(In a second of four-part series of papers elucidating a neuro-inflammatory model of chronic fatigue syndrome, Marco examines a possibility that could explain many symptoms and issue not just in ME/CFS but in other neurological disorders. Learn more about Marco here – Cort).
Glutamate
Could glutamate excitotoxicity be a key player in chronic fatigue syndrome?
Glutamate plays a beneficial and indeed crucial role as the primary excitatory neurotransmitter powering the transmission of messages between neurons. Without glutamate we’d be unable to respond quickly to events but too much glutamate can lead to a condition called excitotoxicity which can damage or destroy neurons.
“Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate…. This occurs when receptors receptors for the excitatory neurotransmitter such as the NMDA and AMPA receptors are overactivated.”
Wikipedia
Interestingly, given the low blood flow problems in chronic fatigue syndrome, central nervous system ischemia (low blood flows) increases glutamate levels and contributes to cellular death.
High glutamate levels shift the central nervous system towards seizure, and indeed, researchers have known for over 50 years that directly applying glutamate to the central nervous system causes seizures. Dr. Paul Cheney has long proposed that a shift towards seizure brought on by overstimulated, overly sensitive neurons explains the ‘wired but tired’ symptoms and sensory overload often experienced in ME/CFS.
“Our neurons (nerve cells) are sensing stimuli and firing when they should not. This causes amplification of sensory input. Light, noise, motion and pain are all magnified. At the beginning of their illness, many patients report feeling exhausted, yet also strangely “wired.” The “wired” feeling is the slight shift towards seizure that occurs as a result of the excitatory neurotoxicity.” From Carol Sieverlings reports
Cheney proposed that overly activated NMDA (glutamate) receptors cause neurons to fire at the slightest stimulation. He suggested people with ME/CFS use Klonopin, Doxepin elixir and magnesium to reduce receptor activation and indeed Klonopin is widely used in ME/CFS.
Normally glutamate is balanced by the inhibitory neurotransmitter GABA. It is likely that the balance between glutamate and GABA may determine the excitatory/inhibitory balance in the central nervous system and hence the ratio of ‘signal’ to ‘noise’. It seems logical that an excess of glutamate might result in increased noise and a deficit in signal gating leading to various ‘overload phenomena’.
Evidence For Excessive Glutamate in Chronic Fatigue Syndrome
Links with Other Disorders
In addition to an inflammatory milieu, oxidative stress and mitochondrial dysfunction (all of which interact), diabetes is a final condition not discussed as yet (and for which no research has been conducted on sensory gating) but which may hold a clue to glutamate as a key driver involved in ME/CFS and other neuroinflammatory conditions.
You may recall that the CDC (Maloney et al, 2010) suggested an association between metabolic syndrome (a precursor to type II diabetes) and ME/CFS, albeit in a study using the empirical criteria. Recent research has identified excess glutamate as a potential mechanism leading to the onset of type II diabetes via the destruction of pancreatic cells by glutamate (Eliana et al, 2011). Kogelnik, in an interview coming up, has reported increased levels of diabetes in his chronic fatigue syndrome patients.
This suggests excess glutamate could be triggering sensory gating problems, diabetes and mood disorders in some patients. Type II diabetes rates are three times higher in patients with bipolar disorder compared to the general population (Calkin et al 2012). In the same vein it’s intriguing that diabetic mothers have a higher risk of having children on the autism spectrum (Krakowiak et al, 2012). .
Notably excess glutamate has also been implicated in most if not all of the conditions discussed here including ME/CFS – indirectly via allostatic load (Goertzel et al, 2006) and the concept of the ‘selfish brain’ (Peters et al, 2004). Glutamate’s key role in neuronal plasticity suggests it could help remodel the nervous systems in people with ME/CFS.
Murrough (2010) did not find altered levels of glutamate or GABA in an ‘exploratory’ analysis of ME/CFS patients. However increased central nervous system glutamate levels have been well-documented in fibromyalgia patients and a study analysing the effects of a glutamate blocker called memantine on pain and glutamate levels is underway. Australian researchers propose that inactivation of glutamate limiting enzyme called GAD plays a key role in FM, and note that being female, poor sleep, sedentariness, anxiety and depression can all depress GAD functioning. Interestingly, given the alcohol intolerance in ME/CFS, alcohol depresses GAD functioning as well.
Glutamate antagonists
N-acetylcsysteine (NAC) is usually thought of as an antioxidant but it also acts as a glutamate antagonist through facilitating the production of GABA. A number of small clinical trials have shown promising results for NAC administration in another disorder with sensory gating issues, Autism Spectrum Disorder (ASD) (Hardan et al, 2012). NAC is also fairly well established in the treatment of trichotillomania (compulsive hair pulling – a form of obsessive compulsive disorder (OCD).
NAC’s effectiveness in ameliorating a sensory gating deficit may therefore lie in its role as a glutamate antagonist instead of (or indeed as well as) its antioxidant properties and role as a glutathione precursor.
Oral GABA supplementation has also been shown to have potential to prevent metabolic syndrome and type II diabetes in a mouse model (Tian et al, 2011). Even more promising, neuronal damage caused by glutamate in ASD may be reversible by attenuating the over proliferation of glutamate receptors in the brain (Baudouin et al, 2012).
Another glutamate inhibitor, low dose naltrexone (LDN) has shown some efficacy with pain and mood in fibromyalgia.
Glutamate and ‘Neuroinflammation’
In fact, research is increasingly suggesting that oxidative stress, mitochondrial dysfunction and glutamate excitotoxicity are intrinsically linked in a range of neuroinflammatory conditions (Coyle and Puttfarcken, 1993) presenting as various symptom complexes
“Thus, two broad mechanisms–oxidative stress and excessive activation of glutamate receptors–are converging and represent sequential as well as interacting processes that provide a final common pathway for cell vulnerability in the brain.
The broad distribution in brain of the processes regulating oxidative stress and mediating glutamatergic neurotransmission may explain the wide range of disorders in which both have been implicated. Yet differential expression of components of the processes in particular neuronal systems may account for selective neurodegeneration in certain disorders.”
In short, the same pathological process can result in a different constellation of symptoms and therefore result in a range of eventual diagnoses.
Oxidative stress, mitochondrial dysfunction and glutamate excitotoxicity may also interact as a ‘feed-forward’ vicious cycle (Nguyen et al, 2011) :
“Our results conclusively demonstrate that not only glutamate excitotoxicity and/or oxidative stress alters mitochondrial fission/fusion, but that an imbalance in mitochondrial fission/fusion in turn leads to NMDA receptor upregulation and oxidative stress. Therefore, we propose a new vicious cycle involved in neurodegeneration that includes glutamate excitotoxicity, oxidative stress, and mitochondrial dynamics.”
Stablon (tianeptine) is an atypical antidepressant that has demonstrated remarkable clinical effectiveness in major depressive disorder that is often resistant to treatment with traditional SSRI’s. The interesting fact about tianeptine is that its efficacy does not conform to the monoamine hypothesis of depression as tianeptine may actually lower serotonin levels. An investigation into the neurobiological properties of tianeptine (McEwen et al, 2010) concludes :
“Converging lines of evidences demonstrate actions of tianeptine on the glutamatergic system, and therefore offer new insights into how tianeptine may be useful in the treatment of depressive disorders.”
Intriguingly the antidepressant and anxiolytic effects (plus protection against cognitive defects) appear to be due to its ability to protect the brain (particularly in the amygdala and hippocampus) against stress induced glutamate excitotoxicity :
“A modification of glutamatergic mechanisms by tianeptine may therefore be implicated in its ability to oppose the negative influence of chronic stress upon hippocampal neurogenesis, cell proliferation, and dendritic remodeling, processes profoundly disrupted in depressive states”
Similarly ketamine has a rapid and sustained antidepressant effect through modulation of glutamate neurotransmission as does the novel compound GLYX-13 which has the same beneficial effects without inducing dissociative symptoms usually associated with schizophrenia (Burgdorf et al, 2012)
Mental Fatigue
Wrapped up within the vague notion of ‘fatigue’ in ME/CFS is the rather more specific description contained in the Canadian Consensus Criteria of a “Low threshold of physical and mental fatigability (lack of stamina)”. Mental fatigue is a common symptom following brain trauma and encephalitis and is associated with a number of neuroinflammatory and neurodegenerative disorders and can also result from sleep deprivation. Ongoing research at the University of Gothenburg, Sweden has implicated glutamate dysregulation in mental fatigue (Rönnbäck, Hansson, 2004) which they define as :
“a decreased ability to intake and process information over time. Mental exhaustion becomes pronounced when cognitive tasks have to be performed for longer time periods with no breaks (cognitive loading).”
and :
“In addition to the fatigue itself, the patient with mental fatigue often suffers from loudness and light sensitivity, irritability, affect lability, stress intolerance, and headaches”
The researchers’ University of Gothenburg home page also describes over-exertion leading to a state of mental “deadlock” :
“Intense mental activity with high glutamate signalling can lead to astrocytes swelling, especially if their glutamate uptake capacity is impaired. This state, which is locked, may resemble the feeling of cramp in a muscle and the signalling takes a long time to be restored. This may explain the total exhaustion experienced by a person suffering from mental fatigue, when being too active and doing too many things.”
Rönnbäck and Hansson propose an inflammatory state where the efficient transmission of information via glutamate is disrupted with a decrease in the ability to discriminate signal from noise; in effect, the sensory filter ‘disintegrates’ :
Cytokines associated with chronic fatigue syndrome could help produce the sensory overload and fatigue in the disorder
“Based on this literature and observations from our own laboratory and others on the role of astroglial cells in the fine-tuning of glutamate neurotransmission we present the hypothesis that the proinflammatory cytokines tumor necrosis factor-α, IL-1β and IL-6 could be involved in the pathophysiology of mental fatigue through their ability to attenuate the astroglial clearance of extracellular glutamate, their disintegration of the blood brain barrier, and effects on astroglial metabolism and metabolic supply for the neurons, thereby attenuating glutamate transmission.”
TNF-a and IL-6 have, in separate studies, both been identified as potentially key immune factors in ME/CFS
The authors go on to note that, in some cases, mental fatigue persists long after the identified neural trauma has been resolved (perhaps due to a genetic predisposition or due to dendritic remodelling) and emphasise the importance of early treatment to prevent the problem becoming chronic :
“Providing information about mental fatigue, its cause and the prognosis, is of utmost importance for breaking the vicious circle, which comes with the risk for secondary anxiety and depression.
Furthermore, it is important for the patient to imagine and learn how much sensory stimulation they can tolerate prior to feeling too exhausted.
Due to recent results on changes in cell signaling and neuronal plasticity, it may be important to identify the symptoms and treat them as early as possible to avoid formation of new and functionally disturbing neuronal circuits due to overstimulation of neuronal-glial units.
If our hypothesis is correct, it may be possible to further improve the symptoms by suppressing the production of proinflammatory cytokines and, thereby, restoring the normal astroglial glutamate uptake.”
It goes without saying that exacerbation of symptoms in response to physical or mental stressors is as emblematic of ME/CFS as the PEM that follows and that, by definition (with most case definitions requiring new onset ‘fatigue’ of at least 6 months duration), in ME/CFS mental fatigue may have already become a chronic condition. Studies and anecdotal reports from doctors suggest that early treatment leads to better results in this disorder.
A Predisposition to Glutamate Excitotoxicity in Chronic Fatigue Syndrome?
If such a vicious cycle of glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunction does indeed underpin ME/CFS pathology, it may not be clear where exactly the root problem lies.
Oxidative stress/weak or compromised antioxidant capacity; mitochondrial dysfunction or glutamate/GABA imbalances could all be the initiating factor.
Genetics
Again gene studies may shed some light on what could be a predisposing factor for developing ME/CFS and other neuroinflammatory conditions.
Some evidence suggests people with chronic fatigue syndrome may have a genetic risk for developing glutamate toxicity and neuroinflammationi
A recent CDC study (Smith et al 2011) carried out a genome-wide mapping of gene SNPs and gene expression in 40 CFS patients and 40 controls. Following statistical analysis to reduce the risk of ‘false positive’ associations two genes remained that showed statistically significant differences between patients and controls on both SNP and gene expression analysis.
The genes identified were NPAS2 – involved in circadian rhythms and GRIK2 – a gene involved in glutamatergic neurotransmission.
The authors note that these genes are not only associated with key functions such as cognition, sleep and memory that are impaired in ME/CFS but also with those symptoms (mood disorders and anxiety) in which ME/CFS symptomology often overlaps with ‘psychiatric’ disorders raising the possibility of shared neurological underpinnings.
They also note that the same polymorphisms of glutamate receptors:
“have also been associated with a number of neuropsychiatric disorders including autism, Huntington’s disease, ADHD, OCD …”
The authors conclude that
“Replication of these findings will open novel avenues for the study of CFS pathogenesis”
Research into the genetics of Huntington’s disease suggest that a combination of polymorphisms in the GRIK2 gene and PPARGC1A (also called PGC1-alpha – the master regulator of mitochondrial biogenesis and function) may determine the age of onset of the disease (Gusella, Macdonald, 2009).
Notably, in animal (rodent) models of schizophrenia and autism, maternal infection with the H1N1 virus results in prenatal alterations in the genes of the offspring which include changes to GRIK2 and GABAergic genes leading to structural changes in the brain and adverse effects on behaviour (Hossein Fatemi, Powerpoint presentation, 2011).
Glutamate Kindling
An imbalance between GABA and glutamate can also result in a phenomenon called kindling, defined in neurology as :
“a process in which repeated stimuli sensitize the brain to react when the stimulus is re-applied. Used in explaining increased frequency of seizures in epilepsy and progression of bipolar disorder in humans.”
Jason et al have recently (2011) proposed kindling as an etiological model for ME/CFS :
“Kindling might represent a heuristic model for understanding the etiology of Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Kindling occurs when an organism is exposed repeatedly to an initially sub-threshold stimulus resulting in hypersensitivity and spontaneous seizure-like activity. Among patients with ME/CFS, chronically repeated low-intensity stimulation due to an infectious illness might cause kindling of the limbic-hypothalamic-pituitary axis. Kindling might also occur by high-intensity stimulation (e.g., brain trauma) of the limbic-hypothalamic-pituitary axis.
Once this system is charged or kindled, it can sustain a high level of arousal with little or no external stimulus and eventually this could lead to hypocortisolism. Seizure activity may spread to adjacent structures of the limbic-hypothalamic-pituitary axis in the brain, which might be responsible for the varied symptoms that occur among patients with ME/CFS. In addition, kindling may also be responsible for high levels of oxidative stress, which has been found in patients with ME/CFS.”
Once ‘primed’ (which may reflect structural changes to the brain) very little stimulus is needed to trigger a flare of neuroinflammation.
Neurological kindling is frequently encountered in the clinical or recreational use and/or abuse of certain GABA modulating drugs, most notably benzodiazepines and alcohol.
Some researchers think ‘kindling’ may have supercharged the limbic system in chronic fatigue syndrome (ME/CFS)
Withdrawal from GABAergic acting sedative-hypnotic drugs causes acute GABA-under-activity as well as glutamate over-activity which can lead to sensitization and hyper-excitability of the central nervous system, excito-neurotoxicity and increasingly profound neuroadaptions.”
Wikipedia – Kindling (sedative-hypnotic withdrawal)
Similarities Between Kindling in ME/CFS and Other Kindling Disorders
ME/CFS shares many symptoms with ‘benzodiazepine withdrawal syndrome’ including: agitation, chest pain, dizziness, fatigue and weakness, flu-like symptoms, irritable bowel syndrome, hot and cold flushes, orthostatic intolerance, restless leg syndrome, stiffness, tachycardia, sensitivity to touch and sound, indecision, etc.
Reports have recently appeared in the press suggesting that the routine use of benzodiazepines as a sleep aid in care homes for the elderly increase the risk of developing Alzheimers disease as each cycle of benzo withdrawal results in a rebound ‘spike’ of excitotoxic glutamate.
Similarly glutamate kindling in chronic alcohol abuse leads to multiple physical and neurological impairments and can result in permanent brain damage which impacts on important cognitive capacities such as executive function (decision making) a deficit also found in ME/CFS (Prasher et al, 1990, Jason, 2011). Chronic alcohol abuse is, of course, one of the exclusionary conditions in most if not all ME/CFS case definitions which might suggest that without this disclosure they might meet the criteria for a ME/CFS diagnosis.
Baclofen is a GABA-B receptor agonist (originally used as an antispasmodic) that has recently been licensed for use in France for the treatment of alcohol dependence and withdrawal. This resulted from an intriguing tale of how Olivier Ameisen, M.D, a lone French-American doctor, self-treated his own lifelong anxiety and alcoholism with high dose Baclofen, wrote a book and spawned a growing on-line community who, following his lead, also found in many cases that their lifelong anxiety (and potentially the root cause of their alcohol abuse) was resolved. Presumably the fact that Baclofen acts on GABA-B receptors rather than GABA-A (like benzodiazepines) and/or the particular treatment regime used avoids kindling due to repeated administration and withdrawal.
Glutamate Induced Peripheral Damage
Neural damage due to glutamate excitotoxicity may not be restricted to the central nervous system. Peripheral neuropathy is a common complication in diabetes (and metabolic syndrome) and often results from chronic alcohol abuse.
Small fibre polyneuropathy can result not only in neuropathic pain and other sensations such as pins and needles or itching but also, interestingly, in a very wide range of (familiar) autonomic symptoms including (but not restricted to) dry eyes, dry mouth, orthostatic dizziness, constipation, bladder incontinence, sexual dysfunction, trouble sweating etc (Tavee, Zhou, 2009).
Update! Check out recent study which suggested that the small fiber neuropathy in fibromyalgia and ME/CFS may be caused by increased glutamate levels in the brain
One recent study (Oaklander, 2012, press article) reports that almost 50% of a cohort of fibromyalgia patients showed objective evidence of small fibre polyneuropathy via skin biopsy sufficient to meet strict diagnostic criteria for that condition. A study at CDMRP Boston is currently recruiting to study small fibre polyneuropathy in Gulf War veterans.
Glutamate, Chemotherapy, Fatigue, Cognition and HHV6
As discussed earlier, chemotherapy treatment frequently results in ‘chemo fog’ and ‘chemo fatigue’ and a high proportion of those treated for breast cancer develop the symptoms of post-traumatic stress disorder or full-blown PTSD. Peripheral neuropathy is also a common complication of chemotherapy which places an upper limit on the dosages used (Pachman et al 2011).
Glutamate is strongly implicated in chemotherapy neurotoxicity (Carozzi et al, 2009) and compounds that inhibit glutamate production have been shown to reduce neuronal damage (particularly in the dorsal root ganglia) in rat models (Carozzi et al). Intriguingly, the Light’s believe damage to the dorsal root ganglia (DRG) in chronic fatigue syndrome patients may contribute to the sensory overload present there. The dorsal root ganglia also often harbor herpesvirus infections. Could glutamate excitotoxicity in the DRG lay the foundation for herpesvirus activation there?
Or vice versa? HHV6 can cause dysregulation of glutamate transport in neural astrocytes with the potential for similar effects on the peripheral sensory neurons in the DRG : Human herpesvirus 6 (HHV-6) induces dysregulation of glutamate uptake and transporter expression in astrocytes.
Inhibition of the glutamate forming enzyme glutamate carboxypeptidase II (GCP II), may help prevent both peripheral and central nervous system damage during chemotherapy and has been proposed as a possible treatment for amyotrophic lateral sclerosis (ALS), stroke, and even Multiple Sclerosis plus other ‘neuropsychiatric’ diseases (Rahn et al, 2012).
The Multiple Sclerosis Connection
Multiple sclerosis has several intriguing associations with ME/CFS including an infectious mononucleosis trigger, a relapsing/remitting nature, possible herpesvirus activation and high rates of fatigue (that are not associated with demyelination). The neuroprotective effects of a novel oral treatment, BG12 (dimethyl fumarate) has been recently shown to slow disease progression in relapsing/remitting MS in phase III trials. Neural degeneration in MS is believed to be mediated by oxidative stress and an analysis of the neuroprotective effects of dimethyl fumarate suggests that these effects are due to enhancing the recycling of glutathione, a key antioxidant. (Lee et al, 2012).
This is intriguing because the experimental model used to simulate neurodegeneration in MS involves both glutamate toxicity and glutathione depletion. It suggests that extracellular glutamate leads to deprivation of cystine and its reduced form cysteine, which is the rate-limiting substrate for the synthesis of glutathione. The subsequent glutathione depletion gives rise to the accumulation of reactive oxygen species and cell death by oxidative stress (Albrecht et al, 2012).
An Autoimmune Disorder?
As a final thought, the potential efficacy of Rituximab in treating ME/CFS (Fluge et al, 2011) has not only raised hopes amongst patients but also suggests that ME/CFS may be an autoimmune disease although Fluge and Mella themselves have not yet reached this conclusion.
To examine the potential mechanisms of the reported efficacy of Rituximab for ME/CFS, a recent study (Bradley et al, 2012) compared B cell subpopulations in ME/CFS patients and healthy controls and found subtle yet significant differences that they could not explain but which prompted them to conclude that this “may suggest a subtle tendency to autoimmunity”.
In the context of the association between neuroinflammatory conditions and metabolic syndrome/type II diabetes (in which glutamate may pay a key role), Stanford researchers (Winer et al, 2011) have demonstrated the effectiveness of Rituximab treatment in mice in an autoimmune model of type II diabetes :
“B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies.
Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies.
These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.”
Anti-NMDA receptor encephalitis and late onset autism are recently recognised and related autoimmune disorders involving antibodies to NMDA (glutamatergic) receptors with prodromal symptoms reminiscent of a viral infection and that result in a wide range of movement and neuropsychiatric symptoms and neuroinflammation. (Dalmau et al, 2011).
Autoimmune encephalitis (where symptoms include psychiatric features, confusion, memory loss and seizures followed by a movement disorder, loss of consciousness and autonomic fluctuations) and related disorders have also been associated with anti GABA-B receptor antibodies and/or glutamic acid decarboxylase (GAD – the enzyme responsible for converting glutamic acid to GABA) antibodies (Boronat et al, 2011). One recent hypothesis (Fitzgerald, Carter, 2011) proposes decreased GAD expression or activity as playing a key role in fibromyalgia.
Rituximab has also been used to treat anti-NMDA receptor encephalitis (Ikeguchi et al, 2012) supporting a close link between autoimmunity, glutamate/GABA and encephalitis.
Conclusions
Could a GABA/Glutamate imbalance be driving much of the ‘arousal’ and many of the symptoms in chronic fatigue syndrome (ME/CFS)?
A range of neuroinflammatory/neurodegenerative and ‘psychiatric’ conditions show evidence of various overload phenomena and when tested show evidence of a sensory gating deficit. These conditions have also been associated with immune dysregulation, inflammation/oxidative stress and mitochondrial dysfunction. Similar markers have also been found in ME/CFS patients who also experience various forms of ‘overload’.
A glutamate/GABA imbalance is increasingly implicated in most if not all of these conditions which results in a disruption in the brain’s ability to efficiently process information and in time can lead to lasting neuronal damage both centrally and peripherally. A sensory gating deficit is likely an epiphenomenon resulting from this loss of efficient sensory ‘filtering’ due to an imbalance of glutamate and GABA.
Dopamine as the ‘Gatekeeper’?
Dopamine may still play a role in this scenario. Despite the recent focus on glutamate, the ‘dopamine hypothesis’ of schizophrenia is well established and compounds that raise dopamine levels (e.g. Ritalin and Adderall) are standard treatments for ADHD and have also shown some promise in relieving fatigue and concentration difficulties in ME/CFS (Blockmans et al, 2006). It appears that dopamine plays a key role in regulating glutamate neurotransmission. Dopamine acts as a sort of ‘gatekeeper’ of glutamatergic input, boosting strong glutamate signals while suppressing weaker ones (Horvitz, 2002). Again an adequate level of dopamine is necessary for the efficient filtering of salient information from extraneous noise.
A Gender Effect?
Additionally, as might be expected, dopamine, glutamate and GABA do not act independently. In Part I we discussed the potential role of the COMT gene in disorders such as schizophrenia, bipolar disorder and possibly ME/CFS and that the RORA gene may help explain the gender imbalance in ASD. As previously discussed, COMT polymorphisms affect dopamine levels and recent research strongly suggests that gender (or more specifically the effects of estrogen) impact on COMT function leading to sexually dimorpic effects on brain function (Tunbridge, Harrison, 2011). Sex differences in ‘psychiatric’ disorders have long been recognised :
“ the Val(158)Met polymorphism in COMT is associated with obsessive-compulsive disorder in men, with anxiety phenotypes in women, and has a greater impact on cognitive function in boys than girls”
…… with COMT activity, on average, being lower in women than men due partly to its suppression by estrogen (Harrison, Tunbridge, 2008).
Of particular relevance to the current discussion is the fact that the COMT and GAD genes (where, as discussed above, antibodies to GAD are found in autoimmune encephalitis) regulate cortical GABA function (which opposes glutamate) although sometimes not in the expected direction (Marenco et al, 2010) :
“These results support the importance of genetic variation in GAD1 and COMT in regulating prefrontal cortical GABA function. The directionality of the effects, however, is inconsistent with earlier evidence of decreased GABA activity in schizophrenia.”
Thus, gender may influence the type of condition that results from the same neuroinflammatory process through the modulating effect of estrogen on genes. Could it be that the effects of estrogen on RORA provide protection against developing ASD while its effects on COMT predispose more females to developing conditions like ME/CFS?
A Neuroinflammatory Vicious Cycle
Are people with ME/CFS caught in a glutamate driven self-perpetuating cycle of neuroinflammation?
Glutamate excitotoxicity, oxidative stress, and mitochondrial dynamics may represent a self-perpetuating ‘vicious cycle’ which in time may lead to neural remodelling making future excitoxicity more likely and requiring little outside stimulus.
Because glutamate signalling is ubiquitous in the brain (and concentrated in other tissues such as the heart, adrenal glands and the gastrointestinal tract – Julio-Pieper et al 2011) this neuroinflammatory cycle can result in a wide range of symptoms that then result in a variety of ‘differential diagnoses’.
Identifying a sensory gating deficit in ME/CFS may help to identify the core pathology as the same neuroinflammatory cycle identified in other conditions and better insights (and treatment options) might come from those other conditions that share the same basic pathophysiology but where the pathological process is expressed as a different constellation of symptoms, perhaps due to individual variations in genetic predisposition, developmental stage, environmental stressors and perhaps gender.
- Check out Pt I of the Neuroinflammatory Series: Not Fatigue After All: New Model Suggests Other Symptoms Better Explain Chronic Fatigue Syndrome (ME/CFS)
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Once again, the GABA/glutamate can be explained by poor methylation. Rich Van Konynenburg has already explained this. http://phoenixrising.me/treating-cfs-chronic-fatigue-syndrome-me/treating-chronic-fatigue-syndrome-mecfs-glutathione-and-the-methylation-cycle
Maybe so Caledonia.
My intention in writing this was to try to encourage someone to test the hypothesis (es). There are at least two testable hypotheses. Firstly that ME/CFS patients will have a sensory gating deficit and secondly that a GABA/glutamate imbalance is responsible. There is a fairly standard methodology to test the former. The latter may be tested by various MR techniques or via ‘proof of concept’ pharmaceutical interventions.
Confirmation of either of both of these hypotheses would (in my opinion) be a massive step forward in identifying the core pathology). What is driving the pathology is a further issue. It may be a methylation issue or driven by another or multiple processes.
Unfortunately until rigorous research is done Rich (and Fredd’s) methylation schema remains just one of multiple possibilities.
I’m just trying to point the finger at this possibly glutamate driven neuroinflammatory state as a key driver in ME/CFS based on converging evidence. The biological complexities of this I don’t have the background to address.
What I will say is that conditions such as MDD that appear to be driven by this same neuroinflammatory state can be effectively treated by methods that don’t appear (on the face of it although it can’t be discounted) to address methylation issues.
Such a shame that Rich isn’t still here to ‘pitch in’.
yes, Rich would be all over this…I miss his energy..
Indeed! Such a ‘gentle’man in every sense of the word!
Peggy on Facebook just posted this comment which mentions Deprenyl, another glutamate antagonist
I haven’t read the article yet just skimmed it, but I have been reading about Deprenyl (which I didn’t see included) as a substance that reduces quinolinic acid and has an impact on the glutamate system. Dr. Jay Goldstein of course used Ketamine as part of his “restoration cocktail” which I think probably could benefit a lot of us but most docs are pretty skittish about this drug (despite new research on Ketamine working for depression). I would definitely be interested to hear success stories with any of these drugs, or about anyone who has tried Depenyl.
Dr. Goldstein apparently used this drug alot “There are several medications that have proven to be very useful for patients who have been bedridden for a year or longer. Dr. Goldstein calls these his “resurrection cocktail.” A main component of this “cocktail” is ketamine administered intravenously or through a gel. Other components provided intravenously are ascorbate, lidocaine, and thyrotropin-releasing hormone. Nimotop and Neurontin, both administered orally, are also included in the list of medications most likely to aid CFS patients.”
“Most of Dr. Goldstein’s CFS patients benefit from his therapy. Courmel says that 50% of patients feel dramatically better after the first day. Another 25% feel better the next day and eventually a further 20% substantially improve. That leaves 5% of patients that Dr. Goldstein is not able to help much.”
http://www.prohealth.com/library/showarticle.cfm?libid=9210
Hiho, Cort.
I took deprenyl for a couple of months, mostly in conjunction with nicorettes, aiming to increase my motivation and cognitive power. I tried a very low dose, no more than 5mg/day, often less.
It did give me a kind of blunt drive which enabled me to get on with a lot of painting (art), but not an exceptionally clear and sharp mental state.
It slightly improved my bodily pain, especially in the morning when it is most severe.
On the minus side it induced a slight restless, irritable feeling which i couldnt get to like, and interfered with sleep to begin with.
When my hair started falling out, (side effects of deprenyl or nicotine) i discontinued it.
I would take it again, barring the hair issue, because it was useful for dealing with some of the symptoms of cfs, especially ,getting tasks done.
Some more from Peggy- who is doing her due diligence on glutamate…Might herbs help bring glutamate levels down? Intteresting about Lyme….
Peggy wrote: “Thanks Cort! I have been reading quite a bit about quinolinic acid lately, and thinking about strategies to reduce it via herbs (Japanese Knotweed is supposed to help) or meds (Deprenyl). It is directly related to all of this as explained on Wikipedia:
“When quinolinic acid is at pathological concentrations, a reduction of glutamine synthetase, a critical enzyme in the glutamate-glutamine cycle occurs.[9] This results in a loss of function of the cycle, and results in an accumulation of glutamate. This glutamate further stimulates the NMDA receptors, thus acting synergistically with quinolinic acid to increase its neurotoxic effect by increasing the levels of glutamate, as well as inhibiting its uptake. In this way, quinolinic acid self-potentiates its own toxicity.”
Elevated quinolinic acid is also found in other neurological conditions, in Lyme, and in people who attempt suicide. Since I have had suicides in my family tree as well as neurological diseases like Alzheimer’s, this led me into an exploration of whether there could be some genetic damage to this system. It’s a slightly different angle and might explain why some substances (Ketamine) seem to work and others don’t (Ketamine also has some effect on quinolinic acid).”
Excellent article, Marco.
I’m grateful you have pulled all this together on one page. Tons of references.
Luckily i took Tianeptine quite early on in my illness. It really helped calm my head and body down and has no side effects for me at a low dose.
I am no expert, but if we can believe the scientific postulates, it seems that effectively squelching glutamate excitotoxicity results in less suffering for a ME/CFS person.
I can’t think of a higher priority as the first thing a patient suspecting ME/CFS can do. ( That could be an oversight on my part).
Thanks beaverfury
In the current absence of effective (approved) treatments there may be some pretty straightforward ‘self help’ things we can do.
One (relatively small) cross-over study found beneficial effects for pain and IBS in fibro patients from restricting dietary glutamate intake :
http://www.cortjohnson.org/blog/2013/02/15/glutamate-one-more-piece-in-the-chronic-fatigue-syndrome-mecfs-puzzle-the-neuroinflammatory-series-pt-ii/
Processed foods are now out for me and I tend to avoid cooked tomatoes and cheese like the plague. Still eat too much meat though!
Since discovering the research on Glutamate and EAAT2 (http://www.wellcome.ac.uk/News/2010/News/WTX062574.htm), and already knowing that glutamate causing problems (by personal testing of msg and l-gluatmine supplements), I have been interested in the role and reduction of glutamate in the diet.
Through research, I have decided to move towards eating more plant-based meals and less high protein meals. This reduces the amount of glutamate obtained from protein foods (particularly when they are aged or cooked), without presenting excessive restrictions in food variety. In the end, for all of us, research is helpful for ideas and guidelines, but individual experimentation is the only way forward, since due to genetics and environment we each react differently.
When it comes to cooked tomatoes – while the protein contained in tomatoes is high in glutamic acid (it accounts for 50% of the protein in tomatoes), however, the level of protein in tomatoes is low. There is 5g of glutamic acid in 1kg of fresh tomatoes. This does increase to 4g in 80g of (oil free) sun-dried tomatoes. However, the level of glutamate in wheat is relatively higher, one third of the protein in wheat is from glutamic acid, but 1 slice of bread contains between 3 and 6g of protein, so just one slice of bread contains as much glutamate as at least 200g of fresh tomato.
There is however the theory that the worst form of glutamate is that of dietary free glutamate – i.e. where the protein strings have been processed before consumption, so that the glutamic acid is not longer bound into a protein string, but is ‘floating’. On this premise, then the more processed the food item (broken down, cooked, aged), the more glutamate is available to mess things up.
For myself, I experience Migraines, Fibromyalgia and ADHD – so have been very interested to read about the potential impact of glutamate on these other conditions. I have significant sensory overload problems, and that would love to make progress in reducing the sensory overload above any other symptom that I experience. I just hope that continued work on reducing the effect of glutamate will tone down the sensory problems.
Thanks for this.
I doubt diet alone is sufficient to break this cycle of neuroinflammation but it may be one of a number of ‘lifestyle’ approaches that could help reduce symptoms.
At the end of the day though we need effective meds and for this to happen we need researchers/clinicians to be considering neuroinflammation as a key driver and that any resulting ‘fatigue’ is not due to under but overactivation.
Our sensory problems should be a major clue to this unfortunately they are largely ignored as not central to the problem.
Result – we are offered graded exercise to deal with the consequences of our ‘inactivity’ and cognitive therapies for our ‘catastrophising’.
Very interesting article, thanks! I need to read the whole piece which is not going to work right now, but the first chapters are very interesting! As well as the comments.
Good article. We need to stop wasting time with viral research (another negative study on viruses out last week). We need to focus on the brain, nervous system, neurotransmitters etc. Although he is not very well liked by the CFS community, I tend to agree with Dr Andrew Lloyd that the problem lies in the brain / central nervous system, with triggers likely to be often infectious in nature.
I was interested in Cort’s points on Dr Goldstein. That guy was way ahead of his time with limbic hypothesis etc.
And in my view, we have more reason for hope if the problem is in brain, because there will be opportunity to treat things like glutamate imbalance etc.
Cort what is happening with Baraniuk’s research? that seemed quite promising….
the Swedish research on glutamate and fatigue is interesting…
BTW, has anyone tried acetyl cysteine? supposed to help with glutamate
Hi Matthias
I also find the Swedish research very interesting – I can identify fully with the ‘locked state’ when either mentally or physically ‘overloaded’.
N-acetylcysteine is one of the few supplements I have found some benefit from and as become one of my ‘go-to’s.
I take an over the counter soluble powder format which I find can help prevent PEM and helps me cope with severe heat intolerance.
I take it as needed but intend to try a sustained release version at some stage.
Glad you liked the blog and many thanks for your comments.
This article challenged me, but I am very interested, will look for more on this. Since you spoke of Estrogen, I wondered if those of us taking it should consider slowly going off of it and see if we see a response, such as less fatigue?
Hi Lynn
Well this is just a working hypothesis put up for us to kick around and see if it seems to fit (and hopefully attract some interest from researchers).
While its based on published research a number of the inferences (including the potential impact of estrogen) are my own and much too tentative to suggest any particular course of action regarding meds.
If you feel that supplemental estrogen has made your symptoms worse though the best course of action might be to discuss it with your doctor.
Glad you found it ‘challenging’. In a good way hopefully?
Very interesting indeed. I have been taking GABA and magnesium with very good results. Now I understand why it is helping.
Thanks Sue
If you don’t mind me asking have you found a global improvement or improvement (or even deterioration) in certain symptoms?
Feedback on this model, positive or negative, is very welcome.
I have been improving in all areas. Mostly in pain and sleep improvement. The magnesium supplement I am using is Natural Calm which has completely fixed the bowel issues. The GABA I have been using is called 200 mg of Zen. I am off all other sleep aids and pain meds. I have been slowly improving over the last 2 years due to many changes I have made but these last two really seemed to help. I am back up to about 80%. I started exercising again in October and so far so good. Fingers crossed that this will continue.
Thanks Sue
Its difficult to be sure that any particular approach is really helping and its not just the natural course of the illness but that’s really impressive and highly suggestive.
Exercising as well!
Here’s to further recovery!
Really fascinating. A minor point, but acronyms, if they are acronyms are spelled out the first time they are used with the acronym following in parentheses. I think this may be only a segment of a longer series, but it would help me. Going back, finding and remembering 8 capitalized letter and typing it out after finding the right place in the manuscript should not be daunting.
For me, with books in tow, I am losing ground. I need an old friend or someone else in the same circle to begin to follow what I’ve been doing.who wrote my book by loosely basing character on his non-fiction one. His wife died “of a lingering illness” ended by a fatal heart attack. She was one of the best writers writing. I need Ampligen as much as anyone alive. Books are like babies. You may be hit by a truck, but you just can’t ignore them.
And if you are on an upturn, it is better to not over-think what may come. I read many posts without responding. Thank you for doing all you can to fight this devastating disease. (DDD). We used to call it that. There are so many good D words.
Mea culpa Kathleen
Out of necessity, this has been written in fits and starts over the course of over a year and then split into sections to ‘aid readability’. So yes, its been hard to keep track of it and the use of acronyms etc has suffered with the splits.
I’ll keep an eye out for such issues in the future!
Thanks for raising this.
Only two D’s on the DD.
http://www.cortjohnson.org/blog/2013/02/15/glutamate-one-more-piece-in-the-chronic-fatigue-syndrome-mecfs-puzzle-the-neuroinflammatory-series-pt-ii/
Hi Marco
Very interesting ideas on a sensory gating deficit being central to ME/CFS, and the hypothesis that excess glutamate and over-activated NMDA receptors may be the driving cause of this and many other symptoms of ME/CFS.
I have similar thoughts about glutamate overload being the driving cause of generalized anxiety disorder (a condition that many ME/CFS patients have); these thoughts are detailed in the two threads here:
http://forums.phoenixrising.me/index.php?threads/non-standard-anti-anxiety-treatment.6432/
http://forums.phoenixrising.me/index.php?threads/completely-eliminated-my-severe-anxiety-symptoms-with-three-supplements.18369/
My hunch is that glutamate overload could arise from chronic microglial activation (CMA). One Japanese study showed that CMA is found in ME/CFS patients:
http://ras.ni.brain.riken.jp/neuroscience2011/php/showDetail.php?document_id=895&search_keyword=&key_start_disp_num=0&key_disp_num=10
The very interesting thing about activated microglia is that they can operate in two modes: the neuroprotective mode, where they actually help prevent glutamate overload in the brain; and the neurotoxic mode, where these microglia do the reverse, and actually cause glutamate overload.
In ME/CFS, perhaps the microglia may have been shifted out of their normal neuroprotective mode, and into their undesired neurotoxic mode. In this neurotoxic mode, activated microglia may cause glutamate overload in the brain.
One crucial factor which seems to switch microglia from their neuroprotective mode into their neurotoxic mode is the presence of the bacterial toxin LPS (lipopolysaccharide). So LPS is not only highly pro-inflammatory, it also switches off neuroprotection, and switches on neurotoxicity.
This effect of LPS suggests a link between the gut problems in ME/CFS to the posited glutamate overload in the brain: if you have bacterial overgrowth in the gut, and a degree of intestinal permeability (leaky gut), then LPS from Gram negative bacteria in the gut (or from infected sinuses) may enter the bloodstream and travel to the brain, where this LPS both activates the microglia, and switches these microglia to their neurotoxic mode, thus producing lots of glutamate.
(Though note that this neuroprotective/neurotoxic mode switch is quite context-dependent, and researchers are currently trying to work out exactly when and why these microglia switch from neuroprotective to neurotoxic mode. Perhaps this switch to neurotoxic mode might be fundamental to ME/CFS.)
The anti-anxiety approach I experimented with on myself (which seems to work quite well) involves taking anti-inflammatory supplements and drugs that lower gut and sinus infection/inflammation, and lower lower brain inflammation. This anti-inflammatory approach I suspect reduces chronic microglial activation, and so decreases glutamate overload in the brain (and the amygdala), thus easing or even eliminating anxiety symptoms. Supplements to antagonize NMDA receptors were also taken, to try to prevent glutamate from over-stimulating these receptors.
I had very severe anxiety symptoms, plus considerable sound sensitivity symptoms as part of my ME/CFS symptoms, and both were improved by this approach of reducing gut, sinus and ultimately brain inflammation (my anxiety symptoms have more or less disappeared using this anti-inflammatory approach, and my sound sensitivity is much better than it was; unfortunately this approach involves taking quite a few supplements). Though my fatigue and brain fog symptoms have not really improved that much with this this anti-inflammatory approach.
So it is possible that chronic microglial activation may be driving many cases of generalized anxiety disorder, and also ME/CFS. Though the role of astrocytes in glutamate overload in the brain is another very interesting angle; perhaps both chronic microglial activation and astrocyte glutamate clearance deficits might be present in ME/CFS. Either of these would tend to raise glutamate, and then cause all the ME/CFS that you hypothesize are driven by glutamate.
I look forward to reading your upcoming article on the NMDA/GABA imbalance.
Very, very interesting Hip. Thanks for the info…Congratulations in that dramatic reduction in anxiety…
Hi Hip
I’ve been following your posts and have been leaning to try your suggestions out properly but haven’t been able to due to other things (inc ‘blogging’).
What you’re suggesting seems plausible and fits with my experiences (IBS and anxiety since ‘onset’ with the feeling that the gut may be the origin of my problems). Whether the neuroinflammatory mechanisms involves astroglia or microglia is another level of detail. As I’m sure you can appreciate tying all of these neuroinflammatory conditions together has resulted in a ‘broad brush’ rather than an in depth review.
Anecdotally I’ve had some success with curcumin supplementation although not as spectacular as your own.
On one occasion I did find that a cox-2 inhibitor ‘Celebrex’ taken for a pulled muscle completely abolished my anxiety for a period of a few hours. Unfortunately I haven’t been able to repeat this which may be due to the fact that the tablets are a very old prescription. It does though support the notion that neuroinflammation is responsible for ‘mood’ related symptoms.
I was using high-dose propolis (5000 mg daily) as my COX-2 inhibitor, as well as curcumin. I then decided to get some Celebrex (celecoxib) to try as a comparison. I found that although Celebrex worked a little better as an anti-anxiety medication, is was not that much better than propolis + curcumin, so I stuck with the supplements.
More recently had a lot of anti-anxiety success with the supplement N-acetylglucosamine (NAG), which noticeably reduced the inflammation in my sinus/nasal mucous membranes, and I am guessing NAG’s significant anxiolytic effects may come from:
Reduced sinus inflammation > reduced knock-on effect brain inflammation and CMA > reduced brain glutamate > reduced anxiety symptoms
Around half the people with ME/CFS who tried NAG told me it made a big difference; but the other half did not get improvements in their anxiety symptoms.
The astrocyte angle in ME/CFS is most interesting. One brain autopsy on a ME/CFS patient, whose disease was triggered by enterovirus, found that within the brain tissue, it was only the glial cells that were infected with enterovirus (most glial cells are astrocytes). See: http://www.oocities.org/vitamvas/viralfm.html . Ever since reading that, I became interested in astrocytes.
Another Chinese study on the effect of coxsackievirus B3 (an enterovirus) infection in mice found that, as this virus entered the brain, again it was the astrocyte cells of the brain that were infected with it. See: http://mt.china-papers.com/2/?p=239350
The Chinese study also found that coxsackievirus B3 infection in astrocytes increased the cytokines IL-1, IL-6 and TNF-alpha. As you mentioned in the article, these cytokines act to decrease the ability of astrocytes to clear extracellular glutamate from the brain.
So this astrocyte infection suggests a mechanism by which enterovirus — a virus strongly associated with triggering ME/CFS — may cause glutamate overload in the brain.
I recent bought the drug propentofylline, which increases expression of glutamate transporters (in vitro), and lowers extracellular glutamate in the brain (in animal studies). See: http://www.ncbi.nlm.nih.gov/pubmed/16819765 and http://www.ncbi.nlm.nih.gov/pubmed/1347163. I will be trying this drug soon to see what effects it has on my ME/CFS symptoms. Propentofylline has been tried in Alzheimer’s and dementia, but showed no benefit; but has not been tried in ME/CFS, as far as I am aware.
Thanks Hip
All very interesting stuff.
Good luck with the propentofylline (the list of symptoms in aging dogs sounds familiar!).
I have always became very ill anytime I ate something with added glutamate. Since I was a child I would become very ill anytime I ate at my grandmother’s house. She always added glutamate as a flavor enhancer. I cannot eat anything with even a trace of it. So now I know why, perhaps. A very good article. Thank you.
Hi Cort
Would you know which kind of blood test could be taken to test Glutamate levels?
I would like to get tested on those, as well as my brother. In his case He came up with a PET scan with white spots in the frontal lobe, and they think that it could be the beginning of a dementia, but I heard that glutamate can cause this kind of damage as well in the brain, but I would not know which kind of tests we should order in the lab to check this…
Thanks in advance
C.
Glutamic Acid is included in the Amino Acids portion of the NutrEval test from Genova Diagnostics. I don’t know if there is a direct correlation with glutamate or not though.
So many theories. Hopefully a cure will eventuate. Cure needed a decade ago.
100’s of 1000’s of us are taking Protandim for the removal of 40 to 70% of oxidative stress in 30 to 90 days…look it up on pubmed.gov/oxidative stress/ protandin or http://www.abcliveit.com , an investigative report to disprove Dr. JOE MCORD….
I think the GAB Antibody test was mentioned in another article re: Glutamate issues.
Many insights here… After struggling 20+ yrs with autoimmune issues (Hashimoto’s, Sjogren’s) beginning to look outside that “box” as many of the issues, and therapeutic solutions see to overlap.
Several years ago found an interesting article on the discovery of Deprenyl & pursued taking it, only to find out that it’s contraindicated with any use of narcotic pain relief … As is LDN.
SSRI’s do little for me, and reading Dr. Cheney’s negative nitric oxide consequences with the use of Provigil concerned me, and led me down this Glutamate path…
Stablon, Ketamine & Baclofen all sound helpful but difficult to obtain?
I’ve been prescribed Ritalin / Adderal since childhood for ADD, but have concerns & side effects, similar to Provigil & Noradrenaline reuptake drugs (SNRIs) such as Cymbalta & Savella.
Have had good success with dietary changes, initially to overcome chronic candida (yeast) infections of my sinsuses. Initially white stuff & sugar… Now gluten in general.
I seem to exist on Greek yogurt & salads these days, with meat 1x a week, and eggs 1x a week. The over-cooking /protein bonds connection is very interesting… But the trade off of salmonella or E.coli very distressing.
I’ll continue to follow this closely, as the neurotransmitter / brain inflammation issues are increasingly concerning for me, as my disease has progressed since my youthful years, inspite of adhering to traditional medical treatment, dietary change, Vit D & B12
Thanks for the comments.
I hope to post another article in the next few days which me be of interest.
Amazing post. Thanks!
In my experience, addressing methylation issues helps, but does not solve the issue. After trying Cal-Mag Butyrate I experienced great improvement. Perhaps because of the effects of ‘Gaba/NMDA regulation’? However, I’ve noticed that this supplement has not really been mentioned much when discussing Chronic Fatigue. Thoughts?
(http://books.google.com/books?id=mQ4b_GMFgoIC&pg=PT462&lpg=PT462&dq=butyrate+chronic+fatigue&source=bl&ots=jhpoc8oSk9&sig=pA5YgXxGBKTDRntxWCRxBBba578&hl=en&sa=X&ei=k51nU7rlEMmrsQSc5oHwBQ&ved=0CD4Q6AEwBA#v=onepage&q=butyrate%20chronic%20fatigue&f=false)
Many thanks!
Glad you liked it and please have a browse at the other blogs in the series – they’re all linked :
http://www.cortjohnson.org/authors/marco/
These two aren’t listed there and also touch on the ‘wired and tired’ type and GABA :
http://www.cortjohnson.org/blog/2013/07/28/japanese-sensory-gating-stud-reveals-profound-cognitive-deficits-present-in-chronic-fatigue-syndrome/
http://www.cortjohnson.org/blog/2014/02/26/energy-disorders-diabetes-cfs-fm-can-diabetes-tell-us-chronic-fatigue-syndrome-fibromyalgia/
Cal-Mag Butyrate is a new one for me and good to hear its helping you. Interesting in the context of the research focus shifting to the gut microbiome that its advertised as aiding gut health!
I don’t know why it hasn’t featured in ME/CFS discussions (but then again lots of potentially useful compounds haven’t). As far as academia/researchers are concerned though I personally feel that there’s a tendency to think of ‘fatigue’ as representing a ‘lack’ of energy/activity while my experience of ME/CFS is just the opposite – more ‘mental/sensory’ hyperactivity leading to ‘overload/collapse’.
I’ve been sensitive to glutamine/glutamates for a very long time, with increased sensitivity of late. I was just recently diagnosed with Idiopathic Intracranial Hypertension. I’ve had pressure in my head for at least a few years now, pulsatile tinnitus that started 3-5 years ago and regular tinnitus forever, headache prone my entire life with migraines from time to time chronic neck and trap pain and I’ve never been diagnosed but have suspected cfs for over a decade. I’ve narrowed down many food headache/migraine triggers (many related to glutamines/glutamates) amd also want to look into cranial instability (I’ve read some articles connecting that to cfs/me). I can’t help but think it is all connected. I’m not sure what direction to go in but want to figure out the glutamine/glutamate sensitivity root. I seriously think this would drill down a lot of my problems especially with all of this info presented.
I have found this a fascinating read. Thank you. Through my reading, I have definitely identified a Glutamate issue in my family .
Some family issues have been : SSRI withdrawal, sleep apnea, visual snow, tinnitus, rls, sensory issues, low pain threshold, closed eye visuals, mania, wired tired feeling, pans pandas, histamine issues, suggestions of blood brain barrier permeability, eds, me/ CFS , gluten sensitivity/ celiac, mast cell activation. Montelukast side effects and withdrawal has a big cross over too.
Does this mean that it’s better not to eat monosodium glutamate (MSG, E621)?
GABA helps me relax and breathe less at high dosages, but I will get used to it really quickly, just like to all supplements/meds that work on receptors. Probably because of receptor down regulation. Weird thing is that this remains this way for weeks or even months or who knows forever after taking a substance like GABA or CBD. Have to get the endogenous production going I guess
My experiences with chronic fatigue and research about what is helping me brought me to this article. It has been a decade since it was authored. What has been proven true or has changed from what understood about the role of glutamate and NMDA receptors since 2013?
I’m surprised that glutamate and NMDA receptors have not gotten more attention since then. Off hand I can’t think of anything. I could be wrong, though.
I have walked down various paths of research. Initially, adding dopamine substrates like phenylalanine and tyrosine helped manage the depression that accompanies the central fatigue.
The supplements I now take appear to target various possible root causes: oxidative stress/inflammation, low dopamine, and a dysfunctional glutamate/NMDAR system.
I found that I could prevent or at least reduce the fatigue crashes using citrulline, a precursor to arginine, that ends becoming nitric oxide. Including a low dose of norvaline greatly improved its effect, presumably because it inhibits the arginase pathway.
More recently, I asked to put on bupropion to make raising my dopamine levels cheaper (amino acid supplements can get expensive). Arginine reverses the antidepressant effect of bupropion, so I switched to beetroot powder. That has been life changing.
I take a rehydrated tablespoon in the morning and low doses of vitamin c throughout the day. As the nitrates in beetroot are metabolized to nitrite, vitamin c completes the chemical reaction to become nitric oxide. The production of nitric oxide is rough on the stomach, so be warned. For each “explosion” of it, I get surges of moderate migraines as blood vessels expand in my head, and energy gradually increases throughout my brain and body. Fatigue is often replaced by an abundance of energy for at least a couple of hours.
I take quercetin with an ounce of olive oil (to substantially increase bioavailability) in the morning. I also take NAC and piperine. I still take some phenylalanine and tyrosine. I added standardized l-dopa containing mucuna pruriens. I split doses of green tea extract at breakfast and lunch. I take a couple doses of theobromine during the day.
Through reading research studies and my personal experience, I have identified these benefits:
Phenylalanine/tyrosine/l-dopa: raises dopamine and norepinephrine levels.
Nitric Oxide: raises dopamine, increases cerebral blood flow, and inhibits NMDA receptors.
Beetroot: provides nitrates for nitric oxide and increases the production of butyrate.
Theobromine: decreases fatigue,
inhibits adenosine receptors and may inhibit NMDA receptors in hybrid receptor complexes, and sensitizes dopamine receptors.
Quercetin: inhibits COMT, functions as a weak MAO inhibitor, inhibits NMDA receptor activity, and as I discovered more recently on accident, it inhibits adenosine deaminase to reduce joint inflammation. It also prevents nitric oxide from producing harmful nitric dioxide.
Piperine: functions as a moderate MAO inhibitor, inhibits tyrosine decarboxylase, and modulates glutamate release.
NAC: modulates glutamate release amongst other activities such as being an antioxidant.
Vitamin C: reacts with nitrate to form nitric oxide, prevents quercetin from becoming a pro-oxidant, and is an antioxidant in of itself.
Green tea extract: inhibits amino acid decarboxylase and COMT.
So far, the two main pathways of doperminergic, glutamatergic, and the two nitric oxide subpaths of arginine-NOS-NO and nitrate-nitrite-NO have yielded the most effective results for me.
I will add that using beetroot and vitamin c has reduced the intensity of sensory gating agitation. I work a hybrid office/remote schedule in an intellectually demanding role. The days in the office so exhausted me due to the constant background of scores of other employees that I began to dread coming to the office.
When I first began using beetroot, I was taking 3 1/2 tablespoons doses throughout the day. I did this for probably three weeks. When I learned from research the role that vitamin c has in the nitric oxide conversion, I took 500 mg one afternoon. I became so incredibly ill! It was akin to having the worst stomach bug ever. After a day or so, I recovered enough to go the office for work while continuing to take much smaller doses of vitamin c.
On the afternoon of the second day, it occurred to me that there was background noise. I had not even noticed it for a half and a half.
Even though it bothers me less, I still take measures to reduce the noise effect using headphones. Once the damage is done and fatigue sets in and is followed by depression, it takes a week or longer for me to fully recover.
My working hypothesis is that my brain is letting too much CA2+ into neural cells because of a glutamate imbalance or an upregulation of NMDA or AMPA receptors. I have no “governor” on my brain. I can learn rapidly and employ incredibly complex information even while under time pressure. I pay for it later, though with days, weeks, or even months of recovery time.
It is as though my neurons are overexciting and dying. When I can inhibit the NMDA receptors, modulate glutamate, or dramatically increase cerebral blood flow, it reduces the extent of damage and shortens the recovery period.
Is this blog still active?
This study may be of interest:
https://www.amjmed.com/article/S0002-9343(24)00216-X/fulltext