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Misc can memantine reverse methylphenidate tolerance?

Hello guys , I am doing great I believe that doing cardio and taking piracetam for 5 days (on and off ) is helping boost ltp , but I still believe it's still to early to tell. Maybe , sensitization to concerta is occurring at a slow rate? Anyways, so Cotcha, you are not saying nmda antagonists such as memantine would cause euphoria because of tolerance reversal , rather the euphoria would be caused by an nmda antagonist releasing dopamine/seretonin with concerta which leads to a further pronounced euphoria right? And adding an NMDA antagonist would further develop my tolerance to concerta. So I'll keep up my cardio (nmda downregulation) and piracetam (nmda downregulation) with breaks of course. Since cardio will also grow new dopamine/seretonin cells etc, this could also aid in eliminating tolerance built up to concerta as well as boosting ltp according to what Cotcha said. I also add himalyan pink salt to water in order to restore my electrolytes as well as performing meditation as well btw.
 
If this doesn't work then I guess I'll have to resort to method 2, which is, take a 1 month (or longer) break, do cardio/bulk & piracetam/noopept, take breaks every 5 days and then take concerta by the end of the month and assess the results. Otherwise I'll keep doing the same regime and see how I feel. Appreciate your input guys :)
 
If you don't see success with your current approach you could certainly try memantine, it very likely induces DeltaFosB in the reward region of the brain so you'll get more euphoria.

It turns out as I've recently read that NMDA projections inhibit the reward parts of the brain, so maybe NMDA antagonism results in more reward. If you want more working memory and such however I suggest NMDA agonists instead, NMDA antagonists can lower intelligence long run and might cause other unforeseen problems.
 
So Cotcha, I'll still try this protocol for a little bit , I think it's helping at either a vary slow pace or maybe it isn't. I might try method 2 (above your post) after a while. Anyways, with your post regarding memantine, I'll have my questions listed so it isn't confusing.

1. I thought memantine will block sensitization to amphetamine according to the studies you've posted on page 1. Does this apply to concerta as well?

2. If it blocks sensitization, am I risking my tolerance getting further degraded?

3. Will this finally remove/reduce any tolerance to concerta? won't boost ltp?

4. I heard memantine also releases dopamine and seretonin, so the only way to feel much lowered tolerance to concerta is to take memantine along with it. With memantine/concerta both releasing dopamine and seretonin while memantine is inducing delta-fosb, I should finally feel a productive mood boost after all those months?

Thanks
 
Btw so far with piracetam , I just noticed the concerta lasting longer and the crash is reduced.
 
It's tricky because what we observe in the animals (increased movement around the cage and increased seizures and that sort of thing), might not translate well to humans in terms of increased euphoria. Right now if I had to guess I'd say that overall cognition wise you're better off with racetams but if you wanted specifically euphoria you'd be better off with memantine. But NMDA receptors play very important roles in signaling brain cells to stay alive so I shudder to think what long term NMDA antagonism would do, we simply don't know yet. Also many people end up having manic breaks and stuff with NMDA antagonists, even some extremely intelligent chemists around here on bluelight, and also a friend of mine. It's one of those things that probably only happens with high doses but I suspect you'll have to use around 40mg of memantine to get anywhere.

There is this reward center called the nucleus accumbens. Inhibiting this reward center are these neurons that are called MSN's (inhibitory GABA neurons). NMDA supplies the input to these MSN's, so if you increased NMDA input to these inhibitory neurons it decreases the activity of the nucleus accumbens.

The theory behind why NMDA antagonists are rewarding/reinforcing/addicting (and proven DeltaFosB inducing) is that NMDA has a lot of input to inhibitory neurons so when you block that input with an NMDA antagonist you increase activity of the dopamine/nucleus accumbens.

But honestly at some point in your life you might pay the piper if you keep any of this up, maybe the world will just blow up one day so you don't have to worry about your poor brain when you're 100 but anyways lol just know that euphoria comes at a cost. You can certainly try memantine, I intend to for other purposes.
 
So you mean , memantine is just another dopaminergic booster so to speak. I am seeing this as another drug which will boost concertas ltp when taken in conjunction but will have no affect on tolerance . Plus memantine can also downregulate dopamine and seretonin. So am I correct?

I wouldn't mess with memantine. I would prefer boosting ltp and reducing tolerance the more difficult way (cardio and piracetam) but if this fails me , then I'll take a month or longer break off concerta , take piracetam and do cardio for nmda agonism with breaks. And then take concerta , what do you think? I'm not looking to pay the piper anytime lol , but I will say , prior to initially getting on concerta for the first time. I did heavy cardio and exercise for two straight months which probably caused nmda downregulation. No wonder , I was able to take concerta 27 mg xr for 10 months with tolerance barely showing until , I took the tolerance break for 3 months which then lead to the issue I am having.

Btw , when taking the month or longer break this time , I hope my ltp does not get halted lol. Plus piracetam , noopept , supplemental hgh , cardio and bulking. This could be the jackpot . Fair enough? ..
 
Yes memantine is essentially very similar to a dopamine releasing agent. You will very likely get more euphoria and mood boosting effects from memantine but for focus boosting your NMDA is better.

Dopamine's LTP comes essentially in form of DeltaFosB which memantine causes increases of, so I personally am starting to think memantine might be the way to go for a mood boost. You could probably get away with a couple years of memantine but I don't know about it being a long term thing.

It doesn't look like memantine actually has direct dopamine agonism though (the reports of nmda antagonists having direct D2 agonism all came from one person and nobody has replicated it successfully) all of its dopamine release is probably from NMDA.

So here's a little about the long term picture... So there's this reward center the nucleus accumbens that's responsible for euphoria and such, NMDA inputs inhibit this reward center it turns out so that's why antagonizing NMDA is rewarding. One of the things that happens with NMDA is as you stimulate it, the cell gets stronger and stronger. So if you keep on taking racetams, one might hypothesize that the NMDA input that's inhibiting the nucleus accumbens might grow too strong and depression might result.
 
Wait I'm confused , doesn't concerta antagonize nmda itself? Does that mean when I started concerta for the first time , my nmda were agonized? (hence the mood boost etc) and do I have to keep taking memantine for it to work? If I am off memantine , how long will the results last? Is there an another way around this?
 
Naww concerta is just a dopamine and noradrenaline reuptake inhibitor. What happens as you take something that increases dopamine is the receptors start to disappear, and if there is a drought of dopamine more receptors will pop up. Things like DeltaFosB (to my understanding) cause more receptors to pop up, and NMDA antagonists have been shown in one study I saw to induce DeltaFosB (but only specifically in the nucleus accumbens).

Ritalin mainly works for ADHD by increasing dopamine in the front part of the brain (very far away from the nucleus accumbens).

I think you might try Memantine for a month and see how it goes, from my recent research it seems pretty safe to use for a couple years and you might notice some positive lasting effects but it's hard to say for sure.

Euphoria is a hard goal.
 
Okay , so it won't reverse tolerance or boost ltp because the dopaminergic release in concerta and memantine is thereby giving an illusion that the concerta tolerance is reducing. Such as taking concerta with caffeine (very short duration dopaminergic boost)

Especially, since you said concerta is increasing dopamine in the front part of the brain which is far away from the nucleus accumbens. I don't think it would then rational to take memantine , it's essentially an extra dopamine booster that you take daily , which sensitizes you to concerta? I don't want a dopamine booster lol , if there is a way to truly get rid of tolerance *or almost* as well as problems with ltp without touching memantine , which may or may not work. What could it be , how do I get the same receptors back prior to taking concerta for the first time ? Can a long tolerance break with exercise show promise? Sorry if my questions sound confusing lol.
 
If you want euphoria then memantine will work, I don't think it will actually help your ADHD though. Racetams and boosting NMDA/LTP are going to treat your ADHD better by boosting things like working memory that happen in the front part of the brain - memantine does just about the opposite.

Concerta with racetams will probably be best for treating ADHD while concerta with memantine will probably hamper your intelligence a little bit in the long run but you'll get more mood boosting effects.

Alternatively, just take the concerta and come back to this topic in 10-20 years - we will likely know a whole lot more.
 
Lol when I'll be 40 , Btw I almost forgot !! , the three months that I was off concerta, I was taking kratom to reduce withdrawals . I was wondering as well as ltp being inhibited, did kratom also have a role in stopping ltp or furthering tolerance build up of concerta? And what do you think about magnesium glycinate and its affects of stimulant tolerance?
 
Given the crucial role of NMDA receptor synaptic activation in neuronal plasticity, simplistic interpretation of the observation that a NMDA receptor antagonist such as memantine can improve cognition and neuronal plasticity under pathological conditions might seem to be paradoxical. It should, however, be stressed that divalent cation Mg2+ is an endogenous NMDA receptor channel blocker and its absence leads both to an impairment in neuronal plasticity [49, 74] and neuronal death [81]. Any dysfunction of postsynaptic neurons leading to weakened blockade by Mg2+, e.g. due to partial depolarization as a consequence of an energy deficit, may also trigger prolonged Ca2+ influx and structural (neuronal loss) deficits [54, 230]. Because memantine is more potent and slightly less voltage-dependent than Mg2+ due to its simple monovalent charge, it may thus serve as a more effective surrogate for Mg2+ [198]. As a result of its somewhat less pronounced functional voltage-dependency, memantine is more effective than Mg2+ in blocking tonic pathological activation of NMDA receptors at moderately depolarized membrane potentials. However, following strong synaptic activation, memantine, like Mg2+, can leave the NMDA receptor channel with voltage-dependent, fast unblocking kinetics. In turn, memantine not only suppresses tonic pathological synaptic “noise” but also allows the relevant physiological synaptic signal to be detected. This provides both neuroprotection and symptomatic restoration of synaptic plasticity by one and the same mechanism [54, 196]. Antagonists that have “too high” affinity for the channel or “too little” functional voltage-dependence, such as dizocilpine ((+)MK-801), thus produce numerous side effects, since they essentially act as an irreversible plug of the NMDA receptor channel and block both pathological and physiological function.


So from what I understand from this, Memantine is a noncompetitive blocker of the NMDA receptor that only blocks the NMDA receptor in a noncompetitive manner during hyperpolarization, and leaves the receptor about as quickly as Magnesium, our endogenous NMDA blocker, would?


In that case, it does not seem that there would be any reason for NMDA receptor upregulation to occur. GIven the information, it seems upregulation would only occur during competitive NMDA blockage, especially that which is pathological.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645549/
Click to expand...

Interesting.
 
Kratom is basically an opoid that triggers tolerance to euphoria, I would avoid it. Idk about magnesium glycinate, I mean dietary magnesium is important but I've never seen any studies to support supplementation for something like stimulant tolerance.
 
Hey Cotcha, while in a state of high concern, I found an interesting post on https://drugs-forum.com/forum/showthread.php?t=245683

and check out the posts, especially the last post I sighed a sense of relief and smiled as a sense of hope and calmness set in. " If all else fails, just start running on a treadmill for a month". This made me think , when you said that "exercise is the ultimate form of beating tolerance." I don't mind stopping concerts for a month or longer to do exercise. The question is , should I still

take piracetam for 5 days ON/OFF or will this hinder any progress I made to reduce tolerance/ boost ltp or how about noopept , to grow back dopamine/seretonin cells etc? because I don't care, If I need to stop for a certain period of time to hard reset my brain like how it was before taking concerta. With 3 months off previously , I didn't do any exercise or cardio either which is why I have been dealing with this issue for a while.

Amphetamine takes much longer (thankfully I am not on amphetamine)


Anyway , "However, long term tolerance is caused by BOTH glutamate and dopamine influx. amphetamine doesn't just stimulate release of dopamine, but also glutamate. once glutamate and dopamine enters the post-synaptic neuron, it triggers are series of protein regulated pathways that amplifies the initial signal. Eventually, the pathway ends with the over expression of the delta FosB protein, and inhibition of delta JunD protein. The imbalance of these proteins causes a change within the DNA expression itself, signalling for the destruction of dopamine neurons. These are long term changes that can only be reversed by increasing the activity of delta JunD protein. That takes either time or aerobic exercise".

https://drugs-forum.com/forum/showthread.php?t=245683

A couple of questions and a thumbs up from you , before I proceed :)
 
Sometimes people read things on a study and get a little excited and apply it to humans - stimulant tolerance isn't damage to dopamine neurons. If damage to dopamine neurons was accounting for most of the stimulant tolerance, then we'd be seeing Parkinson's in stimulant users left and right. I'm not saying dopamine neurons don't get killed during stimulant use but it's not the main source of tolerance.

I think cardio will do you good no matter what, and even though it's been shown in studies that NMDA antagonists don't work for stimulant tolerance that doesn't necessarily mean that NMDA agonists will help with stimulant tolerance. So you might try just concerta and cardio for a while. Do it the old fashioned way yknow.

Dopamine neurons are constantly degenerating in normal people. Dopamine itself is harmful to dopamine neurons and is probably responsible for the age related decline in dopamine function. Most people will die before they become Parkinsonian but if everyone lived long enough everyone would become Parkinsonian.

The brightest flame burns quickest.

You could certainly try noopept though, it's neurotrophic effects were very encouraging.
 
Does a 1-3 month off concerta with noopept, cardio and exercise (until I Am satisfied with my gains ) then taking concerta after 1+ month sound like a good regimen to then assess results? All fresh and new lol
 
Idk if I would stop taking concerta, I mean it works the best for ADHD if you take it regularly. But the rest of the plan sounds great.
 
I mean , when I do the cardio/exercise , wouldn't it be best if concerta is out of my system so that way , when I get back on it after 1-3 months my receptors are fresh and with the tolerance reduction, concerta will finally be working for me. Only on 27 mg xr , like it did before?
 
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