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

[TheSwede]

I've heard many people talking about how amphetamines can be neurotoxic both short term and long term. But whenever I ask them, what excactly that means, I can't get an answer. I've been trying to find some information on the internet about it, but I can't figure out, what the neurotoxic effects specifically affect people. I think especially people education young people on drugs should think more about this, cause I think for many young people, "neurotoxic" pretty much has no meaning. I mean the notorious cone snail venoms are neurotoxic as well, but stepping on one of them (depending on species) can be deadly. That's quite far from what people experience on a simple line on street amphetamine, so it has got to confuse some people who think the way I do.

Can anyone give me some examples, so I can better understand it?

 

[Immunator]

I did endless days of research before trying meth. From what I've researched, the 1000-1200% increase of dopamine release causes oxidative stress due to free radicals. If free radicals get out of control, they can cause damage (Anyone feel free to correct me on anything). All of the studies I've read are from addicts and chronic abusers. It could be different for someone who uses once a week, month, year, whatever. Also the studies say nothing about people eating healthy food containing antioxidants, such as flaxseed. The human body is incredible. It still seems everyone is on the fence whether it actually causes damage or just alters the way the brain functions because it has adapted. If one eats tons of antioxidant containing food and extremely healthy before, during, and after meth use, does it actually cause damage in a responsible user?

I believe most of the damage comes from binges. Understanding how tolerance works can dramatically reduce damage, if you have enough to control to not binge. When you release all that dopamine, it takes time for all of it to go away and for the receptors to repair and begin functioning like normal again. When you re-dose, it requires a significantly higher dosage because there isn't that much dopamine in there to release. You must give your receptors time to repair themselves, at the very least a week (and thats with actually eating, staying hydrated, and attempting to sleep on it).

 

[TheSwede]

So you are saying, that the specific neurotoxic symptoms would be identical to the problems caused by lack of dopamine/dopamine receptors? Which I guess would especially mean depression and anxiety?

 

[Immunator]

In a sense, I would say yes. Depression is mostly serotonin, not sure about anxiety. Meth works almost solely with dopamine, but has a little effect on a few others, including serotonin. Dopamine is a pleasure neuron. Your brain releases this when you do things pleasurable; sex, food, etc. Too much or too little has an effect on motor control skills and memory. I don't know of the connection of how that is but that is the gist of it. Some studies have shown a link between abuse in meth and Parkinson and Alzheimer disease (motor control and memory).

Whether the meth is the cause or not can never be determined. There are just too many factors in the world that it is too hard to tell; pollution, smog and bad air, preservatives, stress, fake sugar, and pesticides are all examples of harmful things. Humans have destroyed this earth so much with man-made bullshit that I really don't think its hard drugs you really have to worry about. Abuse and over-doing is a different subject of its own.

 

[BlueHues]

Od--->n&pd

 

[TheSwede]

How about psychosis? Is that due to the neurotoxic effects or rather due to repeated periods of sleep deprivation?

 

[h3lp]

Doing research I found a relatively recent study done on amphetamine and the treatment of ADHD.

Here is a passage:

RESULTS:

In early studies, high doses of amphetamine, comparable to amounts used by addicts, were shown to damage dopaminergic pathways. More recent studies, using therapeutic regimens, appear contradictory. One paradigm shows significant decreases in striatal dopamine and transporter density after oral administration of "therapeutic" doses in primates. Another shows morphological evidence of "trophic" dendritic growth in the brains of adult and juvenile rats given systemic injections mimicking "therapeutic" treatment. Imaging studies of ADHD-diagnosed individuals show an increase in striatal dopamine transporter availability that may be reduced by methylphenidate treatment.

Here it says that original high doses of amphetamine in comparison to the amounts used by addicts were damage dopamine pathwars.

However in comparison studies have indicated decreases in striatal dopamine and transporter density when used on primates. This is when given in Therapeutic value similar to the amounts prescribed to humans as a treatment for ADHD. Another resulted in "trophic" morphinng of dendritic growth in the brains of rats given similar doses. In humans it they found an increase of striatal dopamine transporter availabiltiy which could be counteracted by methyphenidate treatment.

Source:http://www.ncbi.nlm.nih.gov/pubmed/17606768

 

[Immunator]

I have no idea what any of that means lol. But the psychosis is due to the sleep deprivation, and possibly starvation which both make the body and mind weaker.

 

[Seppi]

Transporters aren't really a big deal with subst. amph. neurotoxicity. It's the histological changes (i.e., brain structure/volume).
Amph is a much weaker indirect neurotoxin than meth (in simple terms, the "toxic effects" arising from abuse are milder), and seems to have fewer mechanisms than meth (e.g., doesn't bork your blood/brain barrier). Amph also induces hippocampal neurogenesis in rats (and, based upon the similarity in ΔFosB/hippocampal models, humans too). [Ref - interesting contrast with meth]. Low doses shouldn't produce severe oxidative stress and metabolic dysfunction, so adverse gene transcription doesn't occur, and the neuroplastic changes that result in addiction never come about.
See https://en.wikipedia.org/wiki/Amphetamine for background info on ΔFosB (addiction) and increases in brain volume at therapeutic doses (medical uses).

TLDR: Don't abuse amphetamine and the question won't be relevant to you.

Images/models:

Meth neurotoxicity model (amph doesn't possess all of these)

Simplified/nonspecific model: Neuroplasticity from addiction, which arises partly b/c of neurotoxicity...is a lot more technical. That plasticity is more or less a toxicogenomics issue than a neurotoxicity one.




For psychosis, the current research focuses on white matter abnormalities: http://www.ncbi.nlm.nih.gov/pubmed/?term=white+matter+psychosis
Meth produces more noticeable histological changes in abuse (incl. white matter) than amph - hard to find statements of statistically significant white/gray matter changes in amph abuse.

 

[Trying2Iso]

I read it destroys dopamine and Norepinephrine receptors

 

[Seppi]

I read it destroys dopamine and Norepinephrine receptors

There's literally no evidence of this even in people abusing amphetamine for a decade.
For recreational use over a decade, the studies indicate that there's marginal (p=.05) statistical significance in reduced DAT function.

Methamphetamine has significant effects in under a year of consistent recreational use.

MDMA has evidence of abnormal 5-HT neuron function, but I don't remember the time frame.


http://www.ncbi.nlm.nih.gov/pubmed/23415394


This is very weak neurotoxicity (and only marginally statistically significant) given that:
*some participants had some polydrug use
*dose range: "0.5g-3g" per occasion. The average dose was roughly a full gram.
*the average amount of time that d-amph was used recreationally by the study participants was over a decade:" 13.9 (±8.7) years

 

[Seppi]

I'll just restate this to emphasize/summarize my first post:

The main concern with "Amphetamine" use is neuroplasticity.

The concerns with "Methamphetamine" use are both neuroplasticity and neurotoxicity.

 

[Lightning-Nl]

The main concern of Amphetamine toxicity is excitotoxic cell death caused by sustained, repetitive firing of Glutaminergic neurons. Amphetamine can also induce serotonin syndrome at higher dosages so that's also a secondary toxic action.

Keep in mind, however, that therapeutic dosages of Amphetamine are indeed, quite safe. Recreational dosages, however, tend to be far higher and much more often in dosage (were talking about 40 milligram once a day versus 200 milligrams a couple times every twelve hours).

Methamphetamine appears to be entirely different however. At any dosage it can be neurotoxic to serotonergic neurons and therefore methamphetamine actually promotes serotonin neuron cell death. That's why its classified as a neurotoxin by the FDA. Fun fact: Methamphetamine is the only neurotoxic allowed to be prescribed by doctors (again, because Methamphetamine therapeutic dosages are far lower than recreational ones).

Another interesting note is that amphetamine, at therapeutic dosages taken once daily - actually appears to have neuroprotective actions. Actually, no it doesn't! It actually appears to promote the correction of brain 'circuitry' and therefore could actually be classified as a neurogen (a substance that promotes the formation of new synapses).

 

[sekio]

Fun fact: Methamphetamine is the only neurotoxic allowed to be prescribed by doctors

Look into side effects profiles of cancer chemotherapy drugs and some of the wierder antibiotics sometimes. Meth is far from the only neurotoxin people prescribe. It's certainly one of the most "popular" though...

 

[21p]

I've heard many people talking about how amphetamines can be neurotoxic both short term and long term. But whenever I ask them, what excactly that means, I can't get an answer. I've been trying to find some information on the internet about it, but I can't figure out, what the neurotoxic effects specifically affect people. I think especially people education young people on drugs should think more about this, cause I think for many young people, "neurotoxic" pretty much has no meaning. I mean the notorious cone snail venoms are neurotoxic as well, but stepping on one of them (depending on species) can be deadly. That's quite far from what people experience on a simple line on street amphetamine, so it has got to confuse some people who think the way I do.

Can anyone give me some examples, so I can better understand it?

Let me try to explain this to you in a way that satisfies your request and gives you somewhat of a background... I'm in med school and love to teach.

Neurotoxic can be rephrased as "a substance having a toxic effect on neurons." Notice there's nothing about time/intensity/permanence mentioned. It's just not good for your neurons somehow. The most important thing to remember when reading forum posts is that nobody knows how a drug affects you, regardless of what they may claim. Keeping that in mind, amphetamines can be neurotoxic in a number of ways.

(Short, medium, and long term effects are not set in stone... more of a continuum)
Short term neurotoxicity from amphetamines results from flooding your brain with dopamine and to a lesser extent, serotonin. Dopamine tells your body to go on 'high alert' by telling two fatty lumps above your kidneys to secrete adrenaline, a chemical you probably are familiar with if you've ever jumped out of a plane or had a close call with danger. Whenever your brain is that stimulated for an extended period of time, all the wastes it generates need to be flushed from your central nervous system via chemical reactions occurring during sleep. Most people stay awake for days on end, never allowing the body to restore the dopamine and serotonin levels to normal. Their neurons begin to function abnormally and they may see things, feel anxious, etc... At this point, he or she is experiencing acute neurotoxic effects of amphetamine consumption.

I think you have originally been asking the difference between acute and long-term effects... again, I'm gonna try to help you understand the underlying idea instead of beating you over the head with words. Nobody benefits from that shit, imo.

Here's a diagram of a normal neuron with explanation below

O---->

O = cell body of neuron
--- = part of neuron that carries information
> = part of neuron that gives/receives information

O------>X Short term damage
O--X---> Repairable damage to neuron, loss of function until complete
X-- - Irreparable damage to neuron, no return of function/cell death

The truth is, we don't know what the long long term effects of amphetamine administration at clinical levels will be, because we have just recently begun to understand the brain. While some may disagree, recreational amphetamine use has been shown to cause all three categories of damage (remember, brain chemistry doesn't fit into neat little categories). The more you abuse the drug, the higher the likelihood you will experience these effects. Different types of cells in your body can be damaged by amphetamines besides neurons, but that's another post.

Hope this answers the question to your liking and gives you some insight into the terminology. Holler back if you need more specific answers on other effects/dangers.

 

[Immunator]

Putting all biased and basic harm reduction aside, the issue of prescribed meth (Desoxyn). I've read of doses of up to 60mg a day being prescribed. Are these people at risk for more damage than someone who would use one dose only once a week with a much lower grade of about 80mg plugged or orally? Snorting and smoking are out of the question as they pass the BBB too quickly.

 

[21p]

Putting all biased and basic harm reduction aside, the issue of prescribed meth (Desoxyn). I've read of doses of up to 60mg a day being prescribed. Are these people at risk for more damage than someone who would use one dose only once a week with a much lower grade of about 80mg plugged or orally? Snorting and smoking are out of the question as they pass the BBB too quickly.

It's very rare in the US for someone to have a Desoxyn rx for 60mg a day, but it is prescribed for severe narcolepsy. What do you mean by "lower grade"?

If you're talking street amphetamine, who knows? I can give you what I know and let you decide.

In the case of Desoxyn, the effects will usually stabilize around the six month mark at a given dosage and patients will adjust. The fella who's taking 60mg probably started out at 5mg and worked his way to the current dosage due to extreme tolerance. Again, this case is probably rare, which is why you heard about it. I personally would consider amphetamine therapy ineffective if we started @ 10mg adderall and ended up @ 60mg desoxyn. In fact, we'd never go there unless that sum'bitch had a portable telemetry set for about 6 weeks, but I digress!

The problem with methylated amphetamines isn't necessarily the stimulation of the adrenergic receptors, but the type of adrenergic receptors selected for... meth prefers the adrenergic receptors increasing your heart's output and contractility (pumping strength), all while constricting the peripheral arterioles. Meth's effects on the heart, kidney, and peripheral vasculature is definitely worse for these reasons if we're speaking symptoms...

Mechanically speaking... meth is more potent than regular amphetamine because it more effectively permeates both the CNS and PNS. Methylated compounds are usually metabolized much faster in the liver. Adderall prefers the PNS, which makes it less dangerous with vital functions like core temperature, water balance, and thirst/hunger.

Psychiatric: I think you're setting yourself up for an addiction by chasing the rush dosing once a week. That type of planning makes your recreational activities dependent on a substance. It may be healthier to not plan for it and NOT keep it around the house. If you run into it while you're out, you're more in control because the drug isn't front and center. In the hypothetical scenario you posed, I'd defer to the narcoleptic under close supervision.

 

[Seppi]

Let me try to explain this to you in a way that satisfies your request and gives you somewhat of a background... I'm in med school and love to teach.


Neurotoxic can be rephrased as "a substance having a toxic effect on neurons." Notice there's nothing about time/intensity/permanence mentioned. It's just not good for your neurons somehow. The most important thing to remember when reading forum posts is that nobody knows how a drug affects you, regardless of what they may claim. Keeping that in mind, amphetamines can be neurotoxic in a number of ways.


(Short, medium, and long term effects are not set in stone... more of a continuum)
Short term neurotoxicity from amphetamines results from flooding your brain with dopamine and to a lesser extent, serotonin. Dopamine tells your body to go on 'high alert' by telling two fatty lumps above your kidneys to secrete adrenaline, a chemical you probably are familiar with if you've ever jumped out of a plane or had a close call with danger. Whenever your brain is that stimulated for an extended period of time, all the wastes it generates need to be flushed from your central nervous system via chemical reactions occurring during sleep. Most people stay awake for days on end, never allowing the body to restore the dopamine and serotonin levels to normal. Their neurons begin to function abnormally and they may see things, feel anxious, etc... At this point, he or she is experiencing acute neurotoxic effects of amphetamine consumption.


I think you have originally been asking the difference between acute and long-term effects... again, I'm gonna try to help you understand the underlying idea instead of beating you over the head with words. Nobody benefits from that shit, imo.


Here's a diagram of a normal neuron with explanation below


O---->


O = cell body of neuron
--- = part of neuron that carries information
> = part of neuron that gives/receives information


O------>X Short term damage
O--X---> Repairable damage to neuron, loss of function until complete
X-- - Irreparable damage to neuron, no return of function/cell death


The truth is, we don't know what the long long term effects of amphetamine administration at clinical levels will be, because we have just recently begun to understand the brain. While some may disagree, recreational amphetamine use has been shown to cause all three categories of damage (remember, brain chemistry doesn't fit into neat little categories). The more you abuse the drug, the higher the likelihood you will experience these effects. Different types of cells in your body can be damaged by amphetamines besides neurons, but that's another post.


Hope this answers the question to your liking and gives you some insight into the terminology. Holler back if you need more specific answers on other effects/dangers.

...Did you even read what I wrote before you posted that?

Transporters aren't really a big deal with subst. amph. neurotoxicity. It's the histological changes (i.e., brain structure/volume).
Amph is a much weaker indirect neurotoxin than meth (in simple terms, the "toxic effects" arising from abuse are milder), and seems to have fewer mechanisms than meth (e.g., doesn't bork your blood/brain barrier). Amph also induces hippocampal neurogenesis in rats (and, based upon the similarity in ΔFosB/hippocampal models, humans too). [Ref - interesting contrast with meth]. Low doses shouldn't produce severe oxidative stress and metabolic dysfunction, so adverse gene transcription doesn't occur, and the neuroplastic changes that result in addiction never come about.
See https://en.wikipedia.org/wiki/Amphetamine for background info on ΔFosB (addiction) and increases in brain volume at therapeutic doses (medical uses).


TLDR: Don't abuse amphetamine and the question won't be relevant to you.


Images/models:


Meth neurotoxicity model (amph doesn't possess all of these)


Simplified/nonspecific model: Neuroplasticity from addiction, which arises partly b/c of neurotoxicity...is a lot more technical. That plasticity is more or less a toxicogenomics issue than a neurotoxicity one.








For psychosis, the current research focuses on white matter abnormalities: http://www.ncbi.nlm.nih.gov/pubmed/?term=white+matter+psychosis
Meth produces more noticeable histological changes in abuse (incl. white matter) than amph - hard to find statements of statistically significant white/gray matter changes in amph abuse.

There's literally no evidence of this even in people abusing amphetamine for a decade.
For recreational use over a decade, the studies indicate that there's marginal (p=.05) statistical significance in reduced DAT function.


Methamphetamine has significant effects in under a year of consistent recreational use.


MDMA has evidence of abnormal 5-HT neuron function, but I don't remember the time frame.




http://www.ncbi.nlm.nih.gov/pubmed/23415394




This is very weak neurotoxicity (and only marginally statistically significant) given that:
*some participants had some polydrug use
*dose range: "0.5g-3g" per occasion. The average dose was roughly a full gram.
*the average amount of time that d-amph was used recreationally by the study participants was over a decade:" 13.9 (±8.7) years

Amphetamine isn't a neurotoxin at therapeutic doses - it's neurogenerative, since it *INCREASES* DAT availability and gray cortical matter volume at lower doses - entirely opposite to the "weak neurotoxicity" that I stated exists for harsh long-term abuse directly above.
References:
Lack of neurotoxicity: PMID 17606768 (a review on humans) "Imaging studies of ADHD-diagnosed individuals show an increase in striatal dopamine transporter availability that may be reduced by methylphenidate treatment."
Presence of neurogenesis: I really don't feel like re-stating what I wrote here. Just read the first paragraph of the medical section.

 

[MobiusDick]

Dopamine that has been metabolized by MAO B into DOPAC (Dihydroxyphenylacetic Acid) is itself neurotoxic, especially with depleted glutathione, SOD or methyl donors. One of the hypotheses of late onset Parkinson's disease may be related to oxidative cellular injury from years of dopamine metabolites wreaking havoc in the substantia nigra and mesolimbic pathways, & if antioxidants are depleted, any dopamine reuptake inhibitor or releaser can have this effect. As to whether or not this is the only neurotoxicity associated with methamphetamine is not known. But low dose methamphetamine or methamphetamine use with adequate antioxidants does not appear to be significantly neurotoxic in a 6-OH DA sense like MPP+.

 

[ebola?]

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