wait so how long do you have to abuse it for it to actually cause this much damage?? i haven't done it that much yet really, only probably like 10 times i went over ~30mg, except they were all about 100mg the times i did. i figured that few times wouldn't really affect me that much in the long run... was i wrong though?
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N&PD Moderators: Skorpio | someguyontheinternet
reducing amphetamine neurotoxicity
- Thread starter Merk
- Start date
How much damage is caused isn't a function of how long so much as how much. If you're taking large doses over a long period of time, though, then god help you.
I'd try taking longer breaks, using amphetamines sparingly, using the smallest dose possible, etc... You might also use try memantine. I hear those partial NMDA antagonists can help slow the development of tolerance, although the evidence seems a bit sketchy.
Ibogaine might at least restore your ability to get a high from amphetamines, although it's doubtful that it would alleviate any cognitive decline produced by amphetamine abuse (I'm not actually sure which dopamine receptors are most critical to the production of cognition and intelligence (D1?)). According to one study ibogaine raises glial cell line-derived neurotrophic factor within a brain region associated with pleasure and addiction, the ventral tegmental area; the GDNF produces neurogenesis within that brain region so that the total density of D2 receptors increases, alleviating drug cravings and possibly increasing hedonic tone.
How much wood could a Woodchuck chuck if a Woodchuck could chuck wood?
It's simple. He needs to get 500mgmagnesiumchelate, 500mgtyrosine, 1000mgd-lphenylalanine with vitaminb6 and vitamin6 into his stomach each and every morning.
Sonny Jim, hold your horse up cowboy! Ibogaine is strictly limited to opioid-type drug dependencies. There is no literature published that suggests iboga is an effective method of lowering your tolerance to amphetamines.
To the OP, simple solution, quit using speed!
the way i see it amphetamines shouldn't even be taken for productive purposes except for in emergency situations. If it helps you with productivity, you will keep on using it, possibly until your body wears out .
a few times a week is too much, and 30 mg is no small dose.
maybe like once a month
a few times a week is too much, and 30 mg is no small dose.
maybe like once a month
don't they have 30mg IR adderall though? i always thought if i didn't go above 30 at a time it would be like using it as it would be prescribed, which seemed like it couldn't be that unhealthy. and don't most people with a prescription use it at least 5 days a week or more? does that mean that people who are prescribed that dose are doing damage to themselves? just so you don't get the wrong idea, i'm not saying you're wrong, but i'm just curious.
ebola?
Bluelight Crew
Please "get all fucking crazy" under medical or psychiatric supervision only. 
I'm curious; Are the neurotoxic effects of amphetamine solely related to oxidative stress? Don't amphetamines work mainly by reuptake inhibition rather than DAT reversal, when used at perscribed dosages? In that case I would assume that they would have a similar mechanism as methylphenidate and therefore little worry of toxic effects. Hmm? I must be wrong, but in case I'm not, then the big question would therefore be how much amphetamine is necessary to cross from monoamine reuptake to release.
Im curious as to what people are citing as a source for neurotoxicity of oral d-amp. If its Ricaurte's study than the claim is absolutely absurd because everyone knows he isnt reliable after the mdma debacle. I've been reading abstracts and studies and what not on amphetamine for a good 5 years now and the only time neurotoxicity is mentioned is in connection with IV d-meth use.
It was my understanding that it was speed of onset and not dose curve that caused overstimulation of DAT receptor sites. One of you may be on a complete different level than i am as far as the chemistry goes but if thats the case than where is the research?
I fully agree that use of amphetamine should be with safety in mind simply because of the stresses it causes on the body and psyche but some of the claims in this thread are quite hard to belive. Especially considering that this is one of the longest studied chemicals in human history.
It was my understanding that it was speed of onset and not dose curve that caused overstimulation of DAT receptor sites. One of you may be on a complete different level than i am as far as the chemistry goes but if thats the case than where is the research?
I fully agree that use of amphetamine should be with safety in mind simply because of the stresses it causes on the body and psyche but some of the claims in this thread are quite hard to belive. Especially considering that this is one of the longest studied chemicals in human history.
Vaya
Bluelight Crew
As far as my understanding goes stimulant neurotoxicity is indeed pretty much is limited to oxidative stress; the methylated-amphetamine derivatives like MD(M)A and Methamphetamine are much more lipophilic and are absorbed by the body at a greater percentage and at a higher rate. someone mentioned earlier in this thread that the onset of oral d-methamp is not markedly different from that of d-amp and its sister-salts; I've found this to be completely untrue - Desoxyn, which I am prescribed, is the *only* oral IR (or XR, for that matter) tablet in my life that I've swallowed and - despite a full belly or not - felt within 5-8 minutes. No variation.
So anyway, its rapid absorption, coupled with the fact that the methylated amphetamines are the most potent serotonergic and dopaminergic stimulants, creates the perfect environment for oxidative stress. The high level of serotonin agonism contributes to the release of things like peroxide, hydroxide, some others that are eluding me at the moment - and these oxidative compounds are highly damaging to nerve cells.
Normally, our bodies can deal with the impact of oxidative stress because we naturally produce these compounds on a day-to-day basis; but when there is a supra-efflux of serotonin, their production and thus presence augments greatly and then the marked increase in DA agonism increases body temperature, impairing the nerve cells' ability to repel the deleterious effects of the oxidative compounds. This, in turn and with time, leads to nerve cell death ("apoptosis," it's referred to).
So, to sum it up, the more 5HT and DA agonism a stimulant produces, the more dangerous environment the combination creates for the well-being of our precious neurons. If continuous usage is still going to occur, you should really invest in some anti-oxidants - there was a wonderful thread from a bit back where people were chiming in all sorts of wonderful vitamins, minerals and oils that act as great anti-oxidants that can assist in preventing (or at least inhibiting) the progression of stimulant-bound neurotoxicity. A few that I remember were Vitamin C, Vitamin E, selenium, inosine, alphia-lipoic acid, N-acetyl-cysteine (sp?), and idebenone. Some of these I take already, but being that I'm only two months into my daily consumption of methamphetamine HCl tablets (4x 5mg tab/day = 20mg/day), I haven't quite stock-piled a good selection yet.
I believe this is slightly misinformed - or, rather, DA reuptake inhibition is but a symptom of the pharmacology of amphetamines. Take a quote from THISwebsite, for instance: " Amphetamines’ 3 main effects on dopamine transport are depletion of vesicular dopamine (DA), reversal of DAT (efflux of DA into synaptic cleft), and DA uptake inhibition (Caron et al, 1998).. Methylphenidate is a DATI (dopamine transporter inhibitor), whilst amphetamine and its derivatives and analogues work by DAT reversal. Interestingly enough, I did some research a little while back and discovered that methylphenidate, as a DATI, can actually help prevent amphetamine-induced DA deficiencies! How 'bout that? Solving your amphetamine problems with Ritalin, what a world. But, see for yourself, the following is from a file I wrote up myself with links just so I could wrap my mind around the idea; the links and/or citations following the verification statements, as they are, ought still be valid:
A. Premise:
1. DAT-Inhibitors (DATI's) protect against METH-induced DA deficits
and…
2. Methylphenidate is a DATI
therefore...
3. Methylphenidate should protect against METH-induced DA deficits
----------------------------------------------------------------------------------------------
B. Verification:
1. DAT-Inhibitors (DATI's) protect against METH-induced DA deficits
"Methamphetamine Toxicity and Messengers of Death." Irina N. Krasnova, Jean Lud Cadet. Molecular Neuropsychiatry Research Branch, Intramural Research Program, NIDA/NIH/DHHS, 251 Bayview Boulevard, Baltimore, MD 21224, USA
Accepted 16 March 2009
Available online 25 March 2009
http://www.toxicology.tcu.edu.tw/files/class_0981/神經毒理學特論/980923.pdf
2. Methylphenidate is a DATI
"Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications."
http://www.ncbi.nlm.nih.gov/pubmed/11793423
3. Methylphenidate should protect against METH-induced DA deficits
"Methylphenidate Alters Vesicular Monoamine Transport and Prevents Methamphetamine-Induced Dopaminergic Deficits." Veronica Sandoval, Evan L. Riddle, Glen R. Hanson, and Annette E. Fleckenstein. Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah. Received October 3, 2002; accepted December 4, 2002.
And the last bit from the document I typed up, I apparently didn't deem it necessary to validate this with a reference, but I remember happening across the information (pertinent or impertinent to this discussion, you make the call) as I was doing more in-depth research on the aforementioned subject:
Methamphetamine is a DA reuptake inhibitor.
>Methamphetamine decreases reabsorption of DA by synaptic vesicles, resulting in more DA in the synapse and less DA in the vesicles.
>METH causes DAT (dopamine transporter) upregulation (increase of a cellular component)
Therefore, because methylphenidate works against the DA transporter - and methamphetamine's neurotoxicity is caused in part by its ability to promote the activity of said transporter - methylphenidate fights the neurotoxicity caused by meth on the battleground occupied by these DAT's.
Anyway, I hope what I've said makes sense; sorry to resurrect such an old thread but I found myself doing a bit of investigative research for my own purposes and thought I'd chime in.
~ vaya
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SpunkySkunk347
Bluelighter
- Joined
- Jan 15, 2006
- Messages
- 1,717
I have always had a few questions I never got around to typing out regarding methods for reducing both amphetamine tolerance and toxicity -- as well as methods for having an overall more pleasant experience with amphetamine.
1. Using Magnesium as a Supplement: Allegedly taking magnesium supplements both reduce amphetamine tolerance as well as reduces the negative physical affects of amphetamine. My questions regarding magnesium are:
- If magnesium lowers/prevents amphetamine tolerance by working directly at ion channels to reduce the probability of an action potential being generated, then in addition to reducing the negative effects, wouldn't magnesium inadvertently reduce the positive effects of amphetamine as well, such as euphoria?
- Obviously, pure ionic magnesium is not what is used in magnesium supplements -- the magnesium must be paired with something as a salt to neutralize its destructive properties and make it possible to ingest. What variety of magnesium should be used as a supplement, and why? Which preparation would be the most efficient for getting the magnesium where it is needed at the ion channels in the central nervous system?
- Some sources state that amphetamine use results in depleted magnesium levels and elevated calcium levels in the body (or maybe it is just one or the other; can't remember the exact details) - causing an imbalance at calcium-magnesium ion channels. If this is the case, would magnesium supplements only be beneficial if such an imbalance exists?
- Are there any thorough studies that were done which show that taking a magnesium supplement does indeed reduce amphetamine tolerance and/or toxicity? Or is it just a speculation that became accepted by many as truth?
- Should magnesium be taken before, after, or during the use of amphetamine?
2. The nature of amphetamine tolerance. Unlike receptor agonists such as opiates or benzodiazepines which cause tolerance due to down-regulation t of their corresponding receptors on post-synaptic neurons (mu-opiate and GABA receptors respectively), amphetamine is unique in that tolerance can develop yet doesn't seem to be caused by an increase or decrease in receptors, since amphetamine itself is not an agonist of any particular receptor and is instead theorized to get its effects from causing the release of endogenous dopamine in the CNS (there are a various number of proposed mechanisms as to how amphetamine achieves this).
Amphetamine tolerance could then be theorized as resulting from a few factors (perhaps even a combination of these factors): 1) Depletion of dopamine (and to a lesser extent, norepinephrine and serotonin); 2) Damage to neurons; 3a) Psychological acclimation to the effects - with regular use, the mind begins to consider an amphetamine-induced state as being "normal", and since euphoria/pleasure are the mind's 'rewards' reserved for instances which exceed normal, the pleasure/euphoria is no longer experienced; 3b) Psychological acclimation to the physiological effects - the mind begins associating the amphetamine-induced bodily damage (vascular damage, muscle damage, hyperthermia, nerve death, etc) with the effects of amphetamine, and "shuts down" pathways responsible for those effects. Or perhaps the body's physiological resources (glucose, etc) are low, and the body can not handle the amount of activity invariably resulting from amphetamine use, so the mind ends up 'ignoring' the amphetamine in a sense.
I am one of many who speculate that amphetamine tolerance is subject to a 'mind over matter' phenomenon -- that amphetamine's positive effects (and perhaps its negative effects as well) can be potentiated (or mitigated) merely as a result of the user's expectations. This could be because of the fact that, on a synaptic level, amphetamine's effects are caused by endogenous neurotransmitters and not by the amphetamine molecule itself - as such, the effects of amphetamine are much more integrated into conscious control (the brain is, after all, in charge of its own dopamine supply -- and perhaps aspects of neuronal resource-management are partly determined consciously rather than unconsciously).
If we realize that the brain's main function and responsibility is ultimately just resource management and nothing more, then it makes sense that a significant amount of amphetamine tolerance is caused by psychological adaptation; since life is merely a matter of metabolism, homeostasis, and reproduction - or to put it more bluntly: eating, sleeping, urinating/defecating, keeping warm, and having sex, then all the brain really does is figure out the most efficient way to perform these actions. The brain's management of its own neuronal resources is already operating at optimum efficiency (all of our actions are done the way they are because we believe it to be the most efficient way of doing them) -- psychoactive drugs (especially ones which manipulate endogenous neurotransmitter levels directly) could be thought of as disrupting this equilibrium. So why does amphetamine give us effects at all instead of merely causing us to be driven insane due of neuronal de-synchronization? Well, I would theorize that a large portion of the dopamine and norepinephrine released by amphetamine were actually what the brain had set aside for "reserves", which were meant to be used for situations when something peaks the mind's interest. It might even be logical to think of using amphetamine as spending the brain's metaphorical "retirement fund".
Those who believe that amphetamine's tolerance is influenced by "mind over matter" also usually believe that amphetamine tolerance can be consciously manipulated. By 'expecting' a certain outcome for an amphetamine experience (whether amphetamine will produce mostly positive psychological effects or negative physical & psychological effects), the brain prepares itself accordingly, thereby bringing the mind's expectations into reality. We could perhaps consider this manipulation of tolerance as being a form of meditation.
I have begun experiencing this phenomenon with opiates as well -- I have found that the effects of opiates either increase or decrease merely by expecting one or the other, so perhaps this psychological exercise is not merely limited to amphetamine. Or perhaps the meta-cognition induced by amphetamine permanently causes the mind to have more conscious control over otherwise unconscious activity.
What are your opinions on how valid all of this is? Please be as detailed as you'd like, I'm not going to be offended if you want to give me a crash course on neurology.
Also, here is some common advice for the layman amphetamine user on managing amphetamine tolerance and toxicity:
As most amphetamine users learn from experience, if you're not in the 'mood' for using amphetamine, or if you lack sleep, are stressed, or are malnourished, then amphetamine is likely not to produce desirable effects.
Most users will tell you that once the initial euphoric amphetamine "glow" is gone and isn't regained by repeated dosing or raising the dose, then the only thing you can do is stop using for a while (days, weeks, months) to get some of the euphoria back.
Taking repeated doses is usually more pleasant than taking higher doses. Taking 120mg of d-amphetamine all at once can be very physically uncomfortable - but taking 120mg over the course of hours might not only be less of a body-load, but also more pleasurable and euphoric overall. Don't forget that amphetamine is also affecting your peripheral nervous system, causing vascular constriction and other things which contribute to the "body load"; by taking your dose over a period of time rather than all at once, you're giving your body time to adjust to vascular constriction and other physical effects.
1. Using Magnesium as a Supplement: Allegedly taking magnesium supplements both reduce amphetamine tolerance as well as reduces the negative physical affects of amphetamine. My questions regarding magnesium are:
- If magnesium lowers/prevents amphetamine tolerance by working directly at ion channels to reduce the probability of an action potential being generated, then in addition to reducing the negative effects, wouldn't magnesium inadvertently reduce the positive effects of amphetamine as well, such as euphoria?
- Obviously, pure ionic magnesium is not what is used in magnesium supplements -- the magnesium must be paired with something as a salt to neutralize its destructive properties and make it possible to ingest. What variety of magnesium should be used as a supplement, and why? Which preparation would be the most efficient for getting the magnesium where it is needed at the ion channels in the central nervous system?
- Some sources state that amphetamine use results in depleted magnesium levels and elevated calcium levels in the body (or maybe it is just one or the other; can't remember the exact details) - causing an imbalance at calcium-magnesium ion channels. If this is the case, would magnesium supplements only be beneficial if such an imbalance exists?
- Are there any thorough studies that were done which show that taking a magnesium supplement does indeed reduce amphetamine tolerance and/or toxicity? Or is it just a speculation that became accepted by many as truth?
- Should magnesium be taken before, after, or during the use of amphetamine?
2. The nature of amphetamine tolerance. Unlike receptor agonists such as opiates or benzodiazepines which cause tolerance due to down-regulation t of their corresponding receptors on post-synaptic neurons (mu-opiate and GABA receptors respectively), amphetamine is unique in that tolerance can develop yet doesn't seem to be caused by an increase or decrease in receptors, since amphetamine itself is not an agonist of any particular receptor and is instead theorized to get its effects from causing the release of endogenous dopamine in the CNS (there are a various number of proposed mechanisms as to how amphetamine achieves this).
Amphetamine tolerance could then be theorized as resulting from a few factors (perhaps even a combination of these factors): 1) Depletion of dopamine (and to a lesser extent, norepinephrine and serotonin); 2) Damage to neurons; 3a) Psychological acclimation to the effects - with regular use, the mind begins to consider an amphetamine-induced state as being "normal", and since euphoria/pleasure are the mind's 'rewards' reserved for instances which exceed normal, the pleasure/euphoria is no longer experienced; 3b) Psychological acclimation to the physiological effects - the mind begins associating the amphetamine-induced bodily damage (vascular damage, muscle damage, hyperthermia, nerve death, etc) with the effects of amphetamine, and "shuts down" pathways responsible for those effects. Or perhaps the body's physiological resources (glucose, etc) are low, and the body can not handle the amount of activity invariably resulting from amphetamine use, so the mind ends up 'ignoring' the amphetamine in a sense.
I am one of many who speculate that amphetamine tolerance is subject to a 'mind over matter' phenomenon -- that amphetamine's positive effects (and perhaps its negative effects as well) can be potentiated (or mitigated) merely as a result of the user's expectations. This could be because of the fact that, on a synaptic level, amphetamine's effects are caused by endogenous neurotransmitters and not by the amphetamine molecule itself - as such, the effects of amphetamine are much more integrated into conscious control (the brain is, after all, in charge of its own dopamine supply -- and perhaps aspects of neuronal resource-management are partly determined consciously rather than unconsciously).
If we realize that the brain's main function and responsibility is ultimately just resource management and nothing more, then it makes sense that a significant amount of amphetamine tolerance is caused by psychological adaptation; since life is merely a matter of metabolism, homeostasis, and reproduction - or to put it more bluntly: eating, sleeping, urinating/defecating, keeping warm, and having sex, then all the brain really does is figure out the most efficient way to perform these actions. The brain's management of its own neuronal resources is already operating at optimum efficiency (all of our actions are done the way they are because we believe it to be the most efficient way of doing them) -- psychoactive drugs (especially ones which manipulate endogenous neurotransmitter levels directly) could be thought of as disrupting this equilibrium. So why does amphetamine give us effects at all instead of merely causing us to be driven insane due of neuronal de-synchronization? Well, I would theorize that a large portion of the dopamine and norepinephrine released by amphetamine were actually what the brain had set aside for "reserves", which were meant to be used for situations when something peaks the mind's interest. It might even be logical to think of using amphetamine as spending the brain's metaphorical "retirement fund".
Those who believe that amphetamine's tolerance is influenced by "mind over matter" also usually believe that amphetamine tolerance can be consciously manipulated. By 'expecting' a certain outcome for an amphetamine experience (whether amphetamine will produce mostly positive psychological effects or negative physical & psychological effects), the brain prepares itself accordingly, thereby bringing the mind's expectations into reality. We could perhaps consider this manipulation of tolerance as being a form of meditation.
I have begun experiencing this phenomenon with opiates as well -- I have found that the effects of opiates either increase or decrease merely by expecting one or the other, so perhaps this psychological exercise is not merely limited to amphetamine. Or perhaps the meta-cognition induced by amphetamine permanently causes the mind to have more conscious control over otherwise unconscious activity.
What are your opinions on how valid all of this is? Please be as detailed as you'd like, I'm not going to be offended if you want to give me a crash course on neurology.
Also, here is some common advice for the layman amphetamine user on managing amphetamine tolerance and toxicity:
As most amphetamine users learn from experience, if you're not in the 'mood' for using amphetamine, or if you lack sleep, are stressed, or are malnourished, then amphetamine is likely not to produce desirable effects.
Most users will tell you that once the initial euphoric amphetamine "glow" is gone and isn't regained by repeated dosing or raising the dose, then the only thing you can do is stop using for a while (days, weeks, months) to get some of the euphoria back.
Taking repeated doses is usually more pleasant than taking higher doses. Taking 120mg of d-amphetamine all at once can be very physically uncomfortable - but taking 120mg over the course of hours might not only be less of a body-load, but also more pleasurable and euphoric overall. Don't forget that amphetamine is also affecting your peripheral nervous system, causing vascular constriction and other things which contribute to the "body load"; by taking your dose over a period of time rather than all at once, you're giving your body time to adjust to vascular constriction and other physical effects.
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Vaya
Bluelight Crew
Cheleated Magnesium is the only form of Magnesium I know of with an absorption rate (or bioavailability, if you like) of ~85%. It is the form that you should use.
Also, here is a useful diagram explaining the mechanism by which amphetamine exerts its neurotoxicity
I would say, to your ending question, no - they would be helpful regardless. With the chronic use of amphetamines, or even amphetamine binges that don't become a daily happenstance, there will come a time when the imbalance will present itself. IMO, one ought to be pre-emptive in dealing with this.
Your original statement regarding the relationship between depleted magnesium and elevated calcium seems to be substantiated.
The following excerpt from THIS website substantiates that claim (read the whole page, too - it's a wonderful resource on Magnesium)
As long as enough of it is sufficiently absorbed by your brain (via the aforementioned Cheleated Magnesium at 85% B.A.), you're doing yourself a favor. As is my understanding, magnesium's relationship to amphetamines is not like that of 5-HTP to MDMA, whereby taking 5-HTP in all three circumstances (before, during AND after) appears to be the best way to maintain serotonergic homeostasis. Keeping a basic healthy level of Magnesium in your brain will deter the imbalances you refer to from being able to come about in the first place.
This is a very interesting question, and one that I am unfortunately unable to answer at the moment. I am unsure as to the relationship between the hyperpolarization of a nerve cell and its impact on the euphoric properties of amphetamines. I'm not sure that it matters, because the excess dopamine released by the amphetamine, and whose uptake back into the synaptic vesicles is impaired, effluxes predominately to the mesolimbic reward system and the prefrontal cortex where it remains in the synaptic cleft (or synapse). This steep presence of dopamine moving freely about our reward system and center of executive function is likely where the 'euphoria' from amphetamines comes from. If you want to get really technical, it has been theorized in numerous pieces of literature that this can be traced back to a brain structure called the ventral tegmentum - largely seen as the "seat of addiction," as opposed to, say, the ventrolateral prefrontal cortex, which is thought to be the "seat of the soul/self."
In essence, my conception is that the premise you base your question on (magnesium decreasing the chances of a successful action potential) and the mechanisms underlying amphetamine's euphoriant properties are somewhat unrelated. That is to say, I do not believe that they are as directly related as your question suggests. Amphetamines essentially work by reversing the DAT, which increases, as I mentioned, the amount of DA in the cytoplasm. The exact mechanism by which this process occurs is a decrease in VMAT2 activity.
I'm not quite sure I agree with this, although by all means, feel free to contest me. Think of it this way: When someone ingests alprazolam (Xanax, or any benzodiazepine for that matter), the process is essentially the same - the sedation and anxiolysis are not caused directly by the molecule we term 'alprazolam,' but by alprazolam's mediation of the endogenous neurotransmitter gamma amino-butyric acid (GABA). So, too, is it with amphetamines and dopamine/norepinephrine (and serotonin, especially with the methylated amphetamines and their analogues/derivatives). How is the fundamental premise behind the action of a benzodiazepine different from that of an amphetamine? (Pardon me if that is not what you were suggesting; it is how I interpreted your series of statements)
The manner in which tolerance to amphetamine develops is not directly by means of up- or down-regulation of receptors - although chronic amphetamine exposure can lead to NMDA receptor downregulation due to excessive levels of the excitatory neurotransmitter glutamate. This is why the drug Memantine can protect against both MD(M)A and amphetamine neurotoxicity. The general idea is that amphetamine tolerance is caused by over-activation of NMDA receptors. Ingesting amphetamines enhances the release of glutamate at NMDA sites within the mesolimbic region of the brain that I mentioned before. Essentially, the influx of glutamate agonizes the NMDA receptors too greatly, resulting in tolerance.
Lastly, one very important thing to remember is that long-term amphetamine toxicity is caused not by downregulation of receptors, but by a progressive decrease in neuronal density. One explanation for a decrease in the density of neurons is that by the point you've reached clinical toxicity, nerve cells have already begun dying (again, apoptosis). Interestingly, for a very long time it was thought that no brain cells ever regenerate once a human being reaches adulthood; it is only within the past five or ten years that we, as a scientific community, have discovered that nerve cell regeneration - as well as synaptogenesis - can and does occur past the onset of adulthood, albeit very minimally. The area where the growth of new neurons can feasibly occur is the prefrontal cortex - that region of our brain that allows us to empathize, plan, motivate, read social cues - any number of things that dopamine-releasing agents can enhance remarkably.
Alternatively, receptor density is affected by the amount of 'downstream' signal being sent - the less signal being sent, the less these receptors will be expressed in the brain. This type of neuronal pruning is of the reversible type; as I mentioned regarding Memantine, its exertions on NMDA receptors and on the presence of glutamate reverses the signal direction, and slowly over periods of under- and over-compensation, neuronal density can return to what was before considered its 'baseline.'
But, yeah. Talk about a complicated world in between our ears... 8( Hopefully I answered some of your questions.
Take care!
~ vaya
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Vaya
Bluelight Crew
Additionally, here are some great articles and references if you'd like to learn more or expand your understanding further!
Acute Amphetamine Exposure Selectively Desensitizes κ-Opioid Receptors in the Nucleus Accumbens
Enhancement of apomorphine and l-amphetamine-induced behaviors by magnesium
Neurochemical markers of degenerative nervous diseases and drug addiction
Hope some of these generally help.
Peace,
~ vaya
Acute Amphetamine Exposure Selectively Desensitizes κ-Opioid Receptors in the Nucleus Accumbens
Enhancement of apomorphine and l-amphetamine-induced behaviors by magnesium
Neurochemical markers of degenerative nervous diseases and drug addiction
Hope some of these generally help.
Peace,
~ vaya
SpunkySkunk347
Bluelighter
- Joined
- Jan 15, 2006
- Messages
- 1,717
I don't think that alprazolam 'releases' GABA in the same manner that amphetamine 'releases' dopamine/NE. If I'm correct, I believe that alprazolam merely enhances the activity of pre-existing GABA in the synaptic cleft, by letting more chloride ions pass through the ion channel.
Certainly. I didn't mean to imply that amphetamine causes up or down regulation of receptors, but my point was that amphetamine was unique because it doesn't affect the regulation of receptors, yet still produced tolerance, which can only lead us to a number of other explanations for amphetamine's tolerance: neural death, depletion of DA/NE, or psychological adjustment to the effects or a possible psychological retaliation to the physically damaging effects; whether the latter could be true or not depends on how much credit you give to our subconscious mind for making changes at the cellular level.
A lot of people dismiss 'placebo' effects as being faulty - when in reality, the occurrence of a "placebo effect" has just as much of a neurological basis as the effects of recreational drugs do. If mental qualia or a particular mental sensation is occurring (be it euphoria, analgesia, anaesthesia, etc.), the neurons responsible for those sensations must be firing, otherwise we wouldn't be feeling it. Our confidence in the cause of a sensation determines how valid and powerful we consider that sensation to be - but just by considering a sensation to be powerful we, in fact, make it more powerful. This type of "self-fulfilling prophecy" is very common when it comes to drug-use -- a good example would be with psychedelics, where the user's expectations of the trip will determine whether the trip becomes a pleasant or traumatizing experience. The type of 'expectations' I'm referring to are "mental preparations".
Then again, I may be disillusioning myself with how much control our mind has, and perhaps our cognition is merely slave to the emotions which prioritize it, and we are simply 'locked in for the ride'. But if that's the case, it would be a waste of resources for the brain to think of itself as being in control, if it actually wasn't.
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Vaya
Bluelight Crew
Ah for sure, we merely misunderstood one another. You're more than correct about the (well, hypothesized) pharmacological profile of the benzodiazepines. The theory goes that benzodiazepines enhance the activity of GABA at the GABA-a binding site, which itself has (I believe) six subreceptors which various benzos interact with to varying degrees based on where their chemical substitution lies.
And as for amphetamines - well, you're right. The frustrating thing about delving into all of this, is that I know anything I say is based of theoretical inquiry (as in, just as we don't know precisely how GABA exerts its therapeutic effect, so, too, don't we know precisely how amphetamine exerts its effects on tolerance). Sometimes I'd love a set-in-stone answer, but I suppose it's further testament to how utterly complex we are as a species! You had some really fantastic questions, though - they really forced me to think for a bit in how to convey what I was trying to say.
~ vaya
Vaya
Bluelight Crew
BTW man I want to reiterate how great a job this book excerpt (same as 3rd link above) does at modeling down what is likely happening with regards to amphetamines, the cortical striatum, synaptic terminals, glutamate/NMDA, the whole gambit. Unfortunately it wasnt related to calcium or magnesium, however :/ if I find something I'll toss it your way.
~ vaya
EDIT: and another great one!
"Evidence for and Mechanism of Action of Neurotoxicity of Amphetamine Related Compounds"
~ vaya
EDIT: and another great one!
"Evidence for and Mechanism of Action of Neurotoxicity of Amphetamine Related Compounds"
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Epsilon Alpha
Bluelighter
I go over the research in my thread on the topic, but low dose ASA (aspirin) shows a lot of promise in reducing neurotoxic effects. Antipyretic and anti-inflammatory actions are a big plus when it comes to neuronal survival, not to mention its safe and well documented to provide cardiovascular benefits.
Vaya
Bluelight Crew
I was actually just reading your thread, I happened to stumble upon it during a semi-unrelated search. Really well done, Epsilon. Thank you for the information provided within, where I have found a veritable treasure-trove of information to explore and ideas to consider with regard to my own treatment with Desoxyn.
In regards to the above quotation, what amount of ASA is considered "low dose" in the context of reducing amphetamine-induced neurotoxicity? I had not ever heard that before, but the idea is intriguing and the medicine is extremely cheap and accessible, making for a pretty appealing option.
Kudos to your efforts.
~ vaya
Epsilon Alpha
Bluelighter
Thanks man :D
I'd personally consider 81mg a day low dose if you use a extended release heart or arthritis formulation.
I'd personally consider 81mg a day low dose if you use a extended release heart or arthritis formulation.