Chronic Fatigue Syndrome Linked to Low T3 Syndrome

Some people with the condition known as chronic fatigue syndrome (CFS) have low circulating levels of the thyroid hormone triiodothyronine (T3) and normal levels of thyroid-stimulating hormone (TSH), new research shows. The results suggest these patients may be in a hypometabolic state, but one expert thinks the low levels are more likely a consequence, rather than a cause, of CFS.

The findings, based on 98 patients with CFS and 99 age- and sex-matched controls, were published online March 20 in Frontiers in Endocrinology by Begoña Ruiz-Núñez, a PhD student at the University of Groningen, the Netherlands, and colleagues.

Several CFS symptoms resemble those of hypothyroidism but without the marked increase in TSH. This is also the case, the authors point out, in the so-called low T3 syndrome. Low T3 syndrome, also known as euthyroid sick syndrome, is characterized by decreased serum T3 and/or thyroxin (T4) levels, increased reverse T3 (rT3), and no significant increase in TSH.

This low T3 syndrome might be in line with recent metabolomic studies that point to a hypometabolic state (Proc Natl Acad Sci U S A. 2016;113:E5472-E5480), and if confirmed, T3 and iodide supplements may be indicated as treatments, say Núñez and colleagues.

But endocrinologist Willard H Dere, MD, professor of internal medicine at the University of Utah, Salt Lake City, isn’t convinced.

“The limited data are consistent with what is seen in other inflammatory and chronic disease states. There is no current evidence that thyroxine or tri-iodothyronine replacement in those with low T3 syndrome is beneficial. Furthermore, in hypothyroid patients on thyroxine replacement, the use of tri-iodothyronine, along with L-thyroxine, is thought by some experts to be beneficial, but this view is not a consensus,” he told Medscape Medical News.

Differences Seen in Thyroid Hormones, Inflammatory Markers

The patients were recruited from a single clinic in Amsterdam, and all had been diagnosed with CFS based on 1994 criteria. However, those criteria differ in several ways from more recent definitions of what is now termed myalgic encephalomyelitis (ME)/CFS, including those published by the US Institute of Medicine (IOM) in 2015.

Both definitions include disabling fatigue that lasts more than 6 months and does not improve with rest, and cognitive impairment. However, the IOM criteria place post-exertional malaise as central to the diagnosis, whereas it’s not required in older definitions. Moreover, the IOM criteria don’t require that other potentially fatiguing illnesses be ruled out before making the diagnosis, whereas the older definition does.

In the current study, the 21 men and 77 women with CFS had a mean age of 43 years and body mass index (BMI) of 22 kg/m2. The 23 men and 76 women who were control participants had a mean age of 39 years and BMI of 23 kg/m2, which were not significantly different from the CFS group.

Compared with controls, the CFS group had lower levels of free triiodothyronine (FT3), total T4 (TT4), total T3 (TT3), percent TT3, sum activity of peripheral deiodinases (SPINA-GD), and secretory capacity of the thyroid gland (SPINA-GT), as well as lower ratios of TT3/TT4, FT3/FT4, TT3/FT3, and TT4/FT4, and higher percent rT3 and rT3/TT3 ratio.

There were no differences between groups in other thyroid hormone parameters, notably TSH, FT4, rT3, and percent TT4.

FT3 levels below the reference range were more frequent in the CFS group (16/98) compared with controls (7/99; P = .035), with an odds ratio of 2.56 (95% CI, 1.00 – 6.54).

However, Dere commented, “The subset of patients with the low T3 syndrome is relatively small, and their laboratory values don’t vary substantively from that of the control group. Overall, I think the probability of a low T3 syndrome causing ME/CFS is low.”

In measures of metabolic inflammation, no significant differences were found in white blood count, high-sensitivity C-reactive protein (hsCRP), tryptophan/kynurenine ratio, or urinary isoprostanes, but the CFS group did have lower kynurenine and tryptophan levels than controls.

Ferritin was higher and HDL-cholesterol was lower in patients with CFS. Zonulin, a parameter of intestinal permeability, was also lower in patients with CFS compared with controls.

Measures of nutritional factors influencing thyroid function and inflammation that differed between the groups included 24-hour urinary iodine output, a proxy of iodine status, which was lower in patients with CFS. Plasma selenium was similar, but intracellular selenium was higher in patients with CFS. Vitamin D [25(OH)D] status of patients with CFS was higher, but 59% of patients with CFS and 83% of controls presented with 25(OH)D levels below the optimal cutoff of 80 nmol/L, Ruiz-Núñez and colleagues report.

In two sensitivity analyses that excluded patients with the highest levels of inflammatory markers, all the prior findings remained significant except FT3, which was no longer significantly lower in the CFS group.

Markers of Inflammation: Cause or Consequence?

Overall in both groups, FT3, TT3, TT4, and rT3 were positively related with hsCRP.

“The limited data from this study correlates other markers of inflammation with the presence of low T3 and high reverse T3, and are consistent with what is seen with other inflammatory and chronic disease states,” Dere noted.

He added that the low T3 state “seems to be the result, not the cause, of a systemic or localized inflammatory or chronic disease state. During caloric deprivation, the fall in T3 is believed to be an adaptive response directed to saving energy and protein for enduring this acute stress. Thus one can speculate that with some chronic disorders, the diminished plasma T3 helps to preserve caloric expenditure.”

Overall, Dere said he wouldn’t change clinical practice based on these findings. “A serum TSH is a good screening test to rule out primary thyroidal disorders.”

My Battle with Guideline Fatigue Syndrome

It started slowly. My former resident and present colleague Terry Shaneyfelt first authored, “Are Guidelines Following Guidelines? The Methodological Quality of Clinical Practice Guidelines in the Peer-Reviewed Medical Literature.”

This paper alerted us to the problem. But guideline fever continued to rage. Almost every specialty and subspecialty society decided that they needed to join the guideline movement. They needed to tell us the right way to practice medicine.

While I understood the problems of guidelines (I had found a 40-page guideline on cerumen), it had not yet become visceral. Then the great pharyngitis controversy of the early 21st century made it personal. In 2001 the ACP (endorsed by the CDC and AAFP) published, “Principles of Appropriate Antibiotic Use for Acute Pharyngitis in Adults.”

This guideline endorsed the Centor score to exclude testing or treatment for 0 and 1, test 2, and either test or treat with narrow-spectrum antibiotics 3 or 4. The next year, the IDSA published, “Practice Guidelines for the Diagnosis and Management of Group A Streptococcal Pharyngitis.”

That guideline argued for testing 2-4, again neither testing nor treating 0 or 1. Some authors of that guideline then published an editorial that “took the ACP to task” for suggesting empiric treatment of some patients: “We must conclude, therefore, that the algorithm-based strategy proposed in the ACP-ASIM Guideline would result in the administration of antimicrobial treatment to an unacceptably large number of patients with non-streptococcal pharyngitis.

I strongly disagreed with the IDSA position but remained puzzled how two reputable organizations could review the same data in an evidence-based manner and have such disparate recommendations. And then it gets even worse. The Annals of Family Medicine published this article from Europe, “Differences Among International Pharyngitis Guidelines: Not Just Academic”:

“Although the evidence for the management of acute sore throat is easily available, national guidelines are different with regard to the choice of evidence and the interpretation for clinical practice. Also, a transparent and standardized guideline development method is lacking. These findings are important in the context of appropriate antibiotic use, the problem of growing antimicrobial resistance, and costs for the community.”

That 2007 study preceded this 2011 study, “Analysis of Different Recommendations from International Guidelines for the Management of Acute Pharyngitis in Adults and Children.” That study compared 12 guidelines and found great disparities in recommendations.

Now, I was certain that the guideline process had a major limitation. For the occasional question, the data are clear, and all parties agree, but too often different guideline committees have differing values. And values influence how we view data and certainly what we value in developing our guidelines.

You likely know several examples of “dueling guidelines” – breast cancer screening, prostate cancer screening, and goals of diabetes control. Recently, we have guidelines for hypertension that give significantly different recommendations.

I realized that I had Guideline Fatigue Syndrome (GFS), when I wrote about an excellent IDSA article,”The IDSA takes an admirable position in not endorsing the new Sepsis Guidelines.”

So what causes this syndrome? We want to believe that guidelines come from evidence, but we forget the famous Nietzsche quote, “There are no data, only interpretation.” Depending on our belief system, we value outcomes differently. In the sepsis example, the critical care doctors want sensitivity (few false-negatives) and do not see problems with lower specificity (i.e., giving antibiotics to some patients who do not need them). The IDSA worries (appropriately) about antibiotic resistance and antibiotic side effects. So they prefer to maximize specificity and wait for more data in some patients.

Too often guidelines are considered rules. They were always meant to be guides, and clinical judgment should always trump the guides. But each time a major guideline appears, we read about it in The New York Times. Practicing physicians do not know what to believe because of guideline bloat and controversy. We do not need 12 pharyngitis guidelines. We should not even call specialty and subspecialty opinions guidelines. They are making recommendations based upon their view of medicine. We all have biased views of proper medical care.

Guidelines can have serious unintended consequences. When we label our opinions as guidelines, we put all physicians in an uncomfortable and even untenable situation.

So, I have no idea how to evaluate the seemingly never-ending supply of guidelines. I have no idea how to interpret them recognizing the biases involved in creating them.

Please join me and admit that you too have GFS. I fear this syndrome has no cure. It is pervasive and growing. It is not a rare disease.


The science supporting the efficacy of magnesium for major depression and other psychiatric disorders, testing for magnesium deficiency, and which forms and dosages are most effective.

Depression, a life-threatening psychiatric disorder, lies at the confluence of biochemical, hormonal, immunological, and neurodegenerative variables, which intersect to generate the pro-inflammatory state with which depression is associated. A major public health issue, depression is estimated to become one of the top three contributors to the global burden of diseases within a few years. Not only does depression consume a sizable portion of health care expenditures, but it is considered to be an independent risk factor for metabolic, cardiovascular, and neuropsychiatric disorders (1).

Current treatments are predicated upon a misguided serotonin theory of depression, and are accompanied by a laundry list of deleterious side effects ranging from sexual dysfunction to homicidality (2, 3, 4). Antidepressant medications likewise significantly increase the risk of all-cause mortality, or death from any cause, as well as heart disease, leading researchers to deem this class of pharmaceuticals as harmful to the general population (5). This, in combination with data indicating that antidepressants are clinically equivalent to placebo, render them an unfavorable option (6), especially considering that they offer little in the way of resolving the root cause.

Magnesium: The Miracle Mineral

Rather than resorting to psychotropic drugs, it would be prudent to explore whether magnesium (Mg) supplementation improves depression, since this essential mineral is implicated in the pathophysiology of this disorder. Magnesium may be indeed branded as miraculous given its essentiality as a cofactor to over three hundred enzymatic reactions (7). It is second only to potassium in terms of the predominant intracellular cations, or ions residing in cells that harbor a positive charge (7).

 Magnesium is fundamentally involved in protein production, synthesis of nucleic acids, cell growth and division, and maintenance of the delicate electrolyte composition of our cells (7). It also imparts stability to the membranes of the energy factories of our cells called mitochondria (7). As articulated by researchers, “The physiological consequences of these biochemical activities include Mg’s central roles in the control of neuronal activity, cardiac excitability, neuromuscular transmission, muscular contraction, vasomotor tone, and blood pressure” (7).

The biological effects of magnesium are widespread. When deficient, magnesium is correlated with systemic inflammation. Not only does magnesium sufficiency promote cardiovascular health, relaxing the smooth muscles that comprise blood vessels and preventing high levels of vascular resistance that cause hypertension, but it also plays a role in musculoskeletal health and prevents sarcopenia, osteoporosis, and fractures (8). Magnesium is essential to regulation of sleep (9) and vitamin D metabolism (10) as well as neural plasticity and cognitive function.

However, food processing and industrial agriculture, including monoculture crop practices and the use of magnesium-devoid fertilizers, have led to soil erosion and depletion of magnesium content in our food (7). Magnesium is likewise removed from most drinking water supplies, rendering magnesium deficiency an inevitability (11). As such, our daily intake of magnesium has steadily declined from 500 milligrams (mg) per day to 175 mg per day (7). The nutrient-poor, energy-dense dietary patterns which have come to dominate the industrialized landscape are also insufficient in the fiber-rich fruits and vegetables which contain magnesium.

Animal Studies Propose a Role for Magnesium in Depression

Preliminary animal studies pointed to a role of magnesium in depression, as depletion of magnesium in the diet of mice lead to enhanced depression- and anxiety-related behavior such as increased immobility time in the forced swim test (12). In the forced swim test, a common assay for examining depression-like behavior in rodents, the animal is confined to a container filled with water and observed as it attempts to escape. The time in which the animal exhibits immobility is used as a barometer of despair, indicating that the animal has succumbed to a fate of drowning (1).

This model is confirmed by studies showing that administering substances with antidepressant properties such as Hypericum perforatum, also known as St. John’s Wort, can significantly decrease the time the animal spends without locomotor activity (12). In addition, the time the animal spends immobilized is influenced by many of the factors that are changed as a consequence of depression in humans, such as drug-withdrawal-induced anhedonia, impaired sleep, and altered food consumption (1).

Human Studies Confirm the Role of Magnesium in Depression

There is a paucity of research on the influence of specific micronutrients in depression and results are inconsistent, but several studies have revealed low serum magnesium in this mood disorder. It is well-documented, for example, that dietary magnesium deficiency in conjunction with stress can lead to neuropathologies and symptoms of psychiatric disorders. Researchers echo this sentiment, stating that, “Dietary deficiencies of magnesium, coupled with excess calcium and stress may cause many cases of other related symptoms including agitation, anxiety, irritability, confusion, asthenia, sleeplessness, headache, delirium, hallucinations and hyperexcitability” (11, p. 362).

The Hordaland Health study in Western Norway illustrated an inverse association between standardized energy-adjusted magnesium intake and depression scores, meaning that people who consumed less magnesium had higher rates of depression (13). When the serum and cerebrospinal fluid of acutely depressed patients diagnosed with major depressive disorder or bipolar patients in a depressive episode were compared to healthy controls, the calcium to magnesium ratio was found to be elevated in the former (14). Calcium and magnesium are minerals which antagonize one another and compete for absorption, since each of these minerals is a divalent cation (a positive ion with a valence of two). Suicidality, one of the primary manifestations of severe depression, is accompanied by low cerebrospinal fluid levels of magnesium despite normal calcium levels, lending credence to the role of magnesium in positive emotionality (15).

Magnesium Effective in Bipolar Disorder, Fibromyalgia, PMS, and Chronic Fatigue Syndrome

A formulation of magnesium aspartate hydrochloride known as Magnesiocard has been shown to invoke mood-stabilizing effects in patients with severe rapid cycling bipolar disorder in one open study label (16). In half of the patients treated, this magnesium preparation had results equivalent to lithium, the standard of care for this patient population, such that the researchers suggested: “The possibility that Magnesiocard could replace or improve the efficacy of lithium as a preventive treatment of manic-depressive illness merits further clinical investigation” (16, p. 171). When used as an adjunctive therapy in severe, therapy-resistant mania, magnesium sulphate infusions significantly reduced the use of lithium, benzodiazepines and neuroleptics, so much so that the researchers concluded that it “may be a useful supplementary therapy for the clinical management of severe manic agitation” (17, p. 239).

In another randomized trial of elderly patients with type 2 diabetes and magnesium deficiency, elemental magnesium administered at 450 mg per day was found to have equivalent efficacy to 50 mg of the antidepressant drug Imipramine in treating depressive symptoms (18). Magnesium citrate taken at 300 mg per day has likewise been shown to decrease depression and other symptoms in patients with fibromyalgia as indicated by significant decreases in the fibromyalgia impact questionnaire (FIQ) and Beck depression scores (19).

Data also indicate that supplementation with 360 mg of magnesium administered to women with premenstrual syndrome (PMS) three times a day in the second half of the cycle is effective for so-called negative affect and other premenstrual-related mood symptoms (20). Lastly, intramuscular magnesium sulphate administered every week for six weeks has been proven to be effective in improving emotional state and other parameters in chronic fatigue syndrome (CFS) (21).

Mechanism of Action for Antidepressant Effects of Magnesium

According to researchers, “Biological systems discussed to be involved in the pathophysiology of affective disorders and the action of mood stabilizing drugs are affected by Mg, such as the activity of the hypothalamus–pituitary–adrenocortical (HPA) system, corticotropin releasing factor (CRF)-, GABA- and glutamatergic (via NMDA receptors) neurotransmission and several transduction pathways including protein kinase C” (12). Not only that, but magnesium elicits similar effects on nocturnal hormonal secretion and sleep brain waves to lithium salts, which are used as a treatment modality for bipolar disorder, supporting the role of magnesium as a mood stabilizer (22).

Magnesium operates as an agonist, or a stimulatory molecule, for γ-aminobutyric acid (GABA) receptors (22). GABA is the main inhibitory neurotransmitter in the central nervous system. By binding to the GABA receptor and replicating the effects of GABA, magnesium may alleviate anxiety. Magnesium may also elicit its antidepressant effects by acting as an inorganic antagonist of N-methyl-d-aspartic acid (NMDA) receptor function (Poleszak et al., 2007). Receptor antagonists are ligands, or substances, which bind to a receptor but inhibit its activity rather than activating it. NMDA receptors, which occur on the surface of nerve cells, are activated in part by glutamate, one of the excitatory amino acids in the brain.

Researchers state that, “Dysfunction of NMDA receptors seems to play a crucial role in the neurobiology of disorders such as Parkinson’s diseaseAlzheimer’s diseaseepilepsy, ischemic stroke, anxiety and depression,” such that, “ligands interacting with different sites of NMDA receptor complex are widely investigated as potential agents for the treatment of a variety of neuropsychiatric disorders” (22). In fact, drug inhibitors at the NMDA receptor complex, such as ketamine, demonstrate antidepressant effects (23, 24), but also induce such severe side effects that their clinical utility is limited (31). Magnesium, on the other hand, may have a similar mechanism of action by interfering with NMDA receptor activation without the adverse consequences of drug-induced NMDA receptor blockade (25).

Recent Study Proves Efficacy of Oral Magnesium for Depression

A recent open-label, randomized, cross-over trial was conducted in outpatient primary care clinics on 126 adults diagnosed with depression (26). During the intervention, 248 mg of elemental magnesium chloride per day, obtained from four 500 mg tablets, was administered for six weeks and compared to six weeks of no treatment, and subjects were evaluated for changes in depressive symptoms (26).

Magnesium administration results in clinically significant improvements in scores on both the Patient Health Questionnaire-9 (PHQ-9), a validated measure of the severity of depression and response to treatment, as well as the Generalized Anxiety Disorders-7 (GAD-7), a sensitive self-reported screening tool for severity of anxiety disorders (26). Impressively, results appeared in as little as two weeks, representing the dramatic improvement that nutrient restoration can facilitate (26). Impressively, however, magnesium exerted anti-depressant effects regardless of baseline magnesium level. It also exhibited efficacy independent of the gender, age, or baseline severity of depression of subjects, as well as their use of antidepressant medications (26). The authors of the study conclude, “Magnesium is effective for mild-to-moderate depression in adults. It works quickly and is well tolerated without the need for close monitoring for toxicity” (26).

Populations At Risk for Magnesium Deficiency

Half of the population of the United States was found to consume less than the recommended amount of magnesium when estimated a decade ago (27). Not only is magnesium lost with certain medical conditions, but this mineral is excreted as a consequence of biological activities such as sweating, urinating, and defecating as well as excess production of stress hormones (7, 11). In addition, because low magnesium has been correlated with various disease states, increasing magnesium status may mitigate risk of these diseases.

For instance, researchers note that, “Low magnesium intakes and blood levels have been associated with type 2 diabetes, metabolic syndrome, elevated C-reactive protein, hypertension, atherosclerotic vascular disease, sudden cardiac death, osteoporosis, migraine headache, asthma, and colon cancer” (27, p. 153). In addition, magnesium deficiency at a cellular level “elicits calcium-activated inflammatory cascades independent of injury or pathogens” (27, p. 153). Low magnesium is associated with systemic inflammation, and inflammation is at the root of most chronic and degenerative diseases.

Testing for Magnesium and Food Sources of Magnesium

While the first inclination of some physicians may be to test magnesium levels for an objective parameter of deficiency, the widely used serum or plasma magnesium does not accurately reflect magnesium levels stored in other tissues (28, 29). In addition, both this hematological index of magnesium status, referred to as total magnesium, and the erythrocyte magnesium level, indicative of the levels of magnesium inside red blood cells, are not negatively affected until severe magnesium deprivation has occurred (7). Therefore, these testing methodologies are not accurate enough to catch preliminary or subclinical magnesium deficiency.

Good food sources of magnesium include pumpkin and squash seed kernels, Brazil nuts, almonds, cashews, peanuts, pine nuts, quinoa, spinach, Swiss chard, beet greens, potatoes, artichoke hearts, dates, bananas, coconut milk, prickly pear, black beans, lima beans, soybeans, and seafood sources including halibut, abalone, anchovy, caviar, conch, crab, oyster, scallop, snail, and pollock. However, it is important to note that magnesium can be leeched from vegetables when food is boiled, and that fiber in excess can decrease magnesium absorption by increasing gastrointestinal motility (7).

Most Bioavailable Forms of Magnesium

As elucidated by the researchers, “Over-the-counter magnesium can be offered as an alternative therapy to those patients hesitant to begin antidepressant treatment and is easily accessible without a prescription” (26). Because the soil is no longer enriched in magnesium, supplementation may be warranted. Organic salts of magnesium, including the acetate, ascorbate, aspartate, bicitrate, gluconate, and lactate forms are more soluble and biologically active over the magnesium mineral salts such as magnesium oxide, magnesium carbonate, magnesium chloride, and magnesium sulfate (7).

However, case studies have shown remarkably rapid recovery from major depression, in less than seven days, when magnesium glycinate and magnesium taurinate are administered at dosages of 125 to 300 mg with each meal and at bedtime (11). Magnesium threonate may also be explored as a therapeutic option, as it may have better penetrance of the blood brain barrier and restore neurological levels of magnesium. This form, which is delivered directly to the brain, may improve cerebral signaling pathways and synaptic connections between nerve cells as well as support learning and memory, although the studies have been conducted in animal models (30).

Researchers report that magnesium is usually effective for treating depression in general use, and that comorbid conditions occurring in these case studies, including “traumatic brain injury, headache, suicidal ideation, anxiety, irritability, insomnia, postpartum depression, cocaine, alcohol and tobacco abuse, hypersensitivity to calcium, short-term memory loss and IQ loss were also benefited” by magnesium supplementation (11, p. 362). Barring abnormal kidney function, the Institute of Medicine sets the upper tolerable limit for intake at 350 mg of elemental magnesium per day, but there are few adverse side effects documented unless consumed in inordinate doses (26).

Before changing your medication or nutraceutical regimen, always consult a functional or integrative medical doctor for contraindications. However, given the benign nature of magnesium supplementation and the ubiquity of magnesium insufficiency, depressedpatients should be offered this as a first line strategy alongside a holistic root-cause resolution approach to treating depression

Another study just linked chronic fatigue syndrome to gut bacteria.

A new study has shown that people with chronic fatigue syndrome have abnormal levels of specific gut bacteria – providing even more evidence that the condition isn’t “just in a person’s head“.

For decades, millions of people have reported experiencing symptoms now associated with a condition called chronic fatigue syndrome – a debilitating disease that causes brain fog, severe pain, and exhaustion so extreme, patients can’t go about their daily lives, and sometimes can’t even get out of bed. But a physical cause has been elusive, leaving many feeling that their condition isn’t being taken seriously.

It was only in 2015 that the US Institute of Medicine detailed a comprehensive way to diagnose chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), and earlier this year, scientists linked the condition to faulty cell receptors in immune cells for the first time – which explains why the side effects can be so varied and hard to pin down.

But there are still no effective treatments for the disease, and no cure – some commonly prescribed treatments for the condition have been cognitive behavioural therapy and exercise, neither of which have any evidence to support they work, and could actually be doing more harm than good.

Now, new research has shown that patients with ME/CFS have abnormal levels of specific gut bacteria – and those levels change depending on the severity and type of symptoms they have.

“Individuals with ME/CFS have a distinct mix of gut bacteria and related metabolic disturbances that may influence the severity of their disease,” said one of the researchers, Dorottya Nagy-Szakal from Columbia University’s Mailman School of Public Health.

“By identifying the specific bacteria involved, we are one step closer to more accurate diagnosis and targeted therapies,” added lead researcher Ian Lipkin.

The study adds to research from last year, which showed that up to 80 percent of patients with ME/CFS could be accurately diagnosed by looking at their gut bacteria.


And it’s also known that up to 90 percent of ME/CFS patients have irritable bowel syndrome (IBS), so the latest research began to untangle the specific gut bacteria changes associated with each condition.

The team followed 50 ME/CFS patients and 50 healthy controls, who had been carefully matched. They tested the number of bacterial species in faecal samples, and looked at the immune molecules in their blood.

They found that seven distinct intestinal bacterial species were strongly associated with ME/CFS, so much so that an elevated presence of all of them could predict a diagnosis.

The strains were:

  • Faecalibacterium
  • Roseburia
  • Dorea
  • Coprococcus
  • Clostridium
  • Ruminococcus
  • Coprobacillus

There were also specific changes seen in the gut bacteria of those who had chronic fatigue syndrome with IBS, and those who didn’t have IBS.

Interestingly, when the team measured bacterial metabolic pathways – the ways that bacteria break down food and send signals to the brain – there were clear differences between the healthy controls and the ME/CFS group.

There were also measurable differences depending on the severity of a patient’s symptoms, which suggests that are different subtypes of ME/CFS that could be identified.

While this study involved only a small sample size, with further verification, this could be the first step towards coming up with targeted ways to not only diagnose the debilitating disease, but also treat it.

“Our analysis suggests that we may be able to subtype patients with ME/CFS by analysing their fecal microbiome,” said one of the team, Brent L. Williams.

“Subtyping may provide clues to understanding differences in manifestations of disease.”

Virology: Fighting for a cause.

When Judy Mikovits found links between chronic fatigue syndrome and a virus, the world took notice. Now, she’s caught between the patients who believe her work and the researchers who don’t.

On a sunny January afternoon in Santa Rosa, California, a small crowd waits patiently for Judy Mikovits to arrive. She is scheduled to deliver a talk on a mysterious virus called XMRV, which she believes underlies chronic fatigue syndrome. Although she’s two hours late — held up by fog at San Francisco International Airport — not a single person has left. And when she arrives, they burst into applause.

To a rapt audience, she gives a chaotic and wide-ranging talk that explores viral sequences, cell-culture techniques and some of the criticisms that have been thrown at her since she published evidence1 of a link between XMRV and chronic fatigue in 2009. Afterwards, Mikovits is swarmed by attendees. A middle-aged woman who spent most of the talk in a motorized scooter stands up to snap pictures of her with a digital camera. Ann Cavanagh, who has chronic fatigue and has tested positive for XMRV, says that she came in part for information and in part to show her support for Mikovits. “I just wish there were a hundred of her,” Cavanagh says.

The event was “surreal”, says Mikovits, a viral immunologist at the Whittemore Peterson Institute for Neuro-Immune Disease (WPI) in Reno, Nevada. She is discomfited by the attention from patients, which at times borders on adulation. But her reception among scientists has been markedly cooler. Numerous follow-up studies have found no link between the virus and the disease; no group has published a replication of her findings; and some scientists argue that XMRV is an artefact of laboratory contamination. Now, even some of Mikovits’s former collaborators are having second thoughts.

Mikovits has dug in, however, attacking her critics’ methods and motives. She says that their distrust of her science stems from doubts about the legitimacy of chronic fatigue syndrome itself. Chronic fatigue, also known as myalgic encephalomyelitis, affects an estimated 17 million people worldwide, but it is extremely difficult to diagnose. Many with the disorder are told that their symptoms — which include exhaustion, joint and muscle pain, cognitive issues, and heart and respiratory problems — are psychosomatic. “I had no idea there was that much bias against this disease,” Mikovits says.

The stakes are high and many are taking the risks seriously. Several countries have barred people with chronic fatigue from donating blood in case the virus spreads (see ‘Something in the blood’). And the US government has launched a US$1.3-million study to investigate the link. Patients are already being tested for XMRV, and some are taking antiviral drugs on the assumption that the virus causes chronic fatigue by attacking their immune defences. Many say that such action is premature, but Mikovits is steadfast. “We’re not changing our course,” she says.

First findings

In October 2007, Mikovits attended a prostate-cancer meeting near Lake Tahoe, Nevada, where she met Robert Silverman, a virologist at the Cleveland Clinic in Ohio. Silverman co-discovered XMRV, which stands for xenotropic murine leukaemia virus-related virus2. While examining human prostate tumours, he and his collaborators found genetic sequences that resemble retroviruses found in the mouse genome. Like all retroviruses, XMRV rewrites its RNA genome into DNA on infection, then slips the DNA into the genomes of host cells. Ancient remnants of such viruses litter animal genomes. But the only active retroviruses conclusively linked to human disease are HTLV-1, which causes leukaemia, and HIV.

At the meeting, Silverman was presenting research linking XMRV to deficiencies in a virus-defence pathway. Mikovits recalled that the same pathway was weakened in some patients with chronic fatigue. She wondered whether the prostate-tumour virus could also be behind chronic fatigue. After the meeting, Silverman sent Mikovits reagents to test for XMRV.

The idea excited Mikovits, but she had other priorities. After stints in industry and at the US National Cancer Institute (NCI) in Maryland, she had recently joined the WPI to lead its research programme. The WPI was founded in 2006 by physician Daniel Peterson, an expert on chronic fatigue, and by Annette Whittemore, the wife of a well-connected Nevada businessman, whose daughter Andrea has had chronic fatigue for more than 20 years. The Whittemores spent $5 million establishing the WPI, and several million more to support Mikovits’s research, which has attracted few other grants.

At the WPI, Mikovits established a sample collection from Peterson’s patients and began screening it for signs of an infection. A litany of pathogens has been linked to chronic fatigue over the years, including Epstein-Barr virus, Borna disease virus, human herpes virus 6 and HTLV-2. None panned out. Still, the disorder bears some hallmarks of an infection. Many patients report acute illness before chronic symptoms appear, and their bodies often show signs of an immune system at war. The disease can also crop up in apparent outbreaks, including one characterized by Peterson near Lake Tahoe in the 1980s.

Just before Christmas 2008, Mikovits turned her attention to Silverman’s reagents. She and her postdoc, Vincent Lombardi, known as Vinny, asked a graduate student to test for XMRV DNA in white blood cells from some of the most seriously ill people being studied at the WPI.

The first try turned up just two positives out of 20. But by tweaking the conditions of the test, Mikovits says her team found XMRV in all 20. “Vinny and I looked at each other and said, ‘Well, that’s interesting’,” she says. They spent the next few weeks convincing themselves that they were onto something, and soon conscripted Silverman and Mikovits’s former mentor at the NCI, Frank Ruscetti, to help prove that XMRV infection was behind chronic fatigue.

“We really retooled our entire programme and did nothing but focus on that,” she says. They kept the effort under wraps, dubbing it ‘Project X’. Even Peterson and the Whittemores weren’t clued in. Mikovits says that the secrecy was necessary because her team also found XMRV in the blood of some healthy people, raising concerns about blood products. She hoped to build an airtight case because she worried that sceptical public-health officials would undermine her work.

In May 2009, the team submitted a paper to Science reporting the identification of XMRV genetic material in two-thirds of the 101 patients with chronic fatigue they had tested and in 3.7% of 218 healthy people. They also included data suggesting that infected white blood cells could pass the virus on to uninfected cells.

“They call me every single day. I spend so much time trying to understand the patients, to understand this disease.”

Reviewers wanted more evidence: a clear electron micrograph of virus-infected cells, proof that patients mounted an immune response to the virus, an evolutionary tree showing XMRV’s relationship to other viruses and the locations where viral DNA was integrating into patient genomes. Mikovits’s team went to work. “None of us took any time off, not even a weekend,” she says. They resubmitted the paper in early July with everything the reviewers had asked for, except the DNA integration sites, which many scientists consider a gold standard in proving a retroviral infection.

Later that month, NCI officials who had learned about the work invited Mikovits to give a talk at a closed-door meeting with other XMRV researchers and government scientists. “When I finished speaking you could’ve heard a pin drop,” she says. Mikovits says she thinks at least one of her manuscript’s reviewers was at the meeting, because soon after, she got a call from a Science editor. Their paper had been accepted.

Jonathan Stoye, a retrovirologist at the MRC National Institute for Medical Research in London, wrote a commentary about the paper for Science3. He had never heard of Mikovits, but Frank Ruscetti’s name on the paper gave him confidence, he says, and “if it were true, it was clearly very important”. Stoye’s co-author John Coffin, a retrovirologist at Tufts University in Boston, Massachusetts, says he was satisfied with the data and thought it was time to “let the field and public chew on them”.

The BBC, US National Public Radio, The New York Times, The Wall Street Journal and dozens of other news outlets covered the research. “Prostate cancer pathogen may be behind the disease once dubbed ‘yuppie flu’,” Nature announced on its news website the day the paper came out. Phoenix Rising, a forum for patients with chronic fatigue that has become a hub for all things XMRV, called the work a “game changer”, and patients flocked to learn more about a virus that they hoped would explain their condition. But others, including Britain’s leading chronic fatigue patient group, urged caution until more research buttressed the link.

The first negative findings started to arrive in January 2010 — failing to find XMRV in 186 people with chronic fatigue from the United Kingdom4. A month later, a team including Stoye published a paper5showing no evidence of XMRV in more than 500 blood samples from patients with chronic fatigue and healthy people. One day later, theBritish Medical Journal accepted a paper reporting more negative results in Dutch patients6. Studies began piling up so fast that Coffin made a scorecard to show at talks. “I’ve lost count now,” he says.

Mikovits says that the discrepancies can be explained by differences in the geographical distribution of XMRV or in the methods used.

Judy Mikovits says that she will not abandon the hypothesis that XMRV and related viruses cause chronic fatigue syndrome, despite a growing chorus of critics.

The most common way to detect XMRV is PCR, or polymerase chain reaction, which amplifies viral DNA sequences to a level at which they can be identified. Mikovits and her team used this method to detect XMRV in some of their patients, but she contends that the most sensitive way to detect the virus is to culture patients’ blood cells with a cell line in which the virus replicates more quickly. This should create more copies of the virus, making it easier to detect with PCR and other techniques. She says that none of the negative studies applied this method exactly, a fact that annoys her. “Nobody’s tried to rep-li-cate it,” she says, sounding out each syllable for emphasis.

In summer 2010, some evidence emerged in Mikovits’s corner. Harvey Alter, a hepatitis expert at the NIH’s Clinical Center, and his team identified viruses similar to XMRV in 32 of 37 people with chronic fatigue and in 3 of 44 healthy people. They were preparing to publish their results in the Proceedings of the National Academy of Sciences. But scientists at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, were about to publish a negative report. The authors delayed publication of both papers7,8for several weeks to assess discrepancies. The move agitated Mikovits as well as the chronic-fatigue community, who suspected that important data were being suppressed.

When Alter’s work came out in late August7, Mikovits was ecstatic, and the WPI released a YouTube video of her touting it. For other researchers, however, the new paper had shortcomings. The viral sequences from Alter’s paper differed from XMRV, says Greg Towers, a retrovirologist at University College London. “He doesn’t get variation, he gets a totally different virus.” Towers says that mouse DNA, which is chock-full of virus sequences like those Alter’s team found, probably contaminated their samples, which were collected in the 1990s. But Alter says that his team found no contamination from mouse DNA and recovered the same viral sequences from the same patients sampled a decade later.

Contamination became a dirty word for Mikovits. Just before Christmas 2010, Retrovirology published four papers9,10,11,12 that highlighted laboratory contamination as a possible explanation for her findings. One showed, for example, that mouse DNA contaminates an enzyme from a commercial kit commonly used for PCR. Coffin, an author on two of the Retrovirology papers, urges caution against over-extrapolating. These papers do not say that contamination explains Mikovits’s results, he says, just that extreme care is required to avoid it.

Towers and his colleague Paul Kellam, a virologist at the Wellcome Trust Sanger Institute near Cambridge, UK, are less charitable, however. Their study12 showed that the XMRV sequences that Mikovits and Silverman had extracted from patients lacked the diversity expected of a retrovirus that accumulates mutations as it passes between patients. “This doesn’t look like an onwardly transmittable infectious virus,” says Kellam. A press release for the paper issued by the Sanger Institute put it more bluntly: “Chronic fatigue syndrome is not caused by XMRV.”

Mikovits is riled when the topic turns to Towers’s paper over dinner one night in Reno — “Christmas garbage”, she calls it. Contamination cannot explain why her team can reproduce its results both in her lab in Reno and at Ruscetti’s at the NCI, she says. Her team checks for contamination in reagents and in the cells it grows the patients’ samples with. She says that her team has also collected viral sequences that will address Towers’s and Kellam’s criticism but that it hasn’t yet been able to publish them. Meanwhile, an unpublished study of patients in Britain with chronic fatigue bears out the link to XMRV, she says. “I haven’t for one second seen a piece of data that convinced me they’re not infected.”

Jay Levy, a virologist at the Univer­sity of California, San Francisco, has a window in his closet-sized office that looks out into the laboratory where, in the 1980s, he became one of the first scientists to isolate HIV. After his discovery was scooped by other researchers, Levy turned his attention to chronic fatigue and started a long but fruitless search for an infectious cause.

Now, Levy is putting the finishing touches on what could be the most thorough response yet to Mikovits’s Science paper, adopting the same cell-culture techniques to detect the virus and using samples from the same patients. He’s done this with the help of Daniel Peterson, who left the WPI in 2010 for what Peterson says are “personal reasons”. Peterson has questioned the institute’s singular pursuit of XMRV, a research direction that was pursued without his consultation.

Mikovits says that she kept the XMRV work secret from Peterson over fears he would tell his patients, and left his name off the original Science manuscript until a reviewer questioned the omission. When asked whether that episode contributed to his departure, he says, “I was surprised at the secrecy and lack of collaboration.” As for his motivation to team up with Levy: “I’m just trying to get to the truth. It’s my only motive, because this is such a deserving group of patients who need to know what’s going on.”

Others, too, are rallying for a definitive answer. Ian Lipkin, a microbial epidemiologist at Columbia University in New York, has a reputation for getting to the bottom of mysterious disease–pathogen links. His team debunked the association between Borna disease virus and chronic fatigue, for example. Now he is spearheading the $1.3-million effort funded by the US government. He is leaving the testing to three labs: Mikovits’s at the WPI, Alter’s at the NIH and the CDC. Each will receive coded samples of white blood cells and plasma from 150 patients with chronic fatigue and from 150 healthy controls. The labs will test for XMRV using their method of choice. Lipkin will crunch the data and unblind the samples.

But even if a study confirms the link to chronic fatigue, it won’t be able to determine whether the virus is the cause. XMRV could, for example, be an opportunistic infection affecting those whose immune systems are already dampened by chronic fatigue. Even Mikovits can only hypothesize as to how it might cause disease.

The virus might not even exist as a natural infection. At a retrovirus conference this month in Boston, Massachusetts, Coffin and his colleague Vinay Pathak at the NCI in Frederick, Maryland, presented data showing that XMRV emerged in the 1990s, during the development of a prostate-tumour cell line called 22Rv1. Developing the line involved implanting a prostate-tumour sample into mice, retrieving cells that might divide indefinitely and repeating the process. But looking back at DNA samples taken throughout the cell-line’s development showed that human cells became infected only after passing through several different mice. Importantly, XMRV’s sequence seems to have come from two different mouse strains. “They just sort of snapped together like two puzzle pieces,” says Coffin, an event extremely unlikely to have happened twice.

Bumper stickers are just one of the supportive gifts given to the WPI.D. 

XMRV sequences retrieved from patients with prostate cancer and chronic fatigue — including some who have had chronic fatigue since the mid-1980s — are nearly identical to the virus from 22Rv1 cells. The implication, says Coffin, is that this virus, born in a laboratory, has probably been infecting samples for more than a decade, but not people. “Although people on the blogs aren’t going to believe me, I’m afraid this is by far the most reasonable explanation for how XMRV came to be,” says Coffin, who hoped that the association with chronic fatigue would pan out and still thinks some pathogen other than XMRV could explain the disease.

Silverman, who no longer works with Mikovits, says that he wasn’t using 22Rv1 cells when XMRV was discovered. Nonetheless, the work has rattled his confidence in XMRV’s link to both prostate cancer and chronic fatigue.

Mikovits, however, is undeterred. The WPI owns a company that charges patients up to $549 to be tested for XMRV, and Mikovits believes that patients who test positive should consult their doctors about getting antiretroviral drugs normally prescribed to those with HIV. Levy and others worry that she is overreaching. “That’s scary for me. These antiretroviral drugs are not just like taking an aspirin,” he says. Mikovits argues that they might be some patients’ only hope. “The people who we know they’re infected should have a right to get therapy,” she says, “They have nothing. They have no other choice.”

Context and debate

Back in her Reno laboratory two days after the talk in Santa Rosa, Mikovits examines a stack of small plastic flasks under a microscope. Some contain patient cells that she hopes will turn into cell lines and churn out XMRV. “On Wednesdays I get to take care of my cells, and that’s where I’m the happiest,” she says.

She has just come off the phone from a sobbing patient infected with XMRV whose symptoms had worsened. “They call me every single day,” Mikovits says. “I don’t do science any more. I spend so much time trying to understand the patients, to understand this disease. People have moved to Reno to be here,” she says. They’ve left gifts: stuffed animals, and stacks of bumper stickers that say “Today’s Discoveries, Tomorrow’s Cures” and, more boldly, “It’s the virus XMRV”.

Mikovits clearly shares in the frustration of those with chronic fatigue who have been marginalized over the years and told that their disease is not real. She says that this disbelief in the disorder drives the criticism of her work. Kellam and the others say that this isn’t true. They don’t deny the existence of the syndrome or even the possibility of an infectious origin. “What we’re trying to understand is the aetiology,” Kellam says. “It’s a scientific debate.”


Mikovits says that she’s analysed all the papers critical of her work and found flaws in each of them. Nevertheless, she’s quick to endorse findings that support her work. She claims that Coffin and Pathak’s study, for example, “says nothing about human infection”. Yet new work presented at a different meeting that found XMRV using next-generation DNA sequencing offers “no doubt it’s not contamination — that the whole story’s real”, she says.

Despite the growing choir of sceptics, Mikovits says that she has simply seen too many data implicating XMRV and other related viruses in chronic fatigue to change her mind. For her supporters, that steadfastness offers legitimacy and hope. “The scientists are moving forward,” she announced at her talk in Santa Rosa, “and I think the politics will go away shortly.” The crowd responded with vigorous applause. 

Ewen Callaway writes for Nature from London.

  • References

    1. Lombardi, V. C. et al. Science 326, 585-589 (2009). | Article | PubMed | ISI | ChemPort |
    2. Urisman, A. et al. PLoS Pathog. 2, e25 (2006). | Article | PubMed | ChemPort |
    3. Coffin, J. M. & Stoye, J. P. Science 326, 530-531 (2009). | Article | PubMed | ChemPort |
    4. Erlwein, O. et al. PLoS ONE 5, e8519 (2010). | Article | PubMed | ChemPort |
    5. Groom, H. C. et al. Retrovirology 7, 10 (2010). | Article | PubMed | ChemPort |
    6. Van Kuppeveld, F. J. et al. Br. Med. J. 340, c1018 (2010).
    7. Lo, S. C. et al. Proc. Natl Acad. Sci. USA 107, 15874-15879 (2010).
    8. Switzer, W. M. et al. Retrovirology 7, 57 (2010).
    9. Robinson, M. J. et al. Retrovirology 7, 108 (2010).
    10. Oakes, B. et al. Retrovirology 7, 109 (2010).
    11. Sato, E. , Furuta, R. A. & Miyazawa, T. Retrovirology 7, 110 (2010).
    12. Hué, S. et al. Retrovirology 7, 111 (2010).


One of the Biggest Myths About Chronic Fatigue Syndrome Just Got Debunked

Chronic fatigue IS a real disease.

Chronic fatigue syndrome (CFS) or Myalgic Encephalomyelitis (ME) is one of the most perplexing conditions out there. It affects up to 1 million Americans and 2.6 percent of the global population, often triggering exhaustion so severe that patients can’t work or study.

But for decades, researchers have struggled to find an underlying cause, leading to an assumption by many doctors that it’s ‘not a real disease’. Now, Australian researchers have blown that myth wide open, showing for the first time that CFS is linked to a faulty cell receptor in immune cells.

“This discovery is great news for all people living with Chronic Fatigue Syndrome (CFS) and the related Myalgic Encephalomyelitis (ME), as it confirms what people with these conditions have long known – that it is a ‘real’ illness – not a psychological issue,” said Leeanne Enoch, the Science Minister of Queensland – the Australian state that’s supporting the research.

“CFS and ME are notoriously difficult to diagnose, with sufferers often going for years without getting the proper care and attention they need.”

Not only is this the first research to show how the faulty cell receptor causes the immune system changes seen in CFS/ME, it also offers researchers a long-sought-after target for future treatments and tests.

It was two years ago that the US officially listed CFS/ME as a disease, but there’s still no way to test for the disease, and no effective treatment.

In fact, the two most commonly prescribed treatments for the condition are cognitive behavioural therapy and exercise, neither of which have any evidence to support they work – and many feel could actually be doing more harm than good.

Now, the latest study shows the disease actually has a serious cell receptor dysfunction at its core.

The breakthrough came after researchers from Griffith University identified that patients with CFS/ME were far more likely to have single nucleotide polymorphisms – DNA typos – in the genetic code for certain cell receptor.

This cell receptor is known as transient receptor potential melastatin 3 (TRPM3), and in healthy cells it plays a crucial role – transferring calcium from outside the cell to the inside, where it helps regulate gene expression and protein production.

But in several peer-reviewed papers published by the Griffith team last year, they showed that in CFS/ME patients, something seemed to be going wrong with TRPM3.

In the latest study, the team looked at blood samples 15 CFS/ME patients and 25 healthy controls, and found that immune cells in chronic fatigue patients had far fewer functioning TRPM3 receptors than those of healthy participants.

As a result, calcium ions weren’t making it inside the cell like they should be, meaning cell function was impaired.

What makes matters worse is that TRPM3 isn’t just found in immune cells. The team tested its presence on immune cells as they’re easy to access in blood samples, but the receptor is found on every single cell in the body, which not only explains why CFS/ME has been so difficult to diagnose, but also why it’s so severe.

“This is why it’s such a devastating illness, and why it’s been so difficult to understand,” one of the researchers, Don Staines, co-director of Griffith University’s National Centre for Neuroimmunology and Emerging Diseases, told ScienceAlert.

“This dysfunction affects the brain, the spinal cord, the pancreas, which is why there are so many different manifestations of the illness – sometimes patients will suffer from cardiac symptoms, sometimes it will be symptoms in the gut.”

It’s something that’s confused doctors for decades, and has lead to much of the misdiagnosis of the condition – but the new research suggests that all of the common CFS/ME symptoms can be explained by these faulty calcium ion channels.

“We now know that this is a dysfunction of a very critical receptor and the critical role that this has, which causes severe problems to cells in the body,” said Staines.

To be clear, the research is still in its early phases – all we know for now is that these dysfunctional TRMP3 receptors are involved in the disease, and there’s a lot more work to be done.

But Staines suggests that the involvement of TRPM3 receptors could explain why so many patients appear to experience CFS/ME following a traumatic event or serious infection.

The class of receptors TRPM3 belongs to are also known as ‘threat rececptors’, because they’re upregulated when the body is under any kind of threat, such as infection, trauma, or even childbirth.

Staines and his colleagues predict that it’s this upregulation that causes the the faulty genetic receptors to get over-expressed and then take over, messing up the calcium transfer in a range of cells.

For now, that’s just a hypothesis. But it’s a much-needed starting point for researchers to look into further.

Already, Staines and his team are working to figure out the best markers that can be used to test for these faulty receptors, so they can begin to create a CFS/ME test.

They’re also looking for medications that act on these specific calcium ion channels in the hopes of finding potential treatments for the disease.

“We don’t know that we can necessarily cure the illness but we can help people lead a normal life,” Staines explained.

In the meantime, the research is a stark reminder of how serious CFS/ME can be – and how useless, and potentially even damaging, current treatment options are.

“This is a much more debilitating illness than people have realised – people die from CFS/ME because they’re not taken seriously,” Staines told ScienceAlert.

“The new research also suggests that diagnosing exercise is just unbelievably bad as it can put the body under further stress,” he added.

“This is why we’re working day and night to develop a test – so that people start taking the disease seriously.”


Chronic Fatigue Syndrome Starts in Your Gut

Chronic Fatigue Syndrome

Story at-a-glance

  • Chronic fatigue syndrome or myalgic encephalomyelitis can be debilitating and devastating to the individual and their family members
  • Leaking waste products and bacteria from your gut may trigger an inflammatory response, resulting in physical symptoms and neurological changes
  • Eliminating carbohydrates like sugars and grains, especially wheat products, and including high-fiber and fermented foods may help heal your gut and improve your symptoms

Chronic fatigue syndrome (CFS) can be debilitating, causing sufferers to experience unrelenting fatigue no matter how much rest they get. Other symptoms are related to pain and an inflammatory response throughout your body. The medical term for the condition is myalgic encephalomyelitis (ME).

In years past, without an ability to pinpoint a cause, many physicians attributed the condition to psychological origins. No physiological or anatomical commonalities were found between large groups of patients that might have separated the condition from other comparable illnesses.

Widely known as ME/CFS, reports of the condition were first made public in the literature as far back 1934.1 Recently, research from Cornell University discovered biological markers in both microbes in your blood stream and bacteria in your gut.2

With diagnostic changes, in combination with changes discovered in brain tissue of individuals with ME/CFS, it appears scientists may be close to finding a causative agent, potentially improving treatment options.

What Is Chronic Fatigue Syndrome?

Until recently, the diagnosis of ME/CFS has been one of exclusion. This meant all other illnesses mimicking the symptoms of ME/CFS must first be ruled out before doctors could suggest you were suffering from ME/CFS.

Symptoms of ME/CFS can vary widely from one individual to the next. The most common symptom is one of overwhelming exhaustion that worsens with physical or mental energy expenditure and does not get better with rest.3 It may take up to 48 hours after activity to experience the full extent of the exhaustion.

Additional symptoms of the condition may mimic other medical conditions, and include:4,5,6

Muscle pain Memory problems Headaches
Sore throat Pain in multiple joints Difficulty sleeping
Tender lymph nodes Visible muscle twitching (fasciculations) Difficulty concentrating
Short attention span Word find problems Excessive sweating
Palpitations Fainting Clumsiness
Enlarged glands Intermittent flu-like symptoms Alcohol intolerance
Irritable bowel-like symptoms Mood swings Temperature control
Food intolerance Gastrointestinal problems Hypersensitivity to light and noise

While the symptoms are well-documented, to date the cause has not been identified. Possible further complications from the condition include depression, social isolation, lifestyle restrictions and increased absences at work related to your inability to function optimally.

People of all ages, ethnic and racial groups and socioeconomic status are affected by the condition.7 However, women report symptoms four times more often than men, and although people of all ages may have the condition, more report symptoms during their 40s and 50s.

The list of symptoms isn’t a complete indication how people with ME/CFS suffer. David Tuller, coordinator at the University of California (UC), Berkley writes in Virology:8

“In an interview with The New York Times earlier this year, best-selling author Laura Hillenbrand (“Seabiscuit,” “Unbroken”), who has lived with CFS for decades, called the name of the illness ‘condescending’ and ‘so grossly misleading.’

She added: ‘The average person who has this disease, before they got it, we were not lazy people; it’s very typical that people were Type A and hard, hard workers …

Fatigue is what we experience, but it is what a match is to an atomic bomb. This disease leaves people bedridden. I’ve gone through phases where I couldn’t roll over in bed. I couldn’t speak. To have it called ‘fatigue’ is a gross misnomer.’”

Links to ME/CFS Found in Your Gut

In a study released in the journal Microbiome, researchers from Cornell University evaluated the blood and stool of 48 people diagnosed with ME/CFS and compared the results to those from 39 healthy people.9

What they found may shed new light on diagnostic procedures for the condition and may lead to specific strategies for treatment and prevention. Differences were revealed in both stool and blood samples.

Using DNA sequencing, a process of determining the precise order of nucleotides in a DNA molecule, they found a distinct lack in diversity in the gut microbiome in affected individuals and inflammatory markers in the blood.10

Although these changes could not be clearly identified as either the cause or consequence of ME/CFS, researchers were heartened by the presence of these markers in 83 percent of the samples, and the possibility of treatment options to reduce symptoms.

Quoted in the Washington Journal, professor of molecular biology and genetics at Cornell University, Maureen Hanson, Ph.D., said:11

“Our work demonstrates that the gut bacterial microbiome in chronic fatigue syndrome patients isn’t normal, perhaps leading to gastrointestinal and inflammatory symptoms in victims of the disease.

Furthermore, our detection of a biological abnormality provides further evidence against the ridiculous concept that the disease is psychological in origin.”

Leaky Gut Might Be Key

As reported in The Washington Post, researchers from Cornell University theorize the inflammatory markers in the blood could be the result of a “leaky gut from intestinal problems that allow bacteria to enter the blood.”12

Leaky gut is triggered by the development of “gaps” between membrane cells that line your intestinal tract. These tiny gaps allow material meant to remain in your intestinal tract, to leak into your bloodstream. Materials such as undigested food, bacteria and waste products may escape through these gaps.

There is a distinct link between the development of these gaps between cells and the food you eat each day. Grains are particularly troublesome. Research shows that gluten stimulates a molecule in your gut called zonulin, a protein that triggers the opening of junctures between the cells in your gut lining.

In essence, it makes your gut more permeable, allowing food particles to escape into your bloodstream, causing inflammation, immune reactions and raising your risk of various autoimmune disorders.

Not all people with a leaky gut have ME/CFS. However, healing and sealing your gut and reducing the inflammatory response in your body may result in a significant reduction in symptoms. A decline in symptoms is not a cure, but rather supports your body’s immune system.

Brain Changes Associated With ME/CFS

In 2014, researchers from Stanford University uncovered changes in white matter in the brains of those who suffered from ME/CFS, finally giving doctors and patients concrete evidence of neurological changes resulting from the condition.13

Imaging studies using new technology, can now distinguish differences between the brains of people suffering with ME/CFS and healthy individuals.

Those differences included both a diminished amount of white matter and abnormalities in the right hemisphere of the brain.14,15 According to a press release from Stanford Medical Center:

“It’s not uncommon for CFS patients to face several mischaracterizations of their condition, or even suspicions of hypochondria, before receiving a diagnosis of CFS. The abnormalities identified in the study … may help to resolve those ambiguities, said lead author Dr. Michael Zeineh, assistant professor of radiology.”

This study revealed three noteworthy findings scientists may be able to use in an effort to find the cause and cure for this devastating condition.16 The first finding, a reduction in brain white matter responsible for transporting information throughout the brain, was not unexpected. Chronic inflammation has a known effect on white matter.

A consistent abnormality in the right brain hemisphere of people suffering from ME/CFS was a surprise. This area, which connects the frontal and temporal lobes demonstrated an abnormal appearance in advanced imaging techniques. The degree of abnormality was strongly correlated with the severity of the patient’s symptoms. A third finding, thickening of the gray matter on either end of the white matter between the temporal and frontal lobes, makes it unlikely that these findings are coincidental.

Support and Treatment Options at Home

Recent research links an alteration in your gut microbiome, resulting in loss of bacteria and waste products from your intestines, to an increased inflammatory response in the body. Neurological changes found in individuals with ME/CFS are also linked to inflammation, possibly the result of changes in your gut.

While improving the health of your intestinal walls and gut microbiome may not eliminate your symptoms, it will likely improve them. Practical changes to your nutritional plan may help heal the gaps in your intestinal membranes.

Avoid gluten and wheat products: in the U.S., we’re told to increase our whole wheat consumption as a part of a balanced diet and to increase fiber. However, this may actually be damaging your gut health. Gliadins, a component of gluten, are a class of protein found in wheat and cereals. These proteins increase the permeability of your gut.17 Keep in mind that gluten can also be found in other grains, not just wheat.

Wheat germ agglutinin (WGA) is a lectin, or plant protein found in high concentration in seed form. Bread wheat is a relatively new form of wheat that has a resilient and problematic form of WGA.18 It plays a key role in a toxic effect on your kidneys, and there is evidence it increases the damage to your intestinal membrane walls.

Reduce your net carbs: the carbohydrate sugar, like grains, will upset the balance of microbes in your gut. Sugar is the food source for bacteria that can prompt damage to your intestinal walls, while fiber is the food source for bacteria that build your intestinal membranes.

Your net carbs are the total grams of carbohydrates you’ve eaten in a day, minus the grams of fiber you’ve eaten. The difference is your net carbs. Seek to reduce your net carbs to 50 grams per 1,000 calories of food eat each day.

Increase your fiber intake: the fiber you eat from whole foods is the nutrient source for bacteria in your gut that help maintain and build the membrane cells in your intestinal walls. This helps to seal the “gaps” between the cells and reduces any leakage of waste products and bacteria into your blood stream. Focus on eating whole food vegetables, nuts and seeds, such as:

Chia seeds Almonds Beans Berries
Cauliflowers Green beans Peas Broccoli
Brussels sprouts Onions Sweet potatoes Psyllium husk
Flax seeds Beets Parsnips Turnips

Eat fermented foods: although the idea of eating “fermented” foods may sound distasteful, you might be surprised by the list of tasty delicacies produced through this ancient preparation and preservation technique. By breaking down carbohydrates and proteins using bacteria, foods become functional, delicious and a source of natural probiotics to feed your gut.

Olives, pickles, grass-fed cheese, homemade yogurt and sauerkraut are just a few of the foods you may not have considered. Your best bet is to make your own. In this video, Julie and I demonstrate how to make your own fermented vegetables at home.

PLAGUE – A Story Embraced By The Chronic Fatigue Syndrome and Autism Communities

PLAGUE - The Chronic Fatigue Syndrome and Autism Communities Are Embracing This Story!

It’s always nerve-wracking when one writes a book and waits for the public reaction.  Especially in a book like the one I’ve co-written with Dr. Judy Mikovits, PLAGUE: One Scientist’s Intrepid Search for the Truth about Human Retroviruses, Chronic Fatigue Syndrome (ME/CFS), Autism, and Other Diseases, in which we are attempting to unite various disease communities.

I’m known as an autism advocate so I wondered whether my fellow advocates would question why I spent years chasing down this story of a scientist known mostly for her investigations ofchronic fatigue syndrome (ME/CFS).  And for those in the chronic fatigue syndrome (ME/CFS) community, would they think we have done justice to their suffering?  These are the questions that have kept me up many nights over the past two and a half years.

But it seems that we may have threaded the eye of that very narrow needle.  PLAGUE now has 26 reader reviews on the various Amazon platforms, and they have been … well, I’ll give you a few excerpts:

From Carol Fisch, a retired microbiology and stealth pathogen researcher:

“I have waited for this book for well over a year.  I read it in three days as I couldn’t put it down!  So many need to thank Judy Mikovits, PhD, for risking her career to fight as a scientist should, to tell the truth …”

JT wrote on his Amazon review:

“I encourage everyone to read this book.  The authors have made tremendous efforts to make this book understandable to most people.  Anyone interested in chronic diseases (auto-immune, chronic fatigue syndrome, fibromyalgia, gulf war syndrome, autism, vaccines, bio-pharmaceuticals) and how academic/government research and government agencies handle these topics will be enlightened …”

Another reader wrote on Amazon:

“Just finished Plague this morning.  It was riveting and hard to put down.  It’s a very well-written book and I enjoyed reading it.  The authors did an excellent job of breaking down the science and keeping it very simple …”

Mark Blaxill, a Harvard MBA and the founder of Safe-Minds, an autism advocacy group writes:

“A fascinating combination.  The authors weave together a fascinating medical history, a modern day scientific drama and a legal thriller in a unique narrative that calls attention to the deep dysfunction and corruption in the heart of the medical industrial complex … If anyone ever tries to tell you that mainstream scientists (and the poo-bahs that walk the halls at the National Institutes of Health) operate with higher standards of honesty and intellectual rigor than the rest of the world, give them this book!  Any eye-opening account and a must read.”

From Thomas Smith, a reader on Amazon UK:

“PLAGUE is well written, I’m impressed, it’s far better than I imagined considering the pressures of time placed upon the authors.  PLAGUE reads in a style of a review by co-author Kent Heckenlively, not in the ‘lead’ authors own words of detailed lament.  This was a sensible approach as otherwise PLAGUE may have been open to obvious ‘bias’ of a scientist who has a very real axe to grind.  PLAGUE not only avoids bitterness, but instead manages a back and forth detailed look at various players in the saga of what happened to ‘XMRV’ and its association to ME (CFS), and it does so with over 700 references, many of which are direct quotes …”

Jane Austin, also a reader from the Amazon UK site writes:

“It reads like a sinister thriller and will surely have the makings of a major movie …”

Louise Ramage writes on the Amazon site for Canada:

“An excellent true story about the injustices and cover-ups town myalgic encephalomyelitis.  This book reads like fiction with twists, turns, injustices, cover-ups and even the wrongful imprisonment of Dr. Judy Mikovits (a scientist who uncovered shocking revelations!)  Why doesn’t the medical profession want you to know the truth?”

For those of you who are interested in health, how can you not afford to read this book about a bold and courageous scientist?

Is chronic fatigue syndrome finally being taken seriously?

Once dismissed by many doctors as a psychological illness, new research suggests CFS has its roots in infection – and there is hope of successful treatment
Woman with hands over her eyes
CFS is estimated to affect 250,000 people in the UK Photograph
Jose Montoya was a trainee doctor when his supervisor told him that if he continued specialising in treating chronic fatigue syndrome (CFS), he would end up homeless. “About 15 years ago, I started working with 10 patients who’d had their lives devastated by this illness,” says Montoya, now a professor at Stanford University and one of the world’s leading experts on the disease. “I had been able to help them, so I took my results to my academic mentor and he told me: ‘You are committing academic suicide. You’re turning your career into a mess.’”

Months later, Montoya, was travelling to a conference in Paris with his mentor when the subject came up again. “There was a homeless man lying drunk in the street, and he pointed to him and told me: ‘That’s how you’re going to end up if you keep studying chronic fatigue syndrome.’”

CFS is believed to affect around 1 million Americans and approximately 250,000 people in the UK. The effects can be devastating. “My son has CFS and is only able to get out of bed for half an hour a day,” says Mary Dimmock, a CFS activist who worked in the pharmaceutical industry for 30 years. “The disease isn’t so much about tiredness, it’s that the patients just collapse if they go beyond their available energy. These people are so sick that they may only have enough energy to brush their teeth or chew their food.”

Yet for much of the past three decades, CFS has been treated as the proverbial skeleton in the closet of the medical world. Potential researchers have been scared off by the stigma associated with the disease, and government funding has been nonexistent. “When I was a medical student in the 90s, we were instructed that CFS patients could not be seen in our clinic,” Montoya recalls. “And a letter was sent out to those patients telling them not to come.”

To understand why the medical industry has treated the illness with such disdain, you have to go back to 1955 and a sudden outbreak of CFS at the Royal Free Hospital in London which affected approximately 300 people and led to the closure of the hospital for three weeks. The causes of this mystifying epidemic were unknown, but pathology findings suggested something had triggered inflammation in the brain and spinal cord, but with no obvious cause, health officials charged with investigating the outbreak two decades later concluded it had been down to mass hysteria. In the 1980s, psychiatrists in the US and UK involved in investigating a similar CFS epidemic in Nevada decided the illness was largely psychogenic, a result of patients believing they were really ill and allowing themselves to become deconditioned. It’s a tag that has stuck to this day. In 2011, the Pace trial – a five-year study of CFS funded by the UK government, recommended cognitive behavioural therapy and graded exercise regimes as treatments for the disease.
Over the past 20 years, though, a handful of scientists have defied convention by looking deeper into the disease than ever before, sometimes inspired by chance events. Professor Garth Nicolson, founder of the Institute for Molecular Medicine in California, noticed a wave of CFS in soldiers returning from the 1990-91 Gulf war, among them his own daughter. “The more we looked into it, the more we found that infections appeared to be the root cause, which was why some of the sufferers transmitted CFS to family members,” he says. “Infections aren’t a universal cause, but they are definitely one of the main contributors.”


Nicolson and others believe that as with so many complex diseases, CFS is really an umbrella term for a whole variety of underlying illnesses – some psychological or due to anxiety-related exercise intolerance, but many others down to neurological impairment, energy-production impairment or even autoimmune dysfunction. “We’ve been taking diseases that aren’t even related to each other, but because fatigue is the unifying symptom, we’ve thrown them in the same bucket and treated them the same,” Dimmock says. “If you prescribe a graded exercise regime to a CFS patient with an energy-production impairment, you can do a lot of harm. It’s like taking patients who all suffer from shortness of breath, but the root causes range from asthma to angina. You would never treat them as the same group of patients.”

Montoya believes that around 80% of the CFS patients he treats have developed their condition as a result of infection. But because few of them get to see a specialist until they have been ill for many months or even years, the bacteria or viruses responsible have long gone into hiding inside the body’s cells, meaning that many standard blood tests appear to show there is nothing wrong. “This is why so many doctors have dismissed CFS as psychological in the past,” he says.

At the Mailman School of Public Health at Columbia University, Professor Mady Hornig studies the various causes and potential treatments for CFS. “The range of symptoms across CFS patients is extremely diverse,” she says. “In some cases, something may have damaged the mitochondria which provide energy for immune cells, brain cells and your muscle cells.” Other researchers in the US have suggested that such patients can improve a lot from treatments such as a membrane lipid replacement. “For others, viruses or bacteria appear to have induced antibodies that can react against parts of your bodily organs, including your brain and muscle tissue, causing disruption,” Hornig says. “There’s a group in Norway who have had success using immunotherapy to treat some CFS patients.”

But while these scientists have been fighting a lone battle for many years, the tides of change seem to be finally sweeping through the medical community. Last year, the Institute of Medicine in the US issued a report describing CFS as a “serious, chronic, complex and systemic disease”. Many hope this will lead to new investment and new treatments. “Pharmaceutical companies have not been able to invest in the disease in the past as there’s been such little funding for academic research,” Dimmock says. “The companies need that knowledge to try to develop medicines.”

Montoya and Hornig have both received grants from the National Institute of Health to identify the subgroups of patients within CFS more accurately. “We need to try to develop biomarkers for CFS that pinpoint what the root causes are,” Hornig says. “For some people it may be abnormal gut bacteria which can damage immune system function, and so probiotic treatment may help. Others may have more profound brain fog and sleep disturbances which could be due to an infection moving into their spinal fluid and brain, so they may respond preferentially to antibiotic or antiviral treatment.”

But, ultimately, the holy grail for all CFS researchers is to understand why some people are susceptible to the illness while others may be exposed to the same infections or causes, and yet experience little change. “That really is the big question,” Montoya says. “If you take Epstein-Barr virus, which causes glandular fever, only about 10-15% of people tend to go on to have a prolonged case of the disease leading to CFS. But why do this set of individuals have this type of response to certain viruses while others don’t? Are there genetic factors, is it actually a completely different pathogen which we haven’t discovered yet? We don’t know but with more financial resources being committed and institutes across the world concluding this is a disease which requires serious research and attention, I believe we will know the answer within the next five to 10 years.”

Hope for Chronic Fatigue Syndrome

The debate over this mysterious disease is suddenly shifting.

That might sound like good news—but I knew these researchers’ past work very well, and it had only added to the misery of CFS patients like me. Back in 2011, I watched the headlines spread around the world when the team, funded by the British government, published the first results in the Lancet—while I was desperately ill in bed, reading the news on my phone, too weak to sit up to use my computer.

 I—and a lot of other people with knowledge of CFS—couldn’t believe what we were reading. Psychotherapy had helped me keep my sanity while my body fell apart, but it had never made me less sick. And the hallmark symptom of the illness is that exertion can make patients much, much worse. I’d learned through hard experience that the only way I could exercise safely was to stop as soon as the thought “I’m a little tired” wafted through my brain. Walking five minutes yesterday was no guarantee I could safely walk six minutes today—and if I misjudged and overdid it, I’d be semi-paralyzed later.

But according to the theory underlying this psychiatric research, my problem was that I was out of shape, afraid of exercise, and obsessed about my symptoms. The path to wellness was to drop the idea that I had a physical disease and steadily increase my exercise, no matter how bad it made me feel.

Patients rapidly discovered serious scientific problems with the 2011 Lancet paper. Despite these errors, the study, known as the PACE trial, went on to inform recommendations from such influential bodies as the Centers for Disease Control and Prevention, the Mayo Clinic, and the British National Health Service. So the new follow-up study, I feared, seemed destined for a warm and uncritical reception from the medical establishment regardless of whether its findings were legitimate.

But just days before the new study was released, on Oct. 21, the San Francisco journalist David Tuller published a major investigation exposing deep methodological flaws in the entire PACE trial that put its validity in serious doubt.

And this time, the new study has been met with intense criticism from outside the world of patients and advocates. On Friday, six researchers, including prominent scientists such as virologist Vincent Racaniello of Columbia University and geneticist Ronald Davis of Stanford University, released an open letter to the Lancetdemanding an independent review of the PACE trial.

“The whole study is unbelievably amateur,” says Jonathan Edwards, a biomedical researcher at University College London who signed the letter. “The trial is useless.”

The PACE trial has exerted a strong influence on American physicians: If you ask your doctor about CFS, odds are good you’ll hear that cognitive behavioral therapy (the flavor of psychotherapy used in the trial) and exercise are the only proven treatments for CFS.

The American scientific research community, on the other hand, has rejected the psychiatric model that PACE epitomizes and is instead looking for physiological explanations for the disease. Research efforts have been hamstrung, though, by scarce funding: the National Institutes of Health spends $5 million to $6 million a year on a disease that affects a million Americans. (For comparison, about the same number of people with HIV/AIDS, which receives $3 billion in NIH funding.)

Just two days after the follow-up PACE study was released, the NIH made the stunning announcement that it is starting a program to study CFS (which is also referred to as myalgic encephalomyelitis or ME/CFS) at the NIH Clinical Center in Bethesda, Maryland. Francis Collins, the director of the NIH, has also promised increased funding for universities to research the illness. “It will be substantially greater than the current $5 [million] or $6 million a year,” he told NPR. “We are going to ramp this up.”

After so many years of scarce funding, bad science, and uncritical journalism, the events of the past few weeks have left me feeling something I’ve never felt before about this illness: hope. It almost frightens me to say it, but we may be on the verge of clearing up the massive misunderstandings about this disease—and even of starting to figure the damn thing out.

Questions about the 2011 Lancet paper emerged soon after the PACE team announced its first results at a press conference. One of the researchers said that, compared with other study subjects, “twice as many people on graded exercise therapy and cognitive behavior therapy got back to normal.” In a follow-up paper two years later, the researchers claimed that 22 percent of participants who received cognitive behavioral therapy or exercise on top of regular medical care “recovered” by the end of the trial.

But patients who analyzed the PACE trial and its follow-up studies discovered that these statements depended on a remarkably weak definition of “recovery”—one so weak that participants could enter the trial, get worse on two out of four criteria, and then be called “recovered.” These supposedly recovered patients could furthermore have poorer physical function than 92 percent of the British working-age population. And 13 percent of participants qualified as “recovered” on at least one of the criteria even before they received treatment.

Peter White, a psychiatrist at Queen Mary University of London and the lead PACE investigator, told me by email in late October that “some small overlap might be expected” between the criteria for entry into the trial and those for recovery, and he pointed out that there were two additional criteria. He didn’t, however, mention that those criteria were also weakened. When I inquired why such an overlap “might be expected,” he declined to answer further questions.

Starting in 2011, patients analyzing the study filed Freedom of Information Actrequests to learn what the trial’s results would have been under the original protocol. Those were denied along with many other requests about the trial, some on the grounds that the requests were “vexatious.” The investigators said they considered the requests to be harassment.

The patients found many other problems as well. The study participants hadn’t significantly improved on any of the team’s chosen objective measures: They weren’t able to get back to work or get off welfare, they didn’t get more fit, and their ability to walk barely improved. Though the PACE researchers had chosen these measures at the start of the experiment, once they’d analyzed their data, they dismissed them as irrelevant or not objective after all. In addition, the patients researching the study found statistical errors, actions that might have pumped up the subjective ratings, measurement problems that allowed participants to deteriorate without being detected, conflicts of interest, and more.

The patients wrote detailed letters to the Lancet and other journals describing PACE’s scientific shortcomings. In responding, the researchers either didn’t address the core problems, dismissed them as unimportant, or accused the critics of beingprejudiced against psychiatry.

Richard Horton, the editor of the Lancet, aggressively defended the trial. In a radio interview, he called the critics “a fairly small, but highly organized, very vocal and very damaging group of individuals who have, I would say, actually hijacked this agenda and distorted the debate so that it actually harms the overwhelming majority of patients.” He didn’t address the substance of the criticisms.

 In the United States, ME/CFS researchers largely dismissed the PACE trial findings. Their research on the role of exercise in the illness has instead focused on unraveling the physiology of patients’ abnormal response to it. Multiple teams found that when patients exercise to exhaustion two days in a row, their performance drops dramatically the second day, as shown by physiological indicators that can’t be faked. Other researchers documented changes in how genes function in patients after moderate exercise.
Jennifer Brea and her partner, Omar, visiting a nature preserve near their home, where she once had been able to walk for a mile but can’t anymore.

Courtesy of Canary in a Coal Mine

Still, each time the PACE team publishes a new follow-up study, a flurry of ill-informed news coverage follows, including after the release last month. The Telegraph front page blared “Chronic Fatigue Syndrome Sufferers ‘Can Overcome Symptoms of [Myalgic Encephalomyelitis] with Positive Thinking and Exercise’: Oxford University has found ME is not actually a chronic illness.”

When I read the study itself, I quickly found that this headline went far beyond even the researchers’ claims—but I also saw that the researchers’ claims went far beyond their own data.

According to the researchers, their work proved that the purported improvements from cognitive behavioral therapy and exercise stood up over time. But what the data actually showed was that after 2½ years, the benefits of CBT and exercise had entirely vanished. The patients who hadn’t been assigned to those therapies had by then improved as much as those who had, though all groups were still sick.

The PACE researchers acknowledged this but discounted the significance of the improvement of the patients who hadn’t received therapy or exercise. They pointed out that some of these patients had received CBT or exercise after the trial had ended, and they argued that this might explain the improvement. However, their data showed that the additional therapy didn’t help these patients at all.

The reception of this new study among researchers was very different from in the past, in part because Tuller, a public health and journalism lecturer at the University of California–Berkeley, published his long story on the site Virology Blog just days before this latest study came out. His work persuaded researchers outside the ME/CFS community to scrutinize the study for the first time—and they condemned it. For example, James Coyne, a psychologist at the University Medical Center Groningen in the Netherlands, who was previously uninvolved in ME/CFS research, wrote a blog post for the Public Library of Science calling the researchers’ interpretation of their new study “unsubstantiated spin in favor of the investigators’ preferred intervention.”

And now researchers and patients are demanding that the PACE team release its data (with any patient-identifying information made anonymous), either publicly or to a team of highly qualified independent investigators, for re-analysis.

The PACE researchers have refused to release the data in the past, arguing that “activists seeking to discredit the PACE trial and its researchers” would somehow decrypt the anonymous details in the data and publish the names of participants. And White told me that the changes to the original protocol “improved the science and interpretation. We see no reason why we should do a further analysis based on an inferior method.” Horton, editor of the Lancet, didn’t respond to my request for comment.

“The Lancet needs to stop circling the wagons and be open,” says Bruce Levin, a biostatistician at Columbia University who signed the open letter. “One of the tenets of good science is transparency.”

Davis, the Stanford geneticist, has a son with ME/CFS so severe that he can’t walk, talk, or eat. Davis goes even further: “The Lancet should step up to the plate and pull that paper,” he says. “It has lots of flaws, and I worry that it hurts patients.” Davis has now started his own effort to find a cure for the disease, called the End ME/CFS Project. He is collecting a vast amount of data on severe patients like his son, who have almost never been included in studies because they are too frail to go to a doctor or clinic.

Ron Davis and his son, Whitney Dafoe, who has severe ME/CFS, in September 2014. Davis helps his son by shaving his beard and head, since he cannot get out of bed to bathe.

Courtesy of the family of Whitney Dafoe

As encouraging as the public criticism of the PACE trial has been, only one thing is likely to excise the notion from the minds of doctors and the public that ME/CFS is a psychiatric condition: a truly effective treatment for the disease. My condition has improved remarkably after I pursued a treatment that has hardly been researched at all: taking extreme measures to avoid mold. But there hasn’t been the money to follow up on promising leads like that one and others.

That makes the NIH announcement of its research plans for the disease a huge step in undoing the damage PACE has caused. The NIH plans to analyze 40 patients whose illness began suddenly with an apparent infection, using big data methods. And if the NIH follows through on its promises for increased funding for research at universities, scientists like Davis will have new opportunities.

Just a year ago, both the public criticism of the PACE trial and the moves by the NIH were nearly unimaginable. But to me, these events feel like the fruits of change that’s been cultivated over years. When the PACE trial first came out in 2011, few journalists took serious interest in the disease, and much of the coverage was dreadful. Now, several journalists, in addition to Tuller,have been producing great work. In 2011, the cadre of dedicated researchers was tiny and isolated. Now, giants in their own fields have become fascinated by the illness. The patient community has long been divided and fractious, but now, platforms like #MEAction are supporting more united action, and patients are developing recommendations for research priorities, modeling their efforts on AIDS and breast cancer activists’ methods to earn respect and influence in the scientific community.

Coyne, the psychology researcher whose interest was sparked by the controversy over PACE, suggested on Twitter that PACE might be the ME/CFS Stonewall, and it does feel like I’m watching the emergence of a new movement.

Of course, there’s still a long way to go. Patients are still suffering, derided, and without treatment. But it no longer seems quixotic to anticipate the day when patients as sick as I was in 2011 won’t have their misery exacerbated by prejudice and bad science.