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I think memantine is the new kid on the block in psychiatry. Some help for people who have ADHD, depression, improve cognition in low dosage.
Probably is good used with stimulant because it’s help for amphetamine tolerance.Memantine (Namenda) is a low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist believed to work by blocking prolonged low-level activation of the NMDA receptor and resultant neuronal damage caused by abnormal glutamatergic activity, yet also allowing normal physiological activity of the NMDA channel.” Memantine has also been shown to upregulate protein expression for BDNF through a mechanism believed to be remote from NMDA antagonism.
would seem to follow from this that that memantine would have the potential to upregulate D4 receptor activity in the prefrontal cortex, which would imply it could be a viable alternative in treating primarily inattentive ADD.
There are some psychiatrists who find Memantine (Namenda) very useful for the treatment of Obsessive-Compulsive Disorder. Other NMDA receptor antagonists such as N Acetylcysteine also are useful in this illness.
I don’t believe Memantine works well for attention deficit/hyperactivity disorder – either primarily inattentive or mixed type. The problem is that Glutamate is useful as a signal to form synapses. Blocking it excessively may impair memory. Additionally, glutamate signaling problems are not the primary issues in attention deficit/hyperactivity disorder (ADHD).
The primary pathologies are problems in nutrition, thyroid hormone signaling, and the immune system. If these areas are optimized in function, then I need to use only very low doses of stimulants to address nervous system problems, if at all. If all one does is improve nutrition and thyroid, most of the problem with attention is already solved for the majority of patients – from those living in poverty to affluent patients.
@DrMariano 4525 wrote:
There are some psychiatrists who find Memantine (Namenda) very useful for the treatment of Obsessive-Compulsive Disorder. Other NMDA receptor antagonists such as N Acetylcysteine also are useful in this illness.
I don’t believe Memantine works well for attention deficit/hyperactivity disorder – either primarily inattentive or mixed type. The problem is that Glutamate is useful as a signal to form synapses. Blocking it excessively may impair memory. Additionally, glutamate signaling problems are not the primary issues in attention deficit/hyperactivity disorder (ADHD).
The primary pathologies are problems in nutrition, thyroid hormone signaling, and the immune system. If these areas are optimized in function, then I need to use only very low doses of stimulants to address nervous system problems, if at all. If all one does is improve nutrition and thyroid, most of the problem with attention is already solved for the majority of patients – from those living in poverty to affluent patients.
Thank for your answer. I think also that are not so much benefice for ADHD depiste that some ADD people take low dose of memantine with chronic use of stimulant for ADHD. Maybe is it’s good candidate for cognitive ability with aging, but I’m sure.
In fact, there are no study about this informatio but some ADHD people have some good result with the combo memantine+ stimulant. But I think it’s not for everybody, perhaps for people who have an down-regualtion of D2 receptors with the chronic use of stimulants.
“It is well established that psychostimulants, including amphetamine, have been shown to increase extracellular glutamate in the nucleus accumbens (NA) to levels of hyperexcitation ([1],[2],[3],[4]). As a result of this glutamate hyperexcitation, NA core (NAc) dopamine (DA) sensitivity is downregulated. It has been found in [5], in rats chronically treated with amphetamine, NA DA neurons were significantly less sensitive to glutamate excitation.
NAc DA sensitivity has large implications for motivation, though. [6] provides a thorough review of just this idea. It mentions studies that have proven ‘NA DA depletions… impair activational aspects of motivation.’ Certainly, it is plausible that these feelings of motivation can have a positive, therapeutic effect on ADD treatment.
Additionally, [5] also found that chronic amphetamine exposure has been shown to increase and decrease, respectively, the responsiveness of NAc neurons to glutamate. This closely matches anecdotal reports of subjective increases in mood and motivation during the beginning of stimulant therapy which then taper off as effects of stimulant treatment normalize.
One possible solution to controlling this glutamate hyperexcitation to restore sensitization of NAc DA neurons and the therapeutic motivational effects of amphetamine is coadministration with memantine. Memantine is an uncompetitive antagonist at glutamatergic NMDA receptors. Most importantly to our purposes, because memantine has a low-to-moderate affinity for NMDA receptors, it does not seem to block normal glutamate transmission; rather, it reduces abnormal neurotransmitter-mediated activation of the receptors [7], thereby potentially reducing excitotoxic neuronal damage. Normal glutamate function, then, is not impinged upon.
Memantine is very well tolerated ([8][9][10]) and does not have drug-drug interactions with amphetamine [8]. Also, memantine has been studied in healthy, non-dementia patients with no signs of problems and, in fact, showed evidence of cognitive enhancements and other beneficial effects in these patients ([11][12][13]). It also provides beneficial, healthful side effects, including an increase in BDNF [[14].
Theoretically, co-administration of memantine and amphetamine is a safe, novel, and promising solution to restore NAc DA sensitivity that is lost by amphetamine-induced glutamate hyperexcitation and, as a result, restore the plausibly therapeutic motivational effects of amphetamine lost in the early stages of treatment.”
[1] PMID: 11487659
[2] PMID: 9266771
[3] PMID: 12491026
[4] PMID: 8667013
[5] PMID: 7714800
[6] PMID: 12445713
[7] PMID: 15717010
[8] http://www.frx.com/pi/namenda_pi.pdf
[9] PMID: 16034889
[10] PMID: 15903287
[11] PMID: 19449331
[12] PMID: 16423331
[13] PMID: 17452287
[14] PMID: 17971830one more article : Memantine: The Next Trend in Academic Performance Enhancement?
http://www.jaoa.org/content/106/6/358.fullAs an alternative to Memantine and N-Acetylcysteine, Vitamin C also happens to be a partial NMDA glutamate receptor antagonist, aside from its antioxidant effects and ability to improve absorption of certain nutrients such as iron, and its role in metabolism.
@DrMariano 4582 wrote:
As an alternative to Memantine and N-Acetylcysteine, Vitamin C also happens to be a partial NMDA glutamate receptor antagonist, aside from its antioxidant effects and ability to improve absorption of certain nutrients such as iron, and its role in metabolism.
Yes also magnesium glycinate. In fact, memantine doesn’t have a strong NMDA antagonist.
I ‘m very interested by improving the cognitive ability with aging and in fact NMDA receptor look interesting, but many study show the NMDA agonist is more crucial for better memory or cognition.
http://radian.org/notebook/wp-content/uploads/2009/04/brain-botox.pdfUnless it is clearly an excess of glutamate that is causing problems – and that is hard to prove – I prefer minimizing its reduction since it is necessary as a signal to form new synapses and memories.
I don’t think glutamate excess hypotheses will be very effective since blockade of NMDA receptors can cause problems too. I also think there are bigger targets to evaluate and treat.
@DrMariano 4587 wrote:
Unless it is clearly an excess of glutamate that is causing problems – and that is hard to prove – I prefer minimizing its reduction since it is necessary as a signal to form new synapses and memories.
I don’t think glutamate excess hypotheses will be very effective since blockade of NMDA receptors can cause problems too. I also think there are bigger targets to evaluate and treat.
Yes I suppose that nutrition deficiency, perturbation of endocrine, immune system and neuronal system have a major effect on cognition than the pre-cognitive enhancing drug on the market today.
Yes I suppose that nutrition deficiency, perturbation of endocrine, immune system and neuronal system have a major effect on cognition than the pre-cognitive enhancing drug on the market today.
In fact, I’m interested by memantine because it’s maybe more effective than supplement to up regulate some dopamine receptors for people who take stimulant for ADD.
NMDAR and stimulant tolerance: ( NMDA antagonists upregulate several dopamine receptors backed up by many people that used it succesfull for stim tolerance).
(PMID: 2671566) Blockade of “reverse tolerance” to cocaine and amphetamine by MK-801
(PMID: 9560846) The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants
(PMID: 11915303) Alteration of neuronal activities following repeated administration of stimulants
ADHD
A pilot evaluation of the safety, tolerability, pharmacokinetics, and effectiveness of memantine in pediatric patients with attention-deficit/hyperactivity disorder combined type.
CONCLUSIONS: This pilot study suggests that a memantine dose of 20 mg/day may be a safe and possibly effective treatment for pediatric ADHD. Further investigations of memantine in ADHD appear to be warranted.NMDA antagonists and dopamine
(PMID: 1382178) Chronic administration of NMDA antagonists induces D2 receptor synthesis in rat.
D2 binding studies carried out in MK-801 chronically treated (0.3 mg/kg/day per os, for 50 days) and control rats revealed an increased receptor density in treated animals without a significant change in receptor affinity.(PMID: 7770607) Effects of the NMDA-antagonist, MK-801, on stress-induced alterations of dopamine dependent behavior.
(PMID: 10443547) Adaptations of NMDA and dopamine D2, but not of muscarinic receptors following 14 days administration of uncompetitive NMDA receptor antagonists.
The same treatment with amantadine did increase [3H]raclopride binding to dopamine D2 receptors by 13.5%.(PMID: 10214758) Decreased striatal dopamine-receptor binding in sporadic ALS: glutamate hyperactivity?
In drug-naïve, sporadic ALS patients we demonstrated decreased striatal D2-receptor binding in vivo that could be partially reversed by the glutamatergic transmission blocker riluzole.(PMID: 12832726 Effect of combined treatment with imipramine and amantadine on the central dopamine D2 and D3 receptors in rats.
We can conclude that repeated administration of AMA, given together with IMI, induces the up-regulation of dopamine D2 and D3 receptors in the rat brain.(PMID: 10096038) Modulation of dopamine D2 receptor expression by an NMDA receptor antagonist in rat brain.
In the striatum, a significant increase in striatal dopamine D2 receptor mRNA levels was shown in animals treated with CPP.(PMID: 14997010) Enhanced expression of dopamine D(1) and glutamate NMDA receptors in dopamine D(4) receptor knockout mice.
The findings suggest that D1, D4, and NMDA receptors might interact functionally and that developmental absence of D4 receptors might trigger compensatory mechanisms that enhance expression of D1 receptors in NAc and CPu, and NMDA receptors in NAc, CPu, and hippocampus. The findings also encourage cautious interpretation of results in knockout mice with targeted absence of specific genes, as complex adaptive changes not directly related to the missing gene might contribute to physiological and behavioral responses.Do you agree Dr Mariano with the memantine utilization for tolerance of chronic use of amphetamine for people who have ADHD ?
I known that there are no study but many people enjoy the result.You do make an interesting point about Memantine.
However, in clinical use, there may be zero effect, negative effect, or positive effect on people who use amphethetamine to treat ADHD. And most of the time, it probably will be a zero effect.
The key is that any desired change toward improvement depends on the summation of multiple signals and conditions.
Getting the desired direction is like trying to conduct an orchestra so that every sound has the right synchronization, tuning, loudness, etc.
One issue is that Memantine has multiple effects itself – that aren’t often discussed since people focus on its effects on NMDA receptors:
- Memantine is an NMDA Glutamate Receptor Antagonist.
- Memantine is also a Serotonin receptor antagonist (particularly 5-HT3 receptors).
- Memantine is also a Nicotine receptor antagonist (particularly Alpha 7 receptors).
Memantine’s effects depends on, among other things,
- Glutamate levels – which may vary tremendously depending on type and stage of illness
- Magnesium levels – magnesium being also an NMDA receptor antagonist
- Dosing of Memantine – where the result can be a negative, positive, or neutral effect.
When the overall changes in signal levels are examined, Memantine
- increased Dopamine
- increased Norepinephrine
- increased Acetylcholine
But the effect depends on location in the brain.
Memantine’s overall effect on thought and behavior, however, will vary depending on all the other signals and all the other processing system outputs in the brain. Predicting, a priori, where it will go is difficult and often ends up being a trial and error event. It is good if it improves function. Most of the time, there may be no improvement.
But I expect much of the time, it will be no improvement since improvement in function in ADHD has larger factors than dopamine. Dopamine receptor density may be a problem in some forms of ADHD, but not the majority, in my experience.
Is Memantine worth a trial on any particular patient? Given the fairly benign adverse effect profile, it may be worthwhile trying it in case a person may have a significant positive effect from it. But, like many things, most of the time it will not work because there are too many other factors involved. For example, if used only in combination with a stimulant in treating ADHD, the other contributing factors are ignored – e.g. nutritional deficiencies, proinflammatory signaling, hormonal problems, etc. etc. These will negate or hide the effects of Memantine even if it has a positive effect.
Thus, if all these other big factors underlying ADHD were addressed and stimulant treatment is still insufficient, then perhaps that is the time to try adding augmenting agents, such as Memantine, whose effects would otherwise be too negated or insignificant or even negative if given too early (e.g. in one study, Memantine increased cocaine use and had worse effect than placebo).
—
Now in regard to the initial point: the development of tolerance to amphetamine treatment:
Amphetamine tolerance is highly dependent on pro-inflammatory signaling and hypothalamic-pituitary-adrenal axis function. The loss of dopamine receptor density is not as big a factor.
Amphetamine use – via increases in sympathetic nervous system signaling – will always activate the immune system’s leukocytes in a pro-inflammatory direction. This in turn can increase nervous system microglial cell proinflammatory signaling. Microglial proinflammatory signaling cleaves synapses, reduces nervous system metabolism, inhibit various motivational circuits, neuron and glial cells size, etc. The overall direct effect is to impair memory, ability to think, ability to attend to tasks. The balance of proinflammatory signals and stimulant signals will help determine one’s ability to attend to task.
Amphetamine use – particularly in chronic use – may lead to HPA Axis dysregulation – which then impairs both one’s ability to control proinflammatory signaling and stress signaling. This may lead then to impaired attention via impairment in function or via excessive norepinephrine increases an increase in distractibility by excessive sensory input. The balance of HPA Axis function and stimulant signaling will help determine one’s ability to attend to tasks.
These are just two of many significant factors that determine whether or not there is tolerance to amphetamine use – aside from a reduction in dopamine receptor density from chronic amphetamine use.
In my experience, when I successfully address these and other factors – such as thyroid function and nutritional status, I am able to chronically use very very low doses of amphetamines or other stimulants in treating ADHD, without development of tolerance. There would be no need to use high stimulant doses since the low doses are sufficient. In many cases, stimulant treatment may be unnecessary since the patient would already have restored dopamine production.
—-
Here are additional references:
Pharmacodynamics of Memantine: An Update (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645549/?tool=pmcentrez)
Changes in cerebral neurotransmitters and metabolites induced by acute donepezil and memantine administrations: a microdialysis study. (http://www.ncbi.nlm.nih.gov/pubmed/16533671)
Cognitive Enhancers in the Treatment of Substance Use Disorders: Clinical Evidence (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114106)
@DrMariano 4626 wrote:
You do make an interesting point about Memantine.
However, in clinical use, there may be zero effect, negative effect, or positive effect on people who use amphethetamine to treat ADHD. And most of the time, it probably will be a zero effect.
The key is that any desired change toward improvement depends on the summation of multiple signals and conditions.
Getting the desired direction is like trying to conduct an orchestra so that every sound has the right synchronization, tuning, loudness, etc.
One issue is that Memantine has multiple effects itself – that aren’t often discussed since people focus on its effects on NMDA receptors:
- Memantine is an NMDA Glutamate Receptor Antagonist.
- Memantine is also a Serotonin receptor antagonist (particularly 5-HT3 receptors).
- Memantine is also a Nicotine receptor antagonist (particularly Alpha 7 receptors).
Memantine’s effects depends on, among other things,
- Glutamate levels – which may vary tremendously depending on type and stage of illness
- Magnesium levels – magnesium being also an NMDA receptor antagonist
- Dosing of Memantine – where the result can be a negative, positive, or neutral effect.
When the overall changes in signal levels are examined, Memantine
- increased Dopamine
- increased Norepinephrine
- increased Acetylcholine
But the effect depends on location in the brain.
Memantine’s overall effect on thought and behavior, however, will vary depending on all the other signals and all the other processing system outputs in the brain. Predicting, a priori, where it will go is difficult and often ends up being a trial and error event. It is good if it improves function. Most of the time, there may be no improvement.
But I expect much of the time, it will be no improvement since improvement in function in ADHD has larger factors than dopamine. Dopamine receptor density may be a problem in some forms of ADHD, but not the majority, in my experience.
Is Memantine worth a trial on any particular patient? Given the fairly benign adverse effect profile, it may be worthwhile trying it in case a person may have a significant positive effect from it. But, like many things, most of the time it will not work because there are too many other factors involved. For example, if used only in combination with a stimulant in treating ADHD, the other contributing factors are ignored – e.g. nutritional deficiencies, proinflammatory signaling, hormonal problems, etc. etc. These will negate or hide the effects of Memantine even if it has a positive effect.
Thus, if all these other big factors underlying ADHD were addressed and stimulant treatment is still insufficient, then perhaps that is the time to try adding augmenting agents, such as Memantine, whose effects would otherwise be too negated or insignificant or even negative if given too early (e.g. in one study, Memantine increased cocaine use and had worse effect than placebo).
—
Now in regard to the initial point: the development of tolerance to amphetamine treatment:
Amphetamine tolerance is highly dependent on pro-inflammatory signaling and hypothalamic-pituitary-adrenal axis function. The loss of dopamine receptor density is not as big a factor.
Amphetamine use – via increases in sympathetic nervous system signaling – will always activate the immune system’s leukocytes in a pro-inflammatory direction. This in turn can increase nervous system microglial cell proinflammatory signaling. Microglial proinflammatory signaling cleaves synapses, reduces nervous system metabolism, inhibit various motivational circuits, neuron and glial cells size, etc. The overall direct effect is to impair memory, ability to think, ability to attend to tasks. The balance of proinflammatory signals and stimulant signals will help determine one’s ability to attend to task.
Amphetamine use – particularly in chronic use – may lead to HPA Axis dysregulation – which then impairs both one’s ability to control proinflammatory signaling and stress signaling. This may lead then to impaired attention via impairment in function or via excessive norepinephrine increases an increase in distractibility by excessive sensory input. The balance of HPA Axis function and stimulant signaling will help determine one’s ability to attend to tasks.
These are just two of many significant factors that determine whether or not there is tolerance to amphetamine use – aside from a reduction in dopamine receptor density from chronic amphetamine use.
In my experience, when I successfully address these and other factors – such as thyroid function and nutritional status, I am able to chronically use very very low doses of amphetamines or other stimulants in treating ADHD, without development of tolerance. There would be no need to use high stimulant doses since the low doses are sufficient. In many cases, stimulant treatment may be unnecessary since the patient would already have restored dopamine production.
—-
Here are additional references:
Pharmacodynamics of Memantine: An Update (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645549/?tool=pmcentrez)
Changes in cerebral neurotransmitters and metabolites induced by acute donepezil and memantine administrations: a microdialysis study. (http://www.ncbi.nlm.nih.gov/pubmed/16533671)
Cognitive Enhancers in the Treatment of Substance Use Disorders: Clinical Evidence (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114106)
I like Dr Mariano, it’s the best doctor I’ve never seen. This is FABULOUS answer.
God bless you
I wait to see you again.I think antagonist of microglia inflammation is a good key to for cognition. Phycocyanine look interesting
Med Hypotheses. 2010 Mar;74(3):601-5. Epub 2009 Jul 2.
Oral phycocyanobilin may diminish the pathogenicity of activated brain microglia in neurodegenerative disorders.
McCarty MF, Barroso-Aranda J, Contreras F.
Source
Oasis of Hope Hospital, Paseo Playas 19, Playas de Tijuana, BC 22504, Tijuana, Mexico. mccarty@pantox.com
Abstract
There is considerable evidence that activated microglia play a central role in the pathogenesis of many prominent neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases. The elevated NADPH oxidase activity of these microglia contributes importantly to their pathogenic impact, collaborating with increased iNOS activity to generate the cytotoxic oxidant peroxynitrite. Phycocyanobilin (PCB), a chromophore derived from biliverdin that constitutes up to 1% of the dry weight of spirulina, has recently been shown to be a potent inhibitor of NADPH oxidase. The possibility that orally administered PCB could reach the brain parenchyma in sufficient concentrations to influence microglial function is consistent with the findings of two rodent studies: orally administered C-phycocyanin (the spirulina holoprotein that includes PCB) suppresses the neurotoxic impact of the excitotoxin kainite in rats, and a diet high in spirulina ameliorates the loss of dopaminergic neurons in the MPTP-induced Parkinsonian syndrome in mice. Hence, supplemental PCB may have considerable potential for preventing or slowing the progression of a range of neurodegenerative disorders. Some of the central physiological effects of PCB may also reflect inhibition of neuronal NADPH oxidase, which is now known to have a modulatory impact on neuron function, and can mediate neurotoxicity in certain circumstances. Neuronal NADPH oxidase activation is an obligate mediator of the central pressor effect of angiotensin II, and there is suggestive evidence that it may also play a role in inflammatory hyperalgesia; these findings point to possible antihypertensive and analgesic applications for PCB. The likely favorable effects of PCB on vascular health may also protect the brain by decreasing stroke risk, and inhibition of NADPH oxidase in rodents has been shown to lessen the neurotoxic impact of temporary cerebral ischemia. PCB may thus have versatile potential for preserving the healthful function of the central nervous system into advanced old age–albeit optimal neuroprotection may require more complex regimens that incorporate PCB along with other well tolerated nutraceuticals and drugs, in conjunction with prudent lifestyle modifications.Microglial proinflammatory signaling is a good target for treatment. However, it may not be beneficial to target it if it is not in excess.
Pro-inflammatory signaling has important positive actions. This includes regulating sleep, appetite, facilitating memory formation, stimulating the immune system to help fight pathogens and cancer, modifying behavior to help recovery from infection, etc.
These and other reasons are why patients on high dose glucocorticoids may have problems functioning – including developing frequent infections since their immune system was excessively suppressed.
An evaluation and balance is necessary as an endpoint.
@DrMariano 4635 wrote:
Microglial proinflammatory signaling is a good target for treatment. However, it may not be beneficial to target it if it is not in excess.
Pro-inflammatory signaling has important positive actions. This includes regulating sleep, appetite, facilitating memory formation, stimulating the immune system to help fight pathogens and cancer, modifying behavior to help recovery from infection, etc.
These and other reasons are why patients on high dose glucocorticoids may have problems functioning – including developing frequent infections since their immune system was excessively suppressed.
An evaluation and balance is necessary as an endpoint.
yes it’s like the balance between anti-oxidant and free radical. Free radical have some health benefices. Mc Carty in this study “Down-regulation of microglial activation may represent a practical strategy for combating neurodegenerative disorders” shown that healthy people desiring to minimize their risk for neurodegenerative disorders could reasonably include the following in their daily supplement regimens : vitamin D, soy soflavones, creatine, selenium, coenzyme Q10, acetylcarnitine, lipoic acid, and taurine. Ingesting several strong cups of coffee daily (or taking a caffeine supplement) can also be recommended in this regard, along with regular physical and mental exercise, and moderation in calorie intake.
http://addiandcassi.com/wordpress/wp-content/uploads/sdarticle.pdf
Maybe this study is incomplete because the authors forgot the integration of hormone deficiencies, probably that dysregulation of HPA or SAM axis, or thyroid, sex hormone, neurosteroid have bad consequence on brain microglia.
And I’m little septic about taking all the time anti-oxidants because this theory is disappointed. I believe more in the theory of HORMESIS. Taking some physical, nutritional, psychological or probably pharmaceutical hormetins is the key for better brain function.
Many numerous of clinical trials and metabolic studies show no benefit, or even harm, from using antioxidant supplements:[/U]
Probably the Nrf2 stimulation with polyphenols It turns on a series of cytoprotective genes, which have been nicknamed “vitagenes” by U. Massachusetts toxicologist and hormesis researcher Edward Calabrese. These vitagenes upregulate the production of endogenous antioxidant enzymes that combat oxidative stress and inflammation.
Best regards.
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