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Amantadine to Reduce Amphetamine Tolerance

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Scarletta

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Nov 17, 2008
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What do people suggest as a dosage for using amantadine to reduce amphetamine tolerance, and for how long? I was prescribed a bunch of amantadine, basically for anhedonia, and it didn't work. I also am prescribed Adderall or Dexedrine. I have developed a big tolerance for it.

While I was taking amantadine along with the Adderall, I noticed less Adderall effects. I did some research and found that amantadine reduces the subjective discrimination of amphetamine and some locomotor effects. That is because it competes with the adderall for dopamine receptors and therefore the Adderall is less effective.

However, in retrospect, it did seem that while taking amantadine my tolerance was lower. I was able to be ok on a smaller dose. Since stopping the amantadine my tolerance has skyrocketed.

Just wondering if anyone has any suggestions. Thanks!
 
Hi scarletta. Amantadine is structurally and to an extent pharmacologically similar to memantine, which a few people -- myself among them -- have reported their experiences with in regards to this ultra-theoretical use: reduction of tolerance to the early and gentle mood-lifting/motivating effects of therapeutic low-moderate dose amphetamine.

I post as 'graatch' on the following forum and here is the thread where I think I went into my greatest detail on this topic:

http://www.mindandmuscle.net/forum/index.php?showtopic=35395

I also recall seeing you on the addforums. I post as 'trying' there but I do not frequent them too much, I am mostly at mindandmuscle and here.

Also included in that thread IIRC is links to andrewb's accounts on the dr-bob forums, another person who logged their experience with this in some detail.

For me, at least, and a few others according to their accounts, memantine has been effective for the purpose I stated. As such the combination has been very helpful for my longtime 'symptoms' which roughly speaking are associated with primarily inattentive ADD, dysthymia, and social phobia. (It has not been a utopia or panacea, however) I am not positive whether or not the combination will work for others. I also have advanced various speculations (again, detailed especially in that thread and on that forum) as to WHY this may be a helpful strategy, and ideas about how to make it work. But these are as completely theoretical as the regimen itself -- hard science simply does not yet exist for this specific line of inquiry (although there is much interesting material that exists peripherally -- e.g. on chronic stress, and glutamate excess desensitizing dopaminergic transmission/sensitivity in the nucleus accumbens and not in the PFC; and on memantine's helpfulness for OPIOID tolerance); there is only anecdote.

You asked about amantadine however. In this post I have written some thoughts about amantadine in this matter, as well as some important ideas regarding strategy; I believe especially important may be my notes about NMDA rebound and requisite dose frequency/timing:

http://www.mindandmuscle.net/forum/index.php?s=&showtopic=35579&view=findpost&p=511349

Also, in the first thread, I talk a bit about early brain-fog and amphetamine-blunting effects of the memantine which seem to occur for people early in dosing, but fade after a few weeks, and I suggest very slow upward titration to avoid this. I speculate that this is related to an effect of nicotinic acetylcholine receptor antagonism that occurs with memantine early in dosing -- upon introduction or increased blood levels, but rapidly desensitizes. This may or may not be what you experienced with amantadine. The drugs have some similarities but differences also.

Good luck if you choose to investigate these questions further. As I said, the first thread I think is a fair introduction to some of the issues involved, if one follows the conversation. If you have any questions/concerns/ideas/insults etc. please feel free to post here or email me at [email protected] ; I'll try my best to get back to you quickly and help you however I can.
 
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Graatch, I see that Amantadine has a half-life of about 24 hours. So it seems it would be appropriate to dose in the morning at about 12 hours later to achieve steady state levels. Is 100 mg twice a day enough, do you think?
 
Hi,

Not sure about dosing with amantadine*. It seems that estimates of amantadine's T-1/2 vary quite a bit. Many of the most obvious sources I found estimated 17 hours in healthy subjects, +/- 4 hours. Well, ultimately it may be up to you to experiment around a bit with this and see what seems to help.

Memantine's half-life is variously estimated at 60-100 hours, but andrewb and I found that, perhaps, a dose split between morning and evening might be helpful for stable effect ... the reasons for this might include memantine's apparently wild variation in excretion rate depending on acidic/alkaline digestive conditions (no idea if this is similar with amantadine, although I wouldn't be surprised if acidity does speed its excretion, due to its similarity to memantine); and also, I suspect, a growing rebound of NMDA transmission as blood levels decrease which competes with the primary effect, subtracts from the curve if that makes sense ...

*(I take 40mg memantine daily and found this to be most effective -- andrewb found 30mg was necessary, whereas at least one other reporting responder found that 10mg was effective.)
 
While simultaneously taking the memantine and the stimulant, you found that for about a week you didn't have very much of a stimulant effect, correct? That the memantine was attenuating the subjective effects of the stimulant? But that they returned after about a week?

From my research it seems apparent that no matter what you do, in order to reduce tolerance you have to have less of the amphetamine hitting your receptors, or more "drug-free time" for them to recover. My research has shown, and my experience has been, that taking amantadine reduces the subjective good effects of amphetamine. Just like anti-psychotics do. Anti-psychotics will lower your tolerance because no matter how much amphetamine you take, it's blocked. Amantadine will lower your tolerance, in my opinion, because it is a dopamine receptor competitor with amphetamine and thus ends up blocking the amphetamine as well.

So in the meantime, your body adjusts to the lesser amounts of amphetamine, and your tolerance goes down. But the "price" you pay is you suffer from the dimimished effects of the amphetamine in the interim. '

Just curious how long it took before you got back to a good effect with amphetamine, and also if you were tempted or did increase your amphetamine during the time the memantine was attenuating it.
 
Yeah, for me, for around one week after introduction of the memantine, and also upon dose increases, both the concentrative and mood-enhancing/motivating effects of the dextroamphetamine are somewhat blunted, and also there is a sense of general "brain fog" and an odd restlessness.

And it is very much so -- in my individual experience- - that these effects have dissipated quickly after that time. I certainly have not felt brain-fogged (relative to my baseline state) with this regimen (otherwise I would not continue) and my response to d-amp seems to be better than ever. To be clear, for me there is really no question that my response is both robust and markedly different in that the 'positive' effects linger, when I am engaged in the course of the adjunct memantine, compared to the rapid tolerance over 2-3 days without it.

Because of (a) the time frame involved, (b) the indications on paper that memantine exerts an early antagonism of nicotinic acetylcholine receptors that dissipates, and also (for what such a subjective consideration is worth) (c) some consonant elements in "how I feel" with the early negative memantine effects and nicotine withdrawal; I have suggested that the early brainfog and diminished amphetamine response that several people have reported in common is related to nACHr antagonism. However this like much I've speculated on is strictly speculation.

It seems to me that nicotinic acetylcholine receptor antagonism appears to not be specific to memantine only, but actually perhaps a typical downstream response that occurs with NMDA antagonists, because there is also research showing nACHr antagonism with all of ketamine, dextromethorphan, MK-801, and amantadine. I have not looked into whether those antagonist responses with these agents similarly desensitize. My intuition is that they probably do ... the nACHr receptors do seem to generally have rather sensitive regulatory controls (see: nicotine*) and I cannot see any reason that it would be different with these agents, but I could be wrong.

In any case, so amantadine shares with memantine "partial" (or "uncompetitive", in this nomenclature: http://en.wikipedia.org/wiki/Receptor_antagonist#Uncompetitive) antagonism at the NMDA receptors with a probably-downstream nACHr antagonism, which I know in memantine to desensitize. That is one possible reason that one might get a diminished response to amphetamine with amantadine. The interesting thing with amantadine is that after all these years th You suggest that dopamine receptor occupancy by amantadine may be preventing amphetamine effect. To be precise, from what I know the bulk of amphetamine's effect is not derived from direct interaction with the dopamine receptor, and amantadine -- still a somewhat mysterious substance in the view of researchers -- does not bind to the dopamine receptors; however amantadine does increase dopamine release (this is similar to other NMDA antagonists and I think the effect derives from that) and also[/]b, interestingly, appears to bind to and block the dopamine transporter (i.e., it is a reuptake inhibitor, like e.g. methylphenidate). The latter effect is I think more unique to amantadine, and indeed in theory could work to diminish amphetamine effect, because amphetamine is going to compete for the dopamine transporter, where its action is to reverse the pump and evoke dopamine release. And I do think there is both research and anecdote suggesting that dopamine reuptake inhibitors like cocaine administered concurrently with amphetamine can attenuate amphetamine's effect.

Dopamine reuptake inhibition does not induce a regulatory response quite as quickly as nACHr antagonism (or, in any case, there is going to be both sensitization and desensitization occuring). I'm not as familiar with amantadine pharmacology as I am with memantine, but it occurs to me now that this dopamine transporter affinity might be a reason that amantadine could be less effective than memantine (lacking said affinity) is, as an amphetamine adjunct. Sorry for not realizing this problem with amantadine and bringing it up sooner, and I'm glad you brought it to light ... again to be clear, it's possible that memantine may be better, and I have also suggested various reasons for its superiority here over many other NMDA antagonists that have been brought up in conversation, but I can't say with any surety whether it or anything will work or not for any individual.

A reduction of amphetamine effect from competition at the dopamine transporter, as you suspected, is certainly one way that a tolerance effect might be reduced. Now, in the theory, the different mechanism (not competition at the dopamine transporter) by which a NMDA antagonist could work to preserve the mood-elevating and motivating effects of amphetamine (and other dopaminergic agents) I have detailed in the threads I linked to, along with what suggestive research and suggestive 'hard' science relating to the matter that I found to exist. Once more (heh), perhaps there will be direct, in-vivo, human research on amphetamine tolerance and memantine at some point; such does not currently exist. So this is an experimental thing, but I think -- in summary of my personal research, distinct positive reaction, and what I can discern from others who wrote about this -- it is a promising thing, at least for those who might be helped by it. I've certainly become quite interested in the broad topic as you can see, and if you do choose to continue experimenting with things I urge you to continue proffering your experience reports; I know they could help people. :)

Uh, and forgive me for my prose style with these posts, which is probably infuriating, with all the repetitive qualifiers ... I only feel that I must delineate a skepticism, with this, and in fact what I think is the shadowy, inconstant, and experimental nature of applied psychopharmacology in general. There are some (often doctors, 'tho not uniquely or always) who would suggest it is a hard science (a numbers game, or a system of levers and on-off switches); I will contend that it is certainly not. More like delving into haunted edifices, with ontological trapdoors ...

Finally, here is some research I just turned up. Note the 5-day period of amantadine before cocaine doses. However it is cocaine not amphetamine, so what goes down at the dopamine transporter surely differs in one way or another:

http://cat.inist.fr/?aModele=afficheN&cpsidt=15370439

Actually, their alternative to cocaine was a $5 merchandise voucher, the fuck? This might be useless ... without seeing the full paper I'm guessing that something like 100% of the patients chose the cocaine 100% of all 5 times!

* (what happens with nicotine is sort of a bouncing back and forth of sensitivity with nicotine agonizing and cotinine antagonizing, and in human smokers the receptors generally end up distinctly upregulated overall, maybe because the lack of agonist doses during sleep tilts in favor of upregulation)
 
You asked about whether I was tempted to up amphetamine dose ... I haven't been, but I should mention I also introduced memantine and slowly titrated it upward (by about 5mg every three days) to most of my current dose (40mg) and then waited until I no longer felt the side effects in question, before reintroducing the d-amp. IIRC I have strongly recommended doing this to others in the threads I linked to ... it seems appropriate and beneficial, although I understand that this may be a difficult practice to some people who are trying such a regimen, that is, I suspect, people who are relying on therapeutic benefit from their amphetamine doses.

I should also mention that there is some research with acute dosing of memantine and methamphetamine or cocaine in humans, where subjective effect was either not significantly affected, or actually increased, contrary to the diminishment that I have suggested (and with some others, experienced) occurs for a few days after memantine introduction, before nACHr response dissipates.
 
Thanks! This is all very helpful. Do you know what is a normal therapeutic dose of memantine? You take 40 mgs, just wondering if that is above the regular dose. I am wondering if 200 mg of amantadine (normal dose) is not acute enough to work with.
 
^^Up to 20mg and in some research 30mg is typically used in the U.S. in Alzheimer's disease, and 40mg-60mg were the effective doses in the early depression research in the U.S. that's been done. In Germany, where the drug has been available for much longer (about 30 years) doses up to 60mg are regularly used in Alzheimer's disease and dementia. It is a actually generally a rather well-tolerated agent, but slow titration is always recommended.
 
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