The Non-Mystery of Chronic Fatigue Syndrome

The-Mystery-of-Chronic-Fatigue-Hadassah-Magazine-Chronic-UNREST-Jennifer-BreaThe Non-Mystery of Chronic Fatigue Syndrome

My wife gave me an article from Hadassah Magazine entitled “The Mystery of Chronic Fatigue Syndrome”, by Carol Saline, about the 2017 documentary on Jennifer Brea called “Unrest”.  The film documents her experience with severe chronic fatigue.(1-3)  Jennifer Brea was a previously healthy robust young women until the onset of immune dysfunction with six different infections, followed by debilitating fatigue and brain fog.  The article goes on to state there is no known cause and no known cure for “chronic fatigue syndrome” also called “ME/CFS”.  This has changed. The mystery has been unraveled by a group from Stanford.  Above image courtesy of Jennifer Brea Unrest Movie.

Gut bacteria dysbiosis clostridiaLeaky Gut – Incriminating the GUT Microbiome

Dr Montoya’s group at Stanford found elevated pro-inflammatory cytokines in chronic fatigue patients, implicating chronic inflammatory up regulation. (4-5)   In an accompanying editorial in PNAS, Dr Anthony Komaroff  explains it nicely with this quote:(5)

“Another way of incriminating infection in CFS (Chronic Fatigue Syndrome) involves the gut microbiome. Several recent studies have reported dysbiosis accompanied by low-grade inflammation and increased permeability of the gut mucosa. This allows bacterial lipopolysaccharide to enter the circulation, possibly activating innate immunity both systemically and in the brain.”

Notice Jennifer Brea’s story includes six different infections, yet the story says nothing about the antibiotics used to treat these infections.  Many of these patients have history of multiple long term antibiotic use implicating gut dysbiosis and leaky gut.   The use of NSAIDS for fibromyalgia pain worsens the leaky gut pathology as discussed in my previous article.

Leaky gut causes low grade endotoxemia which then upregulates inflammatory cytokines which travel to the brain causing upregulated microglia, depression and HPA (hypothalamic pituitary axis) dysfunction, which then causes adrenal, thyroid and gonadal hormone dysfunction leading to severe fatigue and fibromyalgia.  On top of this there is usually a variable element of mitochondrial dysfunction.

Pre-Existing Genetic Defects and Aggravating Conditions

Symptoms are worse in patients with pre-existing genetic defects in methylation pathways such as MTHFR, or COMT (catechol -o-methl-tranferase), or B12 transport protein defects (detected with elevated MMA levels)   Symptoms are worse if there is an aggravating medical condition such as low thyroid, menopausal transition, gluten sensitivity, stressful workplace or home life etc.

Dysregulation of the HPA – Thyroid and Adrenal Dysfunction

Many Chronic Fatigue/Fibromyalgia patients have dysregulation of the HPA (hypothalamic pituitary axis) resulting in adrenal and/or thyroid dysfunction with low AM cortisol and low circulating free T3 levels(19-20). The “hormonal approach ” includes an empiric trial of low dose cortisol (less than 15 mg/day).  This has been found useful in a subset of patients with low adrenal function. (19-20)  Chronic fatigue may be associated with low levels of circulating Free T3 thyroid hormone, described as the “Low T3 Syndrome”.(18)  Even though labs may show a normal range TSH and serum Free T4, these patients may benefit from combination thyroid medication which includes both T3 and T4, such as natural desiccated thyroid.  Bioidentical hormones such as estradiol, progesterone and testosterone may also be useful in this scenario.

Lyme Disease, Autonomic Dysfunction and LDN

Underlying infection with Lyme Disease may be causative of Chronic Fatigue, Pain and Autonomic Dysfunction.(17)  Lyme testing with Western Blot is indicated.(15-16)  Antibiotic Protocols such as Doxycycline and Botanical (non-antibiotic)  Lyme Protocols by Stephen Buhner may prove beneficial.  See Healing Lyme by Stephen Buhner.  Also see Healing Lyme Co-Infections.

Many Chronic Fatigue/ Fibromyalgia patients also suffer from autonomic dysfunction and may benefit from treatments such as LDN (low dose naltrexone), and Benfotiamine (thiamine).(9-13)

Don’t Forget Testosterone !

Many women with fibromyalgia pain and chronic fatigue will report relief with topical testosterone treatment. ( 21)  In 2015, Dr White studied the use of transdermal testosterone gel over 28 days in 12 women with  chronic fatigue and fibromyalgia, finding it the serum testosterone roughly doubled, and the treatment was quite effective for symptom relief. (21) Our clinical experience is in agreement with Dr White’s findings.

Vitamin D3

Vitamin D testing and supplementation has been found useful in fibromyalgia pain.(22-23)

The Mystery Becomes Unraveled

The reason why this disease is a mystery is because the mainstream conventional physician does not bother to test for any of these abnormalities.  Nor do they treat them. We do, and most of our patients eventually get better. That is why Chronic Fatigue/Fibromyalgia is a non-mystery.

Low Thyroid May Cause Chronic Fatigue

Natural Thyroid Toolkit

If you liked this article, you might like my new book, Natural Thyroid Toolkit available on Amazon. Remember to leave a book review. That would be much appreciated. See the book cover, left image.

Jeffrey Dach MD
7450 Griffin Road Suite 180-190
Davie, Florida 33314

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Articles with Related Interest

Adrenal  Fatigue

Michael Maes, Depression and Leaky Gut

LDN Part Four Chronic Pain/Fibromyalgia

Low Level Endotoxemia, Depression and Endocrinopathy

NSAIDS, Small Bowel Damage and Leaky GUT

Links and References

1)  The Mystery of Chronic Fatigue Syndrome By Carol Saline February 2018

2)  Jennifer Brea’s Sundance award-winning documentary, Unrest, is a personal journey from patient to advocate to storyteller. Jennifer is twenty-eight years-old, working on her PhD at Harvard, and months away from marrying the love of her life when a mysterious fever leaves her bedridden. When doctors tell her it’s “all in her head,” she picks up her camera as an act of defiance and brings us into a hidden world of millions that medicine abandoned.
In this story of love and loss, newlyweds Jennifer and Omar search for answers as they face unexpected obstacles with great heart. Often confined by her illness to the private space of her bed, Jennifer connects with others around the globe. Like a modern-day Odysseus, she travels by Skype into a forgotten community, crafting intimate portraits of four other families suffering similarly. Jennifer Brea’s wonderfully honest and humane portrayal asks us to rethink the stigma around an illness that affects millions. Unrest is a vulnerable and eloquent personal documentary that is sure to hit closer to home than many could imagine.
Myalgic Encephalomyelitis (ME), commonly known as Chronic Fatigue Syndrome (CFS) or ME/CFS, is a devastating multi-system disease that causes dysfunction of the neurological, immune, endocrine and energy metabolism systems.
It often follows an infection and leaves 75% of those affected unable to work and 25% homebound are bedridden. An estimated 15-30 million people worldwide have ME.

3)  Psychology Today: Why is Chronic Fatigue Syndrome Still a Mystery?


4)  Montoya, Jose G., et al. “Cytokine signature associated with disease severity in chronic fatigue syndrome patients.” Proceedings of the National Academy of Sciences (2017): 201710519.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) devastates the lives of millions of people and has remained a mystery illness despite decades of research. It has long been suspected that inflammation is central to its pathogenesis. Although only two cytokines were found to be different (TGF-β higher and resistin lower) in ME/CFS patients compared with controls, 17 cytokines correlated with ME/CFS severity. Thirteen of these cytokines are proinflammatory and may contribute to many of the symptoms these patients experience for several years. Only CXCL9 (MIG) inversely correlated with fatigue duration.
Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.


Another way of incriminating infection in CFS involves the gut microbiome. Several recent studies have reported dysbiosis accompanied by low-grade inflammation and increased permeability of the gut mucosa. This allows bacterial lipopolysaccharide to enter the circulation, possibly activating innate immunity both systemically and in the brain (5, 16⇓–18).

5)  Komaroff, Anthony L. “Inflammation correlates with symptoms in chronic fatigue syndrome.” Proceedings of the National Academy of Sciences 114.34 (2017): 8914-8916.

Neuroendocrine studies demonstrate abnormalities of the hypothalamic–pituitary–adrenal axis, of growth hormone secretion, and of adrenergic metabolism in CFS patients that are distinct from those seen in healthy control subjects and in patients with major depression.

Increased lactate levels in cerebrospinal fluid may indicate impaired oxidative phosphorylation, with a consequent shift to anaerobic metabolism. Possible causes of acquired mitochondrial dysfunction in the CNS include infection and cerebral hypoperfusion.

Many studies have found evidence of oxidative stress in CFS patients:

For 17 of the 51 cytokines there was a statistically significant upward linear correlation between the level of the molecule and the severity of the illness, suggesting that the cytokine levels are, indeed, causally associated with the symptoms.

Patients with severe symptoms and increased production of proinflammatory cytokines during the initial illness were the most likely to develop CFS.

Another way of incriminating infection in CFS involves the gut microbiome. Several recent studies have reported dysbiosis accompanied by low-grade inflammation and increased permeability of the gut mucosa. This allows bacterial lipopolysaccharide to enter the circulation, possibly activating innate immunity both systemically and in the brain (5, 16⇓–18).

6)  Blomberg, Jonas, et al. “infection elicited autoimmunity and Myalgic encephalomyelitis/Chronic Fatigue syndrome: an explanatory Model.” Frontiers in Immunology 9 (2018): 229.

7)  Researchers identify biomarkers associated with chronic fatigue syndrome severity
Stanford investigators used high-throughput analysis to link inflammation to chronic fatigue syndrome, a difficult-to-diagnose disease with no known cure. Jul 31 2017  Jose Montoya and his colleagues have found evidence inflammation may be the culprit behind chronic fatigue syndrome, a disease with no known cure. Steve Fisch
Researchers at the Stanford University School of Medicine have linked chronic fatigue syndrome to variations in 17 immune-system signaling proteins, or cytokines, whose concentrations in the blood correlate with the disease’s severity.
The findings provide evidence that inflammation is a powerful driver of this mysterious condition, whose underpinnings have eluded researchers for 35 years.
“Our findings show clearly that it’s an inflammatory disease and provide a solid basis for a diagnostic blood test.”

8)  Scientists zoom closer towards understanding chronic fatigue
Last updated on August 1st, 2017 at 6:43 pm by Mihai Andrei E-mail author
Montoya and colleagues found levels of 17 cytokines dramatically higher than normal in patients suffering from CFS. Out of these 17, no less than 13 were associated with promoting inflammation.


Thiamine and Dysautonia by Derrick Lonsdale

9) Dysautonomia, A Heuristic Approach to a Revised Model for Etiology of Disease. Derrick Lonsdale. Dysautonomia A Heuristic Approach to a Revised Model for Etiology of Disease Lonsdale Derrick eCAM 2009

10) Evid Based Complement Alternat Med. 2006 March; 3(1): 49–59. A Review of the Biochemistry, Metabolism and Clinical Benefits of Thiamin(e) and Its Derivatives by  Derrick Lonsdale

Thiamin, Pyridoxine and other B vit Deficiencies in Agoraphobia, Anxiery Disorders 

11) Agoraphobia Laraine C. Abbey, R.N., M.S.1

The chief symptoms of anxiety neurosis, as noted by Cohen and White, are breathlessness, palpitations, nervousness, fatigability, headaches, irritability, dizziness, chest pain, paresthesias and episodes of extreme tearfulness referred to as anxiety attacks.

LDN and Fibromylgia/Dys-autonomia

12) Younger, Jarred, and Sean Mackey. “Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study.” Pain medicine 10.4 (2009): 663-672.
Fibromyalgia is a chronic pain disorder that is characterized by diffuse musculoskeletal pain and sensitivity to mechanical stimulation. In this pilot clinical trial, we tested the effectiveness of low-dose naltrexone in treating the symptoms of fibromyalgia.
DESIGN:  Participants completed a single-blind, crossover trial with the following time line: baseline (2 weeks), placebo (2 weeks), drug (8 weeks), and washout (2 weeks).
PATIENTS: Ten women meeting criteria for fibromyalgia and not taking an opioid medication.
INTERVENTIONS:  Naltrexone, in addition to antagonizing opioid receptors on neurons, also inhibits microglia activity in the central nervous system. At low doses (4.5 mg), naltrexone may inhibit the activity of microglia and reverse central and peripheral inflammation.
OUTCOME MEASURES: Participants completed reports of symptom severity everyday, using a handheld computer. In addition, participants visited the lab every 2 weeks for tests of mechanical, heat, and cold pain sensitivity.
RESULTS: Low-dose naltrexone reduced fibromyalgia symptoms in the entire cohort, with a greater than 30% reduction of symptoms over placebo. In addition, laboratory visits showed that mechanical and heat pain thresholds were improved by the drug. Side effects (including insomnia and vivid dreams) were rare, and described as minor and transient. Baseline erythrocyte sedimentation rate predicted over 80% of the variance in drug response. Individuals with higher sedimentation rates (indicating general inflammatory processes) had the greatest reduction of symptoms in response to low-dose naltrexone.
CONCLUSIONS: We conclude that low-dose naltrexone may be an effective, highly tolerable, and inexpensive treatment for fibromyalgia.

13) Chopra, Pradeep, and Mark S. Cooper. “Treatment of complex regional pain syndrome (CRPS) using low dose naltrexone (LDN).” Journal of Neuroimmune Pharmacology 8.3 (2013): 470-476.
Complex Regional Pain Syndrome (CRPS) is a neuropathic pain syndrome, which involves glial activation and central sensitization in the central nervous system. Here, we describe positive outcomes of two CRPS patients, after they were treated with low-dose naltrexone (a glial attenuator), in combination with other CRPS therapies. Prominent CRPS symptoms remitted in these two patients, including dystonic spasms and fixed dystonia (respectively), following treatment with low-dose naltrexone (LDN). LDN, which is known to antagonize the Toll-like Receptor 4 pathway and attenuate activated microglia, was utilized in these patients after conventional CRPS pharmacotherapy failed to suppress their recalcitrant CRPS symptoms.

Dysautonomia POTS

14) Weinstock, Leonard B., et al. “Case Report: Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment.” BMJ case reports 2018 (2018). Successful treatment postural orthostatic tachycardia mast cell activation syndrome naltrexone immunoglobulin antibiotic Weinstock Leonard BMJ case reports 2018

Lyme Disease

15) Hatziagelaki, Erifili, et al. “Myalgic Encephalomyelitis/Chronic Fatigue Syndrome—Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus?.” Journal of Pharmacology and Experimental Therapeutics 367.1 (2018): 155-167. Myalgic Encephalomyelitis Chronic Fatigue Syndrome Focal Inflammation in Hypothalamus Hatziagelaki Erifili J Pharm Exper Ther 2018

16) Steere, Allen C., and Sheila L. Arvikar. “Editorial commentary: what constitutes appropriate treatment of post-Lyme disease symptoms and other pain and fatigue syndromes?.” (2015): 1783-1785.

This chronic syndrome, which sometimes meets criteria for fibromyalgia or chronic fatigue syndrome, is not specific for Lyme disease [8].

17)  Are Your Fibromyalgia Symptoms Due to Lyme Disease? Tick-borne disorders often mimic chronic pain syndromes Dec 15, 2013 Richard Horowitz MD PSychology today

18) Ruiz-Núñez, Begoña, et al. “higher Prevalence of “low T3 syndrome” in Patients With chronic Fatigue syndrome: a case–control study.” Frontiers in endocrinology 9 (2018): 97

19) Holtorf, Kent. “Diagnosis and Treatment of Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysfunction in Patients with Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM).” JOURNAL OF CHRONIC FATIGUE SYNDROME 14.3 (2008). Diagnosis_Treatment_Hypothalamic_Pituitary_Adrenal_HPA_Axis_Kent_Holtorf_2008

20) Teitelbaum, Jacob. “Effective treatment of chronic fatigue syndrome.” Integrative Medicine 4.4 (2005): 24. Effective Treatment of Chronic Fatigue Syndrome JAcob Teitelbaum 2005 Integrative Medicine

21)  Treatment fibromyalgia pain with testosterone White Hillary Int immunopharm 2015  White, Hillary D., et al. “Treatment of pain in fibromyalgia patients with testosterone gel: Pharmacokinetics and clinical response.” International immunopharmacology 27.2 (2015): 249-256.

To test our hypothesis that testosterone deficiency plays an important role in chronic pain, a Phase I/II pilot study was initiated with 12 fibromyalgia patients to verify that a daily dose for 28 days with transdermal testosterone gel would 1) significantly and safely increase mean serum testosterone concentrations from low baseline levels to mid/high-normal levels, and 2) effectively treat the pain and fatigue symptoms of fibromyalgia. Pharmacokinetic data confirmed that serum free testosterone concentrations were raised significantly above baseline levels, by assessment of maximum hormone concentration (Cmax) and area under the curve (AUC) parameters: free testosterone Cmax was significantly raised from a mean of 2.64pg/mL to 3.91pg/mL (p<0.05), and 24hour free testosterone AUC was significantly raised from a mean of 35.0pg-hr/mL to 53.89pg-hr/mL. Assessment of the typical symptoms of fibromyalgia by patient questionnaire and tender point exam demonstrated significant change in: decreased muscle pain, stiffness, and fatigue, and increased libido during study treatment. These results are consistent with the hypothesized ability of testosterone to relieve the symptoms of fibromyalgia. Symptoms not tightly related to fibromyalgia were not improved.

22) Wu, Zhenqiang, et al. “Effect of vitamin D supplementation on pain: a systematic review and meta-analysis.” Pain Physician 19.7 (2016): 415-427.

23) Abou-Raya, S., A. Abou-Raya, and M. Helmii. “THU0327 Efficacy of Vitamin D Supplementation in the Treatment of Fibromyalgia: Randomized Controlled Trial.” Annals of the Rheumatic Diseases 73.Suppl 2 (2014): 295-295.

Conclusions Vitamin D may be an effective, cheap and useful addition to the therapeutic armamentarium for fibromyalgia. However, larger, long-term studies are required to confirm the results of the present study.


Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314

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The Non-Mystery of Chronic Fatigue Syndrome
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The Non-Mystery of Chronic Fatigue Syndrome
Chronic Fatigue is a Mystery to Mainstream Medicine, but not to us.
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One thought on “The Non-Mystery of Chronic Fatigue Syndrome

  1. CFS symptoms must be present in a person for at least six months before it can be identified. These symptoms usually worsen during the first few years, but the patient’s condition gradually improves afterward. However, the illness persists for several months or years, and only a minor percentage of people regain their normal health.

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