Misc can memantine reverse methylphenidate tolerance?

[Cotcha Yankinov]

Hahahaha you're eyeballing noopept? That's pretty ballsy lol, the dosage is supposed to be like 10mg-30mg :0

 

[Cotcha Yankinov]

Just posting here because your inbox is full.

Of course I'm glad to be of use I'm just someone who had a lot of issues growing up so I self educated when the doctors weren't useful.

Oh sorry I forgot to mention, Choline is fairly important to take with racetams, some people get bad effects if they don't, racetams generally cause release of the oh so important memory/focus neurotransmitter acetylcholine. Alpha GPC will do fine. Exercise does indeed increase BDNF and NGF, and supposedly from what I've read noopept does as well and has other what they call "neurotrophic and neuroprotective" effects that are beneficial for the brain, I'm sure noopept will stack with exercise very well. If it didn't boost the immune system (a good thing for most people but not what I'm looking for) I'd be taking it myself for sure.

Everything I've read points to NMDA agonism (with racetams) potentiating sensitization to stimulants, so I hope they work out well for you as they have for others. NMDA antagonism is definitely the opposite of what you want, don't listen to the newer people around here unless they've got studies to back it up.

 

[BobbyDick]

Amphetamines (NDRA) reverse the direction of action DAT and NET into synapse, so in synapse is more neurotransmiter. Methylphenidate blocks DAT and NET, so in synapse is more neurotransmiter. Amphetamines throw monoamines into synapse. NDRI retain released monoamines by neuron. That is why adding to amph some NDRI reduces effects of amph.
You see that the mechanism of action is completely reverse. That why NDRI reverse tolerance to NDRA and vice versa.

Tolerance isn't ony LTP and sensitization.
Dependence and tolerance is mainly created in nAchRs.


http://www.tandfonline.com/doi/abs/10.1080/10298420290023954
So sensitization is correlated with develop tolerance and dependence.

But I would add to DXM some ampakine because chronic administration NMDA antagonist cause AMPA desensitization. PAM AMPA reverse desensitization.


http://nutritionreviews.oxfordjournals.org/content/53/10/271.abstract

 

[Cotcha Yankinov]

What I was getting at earlier is that the end result of transporter inhibition or reversal of the transporter is a neurotransmitter binding to a receptor and that tolerance occurs near that phase and not the previous phase of either inhibition or reversal of the transporter, so how the dopamine gets there is not of much concern, all that matters is that it's binding. Tolerance occurs not at the level of the mechanism of action of increasing neurotransmitters but rather the end result of that mechanism of action- the neurotransmitter binding to a receptor.

The studies I posted earlier examined NMDA antagonists and specifically methylphenidate if you care to read them.

I think people are confusing true tolerance (receptor density and such) with 2 substances having a synergystic effect. NMDA antagonists by themselves release neurotransmitters so a subjective determination of tolerance i.e. how much effect is perceived, is not relevant because it does not judge the receptor density or strength of LTP.

Some of LTP is mediated by CREB and you suggested a CREB blocker earlier so we are really going in opposite directions here lol, we're trying to boost Jason's LTP not block it. NMDA antagonists also decrease memory, and I might add CREB downregulation is probably playing a role in Alzheimer's disease, so we really are trying to do the opposite of that.

 

[Cotcha Yankinov]

I'm not debating the validity of NMDA antagonists with opiate use, the studies support that, what the studies don't support is the use of NMDA antagonists with psychostimulants

 

[jasonx11]

It won't harm to also add electrolytes such as calcium , potassium and sodium right? , concerta has a diuretic effect and appetite suppressant effect lol I got vitamin d / milk for calcium , bananas for potassium and Himalayan pink salt for sodium. I am going to start incorporating them in my diet.

 

[Cotcha Yankinov]

Electrolytes are good, make sure you eat healthy by the way, in the end appetite suppression causes tons of problems. I really recommend picking up some whey/soy protein and forcing yourself to drink a cup or two every day and taking a multivitamin. You're also gonna wanna take vitamin E with the racetams for anti oxidant protection - stimulation can result in damaging oxygen species. Alpha lipoic acid is also a great anti oxidant I highly recommend. They're pretty cheap ways to protect your brain.

 

[jasonx11]

Will be taking this into consideration. During the break, will taking caffeine as well hurt or hinder the progress?

 

[Cotcha Yankinov]

Caffeine mostly works by antagonizing a sleepy neurotransmitter called adenosine so no there's no cross tolerance. People really like to combine racetams and caffeine btw.

I would definitely take vitamin E every day though.

 

[jasonx11]

Are you sure it works only on adenosine receptors? , because I noticed this phenomenon, where if I took caffeine within 1-3 hour time span after concerta has worn off, bam , instant energy and motivation for about 40 minutes then it subsides and can't be done again the same day. During the break, if I touch caffeine , I don't want it to further antagonize nmda, dopamine, serotonin receptors etc. Which could halt the recovery process?

 

[Cotcha Yankinov]

Well on some level all neurotransmitters are connected, normally adenosine inhibits other neurotransmitters so an antagonist of adenosine will stop that inhibition. But I wouldn't worry about it, coffee isn't going to make or break your tolerance.

 

[BobbyDick]

More qualified user than me explained me the case.

„The subject is very simple: taking NDRI for years creates a tolerance not only in dopaminergic and noradrenergic receptors (their sensitivity or even quantities), but also in protein reuptake. NDRI no longer work as you need to. Taking DXM, etc. little bit helps, but not enough.
Of course break from NDRI helps, but turns tolerance very slowly.


I think a little about that and below I wrote what I suspect (not necessarily have to be truthful, I did not find adequate research on this topic):
Tolerance to NDRI formed on the specific substances and also includes a tolerance reuptake transporters (DAT, NET and sometimes SERT for SNDRI). For example, a dextromethylphenidate (d-MPH) have Ki value for DAT = 161, for NET = 206. In my opinion, the tolerance undermines this factor and so, for example, after a while the occurrence of tolerance, Ki DAT may be, for example 300-400, and add higher doses refutes for example to 250. In turn tolerance to NET can grow slowly and, for example at the normal dose will DAT Ki = 400, the NET = 206. Therefore, taking the higher dose did not give full effect, and only a partial improvement, but the deterioration of other effects (which is also certainly additional substrate [de]sensitization of receptors). I noticed that at methylphenidate and ethylphenidate there is cross-tolerance, due to the similarity of molecules.


I noticed that at metylofenidacie and metylofenidacie there is cross-tolerance, due to the similarity of molecules.
However, when given another NDRI this tolerance has not occurred (!!!). I tested this with a variety of other NDRI and NRI, including bupropion, reboxetine, 2-DPMP, even low doses of cocaine.
I conclude that tolerance to transporters (I note that this is still only my theory) is selective for certain substances, or one substance can no longer give full effect, but the second one did. That means that it is possible to administering of other NDRI also reverses tolerance to the NDRI which we taken for a long time, but are not just as strong as amphetamines (as describe below).


But this is not the end, another suspect is the acceleration transport reuptake (RE). I suspect that when administered to specified NDRI for a long time reuptake works faster and faster pulls back monoamine from synapses. It is known that type substances NDRI not block 100% monoamine transporter proteins, so some of them still active despite the action of the substance, and I suspect that this part increases the rate of uptake for reduce the effect of transporters blocked.






Here it comes the magical effect of amphetamines, or reversing the direction reuptake. For example, the PEA running on the DAT and the NET in such a way that the uptake is not blocked, but its direction is reversed. So DAT protein, and the NET "take" monoamines with bubbles nerve endings and "throw" them to synapses. PEA is therefore an indirect releaser (through reuptake transporters) and "blocker" (in quotes because uptake is not blocked, but it does not work in the usual way - throw monoamines to the synapse rather than take them into bubbles for future use).


Thus, DAT and NET if they are not blocked by the administration of amphetamine probably slow down the release of monoamines was not so strong. After a long time formed a kind of tolerance on the action of amphetamines on the uptake, but this tolerance is reverse tolerance to NDRI. Not enough, that tolerance to specific substance falls (eg on methylphenidate), it is still probable tolerance "speed" reuptake also falling. As a result, when will occur tolerance for amphetamine, repeated administration of NDRI should have a very strong effect.


I tested this process several times taking in cycles NDRI and PEA + sele. Every time I cycled the PEA when I back to NDRI everything work as it should. So far in my experience, it is the most effective way to reverse tolerance, no other has given me such spectacular results.


If anyone has other suspicions or any other explanation for this effect, let him write go ahead. For me the most important thing is that it works


I think that after such a cycle PEA few months could additionally increase the sensitivity of DA receptors by the administration of light neuroleptics / dopamine receptor antagonists. Currently, I am during administering tests PEA together with such antagonists. The effects of PEA are weaker (eg no euphoria), but still noticeable. For some time I'll report how this process will be effective (I plan to shorten the time needed to reverse tolerance to NDRI from a few months to eg. 2-weeks - months). I am happy to hear your views on this topic, because maybe something I missed and it should be taken into consideration.


Action PEA reversal of tolerance NDRI may also have a relationship with agonism TAAR1.


It is worth to look at the mechanism of action NET frontal lobe. While in other areas of the brain DAT rules the roost as the reuptake of dopamine, but in prefrontal cortex dopamine majority is captured by NET. And this part of the brain is responsible for, among others, planning, logical thinking, problem solving, etc., and is the most stimulating this part we feel eg. the after taken NDRI.”

 

[jasonx11]

Concerta and PEA?

 

[jasonx11]

I don't think it's a good idea to antagonize dopamine receptors. I think cotcha yankinov can explain better since he is more well versed on this than I am.

 

[BobbyDick]

Antagonize dopamine receptors is almost always bad idea. But this guy know what he doing.

 

[BobbyDick]

Concerta and PEA?

No. 5 mg selegiline and after 100 mg PEA once for every two hours.

 

[Cotcha Yankinov]

So I'm glad that they're aware this is just a theory, but with that in mind I would say that because this theory is based on subjective effects of different drugs, the more we can explain the discrepancy of subjective effects between different drugs without invoking differences in the qualities of reuptake transporters and such, the less weight is behind this theory. There are some things that need to be accounted for when comparing substances in order to truly relate the subjective difference of effects to some mechanism of tolerance.

"However, when given another NDRI this tolerance has not occurred (!!!). I tested this with a variety of other NDRI and NRI, including bupropion, reboxetine, 2-DPMP, even low doses of cocaine."
You have to account for
1. Peak/steady plasma concentrations of the drug in question
2. Its ability to penetrate the blood brain barrier
3. In case of TAAR1 agonists, its ability to penetrate the membrane barrier
4. The disassociation half life, i.e. how long it takes for half of the molecules to disassociate from the reuptake transporter - This could account for much subjective differences even if all other things were equal
5. Mechanism of Action, i.e. buproprion, even though it is a weak reuptake inhibitor, is also a releasing agent, and cocaine is probably a DAT inverse agonist
6. Affinity for the reuptake transporter
7. Down regulation of auto receptors concerning continued use
8. Mechanisms of long term potentiation such as DeltaFosB concerning addicting substances - Inducing certain changes in the reward pathways of the brain can increase sensitivity over time rather than as usually thought, decrease sensitivity - This is addiction at it's core, sensitization.
9. Dosage


"I tested this process several times taking in cycles NDRI and PEA + sele. Every time I cycled the PEA when I back to NDRI everything work as it should. So far in my experience, it is the most effective way to reverse tolerance, no other has given me such spectacular results."

First of all, this person is heroic for using PEA + MAO-B. But I see no reason why PEA couldn't cause expression of DeltaFosB in the nucleus accumbens/Induce long term potentiation - This would cause sensitization and result in getting a good high off of both substances all the time.

"I think that after such a cycle PEA few months could additionally increase the sensitivity of DA receptors by the administration of light neuroleptics / dopamine receptor antagonists. Currently, I am during administering tests PEA together with such antagonists." - This would indeed upregulate receptors a tiny bit but it would cause loss of DeltaFosB/LTP. If Jason's increased tolerance upon returning from his concerta break says anything, it says that having the LTP is more important than having naturally (dopamine shortage induced) upregulated receptors. Dopamine antagonists have been shown to block sensitization to dopaminergics. - From a mice study " haloperidol selectively blocked "reverse tolerance" to cocaine-induced stereotypy" - Basically means that you need dopamine working to induce sensitization.

"dextromethylphenidate (d-MPH) have Ki value for DAT = 161, for NET = 206. In my opinion, the tolerance undermines this factor and so, for example, after a while the occurrence of tolerance, Ki DAT may be, for example 300-400" - This would require that the transporters fundamentally change and this could be evidenced with studies if it did happen

"I suspect that when administered to specified NDRI for a long time reuptake works faster and faster pulls back monoamine from synapses. It is known that type substances NDRI not block 100% monoamine transporter proteins, so some of them still active despite the action of the substance, and I suspect that this part increases the rate of uptake for reduce the effect of transporters blocked." - Once again this would require the transporter fundamentally change - What DOES happen is because the concentrations of the neurotransmitter in question are much higher after reuptake inhibition that even though there are less transporters there are more neurotransmitters ready to bind to the transporter, essentially increasing the rate of uptake per transporter with factors independent of the reuptake transporter itself.

I think this theory of some mechanism of tolerance at a transporter level via changes in the transporter's structure/affinity has zero evidence so far. And it still looks like sensitization/LTP reigns king. Any questions are welcome.

 

[BobbyDick]

But the mechanism of action NDRI and amphetamines is truthful.

So, should we switch on or of LTP?

 

[Cotcha Yankinov]

Slight caveat and explanation for why there might be synergy between cycling a DRI and DRA - Some dopamine reuptake transporter inhibitors (such as cocaine and bupropion) up regulate the DAT, this means that you could expect increased strength of amphetamines within the short period that DAT remains up regulated because there will be more transporters available to reverse. But those two I mentioned happen to be a dopamine releasing agent / DAT inverse agonist so the up regulation of DAT is probably a compensation for increased dopamine in the synapse. But ultimately this has nothing to do with actual tolerance because the receptors will still be downregulated with high dopamine transporter concentrations, you'll just get more bang for your buck in terms of dopamine release specifically if using a mechanism that utilizes reversal of the transporter - most importantly, "sensitivity" is still decreased and you could get more overall dopamine activity with up regulated receptors and non up regulated DAT rather than upregulated DAT and down regulated receptors.

We want our LTP, it strengthens the dopamine's signal and increases receptor upregulation in the reward centers.

 

[BobbyDick]

Chamoline and parsley contain luteolin. Luteolin induces LTP and it is a monoamine reuptake activator.