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Reversing amphetamine tolerence?

A

AlexxRed

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Apr 2, 2002
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I found the recent thread on preventing amphetamine tolerance very interesting and I found myself wondering if it was possible to not simply prevent tolerance but actually reverse it - Either by the methods suggested in the tread (partial NMDA antagonists) OR if there are any other theoretical ways that this could be achieved.

My question are

1. Could amphetamine tolerance by reversed by using partial NMDA antagonists whilst not using amphetamine during the process. IE could one theoretically achieve a faster result as opposed to abstaining for a long period of time.

2. Are there any other substances that could be used to achieve such an outcome. Ketamine seems to be the only one that has been suggested to me so far.

I have posed this question to a few people that frequent ADD and would appreciate the input from anyone else that has any ideas and knowledge in this area.

As I added to current preventing amphetamine tolerance thread it is an issue that has actually sparked interested in one of the ADHD forum on the web - one person there suggested the following which seems rather at odds with what is suggested in our thread:

This is the first that I have heard that NMDA receptors play any rols in amphetamine's pharmacology. If I remember correctly, amphetamine doesn't even work via ion-channels, but through a protein-kinase enzyme that phosphorylates an intracellular portion of the dopamine transport protein, inducing reverse uptake.

Now, I suppose that the author may be referring to the action that dopamine has on the postsynaptic neuron, but blocking the NMDA receptor is not going to fix that, because this would reduce activity in that neuron, which is the opposite of what you're trying to do by using amphetamines.

Also, I do not know if magnesium is an NMDA antagonist in high doses, but NMDA antagonists produce some very noticeable effects...NMDA antagonism is responsible for the effects of the dissociative anaesthetics: ketamine, PCP, and dextromethorphan. Dissociative anaesthesia is a fairly intense form of hallucination in which the subject feels as though his mind has been dissociated from his body, similar to an out of body experience.

One interesting side-note, though, is that NMDA antagonists appear to help with Alzheimer's disease, although I'm not sure how. They are sometimes prescribed along with cholinesterase inhibitors (which slow the breakdown of acetylcholine, a chemical involved in memory) to slow the progression of the disease.

From: http://www.addforums.com/forums/arch...hp/t-9575.html
Click to expand...

Sorry if this is doubling up on the existing thread but not only am I interested in seeking opinions on the above re: preventing tolerance but I am especially interested if it is theoretically possible from a pharmacological standpoint to not only prevent but reverse amphetamine tolerance.

Cheers

Alex
 
picacetam is certainly an interesting substance, and in my experience it does potentate stimulants. But i'm not too sure that it would really reverse tolerance - at least I can't find anything to suggest that it would assist with things like dopamine receptor down regulation.

What I'm really interested in is this point:

Now, I suppose that the author may be referring to the action that dopamine has on the post synaptic neuron, but blocking the NMDA receptor is not going to fix that, because this would reduce activity in that neuron, which is the opposite of what you're trying to do by using amphetamines.
Click to expand...

Does this mean that by using a partial NMDA antagonist (IE DXM), as suggested in the thread on preventing amphetamine tolerance that you could in fact experience a decrease in effect when using amphetamine?
 
^ Why? I don't think that piracetam has ever been evaluated in reversing tolerance to amphetamine. Certain piracetam derivitives seem to enhance the focusing effect of d-amphetamine, but I don't think that they necessarily reverse tolerance. The unfortunate fact is that NMDA antagonists only prevent the aquisition of tolerance--they do not appear to reverse tolerance once it has been established. The one caveat, however, is ibogaine. Ibogaine does seem to help reduce tolerance to certain drugs (especially opioids) without the requirement of chronic administration. Alas, ibogaine is far more than an NMDA pore-blocker; from the "receptorome" binding studies I have read, ibogaine seems to be the double-barreled shotgun of neuropharmacology. Name an ionotropic receptor and it is likely that ibogaine affects it somehow. Examples include: (obviously) the NMDA receptor, a3b4 nAChRs, the 5-HT3 receptor and even certain voltage-gated ion channels.

One study that I read (I'll dig up the reference when I have more time) theorized that (d)-amphetamine itself acts as a weak NMDA receptor pore blocker, whereas methamphetamine does not at physiologic concentrations. This might be one reason why (d)-amphetamine tolerance does not acrue as rapidly as methamphetamine tolerance. Unfortunately, the data in this study weren't exactly stellar, so I am still unconvinced.
 
piracetam and other nootropics that potentiate amphetamine may slow down your tolerance by allowing you to take less amphetamine for the same effect. They may also have some neuroprotective properties that reduce toxicity of amphetamine.

Also taking DA supplements may help, but I'm not the best on this I'm already naturally stimulated enough! :)
 
Riemann_Zeta: Could using an NMDA blocker to prevent the acquisition of tolerance result in a decrease in effect from amphetamine?
 
I don't think so. I have used dextromethorphan extensively and have never felt that it altered the qualitative experience of amphetamines. However, I am only one person. I do not know of any studies that have investigated the effect of NMDA blockers on the subjective 'feeling' of amphetamine.
 
i wouldnt bet on ketamine either.
used quite a bit of it during the last 3 months and abstained from e for the same period.

did not notice much of an effect on tolerance.

but im willing to do more experiments ;-)
 
I have used DMX, by itself, I dosed 2 different times before doing amphets and my tolerance decreased considerbly but now I'm having troubles with 5-HTP causing me to hav extremely high tolerance to amphets and coke barely working on me at all.....
 
I made a thread a couple years ago now I think, on this topic. Although amphetamine induced editing butchered it....It was intended in the direction of reverse tolerence and studies on how it occurs...
I'll need to dig that up.

But here now, a couple years later it was indeed successful. This is for Dextroamphetamine, Which seems to be more or less different then how methods would apply to other amphetamines.
As of about 6 months ago, after 5 years of high/low daily inconsistent dosing it seemingly (suddenly). changed...where a simple low dose of 10mg-15mg is all i can take..and i have to moderate it strongly.
I have always kept the concept of tolerance at bay with this method of low inconsistent doses as well as heavy binges. but what has happened now is a complete reverse in tolerance

The main arguement was that intermitten/inconsistent doses and useage would eventually result in a reverse tolerance.
The only thing consistent was that it was that the 360 (5mg tablets). were used within 3rd/4th week per month.
This is no longer the case, as i can barely use half of that.

The above, I keep very seperate from the concept of making the drug "more potent" and "slowing tolerance" which I believe are independent.

The NDMA antagonists, such as magnesium. I did keep on for a couple years, until a year or more ago because of its properties. which extend useful beyond amphetamine.

Slowing and keeping tolerance at bay with amphetamines is easy enough. Magnesium and inconsistency is key there.
But reversing the tolerance to the point where a tiny dose is so strong, must be by a change in the brain on its own. even if it is overtime.
 
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