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Dopamine receptors cannot be restored after amphetamine use?

dopamine amphetamine adderall

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#1 Axmann8

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Posted 07 October 2015 - 07:33 AM


I was just reading this article about a student who killed himself after an Adderall addiction, and I saw this quote from a licensed clinical social worker and addiction specialist:

 

"It tricks the brain that it doesn't need to make dopamine, and dopamine is the only chemical in the brain that once it is damaged, you never get it back."

How much truth is there to this? I am currently still suffering a year later from the aftereffects of Amphetamine overuse (and I never even used it recreationally; I have ADD), and reading this made me very sad.

Is there really no hope?



#2 PeaceAndProsperity

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Posted 07 October 2015 - 07:51 AM

I am ignorant on this subject but I may as well help you by starting the thread off by asking, couldn't an anti-dopaminergic antipsychotic like risperdal force dopamine to come back?

I think it's worth a shot to consider.


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#3 Axmann8

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Posted 07 October 2015 - 08:47 AM

I am ignorant on this subject but I may as well help you by starting the thread off by asking, couldn't an anti-dopaminergic antipsychotic like risperdal force dopamine to come back?

I think it's worth a shot to consider.

 

The mechanisms of amphetamine and dopamine receptor antagonists (like risperidone) are not exactly opposite from each other. Amphetamine is not a simple dopamine receptor agonist (like ropinirole). It is a TAAR1 receptor agonist with far-reaching effects on the transport of several monoamines, not just dopamine.

 

In short, no. Drugs like risperidone probably wouldn't help the issue at all and if anything could make recovery from amphetamines much more difficult (not to mention they exacerbate ADHD).


Edited by Axmann8, 07 October 2015 - 08:53 AM.


#4 gamesguru

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Posted 07 October 2015 - 08:21 PM

My friend, go down to your basement lab, synthesize these, and give them a whirl.  Let me know if you mess yourself up more, in which case, I'll have more chemical suggestions to throw your way :)

Sadly I didn't find many natural products (just one D2 antagonist/D1 agonist), maybe area or other superiors could find more.

 

The preferential dopamine autoreceptor antagonist (+)-UH232 antagonizes the positive reinforcing effects of cocaine and d-amphetamine in the ICSS paradigm.
The dopamine autoreceptor and D3 preferring antagonist [cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin] (+)-UH232, exerts weak stimulatory effects when tested in locomotor activity experiments using habituated animals. (+)-UH232 also blocks d-amphetamine-, cocaine-, and apomorphine-induced hyperactivity, but fails to induce catalepsy. Thus, the behavioral effects of (+)-UH232 appear to be dependent upon the baseline activity of the animal. The antagonistic properties of (+)-UH232 were studied in the intracranial self-stimulation (ICSS) technique in the rat. (+)-UH232 and haloperidol produced inhibitory effects over a wide dose range. Cocaine, GBR12909 and d-amphetamine clearly lowered ICSS thresholds, indicating stimulatory effects. (+)-UH232 antagonized the stimulatory effects of cocaine, GBR12909, and d-amphetamine, whereas haloperidol, at a dose producing an inhibition similar to (+)-UH232, was significantly weaker in antagonizing cocaine- or d-amphetamine-induced stimulation. This difference between (+)-UH232 and haloperidol with respect to stimulant-blocking ability, support the concept that the effects of (+)-UH232 are not representative of either classical DA agonists or DA antagonists.

Effects of the dopamine autoreceptor antagonist (−)-DS121 on the discriminative stimulus properties of d-amphetamine and cocaine
(−)-DS121 [S-(−)-3-(3-cyanophenyl)-N-n-propyl piperidine) is a recently synthesised phenylpiperidine derivative suggested to be a dopamine receptor antagonist acting preferentially at dopamine autoreceptors. The drug exerts ‘agonist-like’ behavioural effects by enhancing dopamine release, but also shares properties in common with neuroleptics. The ability of (−)-DS121 to both generalise to and antagonise the stimulus effects of psychostimulants was determined in rats trained to discriminate d-amphetamine (0.5 mg/kg) or cocaine (5.0 mg/kg) from saline in a two-lever, food-reinforced, drug discrimination task. (−)-DS121 (3.5–14.0 mg/kg) produced small, but significant, increases in drug lever-appropriate responding in both d-amphetamine and cocaine-trained rats. However, there was no indication of a dose-dependent effect in either case. On the other hand, (−)-DS121 dose-dependently reduced response rate. Caffeine produced a higher level of drug lever-appropriate responding than (−)-DS121 in d-amphetamine-trained rats. (−)-DS121 (7.0–14.0 mg/kg) also weakly antagonised the cueing properties of both d-amphetamine and cocaine. A marked response disruption with the drug combination precluded testing of higher doses of (−)-DS121. A combination of subthreshold doses of (−)-DS121 (3.5 mg/kg) and d-amphetamine (0.0625 mg/kg) produced a significant degree of drug lever-appropriate responding, suggesting a synergistic interaction between these drugs. However, such an interaction was not noted with a higher dose of (−)-DS121, or when this drug was administered with a low dose of cocaine (0.25 mg/kg). These results show that (−)-DS121 can exert both weak agonistic and antagonistic effects in animals trained to discriminate between d-amphetamine (or cocaine) and saline. They argue against a close similarity between the subjective effects of (−)-DS121 and the psychostimulants.

Getting specialized: presynaptic and postsynaptic dopamine D2 receptors

Screening and isolation of a natural dopamine D1 antagonist using cell-based assays.

L-stepholidine, a natural dopamine receptor D1 agonist and D2 antagonist, inhibits heroin-induced reinstatement.


Edited by gamesguru, 07 October 2015 - 08:31 PM.

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#5 Axmann8

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Posted 07 October 2015 - 08:54 PM

Does that answer my question in any way?

#6 Area-1255

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Posted 07 October 2015 - 09:21 PM

How to Prevent/Reverse Dopamine Receptor Downregulation from Dopamine Agonists, Stimulants and other Causes
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#7 gamesguru

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Posted 07 October 2015 - 10:17 PM

"It tricks the brain that it doesn't need to make dopamine, and dopamine is the only chemical in the brain that once it is damaged, you never get it back."

First of all, a technical point: ~Avogadro's number of dopamine molecules are "damaged" each day by multiple degradatory enzymes.

 

And basically your problem, I guess, is downregulated autoreceptors, leading to excessive dopamine release, and compensatory downregulation of receptors/ligand reactivity.  Upreglation of autoreceptors can likely be achieved via an antagonist.

 

Effects of low, autoreceptor selective doses of dopamine agonists on the discriminative cue and locomotor hyperactivity produced by d-amphetamine.
The ability of low doses of the dopamine (DA) agonists quinpirole and (+)-3-PPP to reduce the discriminative stimulus properties and locomotor hyperactivity produced by d-amphetamine (0.5 mg/kg) was assessed in two groups of rats. Quinpirole (0.0125-0.05 mg/kg) and (+)-3-PPP (1.0-2.0 mg/kg) completely antagonized d-amphetamine-induced locomotor hyperactivity. In contrast, only single doses of quinpirole (0.025 mg/kg) and (+)-3-PPP (2.0 mg/kg) were effective in the drug discrimination paradigm; the antagonisms were small (18-47%), but significant. The inhibitory effects of quinpirole and (+)-3-PPP in these behavioural models are probably due to their ability to selectively stimulate DA autoreceptors in the nucleus accumbens and reduce the increase in DA release produced by d-amphetamine. It is suggested that the much weaker effects of the drugs in the discrimination paradigm are due to changes produced by the long-term periodic administration of d-amphetamine to these animals, such as a down-regulation in the sensitivity of DA autoreceptors.

 

 

D2 autoreceptors are not involved in the down-regulation of the striatal dopamine transporter caused by alpha-methyl-p-tyrosine.
The mechanisms by which the brain dopamine neuronal transporter is regulated by chronic alteration of dopamine transmission are not well understood. It has been shown previously that chronic inhibition of dopamine synthesis decreases dopamine transporter (DAT) density and function. The purpose of the present study was to determine whether these effects involve dopamine D2 receptors. Chronic treatment with alpha-methyl-p-tyrosine decreased binding of [3H]mazindol and dopamine release by d-amphetamine. The down-regulation of the DAT by alpha-methyl-p-tyrosine was not altered by co-treatment with a D2 receptor agonist or antagonist. However, chronic treatment with a D2 agonist, quinpirole, also decreased mazindol binding and amphetamine-induced release of dopamine. The results indicate that chronic inhibition of dopamine synthesis and stimulation of D2 receptors have similar, but independent, effects on DAT binding and function.

 


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#8 Axmann8

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Posted 09 October 2015 - 05:44 AM

I'm trying to understand which school of thought the person I quoted in my OP is coming from, and whether it is an accurate portrayal? What they seem to be saying is that "amphetamine causes significant, completely irreversible damage." This runs counter to everything I've previously heard.

#9 gamesguru

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Posted 09 October 2015 - 06:20 AM

Amphetamine causes problems, among them dopaminergic oxidation, gene downregulation, loss of synapse and autoreceptor downregulation.  The receptors can be replaced or regenerated without too much work or patience.  The loss of synapse is more or less permanent, well you could always induce a partial repair or regrowth, but not wired the same as before, a new person would emerge out of the healing.

 

This is what I came up with, with regard to serious damage/toxicity

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
http://jpet.aspetjou.../315/1/91.short

Contrasting effects of excitotoxic lesions of the prefrontal cortex on the behavioural response to D-amphetamine and presynaptic and postsynaptic measures of striatal dopamine function
http://www.ncbi.nlm..../pubmed/9276488

Increased oxidative stress after repeated amphetamine exposure
http://onlinelibrary...0318.x/abstract

Effects of amphetamines on mitochondrial function: role of free radicals and oxidative stress
http://www.sciencedi...163725803000524

Amphetamine neurotoxicity: accomplishments and remaining challenges
http://www.sciencedi...149763403001428



#10 Axmann8

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Posted 09 October 2015 - 08:39 PM

What do you mean when you say, "loss of synapse"? I'm a bit confused about that. Also, which genes are affected?

Oxidative stress is an obvious end effect of amphetamine consumption. Just in general, I would think antioxidants supplementation is pretty essential in the world we live in today. I was using Longvida curcumin for a while.

Edited by Axmann8, 09 October 2015 - 08:40 PM.


#11 gamesguru

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Posted 09 October 2015 - 09:27 PM

I mean no synapse 4 u, no synapse 4 teh next guy, no synapse 4 his brother.

 

Also you better be doing lots of antioxidants.  See my profile for cheap GTE powder, get some turmeric/pepper, stock up on wild blueberries, cauliflower/broccoli/spinach, beans even are antioxidant superstars (look it up).

Better just to chronically avoid amphetamine.

 

I became suspicious of persistent cannabis-induced cognitive dysfunction, and one day this lead me to the conclusion all dopaminergics should be approached cautiously, even tyrosine.

A combination of actue excitotoxicity and chronic reduced activity (hebbian theory/LTP/LTD) contribute to the respective death/loss and failure to regrow of synapses in various dopamine regions.  It's a strikingly similar phenomena, albeit on a smaller scale, as to what's observed in methylamphetamine abusers, who on the whole regrettably eat anything but an antioxidant-rich diet.

 

Chronic activation of the D2 dopamine autoreceptor inhibits synaptogenesis in mesencephalic dopaminergic neurons in vitro.
Our results suggest that chronic activation of the D2 autoreceptor inhibits synaptogenesis by mesencephalic dopamine neurons through translational regulation of the synthesis of proteins required for synapse formation

Chronic ?9-Tetrahydrocannabinol Exposure Induces a Sensitization of Dopamine D2/3 Receptors in the Mesoaccumbens and Nigrostriatal Systems
The development of supersensitive midbrain DA autoreceptors following chronic THC is thus expected to result in increased self-inhibition and hypoactivity of DA neurons.

 

 

17 genes are downregulated, forgive my not having the patience or skill to list them all

Gene expression profiling in the striatum of amphetamine-treated spontaneously hypertensive rats which showed amphetamine conditioned place preference and self-administration.

Here, we analyzed striatal transcriptomes in amphetamine-pretreated SHRs (5 mg/kg, i.p. for 7 days [twice daily]), which showed a conditioned place preference to and self-administration of amphetamine. Microarray analyses revealed increased mRNA expression of 55 genes (>1.65-fold increase), while 17 genes were downregulated (<0.6-fold) in the striatum of SHRs.

 

Differences in behavioural effects of amphetamine and dopamine-related gene expression in wild-type and homozygous CCK2 receptor deficient mice.
Neuropeptide cholecystokinin (CCK) interacts with dopamine in the regulation of motor activity and motivations. Therefore, in CCK(2) receptor deficient mice the behavioural effects of repeated amphetamine administration and changes in dopamine-related gene expression were studied. Four-day amphetamine (1 mg/kg) treatment induced a significantly stronger motor sensitization in homozygous mice compared to their wild-type littermates. However, in the conditioned place preference test the action of amphetamine was more pronounced in wild-type animals. As opposed to wild-type mice, amphetamine (1-3 mg/kg) did not cause a significant conditioned place preference in homozygous mice. The expression of Tyhy gene was elevated in the mesolimbic structures and Drd2 gene was down-regulated in the mesencephalon of saline-treated homozygous mice in comparison with respective wild-type group. Four-day treatment with amphetamine induced a significant increase in the expression of Tyhy in the mesencephalon, striatum and mesolimbic structures of wild-type mice, whereas in homozygous mice a similar change was evident only in the mesencephalon. Also, the expression of Drd1 gene in the striatum and Drd2 gene in the mesolimbic structures of wild-type mice were up-regulated under the influence of amphetamine. In conclusion, the present study established differences in the behavioural effects of amphetamine in wild-type and homozygous mice. The increased tone of dopaminergic projections from the mesencephalon to mesolimbic structures is probably related to increased amphetamine-induced motor sensitization in homozygous mice. The lack of development of up-regulation of Drd1 and Drd2 genes after repeated treatment with amphetamine probably explains the reduced place conditioning in CCK(2) receptor deficient mice.

 

Antipsychotic pathway genes with expression altered in opposite direction by antipsychotics and amphetamine.
To develop a new strategy for identifying possible psychotic- or antipsychotic-related pathway genes, rats were treated with clinical doses of haloperidol and clozapine for 4 days, and the altered expression of genes was compared with the genes altered in expression after amphetamine sensitization. The objective was to identify genes with expression altered in the same direction by haloperidol and clozapine but in the opposite direction in the amphetamine-sensitized rat striatum. These criteria were met by 21 genes, consisting of 15 genes upregulated by amphetamine, and 6 genes downregulated by amphetamine. Of the 21 genes, 15 are not presently identified, and only 3 genes (cathepsin K, GRK6, and a gene with accession number AI177589) are located in chromosome regions known to be associated with schizophrenia.

 

I know part of the way Memantine works is because its ,NMDAR antagonism and reduced calcium influx, indirectly inhibit transcript changes:

Amphetamine and Dopamine-Induced Immediate Early Gene Expression in Striatal Neurons Depends on Postsynaptic NMDA Receptors and Calcium

 

"Although the behavioral consequences of treatment with neurotoxic doses of methamphetamine has received some attention (e.g., Itzhak and Ali, 2002), the research in this area is not extensive and has not focused on the question of genetic influences on susceptibility to neurotoxic effects."


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#12 Axmann8

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Posted 10 October 2015 - 02:09 AM

I mean no synapse 4 u, no synapse 4 teh next guy, no synapse 4 his brother.

 

 

How does one "lose" a space between neurons?



#13 gamesguru

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Posted 10 October 2015 - 02:28 AM

one way is thru extreme LTD = synapse loss... prolonged inactivity causes synapses to dissociate.  you want I should crack my head open, and you can watch the process under a microscope?  If the dendrites/axons/terminals are destroyed, there's no synapse.  Think Hiroshima or Nagasaki.

read up on hebbian theory, doesn't seem you have yet.

Persistent synapse loss induced by repetitive LTD in developing rat hippocampal neurons.

 

another way is thru profound oxidation

Take 1700mg MDMA and find out yourself, first-hand experience how it feels.  Tell me if it feels good.

pharmaceuticals-04-00992f2-1024.png

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#14 gamesguru

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Posted 10 October 2015 - 07:28 AM

 

Chronic amphetamine treatment reduces NGF and BDNF in the rat brain.
Amphetamines (methamphetamine and d-amphetamine) are dopaminergic and noradrenergic agonists and are highly addictive drugs with neurotoxic effect on the brain. In human subjects, it has also been observed that amphetamine causes psychosis resembling positive symptoms of schizophrenia. Neurotrophins are molecules involved in neuronal survival and plasticity and protect neurons against (BDNF) are the most abundant neurotrophins in the central nervous system (CNS) and are important survival factors for cholinergic and dopaminergic neurons. Interestingly, it has been proposed that deficits in the production or utilization of neurotrophins participate in the pathogenesis of schizophrenia. In this study in order to investigate the mechanism of amphetamine-induced neurotoxicity and further elucidate the role of neurotrophins in the pathogenesis of schizophrenia we administered intraperitoneally d-amphetamine for 8 days to rats and measured the levels of neurotrophins NGF and BDNF in selected brain regions by ELISA. Amphetamine reduced NGF levels in the hippocampus, occipital cortex and hypothalamus and of BDNF in the occipital cortex and hypothalamus. Thus the present data indicate that chronic amphetamine can reduce the levels of NGF and BDNF in selected brain regions. This reduction may account for some of the effects of amphetamine in the CNS neurons and provides evidences for the role of neurotrophins in schizophrenia.

 

 

D(3) dopamine receptors are down-regulated in amphetamine sensitized rats and their putative antagonists modulate the locomotor sensitization to amphetamine.
"An acute dose of amphetamine leads to downregulation of both D1-like and D2-like dopamine receptors."[1]

Methamphetamine-induced loss of striatal dopamine innervation in BDNF heterozygote mice does not further reduce D3 receptor concentrations.

 

See this post: http://www.longecity...ndpost&p=745430

amphetamine could destabilize or perturb a stable coupled-oscillator system, eg) a negative reciprocal influence induced between BDNF and dopamine (like China used to depend on us for tech, and we [used to] depend on them for junk... well now everyone's making tech and junk and soon no one will want it, ok terrible analogy sorry)

a dopamine D1 receptor agonist increased BDNF

BDNF controls the expression of D3

me, then area, and finally flex. with $0.06


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#15 Axmann8

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Posted 14 October 2015 - 08:54 AM

It's a bit hard to understand your replies.



#16 gamesguru

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Posted 14 October 2015 - 11:49 AM

basically if you reduce dopamine receptors, you thereby reduce BDNF, which further reduces dopamine receptors

likewise, if you reduce bdnf, you thereby reduce dopamine receptors, which further reduces BDNF... like a vicious cycle or negative feedback loop

 

same idea with serotonin

BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders.
Brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT) are known to regulate synaptic plasticity, neurogenesis and neuronal survival in the adult brain. These two signals co-regulate one another such that 5-HT stimulates the expression of BDNF, and BDNF enhances the growth and survival of 5-HT neurons. Impaired 5-HT and BDNF signaling is central to depression and anxiety disorders, but could also play important roles in the pathogenesis of several age-related disorders, including insulin resistance syndrome, Alzheimer's disease and Huntington's disease. Enhancement of BDNF signaling may be a key mechanism whereby cognitive stimulation, exercise, dietary restriction and antidepressant drugs preserve brain function during aging. Behavioral and pharmacological manipulations that enhance 5-HT and BDNF signaling could help promote healthy brain aging.


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#17 Galaxyshock

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Posted 14 October 2015 - 03:52 PM

Jiaogulan has restorative effect at the dopaminergic system.



#18 lemon_

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Posted 14 October 2015 - 05:53 PM

MDMA does not cause damage. its ONLY with long term it can and will fuck you. 



#19 gamesguru

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Posted 14 October 2015 - 05:56 PM

MDMA ... will fuck you. 

QFT

 

btw short-term it an fuck you, depending on dosage. eg) 1700mg



#20 vader

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Posted 15 October 2015 - 09:40 AM

I can't see how amphetamine could cause long-term problems, when dopamine receptors downregulate / upregulate so fast. It is a psychological effect, imho.

 

Now in case of GABA, then you could have PAWS for years, though.



#21 gamesguru

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Posted 15 October 2015 - 03:46 PM

True it happens with benzos and GABA, but this is not the only case.  It happens with other neurotransmitters.

Recently I helped a member identify post-acute opiate withdrawal, and I can't report yet, but I believe his problem will resolve after an opioid antagonist cycle.

The same thing can happen with SSRIs and PSSD.

 

And former methamphetamine abusers sometimes report a feeling of apathy or anhedonia, even during an experience like seeing their children graduate from college, some report feeling nothing.

 

Reduced Striatal Dopamine Transporter Density in Abstinent Methamphetamine and Methcathinone Users: Evidence from Positron Emission Tomography Studies with [11C]WIN-35,428
Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine
Loss of Dopamine Transporters in Methamphetamine Abusers Recovers with Protracted Abstinence

Elevated Plasma Prolactin in Abstinent Methamphetamine-Dependent Subjects
Effects of selective activation of dopamine D2 and D3 receptors on prolactin secretion and the activity of tuberoinfundibular dopamine neurons.

Recovery of dopamine transporters with methamphetamine detoxification is not linked to changes in dopamine release.
Baseline D2/D3 receptors in caudate were lower in MA than in controls and did not change with detoxification, nor did they change in the controls upon retest.
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Interaction between opioid antagonists and amphetamine: evidence for mediation by central delta opioid receptors.
Effects of amphetamine on the human brain opioid system--a positron emission tomography study.

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History of cannabis use is not associated with alterations in striatal dopamine D2/D3 receptor availability
These findings suggest that, unlike other drugs of abuse, a history of cannabis use is not associated with alterations in striatal dopamine D2/D3 receptor availability.


Edited by gamesguru, 15 October 2015 - 03:51 PM.

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#22 drg

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Posted 16 October 2015 - 02:28 PM

Amphetamine can cause permanent though mostly reversible damage. After long-term exposure and high doses. The abcnews article is an exaggeration but there is truth to it. It will mostly heal itself over time. I don't believe there is evidence of permanent damage at therapeutic doses but it could be possible though.

 

I'm trying to understand which school of thought the person I quoted in my OP is coming from, and whether it is an accurate portrayal? What they seem to be saying is that "amphetamine causes significant, completely irreversible damage." This runs counter to everything I've previously heard.

 



#23 gamesguru

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Posted 16 October 2015 - 04:41 PM

I don't believe there is evidence of permanent damage at therapeutic doses but it could be possible though.

 

It is quite possible indeed

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.
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.


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#24 drg

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Posted 16 October 2015 - 05:57 PM

I mean logically speaking if amphetamine is shown to cause damage at high doses, it very possible it can cause some damage at normal doses too. 


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#25 Axmann8

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Posted 20 October 2015 - 07:56 AM

Gamesguru, I don't mean to come across as rude, but I have a serious question. Do you actually read the studies that you quote on Longecity? You've quoted several studies here whose implications are of dubious value, and you seem to leave off important counterpoints that are extremely relevant. For example, in the George, et al. study, if you look further, the authors admit that, at this point, attempting to apply the results to humans is inappropriate, at best. They give the following explanation why:
 

Although the present preclinical observations may have clinical implications, it would be premature to extrapolate them to humans receiving amphetamine treatment for ADHD for several reasons. First, the dopaminergic neurotoxicity may only occur in the context of doses of amphetamine that result in plasma concentrations comparable with those found in these experiments; lower dosage regimens that engender lower plasma amphetamine concentrations may not be associated with toxic effects on central dopaminergic neurons. Second, the mechanisms of amphetamine-induced dopaminergic neurotoxicity are not known, and theoretically, could be operant in nonhuman primates (and rodents) but not in humans. Third, aspects of amphetamine metabolism in nonhuman primates may differ from those in humans, and such differences could potentially result in neurotoxicity in nonhuman primates but not in humans. Fourth, the relative sensitivity of brain dopaminergic neurons to amphetamine toxicity in nonhuman primates and humans is unknown. Fifth, it is possible that the effects observed in normal primates with amphetamine may not be observed in ADHD patients because such patients presumably have abnormal neurotransmitter function, and such abnormalities may influence the expression of amphetamine neurotoxicity. Finally, it is important to note that amphetamine neurotoxicity data from the present studies were obtained in adult nonhuman primates; as such, although they may have implications for adults receiving amphetamine for the treatment of ADHD, their implications for children are less clear, because studies assessing the influence of age on the ontogeny of amphetamine neurotoxicity suggest younger animals are less susceptible to the neurotoxic effects of amphetamine (Cappon et al., 1997; Miller et al., 2000). Future studies in young adolescent primates are needed.

 

 


Edited by Axmann8, 20 October 2015 - 07:57 AM.


#26 gamesguru

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Posted 20 October 2015 - 02:00 PM

It is quite possible indeed...

neurotoxic potential of... amphetamine

 

Do I read the entire study?  No, sorry, if I did that, I would get stuck on one topic all day.  And I like to bounce around between a shitload of different topics.

 

I'm one to err on the side of caution.  While it is true, in the case of NMDAR antagonists and Olney lesions that the neurotoxicity may not apply to humans, you really want to take chances?  And to get on a tangent, it mentions something about genetic susceptibility, how common would such a susceptibility be?  If it's more than 1 in 100, then that's very bad of us, to be doing untold harm, to these 1% of individuals, by a medicine which is only supposed to be helping them.

 

Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD.
OBJECTIVE: A review of amphetamine treatment for attention-deficit/hyperactivity disorder (ADHD) was conducted, to obtain information on the long-term neurological consequences of this therapy.
METHOD: Several databases were accessed for research articles on the effects of amphetamine in the brain of laboratory animals and ADHD diagnosed individuals.
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.
CONCLUSION: Clarification of the neurological consequences of chronic AMPH treatment for ADHD is needed.

Potential adverse effects of amphetamine treatment on brain and behavior: a review
Early amphetamine treatment has been linked to slowing in height and weight growth in some children. Because the number of prescriptions for amphetamines has increased several fold over the past decade, an amphetamine-containing formulation is the most commonly prescribed stimulant in North America, and it is noteworthy that amphetamines are also the most abused prescription medications. Although early treatment does not increase risk for substance abuse, few studies have tracked the compliance and usage profiles of individuals who began amphetamine treatment as adults. Overall, there is concern about risk for slowed growth in young patients who are dosed continuously, and for substance abuse in patients first medicated in late adolescence or adulthood. Although most adult patients also use amphetamines effectively and safely, occasional case reports indicate that prescription use can produce marked psychological adverse events, including stimulant-induced psychosis. Assessments of central toxicity and adverse psychological effects during late adulthood and senescence of adults who receive prolonged courses of amphetamine treatment are warranted. Finally, identification of the biological factors that confer risk and those that offer protection is also needed to better specify the parameters of safe, long-term, therapeutic administration of amphetamines to adults.

Neurotoxicity of drugs of abuse - the case of methylenedioxy amphetamines (MDMA, ecstasy ), and amphetamines
Ecstasy (MDMA, 3,4-methylendioxymethamphetamine) and the stimulants methamphetamine (METH, speed) and amphetamine are popular drugs among young people, particularly in the dance scene. When given in high doses both MDMA and the stimulant amphetamines are clearly neurotoxic in laboratory animals. MDMA causes selective and persistent lesions of central serotonergic nerve terminals, whereas amphetamines damage both the serotonergic and dopaminergic systems. In recent years, the question of ecstasy-induced neurotoxicity and possible functional sequelae has been addressed in several studies in drug users. Despite large methodological problems, the bulk of evidence suggests residual alterations of serotonergic transmission in MDMA users, although at least partial recovery may occur after long-term abstinence. However, functional sequelae may persist even after longer periods of abstinence. To date, the most consistent findings associate subtle cognitive impairments with ecstasy use, particularly with memory. In contrast, studies on possible long-term neurotoxic effects of stimulant use have been relatively scarce. Preliminary evidence suggests that alterations of the dopaminergic system may persist even after years of abstinence from METH, and may be associated with deficits in motor and cognitive performance. In this paper, we will review the literature focusing on human studies.

Neurotoxicity on Tyrosine Hydroxylase mRNA and Protein in Aged Rats1
Four injections (intraperitoneal) of 3 mg/kg amphetamine (2 hr apart) produced pronounced hyperthermia and sustained decreases in dopamine levels and tyrosine hydroxylase (TH) protein levels in the striatum of 15-month-old male rats. A partial recovery of striatal dopamine levels was observed at 4 months after amphetamine. In contrast, TH mRNA and TH protein levels in the midbrain were unaffected at all time points tested up to 4 months after amphetamine treatment. The number of TH-immunopositive cells in the midbrain was also unchanged at 4 months after amphetamine, even though the number of TH-positive axons in the striatum remained dramatically decreased at this time point. Interestingly, TH-immunopositive cell bodies were observed 4 months after amphetamine in the lateral caudate/putamen, defined anteriorly by the genu of the corpus collosum and posteriorly by the junction of the anterior commissures; these striatal TH-positive cells were not observed in saline- or amphetamine-treated rats that did not become hyperthermic. In addition, low levels (orders of magnitude lower than that present in the midbrain) of TH mRNA were detected using reverse transcription-polymerase chain reaction in the striatum of these amphetamine-treated rats. Our results suggest that even though there is a partial recovery of striatal dopamine levels, which occurs within 4 months after amphetamine treatment, this recovery is not associated with increased TH gene expression in the midbrain. Furthermore, new TH-positive cells are generated in the striatum at this 4-month time point.

 

Amphetamines are drugs of abuse that affect monoaminergic systems in the brain, particularly dopaminergic nerve terminals in the striatum (Ricaurteet al., 1980; Seiden et al., 1988). The immediate effect of amphetamines is to increase the release of dopamine from these nerve terminals. However, administration of a single high dose or repeated administration or chronic infusion of moderate doses of amphetamines produces neurotoxic effects. These neurotoxic effects have been most extensively studied in the striatum of rodents and are characterized by sustained decreases in striatal dopamine concentration, TH activity and dopamine transport activity (Hotchkiss and Gibb, 1980; Wagner et al., 1980; Bowyer et al., 1992; Eisch et al., 1992). A number of studies have shown that these amphetamine-induced losses in dopaminergic function are at least partially due to the degeneration of striatal nerve terminals and axons, whereas the midbrain cell bodies from which these terminals arise are relatively spared from damage in rats (Ricaurte et al., 1982; Ryan et al., 1990;O’Callaghan and Miller, 1994). Similar neurotoxic or neuroregulatory effects have been observed in the striatum of primates and humans (Preston et al., 1985; Wilson et al., 1996). The mechanisms responsible for these effects have not been clearly established but may involve interactions among amphetamine-induced hyperthermia, generation of toxic free radicals derived from reactive oxygen species or dopamine itself, depletion of mitochrondrial-derived energy supplies and possibly exitatory amino acids

Effects of amphetamines on mitochondrial function: role of free radicals and oxidative stress
Amphetamine-like psychostimulants are associated with long-term decreases in markers for monoaminergic neurons, suggesting neuronal loss and/or damage within the brain. This long-term “toxicity” results from formation of free radicals, particularly reactive oxygen species (ROS) and reactive nitrogen species (RNS), although the mechanism(s) of ROS and RNS formation are unclear.
Mitochondria are a major source of ROS and mitochondrial dysfunction has been linked to some neurodegenerative disorders. Amphetamines also inhibit mitochondrial function, although the mechanism involved in the inhibition is uncertain. This review coordinates findings on the multiple pathways for ROS and RNS and describes a hypothesis involving mitochondrial inhibition in the initiation of amphetamine-induced cellular necrosis.

Mitochondria: key players in the neurotoxic effects of amphetamines.
Amphetamines are a class of psychotropic drugs with high abuse potential, as a result of their stimulant, euphoric, emphathogenic, entactogenic, and hallucinogenic properties. Although most amphetamines are synthetic drugs, of which methamphetamine, amphetamine, and 3,4-methylenedioxymethamphetamine ("ecstasy") represent well-recognized examples, the use of natural related compounds, namely cathinone and ephedrine, has been part of the history of humankind for thousands of years. Resulting from their amphiphilic nature, these drugs can easily cross the blood-brain barrier and elicit their well-known psychotropic effects. In the field of amphetamines' research, there is a general consensus that mitochondrial-dependent pathways can provide a major understanding concerning pathological processes underlying the neurotoxicity of these drugs. These events include alterations on tricarboxylic acid cycle's enzymes functioning, inhibition of mitochondrial electron transport chain's complexes, perturbations of mitochondrial clearance mechanisms, interference with mitochondrial dynamics, as well as oxidative modifications in mitochondrial macromolecules. Additionally, other studies indicate that amphetamines-induced neuronal toxicity is closely regulated by B cell lymphoma 2 superfamily of proteins with consequent activation of caspase-mediated downstream cell death pathway. Understanding the molecular mechanisms at mitochondrial level involved in amphetamines' neurotoxicity can help in defining target pathways or molecules mediating these effects, as well as in developing putative therapeutic approaches to prevent or treat the acute- or long-lasting neuropsychiatric complications seen in human abusers.

Effects of amphetamines on mitochondrial function: role of free radicals and oxidative stress.
Amphetamine-like psychostimulants are associated with long-term decreases in markers for monoaminergic neurons, suggesting neuronal loss and/or damage within the brain. This long-term "toxicity" results from formation of free radicals, particularly reactive oxygen species (ROS) and reactive nitrogen species (RNS), although the mechanism(s) of ROS and RNS formation are unclear. Mitochondria are a major source of ROS and mitochondrial dysfunction has been linked to some neurodegenerative disorders. Amphetamines also inhibit mitochondrial function, although the mechanism involved in the inhibition is uncertain. This review coordinates findings on the multiple pathways for ROS and RNS and describes a hypothesis involving mitochondrial inhibition in the initiation of amphetamine-induced cellular necrosis.

 

 

straight off reddit...

tl;dr: Be careful, at consistent and high dosage, amphetamines can be neurotoxic resulting in diminished Dopamine receptors and higher chance for psychosis.

I've actually looked into this a bunch when I was coming off amphetamine sulfate last year. Here is an awesome paper that covers almost every aspect of amphetamine use in a strictly scientific manner. The vocabulary can get a bit heavy but really worth looking through if you are a chronic user. I'll highlight the relevant parts.

 

Basic intro, comparison to documented cocaine use

Sustained high-dose administration of amphetamines (especially methamphetamine) to experimental animals produces a persistent depletion of DA which is associated with terminal degeneration (62, 182, 195), as well as neuronal chromatolysis in the brain stem, cortex and striatum (42, 182). In contrast, continuous dosing with extremely high doses of cocaine (100–250 mg/kg/day i.v.) did not induce terminal degeneration in frontal cortex and striatum (62, 183). Recently, Cubellis et al. (36) presented evidence that amphetamine, in contrast to cocaine, induces redistribution of DA from the vesicles into the cytosol; thus, the loss of the protection of the vesicles' relatively reducing environment results in cytosolic oxidative stress that may initiate amphetamine neurotoxicity. The DA depletion is reported to be permanent in the caudate of monkeys (196). The main hypotheses for underlying mechanisms have included 1) the conversion of DA into a hydroxy oxidative metabolite (195, 196); and 2) glutaminergic stimulation of toxicity, which can be inhibited by N-methyl-D-aspartate antagonist MK-801 (200).

Effects of NeuroToxicity

One of the hallmarks of amphetamine-induced neurotoxicity is the loss of DA uptake sites in the striatum and accumbens. These studies of transporters after chronic amphetamine have reported decreases in the range of 30–40% (158). ... Thus, the amphetamine-induced loss of DA uptake sites could have two consequences: 1) a protective mechanism reducing further neurotoxicity, and 2) reverse tolerance to subsequent amphetamine administration, perhaps resulting in adverse symptoms such as paranoid psychosis

Characteristics of Neurotoxicity

These marked neurotoxic effects on the DA systems may underlie the mild Parkinson-like symptoms or "burned out" clinical picture in chronic, high-dose amphetamine abusers. These same individuals have a readily activated stimulant psychosis response

Dose-dependence of neurotoxicity

...amphetamine pretreatment induced neurotoxicity in a dose-dependent manner, while cocaine, even at very high doses, did not. Following continuous methamphetamine or amphetamine infusion via Alza pumps, Ricuarte et al. (173) and Ryan et al. (182) found silver staining histopathological evidence for caudate neurotoxicity at doses above 16–20 mg/kg/day; no significant toxicity was observed at lower doses.

Wikipedia states,

"In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized as reduced transporter and receptor function.[83] There is no evidence that amphetamine is directly neurotoxic in humans.[84][85] High-dose amphetamine can cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine."

 

The problem is, there is no strong consensus on the neurotoxicity of amphetamines due to the inaccuracy of scaling its effects on rats and primates to humans. The paper that I referenced, tends to not delineate the results of studies to humans or animals. If you read my quotes in context of the paper, you can get a clearer idea.

 

My opinion on the matter: The Wikipedia section on the matter seems to downplay the neurotoxicity through the connotation of "indirect." I think that neurotoxicity is dependent on dose (supported by the paper) and is pretty destructive. However, I'm unsure of what dosage begins this neurotoxicity. I assume it is normally distributed on the population and might be slightly affected by tolerance (which the paper goes into).

EDIT: To add the section,

 

Prevention

Methamphetamine toxicity is inhibited by a variety of drug treatments, including: 1) DA synthesis inhibitor alpha-methyl-para-tyrosine; 2) DA receptor antagonists; 3) NMDA receptor antagonists, e.g., MK-801; 4) DA and serotonergic reuptake inhibitors protecting against DA and serotonin toxicity respectively (195). Even though most studies have found that serotonergic and DA reuptake inhibitors specifically protect these two sites, certain reuptake blockers (such as benztropine) do not (195). On the other hand, mazindol, a non-specific blocker, protects against both DA and serotonergic neurotoxicity.

 

I know that is meth, but still. You should also be fine as long as you don't take around 120 mg a day +-20 mg per body weight.
 

 


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#27 Flex

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Posted 20 October 2015 - 07:38 PM

Hope ? Yes. Example:

 

Dopaminergic pathway reconstruction by Akt/Rheb-induced axon regeneration.

 

RESULTS:

Both constitutively active myristoylated Akt and hRheb(S16H) induce regrowth of axons from dopaminergic neurons to their target, the striatum. Histological analysis demonstrates that these new axons achieve morphologically accurate reinnervation. In addition, functional reintegration into target circuitry is achieved, as indicated by partial behavioral recovery.

http://www.ncbi.nlm....pubmed/21437936

 

Activation of mTor Signaling by Gene Transduction to Induce Axon Regeneration in the Central Nervous System Following Neural Injury.

A longstanding concept in neuroscience has been that the mature mammalian brain is incapable of axon regeneration. However, we have shown that it is possible to achieve long range axon growth by re-activation of intrinsic genetic programs that are active during development to mediate axon growth. We have found that activation of Akt/mTor signaling by AAV-mediated transduction...

 

....We have hypothesized that mediators downstream of mTor may diverge in their effects, making it possible to achieve axon growth without oncogenic risk (i.e cancer risk). In Year 01 we have assessed the ability of the mTor target p70S6K to induce new axon growth...

https://ntrl.ntis.go...ADA602707.xhtml

 

So they reactivated a gene in the cells to induce an, at least(?), partial regrowth of the nerves.

They did damaged and killed the nerves with 6-Hydroxydopamine (6-OHDA) which also destroys nerve terminals &etc. like Meth

 

See:

A Guide to Neurotoxic Animal Models of Parkinson’s Disease

http://www.ncbi.nlm....les/PMC3234449/

 

Could be that there are some other targets. Found out that Horny goat weed, Ginseng and another one inhibits NOGO

http://www.longecity...on/#entry734488

 

What is NOGO:

Nerve regrowth: nipped by a no-go

http://web.expasy.or...ack_issues/069/


Edited by Flex, 20 October 2015 - 07:42 PM.

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#28 drg

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Posted 21 October 2015 - 12:42 AM

You should also be fine as long as you don't take around 120 mg a day +-20 mg per body weight.

What does this mean?

#29 gamesguru

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Posted 21 October 2015 - 02:20 AM

That's a guy on reddit, saying if you're a little heavier (100kg?), you can get away with 140mg daily, whereas a skinnier guy (55kg?) should stay below 100mg.



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#30 Axmann8

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Posted 02 November 2015 - 03:38 PM

Do I read the entire study?  No, sorry, if I did that, I would get stuck on one topic all day.  And I like to bounce around between a shitload of different topics.

 

I'm one to err on the side of caution.  While it is true, in the case of NMDAR antagonists and Olney lesions that the neurotoxicity may not apply to humans, you really want to take chances?  And to get on a tangent, it mentions something about genetic susceptibility, how common would such a susceptibility be?  If it's more than 1 in 100, then that's very bad of us, to be doing untold harm, to these 1% of individuals, by a medicine which is only supposed to be helping them.

 

 

When you say "you really want to take chances?" are you referring to abusing amphetamines, or simply using them at all? I never intentionally took them to "get high" or took extra-high doses. If you're asking whether I'd "take my chances" with using them at all, you'd be implying that treating my ADHD (a well-established, lifelong condition with rar-reaching implications on the ability to function in everyday life) is merely a luxury. It really isn't. Amphetamines are the only medication that has ever enabled me to function with some semblance of normalcy. Before I ever got treatment for my ADD (as well as when I go on medication holidays), I did (do) absolutely nothing whatsoever. I just sat in my room playing video games and had literally no drive whatsoever to do anything other than that. The simplest of tasks are extremely difficult.
 


Edited by Axmann8, 02 November 2015 - 03:40 PM.






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