Does Piracetam eventually stop working for everyone?

There is no free lunch in life. This applies to most everything. Our body strives to maintain homeostasis. So when we alter that homeostasis with something like piracetam, there has to be some mechanism that will attempt to reverse those changes. Some build tolerance quickly, like amphetamines and opiates. Some more slowly. However, I feel there is always some level of tolerance to everything.

Over the years, I have used my fair share of racetams. In that time, I did notice their effectiveness waning at times. As I used stronger and stronger racetams, the more subtle ones were less and less noticeable. I chocked it up to my higher-level thought processes just getting used to new baselines. However, I started to think about tolerance as a whole. I researched what causes tolerance to the harder things, like amphetamines and opiates. What I found started to make sense, and seemingly tied back into the "tolerance" I was feeling to racetams.

The most likely mechanism is NMDA receptor mediated. The NMDA receptors are widely known to control tolerance to many things. After digging further, it seems that it is a downstream mechanism called immediate early gene expression. When you take a drug like amphetamine, your body increases the levels of extracellular glutamate. This then binds to your NMDA receptors, opening them to allow calcium to influx into the neuron. This then starts a number of processes like the CAMP/KREB cycle, and cascading signal releases. In response to this, your body down-regulates certain immediate early genes to try and balance that signaling out. This is most likely where long-term tolerance comes from.

Now take racetams for example. They bind to the NMDA/AMPA receptors and positively modulate them. In doing so, they increase those cascading signal releases that we want. But they may also be increasing the down-regulation of those same immediate early genes. So that could also be the mechanism for the observed tolerance to racetams that I and many other people have noticed. This is where I start researching NMDA receptor antagonists to reverse the changes.

The two main NMDA antagonists that I have tested in my quest to reverse tolerance are DXM and memantine. I can tell you without a doubt, they work. I frist tried DXM, as it is easier to acquire than memantine, since you can buy it at any Walgreens over the counter. Taking a low dose DXM dose for a week noticeably decreased my tolerance to stimulants. However, DXM is not ideal, as it is an SSRI and a fairly short half life. This is where memantine comes into play. It has a much longer half life (80 hours), and also binds to a different site on the NMDA receptor than DXM. This allows it to maintain plasma concentrations longer, and be useful for daily use. Since starting on a memantine regimen, I have noticed that stimulants are more effective, along with opioids like kratom. But I also noticed that racetams were affecting me more. So I definitely think there is a balance that needs to be had with one's NMDA/AMPA receptors. Take substances that increase calcium transmission through your NMDA receptors, and down-regulation of certain immediate early genes will happen. This will require blocking the transmission of calcium through said receptors to allow for up-regulation to re-balance things.

Now I need to dive deeper into it, and see if I can find the exact gene expression that could be leading to the tolerance.