How memantine works to reverse amphetamine tolerance

[StarStuff]

I just made a long post in the memantine sticky thread explaining how amphetamine tolerance (or more specifically, desensitization to catecholamines) occurs and how NMDA receptor antagonists such as memantine reverse this process. It is so hard to find this information, because it's not something that has been extensively studied, and it took me a lot of research to compile all of the information needed to gain a comprehensive understanding of this. I'm writing a research paper, and I'm going to share it all with you when I finish revising it. My goal in sharing it with you is to equip you with the scientific understanding necessary to convince your psychiatrist memantine really works in reducing amphetamine tolerance, because many psychiatrists are hesitant to prescribe medication used to treat Alzheimer's Disease for amphetamine tolerance because they don't see the connection between the two. I already made a huge post explaining in layman's terms all of the science behind how it all works, and I'm making this thread now to garner a little more attention. I'm going to copy and paste the post I made on page 31 of the sticky memantine thread now:

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Okay guys, so I'm going to hopefully make a helpful post for everyone. As I've mentioned earlier in this thread, I proposed going on memantine to my psychiatrist, citing that I read on these forums that many people are going on NMDA receptor antagonists to reduce or reverse adderall tolerance. His response was assigning me to write him a research paper on the subject. He basically said, "You're a pre-med student? Show me what you can do, then." So I did a ton of research on how adderall works (the specific mechanisms of action, delving deeper than saying it increases presence of neurotransmitters in the synapses in the interstitial fluid between neurons in the prefrontal cortex), how tolerance/desensitization to amphetamine is built, and how NMDA receptor antagonists such as memantine (also dextromethorphan (in cough syrup), amantadine, acamprosate, and magnesium) can work against what causes tolerance and desensitization.

I'm very happy with the amount of work I've put into this paper. If any of you have ever tried to look for exactly how memantine reverses tolerance, you've probably found that it's very difficult to find a compilation of all of the science behind everything. So I think that my writing this paper with lots of scientific sources can be beneficial to people who are trying to convince their doctors that there is actually very strong scientific support behind how memantine helps in fighting tolerance.

I've learned so much in the last month just by researching this so extensively. When I first began reading about this, I was so uneducated about the workings of many of the components, but this was because this level of detail is more in depth than the level of study that I'm used to learning in my Biology 167 class (which is already hard as it is). Still, I was surprised at how much I had been learning in class, particularly from the Nervous Systems chapter of my textbook, that I could apply to my understanding of amphetamine tolerance and NMDA receptor antagonists' role in stopping it. By studying the individual components involved, I ended up educating myself on how all of the components work, and I know enough about this that I can explain it in layman's terms to people so they can understand it. I think I'm going to share my research paper with you when I'm finished revising it, but for right now I'm just going to give a basic run-down of how it all works in hopes that it might help people who are trying to understand it put simply.

I also want to add that all of my understanding of amphetamine tolerance was pieced together by a multitude of different sources that each revealed to me a piece of the puzzle. There really is no complete compilation of all of this that I can find on the internet, and it was hard to find even the individual pieces of the puzzle alone. It took so much searching through PubMed science journals for me to find the articles that I used, and I found most of them by searching a combination of terms like "NMDA receptor and amphetamine," "glutamate and amphetamine tolerance," "calcium ions and amphetamine tolerance," and "NMDA and amphetamine tolerance." Oh, and by the way, a lot of posts here say that memantine slows or reduces tolerance rather than reverses it, but I've found sources that claim that it actually reverses tolerance as well, and I think that's huge in supporting memantine's use for tolerance reduction and prevention.

Anyway, I'm going to explain now the scientific explanations for all of this while explaining what everything means. I'm basically doing my best to put it in layman's terms by providing necessary background information required to understand all of this dense science stuff.

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First of all, a little on desensitization to stimulation in general. Your body naturally desensitizes itself to constant stimulation. This is the reason why you don't even feel the clothes on your body. Your clothes are constantly activating the touch receptors within your skin, and it would drive you crazy if the neurons in your skin were constantly sending the information to your brain that reminds you you're wearing clothes. This is why sometimes scarves can be uncomfortable in the beginning of the winter, because the touch receptors in your neck don't usually receive constant stimuli, so you notice it when you wear a scarf more than other kinds of clothing like pants and shirts and socks, that you wear year-round. You wear scarves much less often and are thus less desensitized to feeling them.

We also see evidence of desensitization (or lack thereof) in infants and toddlers. Kids are sometimes so hard to keep clothed because the constant stimulation to their touch receptors bothers them so much. The reason why we're able to discipline ourselves to keep clothed later in life is because we get desensitized to it over time, making it not bother us starting at a relatively early age.

Anyway, I'm going to get into what causes amphetamine tolerance now that you understand the basic idea behind desensitization and why it plays an important role in maintaining homeostasis. When we take adderall, we're essentially very radically unbalancing the normal level of chemicals of our brain. Amphetamines enter the brain, and force neurotransmitters such as dopamine, norepinephrine, and serotonin out of the brain. It's very hard on our bodies and our brain seeks to maintain homeostasis by gradually desensitizing us to it, not really realizing that the improved focus is really helping us in our daily lives, not hurting us.

So now you have a basic understanding of what desensitization is and why it occurs. I'm going to explain how our body knows to start to desensitize itself to amphetamine, now. A calcium ion (Ca2+) influx occurs secondary to amphetamine administration, and this is what causes the body to know to desensitize to amphetamine. Your body sees its neurotransmitter levels being messed with so harshly, and it responds by telling itself to react less to diminish the problem.

I'm going to explain now a little bit on NMDA and glutamate and why it's relevant. Glutamate is one of the most important excitatory neurotransmitters in the brain, and NMDA receptors activate by binding to glutamate and glycine. If they are not bound to glutamate and glycine, they are inactive. The NMDA receptor channel is the cite of the Ca2+ influx, so by inactivating the channel, you can essentially stop what causes tolerance and even reverse it. NMDA receptor antagonists such as memantine downregulate glutamate, inactivating NMDA receptor channels, indirectly putting a limit on Ca2+ influx and consequently influencing amphetamine tolerance.

As I said, the effect of NMDA receptor antagonists on amphetamine tolerance have not been extensively studied, but NMDA receptor antagonists on another kind of tolerance have been studied very extensively - opiates. There is an absolute wealth of information and studies on NMDA receptor antagonists reducing opiate tolerance. This is because the body recognizes the calcium ion influx to indicate tolerance to both opiates and amphetamines. I imagine that this trend can only suggest that NMDA receptor antagonists can be used to treat tolerance to a number of different kinds of drugs, so long as they rely on Ca2+ influx to determine desensitization must occur, although this is purely my speculation. I think it deserves to be looked into, however.

I'm going to delve a little deeper into how electrical signals in neurons are generated in order to better explain exactly how the Ca2+ influx works. If you've ever taken a chemistry class, you probably remember that ions are compounds with a charge. They've either lost or gained electrons to become more positive or negative, respectively. Neurons maintain a difference in charge within the cell membrane and outside the cell membrane through maintaining the ionic composition within and outside the cells.

Think of a battery. Potential energy is stored in a battery by holding opposite charges apart from each other. If you have some understanding of basic physics, you know potential energy is energy that is dormant but has the potential to be used. When a nerve cell is stimulated beyond the threshold, it responds by releasing some of the negative ionic compounds within the cell membrane, causing positive ionic compounds to flood in. The change in voltage is what generates the electric signal, and it causes neighboring segments along the length of the axon to release negative ionic compounds as well, which then stimulates its neighboring segments, and so on. This is how an electric signal travels down the axon of a nerve cell, the long string-like connector to the receptor cells.

So now you understand electrical signals in neurons, in a nutshell, and you can make the connection of the role of the positive ionic compound Ca2+ in signaling something to the body.

As I've stated above, NMDA receptor antagonists downregulate glutamate in the brain, which shuts off the Ca2+ influx, telling the body to not desensitize itself to dopamine and norepinephrine and serotonin. This is the mechanism by which they stop tolerance.

I'd like to touch a little on how NMDA receptor antagonists help with Alzheimer's Disease now. Someone responded to a previous poster's assertion that the NMDA receptor antagonist's role in amphetamine tolerance is unrelated to its function for treating Alzheimer's Disease is ridiculous. I want to offer the explanation for why the person who said this was correct that the two functions are unrelated, even though they both rely on downregulation of glutamate. Alzheimer's Disease is a genetic predisposition for upregulation of glutamate in the brain with age. An influx of glutamate in the brain interferes with short term memory, and even long term memory over time. NMDA receptor antagonists slow the mental degeneration characterized by Alzheimer's Disease by downregulating glutamate, because in this case, too much glutamate is causing memory deficiencies.

Remember that when treating amphetamine tolerance, you're downregulating a stable level of glutamate. What you're actually looking to downregulate is the influx of Ca2+, but NMDA receptor antagonists allow you to regulate this indirectly, through downregulation of glutamate causing NMDA receptor channels to inactivate.

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Anyway, I hope this makes sense to some people, haha. I'm really pleased with my work because it was so hard to find all of this information, and as I said there isn't really any compilation of all of this the way I laid it out above. I've been intending to do some research during college, and I would love it if I could get this published as a scientific article of some sort. I think it would look great on my future med school applications to show that I did research on something that hasn't been studied much.

The main goal of sharing this with you though is to better equip the less biology-savvy ADD patients who are suffering from tolerance to adderall. Many psychiatrists are hesitant to prescribe a medication used to treat Alzheimer's Disease for amphetamine tolerance because they simply don't understand how it could possibly help. For anyone who is trying to convince their doctor to put them on memantine, the info I've just provided would be immensely helpful. Within the next couple of weeks I will finish revising my paper and share it with all of you too so you will have all of the scientific sources I used to back my explanations as well.

Now I'm going to make a thread on this in this forum too, to garner a little more attention. I really feel like I'm sharing something that could be beneficial to a lot of people who aren't educated enough to provide the scientific basis needed to convince their doctors to let them try memantine.

Thanks for reading

[tambourine-man]

Good work man. I'm forever posting big, long blocks of info in around here and it is important to remember that this is an ADD forum. LOL. Anyway, I read the whole thing.

On a reccomendation I started taking 5ml of Delsym a day (XR DXM, an NMDA agonist thingy) and I've never noticed any kind of tolerance. My pills do what they always did. The only thing that went away was the side-effects. And I've been on em for a long time.

[jennyjay]

So do you have to stay on memantine forever or would you take it periodically to reduce tolorance?

[StarStuff]

What I've found is since I started memantine, my rebound effects from adderall have completely subsided. I used to get very depressed and unfocused on my off days from adderall, and having to take tolerance breaks to maintain efficacy was very painful because I would be depressed and useless. Since I started memantine, I've been extremely stable. I have some sources that show that memantine can be used for ADD treatment, and I can definitely attest to this in my own experience as well. Now, even when I don't take adderall, the memantine gives me the ability to focus and it makes me extremely emotionally and mentally stable, something that adderall has never done. I used to have crazy ups and downs from adderall, and adding memantine totally smoothed that out. Adding memantine as a supplementary medication was the best thing I've ever done for myself.

[camci]

Bumping this, it deserves more attention. The most discussed topic on this board is tolerance, and this seems very promising.

If you could provide a little more info on your "tolerance proof" info it might make people more curious. . . and remember, this is an ADD board, the long post is probably the reason for lack of comments xP but it's important. I'll start:

*Do you take the tolerance stopper pill everyday?
*Do you take your adderall everyday?/Did you take it everyday before?
*Does the pill have any side effects/negatives/health concerns that would scare us into simply dealing w/ the tolerance instead?

[thomasfx10]

You mentioned magnesium ...

"how NMDA receptor antagonists such as memantine (also dextromethorphan (in cough syrup), amantadine, acamprosate, and magnesium) can work against what causes tolerance and desensitization"

I am a little leery getting on another med with adderall but I would be open to taking magnesium ... Does this work and how much is needed ... I cycle my Adderall on and off ... and the hangovers (withdrawals) kick my butt ...
Thanks

[FireFlyBass]

From the information I've gleaned from this thread and surferdude's, I'm speaking to my doctor tomorrow about Memantine and NDMA acid receptor antagonists. Tolerance has been an issue for me since the beginning, and I've also had some slight issues with short term memory, word-recall, and OCD since treatment began 4 months ago, although much better off than before. This could be the holy grail cocktail for me.

[mattskate19]

Thank you!!!!!
ALOT my biggest problem was the ups and downs, tolerance, and depression once it wore off a few hours later on XR.

[jennyjay]

For all who take Namenda, how do you pay for it?

[Anthony121]

I'm on my fathers health insurance, it cost 3 bucks for 30 10 mg pills..

I'm going to be so upset when I get kicked off his health insurance when I turn 26..

The adderall cost like 3 bucks also..

[siglerja]

I went over this with my shrink because I was curious to hear his take. I'm not so sure this is the safest route a person can take to stretch out their Adderall tollerance.

Virtually all medications that act on dopamine systems lose effectiveness over time. Parkinsons patients have to balance out the amount of medication to ensure that they won't develop a tollerance too quickly and can have the longest sustained period of quality life as possible. Applying all of these different adjustments to an ADHD person's dopamine levels could create a worse problem than the one they started out with. It's perscribed off-label to treat anhedonia caused by stimulants, but I read some reports of doctors getting into trouble over this combination in the past.

There's also pretty good evidence in the history of NDRI medications to show issues with messing with dopamine. Pipradrol, Lefetamine, Fencamfamine and Amineptine all were 86'd because of abuse and dependancy issues. The problem with dopamine medications is that, in virtually every situation, the effects will eventually lessen as the patient develops a tollerance. There isn't a safe way to perpetually maintain an "abundance" of dopamine because the brain simply becomes adusted to it and eventually craves more.

[bof00]

That's a pretty good break down but it's missing some facts. NMDA receptors control not only the influx of calcium ions, but potassium and sodium too, and delivers them as helpers to the AMPA receptors which carry these essential ions throughout the brain. Blockage by means of magnesium and zinc are actually normal and essential. The action of unblocking these passages are what cause learning to take place.

You are right with glutamate neurotoxicity needing to be blocked. But, this shouldn't occur in the first place. When someone is taking too much amphetamine and they take magnesium and say that it takes the edge off, it's because they're brain before was to the point of neurotoxicity and destroying brain cells.

Magnesium glycinate is what should be used and is a natural blocker allowing for learning to take place still, and it helps in eliminating calcium which causes the tolerance trigger. Memantine is a much stronger blocker. Blocking the NMDA receptors with a stronger antagonist is not always good. Here is the down side:

NMDA receptors need to function it order for learning and short term memory to take place. Here's an example:

Rats were trained on the Morris water maze, a spatial memory task in which rats swim in a pool of murky water until they locate the platform hidden beneath its surface. During this exercise, normal rats are expected to associate the location of the hidden platform with salient cues placed at specific positions around the circumference of the maze. After training, one group of rats had their hippocampi bathed in the NMDA receptor blocker APV, while the other group served as the control. Both groups were then subjected to the water maze spatial memory task. Rats in the control group were able to locate the platform and escape from the pool, while the performance of APV-treated rats was significantly impaired. Moreover, when slices of the hippocampus were taken from both groups, LTP was easily induced in controls, but could not be induced in the brains of APV-treated rats. This provided early evidence that the NMDA receptor — and by extension, LTP — was required for at least some types of learning and memory.

Now, on top of what too much NMDA receptor blocking can do, Memantine has other mechanisms in action. It's an acetylcholine antagonist - choline being another essential for learning and memory. It's a serotonin receptor antagonist, which has not been looked at enough in the drug. And it's a dopamine D2 receptor agonist which is the one thing good for ADHD people, other than not allowing your mind to be destroyed if you take too much amphetamine. The only reason it has such good effects in Alzheimer's is because it's blocking glutamate neurotoxicity that would otherwise destroy their brain.

You have to consider the opposite before determining what's good and bad. Opening NMDA receptors with agonists increase learning and memory, ultimately increasing AMPA receptors which have the most powerful cognitive effects on the brain discovered so far (look up ampakines), and opening up acetylcholine receptors improves the speed and accuracy of memory recall. This is all good, unless you're subjecting your mind to too much of a bad substance and letting it flow freely, therefore needing to block it.

Just because a drug has one mechanism that you want, does not mean you want the handful of others that come along with it. Be safe, take the natural blocker that your body uses anyway, magnesium.

[mattskate19]

Not to ruin the thread...
But technically you want tolerance to build up to a low dose.
Soo, during lets say a few days off of any kind of psychostimulant (prescribed) take memantine. Then, start off with the low dose again until tolerance builds up once again. The VERY danger I see with taking memantine and adderall is your brain needs to build tolerance or else its like in short.

Here goes,

lets say for me my 40mg XR is my current its a very strong dose but after 3-4 days I can take it and feel literally nothing.
Soo, lets say I take that same 40mg XR which my brain is TOLERATED to and take memantine to alleviate the tolerance. What basically happens is that 40mg XR that im TOLERATED to after years and years becomes like taking 40mg XR on the first day I started Adderall. What happens? Overflow of dopamine and over inhibition of adderall. What will the brain possibly do If I had continued this for a few days or even the first day of taking it? Dopamine receptors would shut down. So, it basically starts you off at square one AD/HD but even more severe than before. Do you understand what I am trying to explain? This can become a VERY dangerous combo unless the dosage is DRASTICALLY reduced to 10mg IR or XR (
*Without Memantine*

First day of Adderall (IR or XR) 15mg = 15mg in the brain
(lets say that was the original sweet spot dose)

A few years later tolerance builds up and you are up to 40mg.
So the 40mg = 15mg or 20mg in the brain (remember tolerance so you have to ingest more to equal the "first day" of adderall)

*With Memantine*

Same situation with first day of adderall (15mg= 15mg in brain) *tolerance is very low* <(no memantine)

Later on days,weeks,months,years later you build tolerance.
Now your tolerance has built up and you are at 40mg remember tolerated so it equals that same 15mg or 20mg in the brain. (remember its the sweet spot but because of tolerance you have to keep raising the dose)
So you take Memantine to alleviate tolerance very low.

So your 40mg = 40mg in the brain (Memantine alleviated tolerance to very low so you are back at the "first day")

That would become very neurotoxic.
Obviously lots of side effects would occur from that dose but if the person had kept taking that the dopamine receptors would overtime shutdown and you would be living on Adderall instead of your dopamine receptors.

Do you understand?

So for everybody out there reduce your dose DRASTICALLY before starting memantine or else

On memantine

40mg= 40mg in the brain

I'm 16 I obviously didn't take alot of time to explain this thoroughly and I am no med student so please excuse for my lack of knowledge in some areas.

[mattskate19]

Soo you have options here

Memantine Alone

Adderall Alone

Adderall with magnesium (magnesium after medication wears off maybe take it before you go to bed?)

But Adderall and Memantine just seems like a very dangerous and unstudied situation.

Finally came past my mind again... What about the Levoamphetamine? This just sounds like a very dangerous mix.

It just seems way to risky taking memantine and Adderall together.
Memantine actions have still not been fully discovered as stated above.

If I were to choose It would be Memantine easily.

[tambourine-man]

So what about DXM? I've been using low, low doses daily for months and months. So far, no tolerance no side-effects. Is this ok? Am I doing major damage and not realizing it. I don't know where to get the right magnesium.