. This makes a nice little mess in that portion of your brain.

[Your brain also has cells called astrocytes. Their job is the janitor - they go around cleaning and removing any foreign materials.] The astrocytes find the mess in your brain and think it's an intruder. They try to spray down the 'intruder' with chemicals and instead kill the surrounding neurons, causing them to explode and make a bigger mess. This causes the "cascade of death" and kills many neurons.

amphetamines themselves are not neurotoxic but the way the affect neurons is detrimental to the health of your brain.

sources: an intro to neuroscience class & an intro to psychopharmocology class. i made up the analagy, they did not.

Lol. You might want to read PMID 23247506, PMID 24107764, and PMID 22118249 - they happen to contradict your assertion.
It would be so nice if people actually read this thread before they dropped their 2 cents.

Source?

The 3 papers with PMIDs listed above, all of which were already linked on this page of this thread.

 

[Lightning-Nl]

Lol. You might want to read PMID 23247506, PMID 24107764, and PMID 22118249 - they happen to contradict your assertion.
It would be so nice if people actually read this thread before they dropped their 2 cents.


The 3 papers with PMIDs listed above, all of which were already linked on this page of this thread.

Seppi has a Masters in Pharmacology. At least that's what his Wikipedia page says (if I remember correctly).

When I wrote the ADHD section on the Amphetamine article, he edited it for me a bit and linked claims that I knew to be true (but lacked more than one source) to several other studies that had also came to the same conclusion. He knows exactly what he's talking about and is great asset to have here on Bluelight.

You guys should really give him the respect he deserves.

The evidence is very clear and very legitimate. It's been replicated several times and is the truth. Amphetamine is, in fact, neuroprotective at therapeutic dosages.

 

[BallsStapledToLeg]

Seppi has a Masters in Pharmacology. At least that's what his Wikipedia page says (if I remember correctly).

When I wrote the ADHD section on the Amphetamine article, he edited it for me a bit and linked claims that I knew to be true (but lacked more than one source) to several other studies that had also came to the same conclusion. He knows exactly what he's talking about and is great asset to have here on Bluelight.

You guys should really give him the respect he deserves.

The evidence is very clear and very legitimate. It's been replicated several times and is the truth. Amphetamine is, in fact, neuroprotective at therapeutic dosages.

He's a Ph.D student in a stats/finance department as best I can tell, his thesis was in the link he posted a while back. Love the guy because he actually backs his arguments.

I have several reservations with the broadly "non-toxic at therapeutic concentrations", while the three reviews he cites do agree with the generally non-toxic line of thought they don't address several factors.

1) At what dose chronically does human neurotoxicity occur?

Case 1 - You use (non-substituted) amphetamines at therapeutic doses (the larger of 60 mg or 1 mg/kg (i.e. a kg of your body weight) of amphetamine salt, not including Desoxyn (methamphetamine hydrochloride))
Then: Don't do anything and stop worrying about neurotoxicity. This isn't even an issue at twice this range.

Where did this number come from? My personal review of the literature available on pubmed turned up nothing about in vivo toxicity in humans at any specific threshold, what did turn up for human data was blood levels in addicts who were analyzed postmortem and had signs of neurodegradation. Ricaurtes 2005 study shows neurotoxic changes at ~150ng/ml and 1mg/kg in baboons and squirrel monkeys. Also, before people try to attack his research do some reading on the back story behind his infamous redacted MDMA study (which he redacted himself) and it does look like the DEA run supply house he ordered from was behind it. Looking at a similar experiment in peri-adolescent rhesus monkeys which had concentrations of 50–60 ng/ml of d-AMPH and 15–25 ng/ml l-AMPH and 0.7-0.8mg/kg shows no real difference between control and amphetamine treated monkeys. Now, the human threshold for chronic doses to produce neurotoxicity may be above 1mg/kg but I can find no info on it. But, given animal data it seems that the higher therapeutic doses (~1mg/kg) may begin to produce toxic effects. The lack of studies which differentiates between dosage levels in humans also makes it difficult to determine this.

2) Potential for very long term side effects, I would absolutely love if they examined proteasome and autophagy function in living humans who have been using amphetamine chronically. There has been quite a bit of evidence lately that amphetamine inhibits many of the protective pathways that are involved in Parkinson's disease. Now, I would expect the relative risk ratio to be low, but it would be very interesting to see the effects of theraputic amphetamine use on these pathways. Some of these pathways also appear to be time sensitive, so while I don't have any evidence for or against them the rising use of long lasting formulations may have differential effects vs traditional amphetamine formulations due to more consistent blood levels. Preliminary links between amphetamine abuse and Parkinson's have been established, but there has not yet been any evidence regarding therapeutic amphetamine use.

3) Acute vs chronic dosing, it has been shown in lab animals that pretreatment with lower doses of methamphetamine protect against higher doses later. Now, its a little beside the point at hand but as a harm reduction site its relevant to point out that one time doses even within the theraputic range may have different neurotoxic potential in humans relative to past drug exposure. 60mg to a drug-naive individual will likely be a very different experience vs a guy who has been on 20mg a day chronically.

My concern mainly stems from the lack of human data from the high end therapeutic use, most studies don't differentiate by dose used which makes determining if such a threshold exists in humans difficult.

 

[Lightning-Nl]

He's a Ph.D student in a stats/finance department as best I can tell, his thesis was in the link he posted a while back. Love the guy because he actually backs his arguments.

Exactly. Seppi is a rare specimen. Someone without ignorance and always researches the facts before he comes to conclusions. I've made myself this way as well. Always cite studies when I can, provide links, share my knowledge, etc. Seppi has an advantage over myself, however. He appears to have good control over his emotional impulsions - something which I struggle with deeply.

For instance, if you read through many of my posts here on BL you'll see that sometimes I'll get very emotionally impulsive. Anger is something that I have a very hard time suppressing. I've really been trying to mature my anger, and think before I post - but sometimes I'll write up entire page posts on why things anger me. It's a compulsion really - don't have much control over it once I get to that point.

He doesn't seem to have that. Or if he does - not the extent of myself. Something which I envy.

 

[Seppi]

Idk what to say to you guys, but I'm flattered. =P
In any event, I'd actually prefer it if you ignore my background and judge my statements solely on the evidence provided; I'm much more interested in and concerned with discerning truth than winning arguments.

He's a Ph.D student in a stats/finance department as best I can tell, his thesis was in the link he posted a while back. Love the guy because he actually backs his arguments.

I have several reservations with the broadly "non-toxic at therapeutic concentrations", while the three reviews he cites do agree with the generally non-toxic line of thought they don't address several factors.

1) At what dose chronically does human neurotoxicity occur?



Where did this number come from?

PMID 17049170 - although I apparently didn't remember the correct number; it's 2x max as opposed to 2.5x.*** My bad. In any event, that's in rats, so it doesn't necessarily apply to humans. In a nutshell, amphetamine becomes neurotoxic once cellular antioxidant/radical scavenging becomes overwhelmed by dopamine quinones and radical species produced from DA breakdown (both in the cytosol and in the synaptic cleft). With all that said, IF rat/human ROS scavenging is comparable, then the indirectly neurotoxic threshold in rats is a suitable benchmark for the neurotoxic threshold in humans. Even in humans, it's going to vary though. Individuals with abnormally high levels of PEA activity will reach the neurotoxic threshold sooner than people with ADHD. What I said was meant for the average healthy person, provided the bolded statement is valid. At the very least, the 3 studies I linked earlier suggest that the therapeutic range is both safe (i.e., no detectable toxicity) and beneficial in ADHD individuals.

My personal review of the literature available on pubmed turned up nothing about in vivo toxicity in humans at any specific threshold, what did turn up for human data was blood levels in addicts who were analyzed postmortem and had signs of neurodegradation. Ricaurtes 2005 study shows neurotoxic changes at ~150ng/ml and 1mg/kg in baboons and squirrel monkeys. Also, before people try to attack his research do some reading on the back story behind his infamous redacted MDMA study (which he redacted himself) and it does look like the DEA run supply house he ordered from was behind it. Looking at a similar experiment in peri-adolescent rhesus monkeys which had concentrations of 50–60 ng/ml of d-AMPH and 15–25 ng/ml l-AMPH and 0.7-0.8mg/kg shows no real difference between control and amphetamine treated monkeys. Now, the human threshold for chronic doses to produce neurotoxicity may be above 1mg/kg but I can find no info on it. But, given animal data it seems that the higher therapeutic doses (~1mg/kg) may begin to produce toxic effects. The lack of studies which differentiates between dosage levels in humans also makes it difficult to determine this.

2) Potential for very long term side effects, I would absolutely love if they examined proteasome and autophagy function in living humans who have been using amphetamine chronically. There has been quite a bit of evidence lately that amphetamine inhibits many of the protective pathways that are involved in Parkinson's disease. Now, I would expect the relative risk ratio to be low, but it would be very interesting to see the effects of theraputic amphetamine use on these pathways. Some of these pathways also appear to be time sensitive, so while I don't have any evidence for or against them the rising use of long lasting formulations may have differential effects vs traditional amphetamine formulations due to more consistent blood levels. Preliminary links between amphetamine abuse and Parkinson's have been established, but there has not yet been any evidence regarding therapeutic amphetamine use.

Based upon what I wrote here - https://en.wikipedia.org/wiki/Methamphetamine#Comparison_to_amphetamine_pharmacodynamics - I don't really think amph and meth NT is comparable. Meth has several additional biomolecular targets beyond what regular amph has. It's sigmaergic activity is known to be a key component to its neurotoxic effect. Amph has no affinity for sigma receptors in humans (it's listed in 1 of my bookmarked DB's - don't remember which, but I'll look it up if you care to see). That said, excessive doses probably could contribute to Parkinsons in those who have the disease, but I really doubt Amph (as opposed to Meth) could cause it since its pharmacodynamics are literally the same as PEA in DA neurons. In contrast, Meth screws with colocalized sigma receptors in DA neurons.

3) Acute vs chronic dosing, it has been shown in lab animals that pretreatment with lower doses of methamphetamine protect against higher doses later. Now, its a little beside the point at hand but as a harm reduction site its relevant to point out that one time doses even within the theraputic range may have different neurotoxic potential in humans relative to past drug exposure. 60mg to a drug-naive individual will likely be a very different experience vs a guy who has been on 20mg a day chronically.

My concern mainly stems from the lack of human data from the high end therapeutic use, most studies don't differentiate by dose used which makes determining if such a threshold exists in humans difficult.

I think the acute vs chronic dosing phenomenon arises through neuroadaptive processes that occur from repeated exposure. It would make sense that there would be cellular adaptation to prevent further oxidative stress following repeat exposure to oxidative stimulti (very high dose meth or amph).


I'd like to hear what you all think about this. The reasons I bother posting here on bluelight is to challenge my perspective, share ideas, and get feedback on the wiki articles I write, hehe.




***In a couple sources I've come across, the lesser of 1 mg/kg/day or 60mg/day is usually quoted as the maximum recommended therapeutic dose of Adderall (this isn't a regulatory maximum), though I'm not sure what that's based upon. The linked abstract states 2mg/kg taken TID isn't neurotoxic in rats.

 

[BallsStapledToLeg]

http://www.ncbi.nlm.nih.gov/pubmed/25301936

Thought's on how this may effect rhesus macaque to human dose comparisons?

 

[doppelgänger1]

Amphetamine is, in fact, neuroprotective at therapeutic dosages.

Source for this?

 

[poneelovesyou]

Well, like any substance, it's all about the dose and people's specific genetics. From what I understand Methamphetamine can be neurotoxic because it contributes to glutamate excitotoxicity causing oxidative stress, tissue damage and inflammation. This essentially is neurodegeneration, which leads to less synaptic spines and connections or even apoptosis. I personally think neurodegeneration from oxidative stress is the basis for most depression and anxiety, along with other mental illness. But I think the dose is key. Everything is damaging at overly adundant levels, including water. Balance is key!

 

[red22]

Quote from a study:


Amphetamine and its derivatives are known to cause increased production of hydroxyl radical (^•OH) in the brain (Huang et al., 1997; Wan et al., 2000a) resulting in acute striatal DA and serotonin depletion (Kita et al., 1999; Shankaran et al., 1999). It has also been shown to induce neurodegeneration in animals (Wan et al., 2000b; Jeng et al., 2006).

Huang, N.K., Wan, F.J., Tseng, C.J., Tung, C.S., 1997. Amphetamine induces hydroxyl radical formation in the striatum of rats. Life Sci. 61, 2219–2229.

Wan, F.J., Lin, H.C., Lin, Y.S., Tseng, C.J., 2000a. Intrastriatal infusion of D-amphetamine induces hydroxyl radical formation: inhibition by MK-801 pretreatment. Neuropharmacology 39, 419–426.

Kita, T., Takahashi, M., Kubo, K., Wagner, G.C., Nakashima, T., 1999. Hydroxyl radical formation following methamphetamine administration to rats. Pharmacol. Toxicol. 85, 133–137.

Shankaran, M., Yamamoto, B.K., Gudelsky, G.A., 1999. Involvement of the serotonin transporter in the formation of hydroxyl radicals induced by 3,4-methylene-dioxymethamphetamine. Eur. J. Pharmacol. 385, 103–110.

Wan, F.J., Lin, H.C., Huang, K.L., Tseng, C.J., Wong, C.S., 2000b. Systemic administration of D-amphetamine induces long-lasting oxidative stress in the rat striatum. Life Sci. 66, 205–212.

Jeng, W., Ramkissoon, A., Parman, T., Wells, P.G., 2006. Prostaglandin H synthase-catalyzed bioactivation of amphetamines to free radical intermediates that cause CNS regional DNA oxidation and nerve terminal degeneration. FASEB J. 20, 638–650.

Source: 2-Phenylethylamine, a constituent of chocolate and wine, causes mitochondrial complex-I inhibition, generation of hydroxyl radicals and depletion of striatal biogenic amines leading to psycho-motor dysfunctions in Balb/c mice. T Sengupta KP. Neurochemistry International. 11/2010; 57(6):637-46. DOI: 10.1016/j.neuint.2010.07.013

Top of p. 638.

 

[twistedhunter]

ive used mdma and abused the shit out of it, adderal and abused the shit out it, and did meth about 10 times do didnt abuse that one, but the extreme body load after a night of amphetamines sucks. i think they are very bad for body and dont use them anymore. how people can be prescribed amphetines and not abuse them amazes me , because they are so euphoric at first, that i kept chasing the high.

 

[Dresden]

I read this whole thread, and I must say, none of this information scares me enough to want to even attempt to quit amphetamine, methamphetamine, or MDMA (if I could even get it anymore, which I can't). If it is true that speed kills, then it must also be conceded that it does so VERY slowly. These drugs are really not all that dangerous, or Adderall (mixed amphetamine salts) and Desoxyn (methamphetamine sulfate) wouldn't be available, prescription drugs in this country. However, I will also say that methamphetamine especially ages one faster due to lack of beauty sleep and rots one's teeth faster than need be. It is a fairly corrosive (to razor blades, for example) chemical.

 

[endotropic]

I read this whole thread, and I must say, none of this information scares me enough to want to even attempt to quit amphetamine, methamphetamine, or MDMA (if I could even get it anymore, which I can't). If it is true that speed kills, then it must also be conceded that it does so VERY slowly. These drugs are really not all that dangerous, or Adderall (mixed amphetamine salts) and Desoxyn (methamphetamine sulfate) wouldn't be available, prescription drugs in this country. However, I will also say that methamphetamine especially ages one faster due to lack of beauty sleep and rots one's teeth faster than need be. It is a fairly corrosive (to razor blades, for example) chemical.

You can't use a drug's classification under the US system to characterize the damage it does to the user. You could use that same logic to conclude that cannabis is more dangerous than heroin for example. Desoxyn was approved a long time ago, there's no chance in hell it would get through the modern FDA approval process.

Most doctors in the US avoid prescribing Desoxyn except as a last resort because it's pretty much universally accepted that any amount of methamphetamine used long term will end up harming the user. You're telling me you don't care about direct toxicity to dopamine neurons leading to problems with decision making, memory, anxiety, depression and risk of Parkinson's?

 

[Dresden]

I've used Desoxyn, impure crank, pure ice/shards/glass, Adderall, and MDMA extensively, and clinically, none of them has affected me negatively in any long term way. I have never experienced problems with 'decision making, memory, anxiety, depression, or Parkinsonism,' so no I'm not worried about pie in the sky 'neurotoxicity,' a term that thanks to all the bogus MDMA fear mongering studies now means virtually nothing to anyone. If amphetamine and methamphetamine did cause all those listed symptoms, the FDA would never have given its requisite 'safe and effective' stamp of approval to them, allowing them to become prescription drugs both of which are still prescribed to this day. The amphetamines including methamphetamine and MDMA are quite safe, well tolerated, and hard to overdose on. An opiate addiction is far more likely to kill you sooner than any amphetamine habit ever will.

 

[endotropic]

You're free to believe whatever you like obviously, but among the three you listed methamphetamine is demonstrably more harmful than the other two. Do you remember what happened with those bogus MDMA fear mongering studies? They showed dramatic and functionally significant brain damage in a primate model - using methamphetamine instead of MDMA by mistake. It's good to be sceptical but when the evidence is overwhelming at some point you have to accept the risks that go along with the fun.

 

[ebola?]

I still contend that taking MDMA at a dosing schedule typical for methamphetamine addicts would likely prove horribly neurotoxic, likely worse than with methamphetamine used similarly. Here, we would be approaching the ridiculous dosing schedules seen in some of the animal experiments that show mdma to be neurotoxic.

But yes, methamphetamine is rather clearly neurotoxic, to the point that it's unclear what a safe dosing schedule with it would look like. I mean, I'd be surprised if it were horribly destructive at like 10 mg / day or something, but the evidence isn't really conclusive.

ebola

 

[Dresden]

IME a little pure, racemic methamphetamine hydrochloride (say 100mg/day/person) is not going to hurt anybody. Of course, I've seen more than one tweaker mainline 500mg at a time either 1x or 2x per day. I can see how making a habit of that would or at least could be neurotoxic. I've never done that.

 

[endotropic]

IME a little pure, racemic methamphetamine hydrochloride (say 100mg/day/person) is not going to hurt anybody. Of course, I've seen more than one tweaker mainline 500mg at a time either 1x or 2x per day. I can see how making a habit of that would or at least could be neurotoxic. I've never done that.

Medical science aside, have you ever seen someone on this site who used 100mg/day for an extended period of time without any negative effects? Maybe the people that end up with problems just speak up more often, but it sure seems like there's a lot of them.

 

[ebola?]

IME a little pure, racemic methamphetamine hydrochloride (say 100mg/day/person) is not going to hurt anybody.

Is your opinion based on anything in particular?

 

[AlphaMethylPhenyl]

^hope, it's a powerful attribute

 

[golden1]

I've used Desoxyn, impure crank, pure ice/shards/glass, Adderall, and MDMA extensively, and clinically, none of them has affected me negatively in any long term way. I have never experienced problems with 'decision making, memory, anxiety, depression, or Parkinsonism,' so no I'm not worried about pie in the sky 'neurotoxicity,' a term that thanks to all the bogus MDMA fear mongering studies now means virtually nothing to anyone. If amphetamine and methamphetamine did cause all those listed symptoms, the FDA would never have given its requisite 'safe and effective' stamp of approval to them, allowing them to become prescription drugs both of which are still prescribed to this day. The amphetamines including methamphetamine and MDMA are quite safe, well tolerated, and hard to overdose on. An opiate addiction is far more likely to kill you sooner than any amphetamine habit ever will.

you might care more about the shape of your brain as you get older.. when dementia and parkinsons are more common. You know you only start getting the typical parkinson's symptoms after 40-70% of the dopamine neurons have already died off? You lose them as you age too, so you may not "notice" any loss now but it could impact how your brain ages.

also, it is VERY hard to judge your own capabilities and wellbeing in many areas and I'd imagine especially hard if the change is slowly over time.
your report is also only 1 persons experience, not useful. especially when you can find people all over claiming semi-permanent to permanent negative changes from MDMA/METH and even AMP.


Why not take some precaution? There is no reason to disregard the implications and ways to lessen the possible impact.

And wait.. one last thing... the FDA is your authority on if something could be damaging or not? haha