I've done a lot of research on the NMDA receptor antagonist, Memantine. It exhibits neurotrophic and neuroprotectant abilities in the brain, in a host of different circumstances.1 It is currently prescribed for Alzheimers patients, it also shows promise as a standalone treatment for withdrawal, neurotoxicity, depression, OCD, and ADHD. Its unique action in the brain shows the drug has a very synergistic effect when combined with D-amphetamine.
This is a paper I wrote just to teach myself about the chemistry of it all. I also might use this to convince my doctor in providing me an off-label prescription for Memantine. Feel free to use it if you like it as well.
NMDA Receptors, and Excitotoxicity
First of all, I'm no neurobiologist, so I'll explain it in the way that I understand. In our brain, NMDA receptors act as a site for plasticity and memory function. They also have a complex relationship with dopamine (D) receptors. Together, they are responsible for learning, motivation, and many vital processes.
NMDA receptors are activated by glutamate, which open channels, allowing Ca2+ (calcium) to flow into the receptors, starting and stopping certain processes. This activation is a vital process in the brain, but chemicals such as amphetamines can cause receptor dysfunction.
When these sites are exposed to too much glutamate, the channel within the receptors stays open for too long and too much Ca2+ flows into the receptor. These can cause the cell to die. This is known as excitotoxicity.
When the receptor sites aren’t being activated correctly, many dopamine and NMDA related processes are hampered. The implications of dopamine and NMDA dysfunction are huge- depression, OCD, cognitive degeneration, ADD/ADHD, and many other issues.
“DA–NMDA interactions also play an important role in neurodegenerative diseases because unregulated enhancement of excitation, particularly excitation mediated by NMDARs, will cause neuronal dysfunction and disturb structural neuronal integrity. For example, the excitotoxicity hypothesis of HD posits that excessive glutamate release at the corticostriatal terminal or altered sensitivity of postsynaptic NMDARs and their signaling systems may induce cell death”
Adderall and NMDA Toxicity
Two primary effects of dextroamphetamine are the activation of Dopamine (D1) receptors and increased glutamate levels.
Dextroamphetamine increases dopamine release in the prefrontal cortex; activation of the dopamine-2 receptors inhibits glutamate release in the prefrontal cortex. Activation of the dopamine-1 receptors in the prefrontal cortex, however, results in elevated glutamate levels in the nucleus accumbens. An increase of the glutamate levels in the nucleus accumbens is the reason that dextroamphetamine has an ability to increase locomotor activity in rats.
“D1 receptor potentiation of NMDA responses can lead to significant functional consequences. For example, potentiation of NMDAR-mediated responses can emphasize the most important input signals, but can also enhance glutamate activity, predisposing the system to excitotoxicity.”
From this, we can infer that the two primary effects of D-AMP are likely excitotoxic to some extent.
Up the Dosage
This neurotoxicity impairs communication and activity in the brain. D1 receptors are down-regulated; which could be, in part, a result of dysfunction with overexcited NMDA receptors once the drug is no longer in effect.
“The D1–NR1 interaction also enables NMDAR activation to increase membrane insertions of D1receptors [50].”
This down-regulation in D1 receptors coupled with damaged neurons could be responsible for cognitive decline and diminishing returns on chronic doses of D-AMP.
Previously, the only way to reverse tolerance was abstinence from amphetamines. But due to collective ignorance, we users sometimes increase the dose to combat cognitive decline. As even more excitotoxicity occurs, our impaired brain no longer runs at full steam, with or without the medication.
Addiction
Diminishing returns form the drug, along with repeated doses, can enforce addictive behavior. A chemical in the brain called Delta FosB may be a large factor in the learned behavior of addiction.
“Delta FosB has been implicated in the development of drug addiction and control of the reward system in the brain, and is linked to changes in a number of other gene products such as CREB and sirtuins.[5][6][7][8][9][10] “
“In monkeys rendered Parkinsonian by MPTP, there was a modest increase in deltaFosB-like protein(s), while the development of dyskinesia produced by chronic D1-like agonist administration was accompanied by large increases in DeltaFosB-like protein(s). “
Preventing NMDA Toxicity & Dependence
To prevent toxicity from an increase in glutamate, NMDA receptors must be able to resist the influx of calcium into their ion channels. For therapeutic benefit and to limit side effects, NMDA receptors must also be readily available for activation when needed.
This can be achieved by the supplementation of an Uncompetitive Channel Blocker, which antagonizes the NMDA receptor. This protects the receptor from being overexcited by glutamate, but still allows it to function correctly.
Preventing Delta F-osB
Delta FosB is created upon pleasurable experiences to reinforce behavior through neurotrophy. It is also activated through D1 agonists, such as D-AMP.
D2 agonists have been shown to reduce the proteins that are linked to addictive behavior:
“In contrast, administration of the long-acting D2-like agonist cabergoline, which alleviated Parkinsonian symptoms without producing dyskinesia reduced deltaFosB levels to near normal. “
In theory, a D2 agonist could ameliorate the activation of D1 receptors and their resulting increase in DFOSB levels. This could reduce or remove any long-term addictive potential of dextroamphetamine, and even encourage a reduction in therapeutic dose.
Memantine
Memantine is a well suiting antagonist because of its specialized action on NMDA receptors. Its uncompetitive nature allows the receptor to work in a normal fashion, while protecting it when overexcited by the environment.
Memantine is a D2 receptor, which makes it a perfect candidate for keeping Delta F-osB levels at a baseline when supplementing a D1 agonist such as dextroamphetamine.
Memantine also works as a nicotinic receptor antagonist, which results in rapid up-regulation. An increase in these receptors is linked to an increase in cognition.
Memantine has a few mild common side effects, such as confusion, headache, blurred vision, and brain fog. Anecdotally, most of these effects are reported to cease within 1 week after starting Memantine. The drug generally has a safe risk profile. It's a long term building block for cognition, and not a rapid fire fix.
In Summary
Memantine has a neuroprotectant effect in some of the same areas that dextroamphetamine affects. It can drastically slow drug tolerance and may prevent addictive behaviors.
I think Memantine should be prescribed with dextroamphetamine. Unfortunately, some people (I’ve seen on Bluelight) are using Memantine to reduce their tolerance in order to abuse Adderall. I hope that they don’t ruin this great drug for the rest of us.
Anecdotally, I’ve heard a lot of success stories regarding the combination of these two drugs. Memantine keeps tolerance near 0, which allows D-AMP to stay just as effective as it was on week 1. It should also help one taper off of or quit Adderall with less effort, something I definitely aim to do.
This was written haphazardly, and essentially by accident. I just meant to list a few ideas to talk to my doctor, and it turned into a quasi-scientific, bro-sciencey paper.
Sources
http://www.ncbi.nlm..../books/NBK5280/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762361/
http://en.wikipedia....tor#cite_note-2
http://pubget.com/pa...d_d_amphetamine
http://www.ncbi.nlm..../pubmed/8714707
http://www.ncbi.nlm....les/PMC2762361/
http://ehis.ebscohos...3&vid=2&hid=110
http://archneur.jama...rticleid=787144
http://everything2.com/title/Dopamine%252C+Delta-FosB%252C+and+the+nature+of+Addictive+Drugs
