Hey beste mensen,
Ik gebruik zelf graag eens in de zoveel tijd wat speed met plezier maar merk ondertussen (door teveel en te vaak gebruiken) dat de negatieve side-effects wat sneller de kop opsteken en de positieve effecten van speed (euforie, energie) minder worden, oftewel: tolerantie
Nou hoor en lees je verschillende verhalen over waardoor die tolerantie ontstaat en wat je eraan kunt doen (naast niet gebruiken natuurlijk), zoals:
- dat je dopamine voorraad uitgeput zou raken (en dat je dat tegen zou kunnen gaan door gebruik van l-tyrosine / l-dopa / mucina pruriens)
- dat je hersencellen beschadigd raken (en dat je dat tegen zou kunnen gaan door gebruik van anti-oxidanten / ALA / astaxanthine / Vitamine C etc.)
Maar na verder zoeken heb ik wat gevonden dat dan echt de oorzaak aanpakt. Het heeft te maken met de NMDA receptor die we wel kennen van de receptor waar ketamine op werkt. Het stofje heet Memantine
en wordt normaal gesproken gebruikt voor mensen die lijden aan Alzheimer.
Voor meer info het onderstaande verhaal, en ik ben benieuwd of er hier mensen zijn met ervaringen met Memantine!
Vooral voor mensen die dagelijks aan de ADHD medicatie zitten zou dit interessante informatie kunnen zijn!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.
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.