1. How does energy depletion link neurodegenerative, concussions, and diet?
2. Why are diabetics more at risk for concussion and neurodegenerative diseases?
3. What is the NMDA receptor and why should I care?
4. How does the NMDA receptor work normally and in diseases like concussion to protect us?
5. How does glutamate, aspartate, and glycine tie into this story?

This series of blogs is going to focus in on neuronal injuries and how they all have a common tie to defective energy metabolism. The initial blog will be heavy on biochemistry but it will set the tone for you gaining a deeper appreciation of how damage to a receptor in our brains may cause different diseases, but have very common symptoms. I have focused in on energy depletion in some neurodegenerative diseases already, but we need to expand the net to explain how cerebral concussions and dietary choices are linked and can cause a less than optimal result for the person suffering from it. In this series I will also write a blog about chronic traumatic encephalopathy (CTE) since football season is now in session and this injury tends to make news in the fall sports sections. How this ties to diet may be new news for some of you.

In my recent Alzheimer’s blog, we spoke of how neurons in AD become deficient in energy as they slowly die off. This is an example of chronic energy depletion enhancing a pathological cellular process. An example of acute energy depletion is that of a concussed athlete. Once the head is impacted, it causes a dramatic alteration in the neurochemistry of the brain and leaves the person with a constellation of symptoms based upon the severity and duration of the impact. We have all seen pictures or heard stories of how concussions have caused athletes to miss games and have their career’s threatened. The concept of energy deficiency is vitally important to remember when we talk about neuronal injury types. The injury can be from metabolic damage, trauma, or from dietary toxins. We also showed how devastating magnesium depletion is in the development of insulin resistance and diabetes in this blog. Nutrient depletions can play major co morbid roles when energy is also lacking in neurons. These factors alone are bad enough for neurons, but when they are combined, the summated results are even more problematic for the person to withstand.

I have a few patients in my practice whose professional careers were ended because their healthcare providers and employers did not understand these dynamics and how to optimally treat them. The loss of energy in a neuron is the initial critical event that can cause major pathologic problems to develop longer term. This is especially true if the correct information is not given to the person at this time. It is particularly bad if the person is already functioning sub-optimally and has compromised energy generation from leptin resistance, multiple traumas, or other diseases processes that limit us in some way. Even if one is in the best physical and mental shape of their life, it might have devastating consequences if other critical factors are present simultaneously as well.

In 1989, we learned that neurons deficient in energy became much more sensitive to the effects of excitatory neurotransmitters like glutamate and aspartate. I distinctly remember giving several talks about this finding during my residency in neurosurgery. These studies showed that if we took cerebellar neurons in a glass jar and the surrounding terroir was designed to contain high levels of glucose (sugar) and magnesium, that even high levels of excitatory neurotransmitters could not cause neuron cell death. In impact studies we have also found that diabetics cannot withstand head impacts as well as those who were non diabetic. That stands to reason because the cells cannot use glucose normally and diabetics all tend to be magnesium deficient. The most interesting effect occurred when glucose was removed from the neurons surroundings and it was made energy depleted. Then even a small amounts of the excitatory glutamate or aspartate could kill the neurons. Many foods are loaded with these chemicals. The brain is usually protected from the dietary assault by its blood brain barrier, but this is not the case in trauma or in many neurologic conditions. This allows the brain to be further assaulted in these cases. For example, in traumatic injury, right after the impact their is a huge surge of these excitatory chemicals liberated from our damaged brain cells. This clinical situation is important given what we learned from the 1989 experiments cited here. When the researchers then decided to also remove the magnesium from the experimental surroundings of the nerve cells as well, even smaller doses of the glutamate were able to induce neuronal death. The depletion of magnesium and glucose are clearly critical to energy generation in neurons. Energy depletion sensitized the neurons to death or injury depending upon the level of insult. Even today in brain trauma or stroke care, physicians are taught not to start IVs containing glucose so as to protect brain cells from damage and to supplement with magnesium to protect the brain from further injury.

In the human brain glutamate is used as a neurotransmitter in over 50% of the synapses in the neocortex of the frontal and temporal lobes. These are the areas of the brain where many neurodegenerative disorders are also found. This is also happens to be the place where the brain is injured in most cerebral concussions as well. I believe this is not a coincidence either. Glutamate’s main action is to excite the brain and prepare it for action. When this part of the brain is damaged it causes memory loss, learning disability, inability to act and plan, and a loss of cognition. These symptoms are all commonly seen in neurodegenerative disorders, trauma, and metabolic conditions that patients can suffer. These symptoms tend to occur together when excessive glutamate or aspartate is allowed to remain around nerve cells no matter the cause.
The action of glutamate occurs at several receptors. We will focus on the most common receptor in this blog. The most common is the N-methyl-D-aspartate receptor. We refer to it as the NMDA receptor for short. Glutamate, aspartate and glycine (dietary amino acids) can all stimulate this receptor. The NMDA receptor is a non-specific cation channel which can allow Ca2+, Na+, and K+ to pass into the nerve cell under normal conditions to facilitate neurochemical messages between cells. The net influx creates and excitatory post synaptic potential (EPSP) to occur between neurons. This is how nerve cells communicate in learning and memory and to initiate behavior. Mg2+ not only blocks the NMDA channel in a voltage-dependent manner but also potentiates NMDA-induced responses at positive membrane potentials. This means that Magnesium glycinate and magnesium taurinate treatment can be used to produce rapid recovery from depression and in post concussive patients. We know it is very effective in diabetics because of their inherent metabolic depletion. The reason Mg works, is that it blocks the NMDA receptor from firing constantly to cause neurons damage because of the low magnesium levels in those nerve cells. These findings are also seen in concussed depressed patients, those with diabetes, and those with AD or PD too. Na+, K+ and Ca2+ not only pass through the NMDA receptor channel in normal conditions but also modulate the activity of NMDA receptors. Zn2+ (zinc) and Cu2+ (copper) generally block NMDA current activity in a noncompetitive and a voltage-independent manner. However, zinc may potentiate or inhibit the current depending on the surrounding neural activity. The levels of Zn and Cu in the body are directly tied to diet, stress response, and to the integrity of the gut’s brush border. The NMDA receptor therefore functions in the human brain as a “molecular coincidence detector”. Its ion channel only opens when the following two conditions are met simultaneously: glutamate is bound to the receptor, and the postsynaptic cell is depolarized (which removes the Mg2+ blocking the channel). This specific property of the NMDA receptor explains many aspects of long term potentiation (LTP) and synaptic plasticity and it confers to humans the ability to learn and adapt.
NMDA receptor function is also strongly regulated by chemical reduction and oxidation status, via the so-called “redox modulatory site.” Through this site, reductants dramatically enhance NMDA channel activity, whereas oxidants either reverse the effects of reductants or depress native responses. It is generally believed that NMDA receptors are modulated by endogenous redox agents such as glutathione, alpha lipoid acid, and the essential nutrient pyrroloquinoline quinone (PQQ) which is a B vitamin. Glutathione is the bodies major antioxidant and it acts to protect neurons under assault. Alpha lipoid acid and PQQ have major beneficial effects on mitochondrial function in nerve cells and improve energy utilization. I often consider prescribing these to patients who are concussed or suffer from neurodegenerative diseases for this reason. (see my peripheral neuropathy post under the AGE tab)

In the next blog we will see how excitatory amino acids in foods and introduced to our GI tract could cause us some problems with normal functioning, cause plateaus, and interfere directly with weight loss. We will discuss how MSG and Splenda could wreck havoc with the human brain. This is especially true if that brain already has been concussed many times or is afflicted with some neurodegenerative disorder.


1. Henneberry, RD et al., “Neurotoxicity at the NMDA receptor in energy compromised neurons: A Hypothesis for cell death in aging and in disease.” Ann. NY Acad. Sci. 568(1989) 225-33


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  1. Lo September 12, 2011 at 4:50 pm - Reply

    Fascinating stuff, Dr. K. After reading this, I am wondering what the effect of Meningitis would be (short and long term)?? I contracted viral meningitis about 8 years ago and was hospitalized for a week. I seemed to fully recover, but I wonder if there are lasting effects that I should supplement around?

    Thank you.

    • Jack September 12, 2011 at 5:29 pm - Reply

      @Lo. Meningitis can disrupt the blood brain barrier so it can have a major impact if you had other factors crashing down on your brain at the same time. MSG and aspartame being two biggies. I doubt you had any head impact trauma when you were hospitalized! The opening of your BBB could have opened you up to several problems from the gut or from the bad food given at most hospitals. (most of which are processed)

  2. Kaleein September 12, 2011 at 5:29 pm - Reply

    "[b]The depletion of magnesium and glucose are clearly critical to energy generation in neurons.[/quote] Energy depletion sensitized the neurons to death or injury depending upon the level of insult. Even today in brain trauma or stroke care, physicians are taught not to start IV's containing glucose so as to protect brain cells from damage and to supplement with magnesium to protect the brain from further injury. " So, you deplete the magnesium AND glucose to generate energy in neurons? Seems contrary to the rest of the paragraph where you say the supplement with magnesium to protect the brain. I'm wondering if that is correct wording … It is confusing and this is just the beginning. Maybe I need to take more magnesium?

    • Jack September 12, 2011 at 6:01 pm - Reply

      @Kaleein The point is simple. When neurons are depleted of fuels or magnesium (which is a cofactor in energy producing ATPase in the cell) it makes them more sensitive to trauma, MSG, Splenda, Aspartame, and "hydrolyzed vegetable protein". This is especially important if you have a co morbid disease like Diabetes because this disease deplete your magnesium and glucose inside the cell. This is in part why those with diabetes have higher rates of cognitive decline. If an athlete is a diabetic and not in good control and is subject to cerebral impacts it could have bad actions long terms. I often remark to my son how most concussions in the NFL seem to have really devastating affects on the players with high BMI's than those who did not.

  3. Ryan September 12, 2011 at 7:07 pm - Reply

    "These studies showed that if we took cerebellar neurons in a glass jar and the surrounding terroir was designed to contain high levels of glucose (sugar) and magnesium, that even high levels of excitatory neurotransmitters could not cause neuron cell death."

    Where to begin with this statement? Clearly this would be due to the Mg2+ blocking the channel pore not due to increased glucose. Glucose can be neuroprotective (I do not questionthis this fact) but saturating NMDA/glutamate will result in neuronal necrosis unless the NMDA receptor is blocked in any in vitro model of excitotoxicity.

    Secondly, as you are probably well aware, (but clearly didn't discuss it), another major factor in neurodegeneration resulting from traumatic brain injury is a lack of oxygen. Of course, this is the major factor in the rundown of ATP in glial and neurons (not a lack of glucose) which results in glutamate transporters reversing and causing the toxic extraynaptic NMDA currents to elleviate.

    I stress this because no diet is likely to result in a clinically relevant increase in oxyegen to the brain during traumatic brain injury. You are clearly skewing the facts.

    • Jack September 12, 2011 at 9:27 pm - Reply

      Ryan read the cite and how the experiment was done. The researchers altered the neuronal terroir first by decreasing glucose and controlling Mg concentrations and then by eliminating both and looking at the results. The statement is crystal clear from that optic. I suggest you read the cite before you make any further claims of what you thought I said. Moreover, there is also a paucity of data of oxygen tension decreases in neurodegenerative disorders (AD, PD or HD). I have no idea where you got that. It certainly was not from me. In concussions, oxygen is also not a major player. In excitotoxic damage from glutamate or aspartate there is no role of lowered oxygen tension. In hemorrhagic stroke oxygen loss is secondary to arterial rupture and not a primary player. This blog never mentioned ischemic CVA in any way so again I think you inferred something that was not written. And the blog really was not about CVA's at all. Again, I think this is something you inferred.

  4. Mike September 12, 2011 at 8:40 pm - Reply

    Dr. Kruse,

    Will you be addressing supplemental ZMA (Zn monomethionine/Mg aspartate/B6) in this series?

    • Jack September 12, 2011 at 9:30 pm - Reply

      @Mike I am assuming you are speaking of Victor Conte's ZMA. No I wont be talking about this in this series. I know that supplement is very popular in football circles but this series is more about the pathology behind excitotoxic damage.

  5. Humbe September 13, 2011 at 3:15 pm - Reply

    Dr. Kruse, one of the therapies gaining traction in the area of neurodegenerative diseases is that of MCT oil or other ketogenic type therapies precisely to be able to assure an energy supply to the brain. What is your point of view on their efficacy and will you be discussing this approach in your blog?

  6. Perry September 13, 2011 at 4:01 pm - Reply

    Jack, can one feel excitotoxic damage in the muscles as its happening?

  7. Bob September 13, 2011 at 4:07 pm - Reply

    As a forensic pathologist/medical examiner, I see lots of cases of traumatic brain injury from car crashes, falls, etc. One of the things I have noticed is that people with identical brain injuries (diffuse axonal injury) have varied outcomes from near instant death to long term survival in a comatose state. I have always wonder if the victim's dietary status had a big contribution to the outcome. Of course it could be that it is difficult to quantitate the amount of axonal sheering in these cases, so that might be the big difference. This blog is very interesting to me.

  8. Jack September 13, 2011 at 7:16 pm - Reply

    @perry you can. I found this out in residency. I cut my finger butchering some meat and one of my fellow residents put some Accent (MSG) on my cut and my finger began to twitch uncontrollably. Was very odd feeling. I washed off the msg with a coke and it stopped very quickly I have never tried that again. I am not sure if this happens when the msg is ingested in high quantities. I know in lab animals if you give them high doses of msg they vomit it because the brain senses it as toxic.

  9. Jack September 13, 2011 at 7:18 pm - Reply

    @Bob. I agree. The living brain also looks quite a bit different when it is owned by someone who eats badly. I think your observation is spot on.

  10. Kaleein September 13, 2011 at 10:09 pm - Reply

    Thank you for always clarifying when asked. I think I'll be upping my malic acid again. 🙂

  11. Heather H September 14, 2011 at 10:53 am - Reply

    Good stuff! My husband has Huntington's Disease. All the Dr.s say is to eat a lot of antioxidants and take CQ10. Any other supplements we should be looking into? He's also 6'4" and only 145lbs. He has severe hyper-metabolism. Thanks!

  12. Jack September 14, 2011 at 11:41 am - Reply

    @heather…….get him on coconut oil and read all the links I posted about in comment ten above.

  13. Might-o'chondri September 14, 2011 at 1:23 pm - Reply

    Is it possible we may seelow carbohydrate diets increase the risk of cognitive dysfunction in those over 70?

    Since use of insulin administered via the nose seems to prevent cognitive dysfunction the implication is that an insulin spike is beneficial to the brain.

    Could it be that brain insulin contributes to the notable scholastic ability of east Asian students ? Maybe(?) a cognition boost from their white rice induced insulin spikes generated in the context of a low fat meal (when there is no gross malnourishment).

    Then in contrast, might the pastoralists of Mongolia and Africa be less renown for their scholastic agility due to less insulin spikes from their dietary fat?

  14. Shijin13 September 14, 2011 at 2:51 pm - Reply

    Looking forward to the next in this series – as someone who gets migraines- they get exacerbated by MSG and artificial sweeteners, such as splenda and aspartame.

    As I read this it got me thinking about Soldiers returning w/TBI – I wonder if the VA and military docs could really these guys/gals in their recovery by moving them to a paleo way of eating that's high in MCT? Would that help them Dr K?

  15. Jack September 14, 2011 at 4:48 pm - Reply

    @shijin. I actually hit on returning injured GI's and little humans too. And the ones who are still in school……every parent needs to heed this warning. You can save your kids brains and increase their grades with a couple of new rule changes…….and my professional athlete friends better pay close attn.

  16. Susan September 14, 2011 at 9:13 pm - Reply

    Dr. Kruse,

    When I was a small child I was hit by a car which I am sure resulted in head trauma. I also sustained head trauma in two car accidents hitting the area between my eyes. Over the years I have lost my sense of smell, taste only primary tastes, have no sense of direction and when in a noisy environment my sense of touch is also delayed. I also have a difficult time retaining what I read. However, when I am dreaming, I can, occasionally, taste and smell things such as fried chicken and skunks. To your knowledge, are there any supplements that I can take so that my senses are more active while I am awake?

    • Jack September 14, 2011 at 10:00 pm - Reply

      @Susan. My answer for this is usually a zinc or copper problem. Zinc deficient patients are diabetics and HIV patients. Your question however brings in organic brain syndrome. With cranial nerve abnormalities from trauma I am not sure if zinc alone will help. Copper deficiency is extremely rare even on a SAD. So I doubt it's that but you could be tested for it. You could try the zinc and do an N-1 and keep me informed. I have had success with Zn and diabetes,HIV, herpes infection and changes in taste or smell.

  17. Might-o'chondri September 15, 2011 at 3:03 pm - Reply

    Some taking high zinc get a reduction in HDL – in case anyone tracking their HDL concerned.

  18. Susan September 15, 2011 at 5:33 pm - Reply

    DR. Kruse,

    Thank you so much for your response. I am not diabetic nor a HIV patient, and I am of normal weight. I will try zinc supplementation for a while and keep you updated. Again, thank you!

  19. Susan September 15, 2011 at 5:36 pm - Reply


    Thank you for the warning on the HDL. I have good HDL numbers, so I will keep an eye on it also as I do the zinc experiment.

  20. Dexter September 15, 2011 at 7:27 pm - Reply

    Today, ESPN, Inside the Lines, had a piece on Chronic Traumatic Encephalopathy with Dr Robert Cantu. He is advocating limiting hits to the head in youth sports…football, hockey, heading in soccer, and in Lacross….up to age 14-15. Dr Cantu said he sees kids 18 to 20 years old with CTE with lots of neurodegeneration at that age. He talked a lot about the weight/size of the head of youths being large for the size of the body and it is difficult to support the head in head collisions in sports.

    Evidently the push back comes from parents that what their kids doing the manly thing and hitting hard. The leagues seem to be in line with limiting the head knocking.

  21. Might-o'chonri- September 19, 2011 at 6:44 pm - Reply

    Neuro-degeneration (like ischemia, hypoxia/low oxygen and inflammation) involves mitochondrial membrane problems; when a mitochondrial membrane depolarizes and it's membrane potential drops there is the risk of that cell's death. In these types of situations the affected mitochondria can cope by shifting away from continuing to synthesize ATP for general cell metabolic use and instead starts to hydrolize it's ATP to use in order to sustain that mitochondria's membrane potential.

    To do this a cell's nucleus must "order up" enough Inhibitory Factor 1 (IF1), which then binds to a mitochondrial membrane in a process that then leads to inhibition of ATP synthesis. The result is to reduce the proton flux running through the complete process of ATP production and thereby re-orientate to sustain the mitochondrial membrane potential (as explained above). Likewise, in the case of heart ischemia this is what stabilizes the surviving cardio-myocytes' mitochondria.

    Brain neuron cells have more mitochondria than brain astrocytes; and astrocytes, due to their "quirks", don't readily depolarize their mitochondrial membranes. When there is a crisis neurons need to more quickly weather any fading mitochondrial membrane potential by shifting out of ATP synthesis.

    Dr. Kruse's seemingly counter intuitive admonition against immediate IV glucose drip for brain injury is correct; because untimely supply of glucose would push impinged neurons to process (synthesize) ATP in "normal" oxidative phosphorylation (speed up proton flux) and this would only worsen afflicted neuron's mitochondrial membrane potential. This is also part of how fasting the patient has been used for improved results in certain cases of brain injury; it (fasting and thus limited glucose) protects the neuron's mitochondrial membrane allowing recovery from mild trauma.

  22. Joan October 18, 2011 at 3:15 pm - Reply

    Thanks for your reply re the 50g protien at breakfast. I don't always manage it, but I'm getting there. I would like to ask you if you think PQQ would be of help with an essential tremor. I have had this since early childhood in my hands and only lately learned it was hereditary and degnerative. I have never taken medication for it. There are times it seems to be getting worse & sometimes I'll have it in my jaw when really tired. I'm wondering if PQQ would slow it's progression.

  23. brenner November 28, 2011 at 1:52 pm - Reply

    i was wondering if there is a part of your blog that u could dedicate for teaching biochemistry basics?

    • Jack November 28, 2011 at 6:38 pm - Reply

      @brenner Im not planning on it. I would suggest you buy a good biochemistry book. If there is a medical school in your town look for a student who is selling a copy of theirs. That happens often after their biochemistry test is over.

  24. monica Cretella April 26, 2012 at 9:40 pm - Reply

    My Dad also has essential degenerating essential tremors . Maybe the new magnesium from Life Extension would help.

    • Jack April 27, 2012 at 5:54 am - Reply

      @Monica Magnesium threonate would help

  25. […] the first two blogs (1) (2) in this series we looked at the fundamental neurobiology of how excitatory neurotransmitters […]

  26. […] the first two blogs (1) (2) in this series we looked at the fundamental neurobiology of how excitatory neurotransmitters […]

  27. evan April 27, 2015 at 10:53 pm - Reply

    I don’t think I saw the answer to this on here. what are the differences of a diabetic having a concussion and someone that doesn’t have diabetes? I would love to know the answer to this because I am a diabetic myself

    • Jack Kruse April 29, 2015 at 4:56 pm - Reply

      Evan T2D have higher risks because their redox potential is way lower by design. That being said if they are using cold and ketosis to protect the misfolding of proteins in cells they can mitigate the risks somewhat. The key is avoiding head trauma

  28. Julia May 16, 2015 at 11:47 am - Reply

    What would you recommend as supplements for a 35 yr old female that had a concussion 7 years ago, is currently suffering from adrenal fatigue (2years of repair with paleo and rest in, just 25% left to go in recovery), week 8 of your leptin reset (interrupted by 1.5 weeks in Europe) and just received another mild head injury?

    • Jack Kruse May 16, 2015 at 12:19 pm - Reply

      @Julia lots of DHA, spring water and sun light 8-11 AM in spring and summer (15 min) and another 15 min 5-7 PM in Northern hemisphere

    • Jack Kruse May 16, 2015 at 5:02 pm - Reply

      @Julia Read CPC 9 blog. What does it say right there about supplements?

      • Julia May 31, 2015 at 7:48 pm - Reply

        It says that fixing your environment, both externally and then internally with food (+circadian rhythms/sunlight) has a more powerful effect than supplements, which can be detrimental if you are producing things properly on your own. The sunlight tip was most powerful for me, and I woke up on Saturday feeling like a million bucks. I feel like I could dump most of my supplements and move on to just maintain an Epi-paleo diet + primal lifestyle right now. THANK YOU. I welcome anymore thoughts you may have and appreciate the personal response.

  29. Jack Kruse September 14, 2017 at 8:12 am - Reply

    Addiction to blue light devices in your hand 24/7, CTE, parents afraid to let kids play football, sky high prices, and bad coaching, and players that diss the country at the beginning of every game? Gee I wonder why America is turning away in droves?

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