- Glutamate neuroexcitotoxicity appears to be a significant factor in autism, as well as in other neurological diseases and mood disorders.
- Glutamate neuroexcitotoxicity leads to excessive oxidative stress in the brain, causing hyperactivity, seizures and neuronal damage, particularly in the hippocampus—the seat of learning and memory.
- Monosodium glutamate (MSG), which is a common ingredient in processed foods, can cause seizures in mice if it is injected into their bodies.
- Glyphosate works synergistically with glutamate to cause harm.
- In different types of studies with rats, glyphosate has been shown to cause neuroexcitotoxicity in the hippocampus. This is associated with excess extracellular glutamate and overstimulation of glutamate receptors, called NMDA receptors.
- A certified organic whole foods diet is a simple step you can take that will provide protection from glutamate excitotoxicity, while also reducing your family’s exposure to glyphosate.
Katherine Reid, PhD, is a biochemist and the mother of five children, one of whom is a girl who had been diagnosed with autism at age three.1 Dr. Reid saw improvements in her daughter’s autistic symptoms when she put her on an organic diet and eliminated gluten (for example, wheat) and casein-containing foods such as milk.
Although a gluten-free, casein-free diet for people with autism is the subject of heated debate, many parents of children with autism find that when they eliminate gluten and casein from their children’s diets, digestive symptoms improve. Dr. Reid reasoned that products made with gluten and casein are often high in glutamate. She was aware that monosodium glutamate (MSG) is a common additive in processed foods, primarily because it acts as a taste enhancer, and she also knew that glutamate is a neurotoxin.
FREE (UNBOUND) GLUTAMATE
Once she began researching MSG, Reid discovered that there was a large body of literature connecting various illnesses to glutamate dysfunction. Glutamate is essential in that it is one of the twenty or so coding amino acids that are the building blocks of proteins; it is also an alternative fuel for the mitochondria to replace glucose. In addition, glutamate is an excitatory (as opposed to inhibitory) neurotransmitter, stimulating neurons to fire.
Although many foods naturally contain glutamate, it is usually tied up in a long chain of amino acids making up a peptide, which in turn is a segment of an even longer amino acid sequence in a complete protein. That means it gets digested slowly, because the protein has to be disassembled into individual amino acids before it can be absorbed. MSG, on the other hand, is a single free (unbound) glutamate molecule. Figure 1 (next page) shows a free glutamate molecule and a glutamate that is the last residue in a tripeptide (leucine-alanine-glutamate). Ordinarily, the glutamate in the tripeptide would be hooked up to a following amino acid as well (via the COO- in the lower right corner of the figure).
It may be surprising to learn that an amino acid that has so many important roles in the body could be toxic. To understand how glutamate becomes neurotoxic, you need to understand how glutamate is managed in the brain. As an excitatory neurotransmitter, glutamate is a powerful stimulator of nerve cell activity, so it needs to be carefully managed. Normally, glutamate is sequestered inside vesicles in an inactive mode in the nerve cells. It is released into the synapse in order to transmit a signal to a neighboring cell. Following its release, it is quickly cleared by surrounding astrocytes (protective brain cells), which take it up and immediately convert it to glutamine, a benign molecule without any neuroexcitatory effects. The glutamine is then shipped back to the neurons through a pathway not involving the synapse, and the neurons take it up and convert it back to glutamate while inserting it into the sequestered environment of the vesicles.
In unbound form, free glutamate’s rapid uptake past the gut barrier can cause too much glutamate in the blood, and, subsequently, in the brain. This can overstimulate glutamate receptors in the brain and cause excess neuronal firing. In turn, this induces oxidative stress through reactive oxygen species (ROS), which can result in neuronal damage.2 The technical term for a condition of excessive neuronal firing in response to an excitatory stimulus is neuroexcitotoxicity. A neurosurgeon named Russell Blaylock wrote an entire book titled Excitotoxins: The Taste that Kills, focusing on glutamate as well as other neurotoxic food additives such as artificial sweeteners.3
Acting as a neurotransmitter, glutamate has been implicated as an excitatory neurotoxin in the brain not only in autism but also in association with multiple neurological diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis.4
GENERALLY REGARDED AS SAFE?
The U.S. Food and Drug Administration (FDA) has approved MSG as a food additive, designating it as “generally regarded as safe” (GRAS).5 But there are many people who complain of a syndrome aptly named “Chinese Restaurant Syndrome” due to the fact that they often experience symptoms after dining out at Chinese restaurants. (MSG is commonly used to enhance flavors in Chinese dishes.) The condition, though considered a “food intolerance” rather than a food allergy, produces complex and varied symptoms that include muscle pain, heart palpitations, generalized weakness, headaches, nausea, flushing, tingling, chest pain and drowsiness. Individuals also report a connection to migraine headaches.6 People with migraine headaches have been found to have elevated levels of glutamate in their blood.7
Most parents don’t know that free glutamate is a hidden ingredient in many processed foods. It is almost impossible to eliminate free glutamate from your diet completely because glutamate hides behind many disguises on food product labels. These include “hydrolyzed protein,” “hydrolyzed vegetable protein,” “autolyzed plant protein,” “protein isolate,” “soy extracts” and “yeast extract.” After Dr. Reid became conscious of glutamate in foods, she became a very astute shopper at the grocery store. And remarkably, after she switched the family to a diet consisting entirely of whole foods and real foods—eliminating all processed foods—her daughter made a full recovery and lost the autism diagnosis. Reid is now working tirelessly to get the message out to the general public. She has presented her story in a moving TEDx Talk titled, “Unblind My Mind: What are we eating?”8
GLUTAMATE AND GLYPHOSATE
In addition to the presence of free glutamate in processed foods, there is another factor, pervasive in our environment today, that may be causing free glutamate to have an even larger impact on our health. This factor is glyphosate, the active ingredient in the ubiquitous herbicide Roundup. Glyphosate is a contaminant in many common foods, both because it is used to kill weeds—predominantly on GMO Roundup- Ready crops such as soy, corn, sugar beets, canola and alfalfa—and because it is used as a desiccant or ripener just before harvest on many other food crops, including wheat, barley, oats, legumes and sugar cane. While U.S. regulators assure us that glyphosate is practically nontoxic to humans, much recent research is proving that statement false.
Some of this research is highly suggestive that glyphosate—in conjunction with a diet high in free glutamate—could be working synergistically to cause glutamate excitotoxicity in the brain, leading to autism. It is important to understand that free glutamate is, by a wide margin, the most abundant excitatory neurotransmitter in the vertebrate nervous system, accounting for well over 90 percent of the synaptic connections in the brain. The hippocampus is especially rich in glutamate receptors, which are essential for the important role of the hippocampus in learning and memory.9 In fact, the hippocampus depends on glutamate signaling to a greater extent than other parts of the brain. Too much glutamate, however, is dangerous.
A seminal paper on glyphosate and neurotoxicity published in 2014, the title of which speaks for itself, illustrates the risks: “Mechanisms underlying the neurotoxicity induced by glyphosate-based herbicide in immature rat hippocampus: involvement of glutamate excitotoxicity.”10 Simply stated, the study found that glyphosate causes glutamate to become neurotoxic in the hippocampus in young rats.
The study focused on the hippocampus of fifteen-day-old rat pups. In one branch of the study, the investigators fed the mother a low dose of Roundup (40 percent of the No Observed Adverse Effect Level [NOAEL]) every day from day five of gestation until the pups were fifteen days old, thereby exposing the pups to glyphosate in utero and indirectly during lactation. The pups were killed at day fifteen, and hippocampal slices were prepared for examination and analysis. In a second branch of the study, the researchers prepared hippocampal slices from unexposed fifteen-day-old pups and then exposed the samples to glyphosate acutely for thirty minutes at varying concentrations.10
Both branches of the experiment revealed that Roundup increased calcium uptake in the cells by activating NMDA (N-methyl D-aspartate) receptors (a type of glutamate receptor) as well as calcium channels. The researchers observed two actions of Roundup: it increased the amount of glutamate released into the synapse by neurons, and it interfered with the ability of astrocytes to clear glutamate from the synapse. (Recall that astrocytes normally clear glutamate and convert it to glutamine, which does not have neuroexcitatory effects.) Excess glutamate in the synapse led to neuronal burnout in the rat pups, with oxidative stress damaging delicate components of the cells.
In a follow-on study by the same research group, rats exposed to a glyphosate-based herbicide prenatally experienced persistent glutamate excitotoxicity even up until they reached adulthood. At the age of two months, the rats showed behaviors characteristic of depression.11 Interestingly, drugs that suppress the NMDA receptors have been found to have value in treating depression.12
Glutamate and glycine work together to excite the NMDA receptors in the hippocampus. The study with rat pups showed that glyphosate not only causes glutamate to build up in the synapse, but it also acts as a glycine analogue (substitute), binding to the glycine site in the NMDA receptors.10 Ordinarily, magnesium binding to the NMDA receptors suppresses activity, but magnesium is one of the minerals that is chelated by glyphosate, making it unavailable.13 When both the glycine site and the glutamate site are occupied and magnesium is scarce, this is the ideal set-up for activating NMDA receptors and causing neuroexcitotoxicity.
GLUTAMATE OVERLOAD, AUTISM AND EPILEPSY
Epilepsy is a seizure disorder and the fourth most common neurological disorder worldwide. Individuals with autism have a much higher rate of epilepsy than the general population. A long-term study that tracked one hundred fifty individuals diagnosed with autism found that epilepsy developed in 22 percent.14
Studies have shown that activation of the NMDA receptors “kindles” limbic seizures in mice and rats. An experiment on mice that were injected with a solution containing MSG showed that after just two injections, they exhibited behaviors indicative of excessive brain stimulation, such as head nodding, tail stiffness, screeching and “generalized tonic-clonic convulsions” (seizures).15 Another study—which used a measurement technique called microdialysis to obtain samples of fluid in the extracellular environment of neurons in the brain of rats—demonstrated that the extracellular concentration of glutamate increases when a seizure begins.16
GABA (gamma aminobutyric acid) is a naturally occurring amino acid that acts as an inhibitory neurotransmitter, turning down the gain on excitatory stimuli. In a study published in 2010, researchers reported a statistically significant difference between the ratio of glutamate to GABA in the frontal lobes of children with autism compared to controls—the autistic children had more glutamate and less GABA.17 An earlier study (published in 2006) had shown that twenty children with autism had, on average, higher concentrations of glutamate in the right hippocampus compared to thirteen healthy controls.18
Another relevant study, from 2011, looked at the levels of free amino acids in the serum of autistic children compared to children without autism. Remarkably, out of twenty-five amino acids investigated, only glutamate and glutamine stood out as being statistically significantly different between the autistic and non-autistic children. Specifically, glutamate levels were elevated in the autistic children (p < 0.002), and glutamine levels were low (p < 0.004).19
Even before publication of some of these studies, Fatemi in 2008 recognized the important role glutamate plays in neuronal excitation and proposed a “hyperglutamate theory of autism.”20 It has recently been proposed that pharmaceuticals that are antagonists for glutamate receptors (suppress glutamate uptake) might be repurposed to treat autism.21
The gut microbiome likely also plays a role in glutamate overload. A study on the fecal microbiota of autistic children compared to controls revealed that the autistic kids had an overrepresentation of microbes such as certain Clostridia species, which can break down proteins into individual amino acids.22 In addition, the autistic kids showed an overrepresentation of species that are poor at degrading the amino acids, such as Roseburia and Dorea, whereas the normal controls had a much higher representation of species such as Clostridium bartlettii, which are very capable of clearing amino acids. When many proteins are disassembled into amino acids that do not get metabolized by the gut microbes, the consequence is higher levels of free amino acids in the autistic gut. Most problematic is glutamate because of its potential for neurotoxicity.
A ROLE FOR MANGANESE
The cycle that manages glutamate in the brain is clearly derailed if the astrocytes lose their ability to convert glutamate to glutamine. Ordinarily, this is accomplished by the enzyme glutamine synthetase, an enzyme that depends on manganese as a cofactor. However, manganese gets strongly chelated by glyphosate, making it unavailable.
A study on cows looked specifically at the levels of various trace minerals in the blood of cows fed a diet based on GMO Roundup-Ready foods. The researchers found that manganese and cobalt were well below the minimum of the expected range for these minerals in all the cows on eight different farms.23
Together with Anthony Samsel, I published a paper in 2015 which focused on the potential consequences of glyphosate’s disruption of manganese homeostasis in the blood.24 In that paper, we identified several enzymes that would be affected by low manganese levels, identifying glutamine synthetase as one of the most important ones. We also proposed that this could be one of the ways in which glyphosate is causal in autism.
HOW TO STAY HEALTHY
The single most important thing you can do to help protect from glutamate excitotoxicity is to switch to a certified organic whole foods diet—with special attention to purchasing and using organic sugar and wheat products. This will have the two-in-one benefit of reducing your exposure to both free glutamate and glyphosate. It is also important to eat foods that are rich in magnesium and manganese, because magnesium suppresses the NMDA receptors and manganese is essential for converting glutamate to the harmless amino acid, glutamine. Good food sources of magnesium include green vegetables, nuts, seeds, beans, whole grains, wheat germ and oat bran. Many foods contain manganese in small amounts, but seafood (clams, oysters, mussels) is an especially good source. Manganese is also found in legumes (lentils and chickpeas), as well as soybeans, nuts, rice, coffee, tea and many spices.
The Autism Community in Action (TACA), an autism support group, maintains a useful web page that is devoted to glutamate.25 On that page, they suggest a number of supplements that can help reduce glutamate levels through their complex influence on metabolism. These include, in addition to magnesium and manganese, the mineral selenium, vitamin B12, berberine and other herbs, and N-acetyl cysteine (NAC).
Besides the obvious need to avoid all processed foods, there are a number of natural foods that are high in glutamate; they should be consumed infrequently if you are trying to maintain a low-glutamate diet. These include not only gluten and casein (in milk), but also soy, bone broth (especially if it has been simmering for a long time) and some fermented foods, such as kefir, cheese, preserved meats and soy sauce. Unfortunately, these foods are in general quite wholesome. I would maintain that they are a healthy choice, as long as you are eating a mineral-rich diet and are not chronically exposed to glyphosate.
- Geulah MP. Autism recovery story: Dr. Katherine & Brooke Reid. May 4, 2017. https://www.organicbakerymiami.com/single-post/2017/05/04/Autism-Recovery-Story-2-Dr-Katherine-Reid.
- Reynolds IJ, Hastings TG. Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J Neurosci. 1995; 15(5 Pt 1):3318-3327.
- Russell Blaylock. Excitotoxins: The Taste That Kills. Santa Fe, NM: Health Press; 1994.
- Eisen A, Calne D. Amyotrophic lateral sclerosis, Parkinson’s disease and Alzheimer’s disease: phylogenetic disorders of the human neocortex sharing many characteristics. Can J Neurol Sci. 1992;19(1 Suppl):117-123.
- Questions and answers on monosodium glutamate (MSG). U.S. Food and Drug Administration, November 19, 2012. https://www.fda.gov/food/food-additives-petitions/questions-and-answers-monosodium-glutamate-msg.
- Interview with Jodi Ledley. Wise Traditions, Summer 2018. https://www.westonaprice.org/health-topics/interview-with-jodi-ledley/.
- Surbakti KP, Sjahrir H, Juwita-Sembiring R, Mutiara E. Effect of flunarizine on serum glutamate levels and its correlation with headache intensity in chronic tension-type headache patients. Open Access Maced J Med Sci. 2017;5(6):757-761.
- Reid K. Unblind My Mind: What are we eating? TEDxYouth@GrassValley, November 29, 2013. https://www.youtube.com/watch?v=iL4SD5f2toQ.
- Harrison PJ, Law AJ, Eastwood SL. Glutamate receptors and transporters in the hippocampus in schizophrenia. Ann N Y Acad Sci. 2003;1003:94-101.
- Cattani D, de Liz Oliveira Cavalli VL, Rieg CEH, et al. Mechanisms underlying the neurotoxicity induced by glyphosate-based herbicide in immature rat hippocampus: involvement of glutamate excitotoxicity. Toxicology. 2014;329:34-45.
- Cattani D, Cesconetto PA, Tavares MK, et al. Developmental exposure to glyphosate-based herbicide and depressive-like behavior in adult offspring: implication of glutamate excitotoxicity and oxidative stress. Toxicology. 2017;387:67-80.
- Mathews DC, Henter ID, Zarate CA. Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs. 2012;72(10):1313-1333.
- Beecham JE, Seneff S. The possible link between autism and glyphosate acting as glycine mimetic – a review of evidence from the literature with analysis. J Mol Genet Med. 2015;9:4.
- Bolton PF, Carcani-Rathwell I, Hutton J, et al. Epilepsy in autism: features and correlates. Br J Psychiatry. 2011;198(4):289294.
- López-Pérez SJ, Ureña-Guerrero ME, Morales-Villagrán A. Monosodium glutamate neonatal treatment as a seizure and excitotoxic model. Brain Res. 2010;1317:246-256.
- Meldrum BS. The role of glutamate in epilepsy and other CNS disorders. Neurology. 1994;44(11 Suppl 8):S14-23.
- Harada M, Taki MM, Nose A, et al. Non-invasive evaluation of the GABAergic/glutamatergic system in autistic patients observed by MEGA-editing proton MR spectroscopy using a clinical 3 tesla instrument. J Autism Dev Disord. 2011;41(4):447-454.
- Page LA, Daly E, Schmitz N, et al. In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism. Am J Psychiatry. 2006;163(12):2189-2192.
- Shimmura C, Suda S, Tsuchiya KJ, et al. Alteration of plasma glutamate and glutamine levels in children with high-functioning autism. PLoS One. 2011;6(10):e25340.
- Fatemi SH. The hyperglutamatergic hypothesis of autism. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(3):911.
- Rojas DC. The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. J Neural Transm (Vienna). 2014;121(8):891-905.
- De Angelis M, Piccolo M, Vannini L, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One. 2013;8(10):e76993.
- Krüger M, Schrödl W, Neuhaus J, Ali Shehata A. Field investigations of glyphosate in urine of Danish dairy cows. J Environ Anal Toxicol. 2013;3:5.
- Samsel A, Seneff S. Glyphosate, pathways to modern diseases III: Manganese, neurological diseases, and associated pathologies. Surg Neurol Int. 2015;6:45.
- The Autism Community in Action (TACA). Glutamate. https://tacanow.org/family-resources/glutamate/.