What Is ME/CFS? Symptoms, Diagnosis, Possible Mechanisms, and Current Research

“I slept enough, but I still cannot get out of bed.” “A small amount of activity leaves me confined to bed for days.” “My mind feels covered in fog, and I cannot think.” For some people, these symptoms persist for months or even years.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious condition that is fundamentally different from ordinary tiredness. Yet because its name contains the word “fatigue,” it is frequently misunderstood. Many people struggle without adequate recognition or support.

Public awareness of ME/CFS has increased rapidly because of its relationship with post-COVID-19 illness, or Long COVID. Even so, the condition remains poorly understood outside specialist and patient communities.

What You Will Learn

• What ME/CFS is and how it differs from ordinary chronic fatigue
• Its major symptoms and effects on daily life
• Why misconceptions such as “it is just tiredness” or “it is psychological” are harmful
• Mechanisms under investigation, including oxidative stress, neuroinflammation, immune dysfunction, and the gut microbiome
• Its relationship with Long COVID
• Current approaches to care and active areas of research

What Is ME/CFS?

The full name is myalgic encephalomyelitis/chronic fatigue syndrome.

Broadly, ME/CFS is a condition in which disabling fatigue and reduced ability to function persist for at least six months, are not relieved by rest, and cannot be explained by routine clinical evaluation alone¹²³.

Chronic Fatigue and ME/CFS Are Not the Same

The terms sound similar but describe different concepts. “Chronic fatigue” is an everyday expression for persistent tiredness associated with work, caregiving, inadequate sleep, or other circumstances. ME/CFS is a medical condition defined by diagnostic criteria. A fundamental difference is that its symptoms do not resolve with rest or sleep.

How Common Is It?

A US survey found that approximately 25% of people reported chronic fatigue, but only 0.5%—about one in 200—met criteria for ME/CFS³. Japan is estimated to have between 100,000 and 300,000 people with the condition⁴. However, low awareness and diagnostic difficulty make the true prevalence uncertain.

Major Symptoms of ME/CFS

ME/CFS is not a disease of fatigue alone. A defining feature is the overlap of symptoms across multiple domains². Their type and severity vary among individuals.

Core Symptoms

• Persistent, disabling fatigue: Fatigue that does not improve with rest and substantially restricts daily activity. People cannot return to their pre-illness level of function, and the feeling that sleep never restores energy may continue for months.
• Post-exertional malaise (PEM): The most characteristic symptom of ME/CFS. Even minor physical or mental activity can trigger a marked worsening of symptoms that lasts for days or weeks. A shopping trip may lead to being confined to bed the next day, while a short conversation may cause severe exhaustion.
• Sleep disturbance: Unrefreshing sleep is common. A person may sleep for many hours yet wake already feeling exhausted.

Cognitive Dysfunction

• Brain fog: Difficulty organizing thoughts, concentrating, finding words, and retaining short-term information. Many people describe it as one of their most distressing symptoms.

Other Symptoms

• Pain: Headache, muscle pain, joint pain, and sore throat. Location and severity vary.
• Orthostatic intolerance: Dizziness, palpitations, nausea, or a feeling of impending fainting when standing or remaining upright. Postural orthostatic tachycardia syndrome (POTS) frequently co-occurs²⁵.
• Sensory hypersensitivity: Increased sensitivity to light, sound, odors, or chemicals.
• Immune-related symptoms: Swollen or tender lymph nodes, low-grade fever, and recurrent flu-like symptoms.

Postural orthostatic tachycardia syndrome (POTS)

A disorder of autonomic regulation in which heart rate rises abnormally after standing.

A Wide Range of Severity: Performance Status

Severity varies substantially. Some people can continue working with difficulty. Others spend most of their time lying down at home, while those with severe illness may be bedbound and unable to manage daily life without assistance.

A performance status (PS) scale from 0 to 9 is often used in Japan⁶. PS 0 indicates normal health, PS 3 or above meets the level used in Japanese ME/CFS diagnostic criteria, and PS 7 or above indicates major difficulty managing daily life independently.

Dr. Koichi Hirahata of Shibuya Hirahata Clinic, who has treated more than 4,000 people in a Long COVID clinic, has described PS as a simple and useful measure for understanding functional status in Long COVID⁷. PS 6 is comparable to being almost bedbound, and ordinary employment is generally very difficult at PS 5 or above.

Not “Just Tiredness” or “All in the Mind”: Misconceptions and Stigma

Despite the severity of the symptoms, misunderstanding and stigma remain major challenges.

The word “fatigue” in the name may create the impression that people are merely tired, could recover through willpower, or are being lazy. ME/CFS is not malingering. It can produce symptoms severe enough to prevent ordinary daily activity.

Misconceptions add psychological burden and can also obstruct access to appropriate medical care. Clinicians working with Long COVID have reported cases in which people are refused evaluation simply because they have Long COVID or ME/CFS⁷. In many cases, examination is possible if the person’s limited activity tolerance is accommodated.

Accurate understanding by family members, employers, and healthcare professionals can make it easier for people to reach appropriate care.

How ME/CFS Is Diagnosed

Diagnostic difficulty contributes to misunderstanding. No blood test or imaging finding currently serves as a definitive biomarker for ME/CFS. Diagnosis is therefore based on the pattern of symptoms and exclusion of other conditions.

Biomarker

An objectively measurable indicator used to assess the presence or progression of a disease.

Common Features Across Major Diagnostic Criteria

Several diagnostic frameworks are used internationally¹²³. Common elements include:

• Fatigue severe enough to impair daily life and persisting for at least six months
• A new or definite onset not explained by excessive exertion
• Inadequate recovery with rest
• Worsening after physical or mental activity, or PEM
• Cognitive impairment or orthostatic symptoms such as dizziness and palpitations

Clinicians must also evaluate and exclude other conditions that can cause similar symptoms, including hypothyroidism, diabetes, depression, and sleep apnea.

Why Diagnosis Is Difficult

• There is no definitive diagnostic test, so clinical experience and judgment are important.
• Few medical centers have extensive expertise in ME/CFS.
• Symptoms overlap with other conditions, and fibromyalgia and POTS may co-occur.
• Fatigue is subjective and difficult to quantify objectively.

Fibromyalgia

A chronic condition characterized primarily by widespread pain. It frequently co-occurs with ME/CFS.

For these reasons, some people wait years between illness onset and an accurate diagnosis.

Mechanisms Under Investigation

The cause of ME/CFS has not been fully established. Current evidence suggests that it is unlikely to result from a single factor. Several interacting biological mechanisms are under investigation.

Infection as a Trigger

Many cases begin after a viral or bacterial infection. Reported triggers include Epstein–Barr virus, influenza viruses, and enteroviruses⁸. The acute infection may resolve while immune abnormalities persist. Researchers are investigating whether this sustained immune dysregulation contributes to the transition to ME/CFS.

Immune Dysfunction

Studies have observed chronic immune activation and altered immune function in people with ME/CFS⁹. Reported findings include reduced natural killer cell activity and altered cytokine patterns. Similarities with autoimmune disease have also been discussed, although ME/CFS differs from typical autoimmune disorders in important ways. The immune contribution remains an active area of research.

Natural killer (NK) cells

Innate immune cells that rapidly attack virus-infected cells and some cancer cells.

Cytokines

Signaling proteins released by immune cells to communicate and regulate inflammation and other immune responses.

Autoimmune disease

A group of disorders in which the immune system mistakenly attacks the body’s own cells or tissues. Examples include rheumatoid arthritis and type 1 diabetes.

Oxidative Stress and Mitochondrial Dysfunction

Oxidative stress occurs when reactive oxygen species exceed the capacity of antioxidant defenses and damage cells.

Multiple studies have reported higher blood markers of oxidative stress and lower antioxidant capacity in people with ME/CFS than in healthy controls¹⁰. A 2025 study in Proceedings of the National Academy of Sciences reported increased oxidative stress in lymphocytes from people with ME/CFS¹¹. The findings also linked oxidative stress with damage to mitochondria, the structures that produce cellular energy.

Mitochondrial damage can reduce the efficiency of energy production. Researchers are investigating whether this contributes to persistent fatigue and PEM, but a causal mechanism has not been established.

Neuroinflammation

A 2014 PET imaging study by Dr. Yasuhito Nakatomi and colleagues at Osaka City University, now Osaka Metropolitan University, reported widespread neuroinflammation in people with ME/CFS¹². It was the first report of this kind. The findings suggested that brain inflammation may be associated with brain fog, cognitive dysfunction, and fatigue, although further replication and mechanistic research are needed.

PET imaging

Positron emission tomography, an imaging method used to visualize aspects of metabolism, inflammation, and other biological activity in the body.

The Gut Microbiome and the Gut–Brain Axis

Studies have reported characteristic changes in the gut microbiome of people with ME/CFS, including lower microbial diversity and shifts in specific organisms¹³.

The gut and brain communicate through the gut–brain axis. Researchers are examining whether disruption of the gut microbiome influences brain function or systemic inflammation. Another hypothesis proposes that impairment of the intestinal barrier allows substances that would normally remain in the gut to enter the bloodstream and contribute to systemic inflammation.

Autonomic Nervous System Dysfunction

Orthostatic intolerance and POTS occur frequently in ME/CFS. Dysregulation of the balance between the sympathetic and parasympathetic nervous systems may impair control of blood pressure and heart rate, contributing to dizziness, palpitations, and worsening fatigue²⁵.

Relationship With Long COVID

ME/CFS existed long before the emergence of SARS-CoV-2. However, the COVID-19 pandemic accelerated research into post-infectious chronic illness.

Long COVID can involve persistent fatigue, brain fog, PEM, and other symptoms after acute infection. Its symptom profile overlaps substantially with ME/CFS, and some people with Long COVID meet diagnostic criteria for ME/CFS¹⁴.

Possible Shared Mechanisms

The 2025 PNAS study reported increased oxidative stress in both ME/CFS and Long COVID¹¹. Researchers have also proposed shared mechanisms involving neuroinflammation and immune dysfunction¹⁴. These findings indicate overlap but do not establish that the two conditions are identical.

Repeated Crashes May Increase Risk of Persistent Disability

Clinicians emphasize the importance of avoiding a crash, a severe symptom exacerbation after exceeding an individual’s activity tolerance through exercise, stress, or cognitive work. A crash can leave someone largely unable to move for several days. Clinical observations suggest that repeated crashes in Long COVID may be associated with transition to an ME/CFS-like state⁷. Careful management of physical and mental activity from an early stage is therefore recommended to reduce PEM.

Accelerating Research

At least 65 million people worldwide have been estimated to experience Long COVID¹⁵. This large patient population has brought substantial funding and attention to research on post-infectious chronic illness, indirectly accelerating ME/CFS research.

Current Approaches to Care

No curative treatment has been established for ME/CFS. Care therefore focuses on symptom management and preservation of quality of life.

Treatment, Not Training

An important clinical principle is to distinguish treatment from training⁷.

For a healthy person, gradually doing slightly more than before may increase capacity. In ME/CFS, the same approach may trigger a crash and reduce what the person can do. Pushing through symptoms does not necessarily promote recovery. Functional capacity may increase only as the condition is stabilized and treated⁷.

This distinction is important for both patients and the people supporting them.

Pacing

A central strategy is pacing: carefully balancing activity and rest to prevent PEM and crashes. The aim is to remain within an individual’s energy limits rather than repeatedly exceed them⁷.

Excessive exercise can worsen ME/CFS symptoms. In 2021, the UK National Institute for Health and Care Excellence revised its guideline and removed graded exercise therapy—programs that prescribe fixed incremental increases in exercise—from its recommendations¹⁶.

Symptom-Focused Care

• Epipharyngeal abrasive therapy (EAT): A procedure used in some Japanese ear, nose, and throat clinics in which zinc chloride is applied to the epipharynx with a swab. Dr. Hirahata has described it as one of the approaches that may be helpful in some people with Long COVID⁷. Evidence for ME/CFS remains limited, and availability is largely specific to Japan.
• Sleep management: Sleep hygiene and, when appropriate, medication may be used to improve sleep quality.
• Pain management: Analgesics or traditional Japanese Kampo medicines may be used for headache, muscle pain, or joint pain.
• Management of orthostatic intolerance: Approaches may include adequate fluid and salt intake, compression garments, and medications that regulate blood pressure when clinically appropriate.
• Kampo-based care: Some clinicians combine Kampo medicine with conventional approaches.
• Psychological support: Counseling or cognitive behavioral approaches may help with the psychological burden of long-term illness. ME/CFS is not a psychogenic disorder, and psychotherapy alone is not a curative treatment.

Experimental Approaches

Researchers worldwide are investigating antioxidant strategies, methods to modulate neuroinflammation, probiotics, dietary approaches aimed at the gut microbiome, and immune-modulating treatments. None has established efficacy as a general treatment for ME/CFS. As understanding of the underlying biology improves, treatment options may expand.

Summary

ME/CFS is neither ordinary tiredness nor an imagined illness. It is a serious condition associated with substantial functional impairment.

• Disabling fatigue persists for at least six months, does not resolve with rest, and is accompanied by PEM.
• Brain fog, pain, orthostatic intolerance, and other symptoms can overlap; severe cases may be bedbound.
• No definitive diagnostic test exists, and diagnosis requires exclusion of other conditions, so delays are common.
• Research is examining interacting factors including oxidative stress, neuroinflammation, immune dysfunction, the gut microbiome, and autonomic dysfunction.
• The relationship with Long COVID has accelerated research.
• No cure has been established, but pacing and symptom-focused care can help manage the condition while research continues.

Understanding ME/CFS is a first step toward supporting people who live with it.

This article provides general information and does not constitute medical advice. Anyone experiencing possible ME/CFS symptoms should consult a healthcare professional. Medical centers with relevant expertise remain limited, but searches for terms such as “ME/CFS clinic” or “chronic fatigue syndrome clinic” may help identify local services.

References

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3. CDC. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Information for Healthcare Providers. Centers for Disease Control and Prevention (2024). ↩
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11. Shankar V, et al. Oxidative stress is a shared characteristic of ME/CFS and Long COVID. Proc Natl Acad Sci USA 122(28), e2426564122 (2025). ↩
12. Nakatomi Y, et al. Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study. J Nucl Med 55(6), 945-950 (2014). ↩
13. Varesi A, et al. The Emerging Role of Gut Microbiota in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). J Clin Med 10(21), 5077 (2021). ↩
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