What is Memantine?

There is growing interest in Memantine which is a novel unique drug that acts on the glutamatergic system by blocking NMDA Receptors.

It is mainly prescribed for treating Attention Deficit Hyperactive Disorder ADHD, narcolepsy, Alzheimer’s disease, autism and some chemical addictive substance abuse. The mechanism of action of this drug is being closely studied to assess possible use for other illnesses which involve NMDA receptors.

What is the mechanism of action?

The main action of Memantine is the glutamatergic NMDA receptor.

The mechanism of action is actually that Memantine prevents the Ca2+ signal from spiking and essentially this is the mechanism that prevents drug tolerance from developing.

The NMDA receptors are glutamate class receptors and ion channel protein found in nerve cells, activating it causes positive ions to flow through cell membranes. This is a critical part of controlling memory function, and also synaptic plasticity. Calcium flux is one of the main reasons drug tolerances happens (not the only mechanism, but a major one). The mechanism of action has attracted the attention of many researchers who are hypothesizing other psychiatric and behavioral conditions may benefit from Memantine because of the mechanism of action.

There are other secondary actions. Memantine is also a non-competitive antagonist at the nicotinic acetylcholine receptors (nAChRs). It is also an antagonist at the serotonergic 5-HT3 Receptor. Memantine is also an agonist at the dopamine d2 receptor, which is also of interest for people with social anxiety (often associated with the dysfunction of d2), or in ADHD where dopamine function is impaired, it also induces d2 receptor synthesis in rats. Of note chronic administration of NMDA antagonists induces D2 receptor synthesis in rat striatum.

All of the above mentioned results suggest that the synthesis of both striatal D2 receptor isoforms is post-synoptically regulated at the transcriptional level, by events triggered by glutamate through the NMDA-type receptor.

Of the excitatory neurotransmitters in the brain, glutamate is perhaps the most important. NMDA receptors activate by binding to glycine and glutamate. Once they are not bound to glutamate they remain inactive. It is the NMDA receptor channel which is the site for the Ca2+ influx. By inactivating the channel one can halt what causes tolerance and may even reverse it. In summary, memantine as a NMDA receptor antagonist down regulates glutamate, inactivating NMDA receptor channels thus limiting the Ca2+ influx and by so doing influences amphetamine tolerance.


Can Memantine help Adderall Tolerance?

Memantine nootropic is being used to treat Tolerance Reversal. Scientists have discovered other ways Memantine can be used. The most notable mechanism of action of Memantine is its ability to reverse or block tolerance from other drugs, due the aforementioned effect of being a non-competitive NMDA receptor antagonist.

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Studies have been done on tolerance reversal using memantine to treat opiate tolerance. It is well documented that Memantine acts as the NMDA receptor antagonists. We know when there is an influx of calcium ions the body recognizes this to indicate tolerance to not only opiates but also amphetamines.

This has led to the pursuit of Memantine to treat Adderall tolerance as the mechanism of action involves NMDA receptor antagonists. Let’s look closely at Adderall, its use and issues concerning addiction and tolerance.

Adderall contains a combination of amphetamine and dextroamphetamine. Amphetamine and dextroamphetamine are central nervous system stimulants that affect chemicals in the brain and nerves that contribute to hyperactivity and impulse control. It is used primarily to treat the symptoms of attention-deficit hyperactivity disorder (ADHD). It has benefits with sleep disorders and reported off-label utility in managing some forms of severe depression as well.

Owing to the fact that Adderall is a central nervous system stimulant, it speeds up and heightens certain bodily processes. Adderall is an oral medication prescribed by a physician who will normally start a patient on a low dose to avoid unwanted side effects, gradually increasing it as necessary.


Problems with taking Adderall in the long run:

  • Taking a higher dose of the substance than prescribed.
  • Taking the medicine through a non-approved method like snorting.
  • Taking the drug for reasons other than medical need, such as to stay awake for long periods of time.
  • Taking the medication more frequently than prescribed.
  • Taking someone else’s medication.
  • Purchasing the drug from an illicit source for recreational use.

It is possible to develop a dependency for Adderall, especially if large doses have been taken for an extended period of time. However, even if the drug has been used only for a short time, the body may become accustomed to it. Dependency means that the body has become accustomed to having the drug delivered each day and expects the chemicals to be made without an organ’s help. When this is stopped, and the drug is removed from the system, it is hard for the body to work properly. Adderall tolerance may also occur. This occurs when a person takes the drug for a period of time and then needs to increase the dose to feel the same effects. The body is capable of building up tolerance to all types of amphetamines including Adderall.


The Unique Traits that Make Memantine Truly Unique

What makes Memantine so special is that NMDA antagonists have been studied for a long time, in regards with their efficacies to the aforementioned problems above. Memantine has a notable almost non-existent side effect. This is due to memantine being very voltage dependent, non-competitive, and also it only binds under certain conditions, importantly it unbinds upon depolarization of the neurone, coupled with its fast kinetics. This means that memantine escapes from the ion channel quick enough, to allow normal functioning of the NMDA receptors, allowing passage of calcium and sodium ions critical to the operational circuitry of neuronal firing responsible for glutamine cognition.

This one attribute makes Memantine a one of a kind chemical, as it means it has all the advantages of an NDMA antagonist without the disadvantages of one.

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Consequently because Memantine targets the NDMA receptor which is so responsible to some major reasons why drug tolerance develops (there are many). It has ample research to suggest that it has results on huge variety of chemicals.

It is important to note that Memantine is not a magic pill for reducing drug tolerance. There is nothing in our current chemical knowledge that is capable of reversing tolerance whilst escalating euphoric dosages of chemicals.

Tolerance works on many mechanisms, and when you take euphoric dosages of amphetamine, drug tolerance at the neuronal level isn’t the only reason the drug is becoming less effective over time.

With more research the indications is that scientists are understanding much more about drug tolerance and how the mechanism of action of Memantine prevents the CA 2+ signal spiking preventing drug tolerance from developing.

Memantine has incredible potential for a huge variety of tolerance issues. It has the potential to reduce tolerance, or at the very least lessen the impact of rebound and withdrawal. This is due to its incredible action as a moderate affinity, uncompetitive NMDA receptor antagonist with strong voltage-dependency and fast kinetics. This means that it acts as an NMDA antagonist, without affecting receptor function. NMDA part of the glutamate system is a crucial part of the brains nominal function.

NMDA antagonist has promising results in reversing drug tolerance, because, the receptor, when activated, facilitates ions, in particular, Ca2+ ions. The spike in Ca2+ ions is associated with neuronal changes to make further applications of the same drugs less effective. It is this mechanism even though it was not immediately apparent its action to prevent the development of tolerance. This is because receptor changes in neurons happen slowly. Each receptor needs to be built from scratch and this is similar to what happens with muscle recovery.

However this synaptic adaptation is the biggest reason why many drugs eventually become completely ineffective, and on the reverse make the person physically dependent on the drug to simply function.

Consequently, the irony is the spike in Ca2+ ions in excessive amounts is what creates conditions for neurotoxicity in the first place, which is why Memantine is also neuroprotective.

What is the dosage and how should it be taken?

It is recommended to gradually titrate memantine starting with a low dose of 5mg and gradually increasing by 5mg every two weeks. 20-30mg is the maximum dose that should be prescribed and this is important to avoid potential adverse reactions. There have been reports of higher doses inducing psychosis.

Instant tolerance reduction has actually been achieved in some persons with just 10mg given 30 minutes before taking memantine with Adderall. This is remarkable although it is not yet clear why this is so.

This effect noted with memantine can last between 6-8 hours even though the half-life is 60-80 hours.

Potential risk to watch out for

Memantine has a fantastic side effect profile for a drug of its class. There are however a few undesirous effects which are:

  • Impairment of short term memory. This will differ from patient to patient. Luckily the impairment is reversible
  • High doses of Memantine taken with Adderall can induce hallucinations and even psychosis. This is the reasons why exceeding 30 mg is not advised.
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Memantine is very promising to treat conditions which involve the NMDA receptors. On-going studies will clarify much more about this class of drug and we should see a growing list of diseases that can be treated using Memantine.

– Written by Khemcorp and a Third Party Doctor.

– This article is of opinion and experiences and does no way constitute as medical advice. Please consult your doctor first.



Research References









Brain Res Mol Brain Res. 1992 Aug;14(4):363-8.
Micheletti G1, Lannes B, Haby C, Borrelli E, Kempf E, Warter JM, Zwiller J.
1Institut de Physiologie, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France.


Masui. 2009 Sep;58(9):1136-42.
Ueda H1, Matsushita Y.
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523.


Masui. 2009 Sep;58(9):1136-42.

[Anti-opioid action of glutamate-NMDA receptor systems underlying morphine analgesic tolerance].

[Article in Japanese]

Ueda H1, Matsushita Y.

Author information


Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523.

Neuropharmacology. 2007 Nov;53(6):699-723. Epub 2007 Aug 10.

Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system–too little activation is bad, too much is even worse.

Parsons CG1, Stöffler ADanysz W.

Author information


Merz Pharmaceuticals, Eckenheimer Landstrasse 100, 60318 Frankfurt am Main, Germany.

Brain Res Mol Brain Res. 1992 Aug;14(4):363-8.

Chronic administration of NMDA antagonists induces D2 receptor synthesis in rat striatum.

Micheletti G1, Lannes BHaby CBorrelli EKempf EWarter JMZwiller J.


Author information

Institut de Physiologie, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France.

Psychopharmacology (Berl). 2008 Feb;196(3):497-509. Epub 2007 Nov 10.

NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats.

Mendez IA1, Trujillo KA.


Neuropharmacology. 2008 Mar;54(3):588-96. doi: 10.1016/j.neuropharm.2007.11.013. Epub 2007 Nov 28.

The glycine site-specific NMDA antagonist (+)-HA966 enhances the effect of morphine and reverses morphine tolerance via a spinal mechanism.

Adam F1, Dufour ELe Bars D.

Author information

Institut National de la Santé et de la Recherche Médicale (INSERM) U-713, Université Pierre et Marie Curie, Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l’Hôpital, 75013 Paris, Franc



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