Functional Medicine for Chronic Fatigue Syndrome

Holistic Approach to Chronic Fatigue Syndrome: A Functional Medicine Perspective

Functional medicine for Chronic Fatigue Syndrome (ME/CFS) addresses this complex condition from a root cause perspective.

CFS involves far more than “just being tired.” It reflects complex dysfunction in mitochondrial energy production, immune and autonomic regulation, and gut–brain–immune interactions.

This article will explain how infections, environmental toxins, and nutrient imbalances contribute to fatigue. And you’ll learn how a functional medicine approach can support recovery through root-cause interventions.

How to Tell if You Have Chronic Fatigue Syndrome

If you’re living with unrelenting exhaustion, brain fog, tired upon waking, dizziness, and post-exertional crashes that can last for days, you’re not alone. Chronic fatigue syndrome (CFS) is a complex, multi-system illness that disrupts energy production, stress tolerance, and recovery across various systems of the body [1].

It often follows an infection, toxin exposure, or a period of intense stress, and it can overlap with dysautonomia/POTS, mast-cell issues, sleep disruption, and gut problems [2, 3].

This guide breaks down exactly what’s going on at a cellular level and how a functional medicine approach can help you rebuild your energy safely and sustainably.

Functional medicine employs a systems-biology approach to CFS by identifying and addressing root causes, including mitochondrial dysfunction, environmental toxicants, chronic infections, gut dysbiosis, and nutrient imbalances [4, 5].

This model aligns with emerging research highlighting that CFS involves disturbances in cellular energy metabolism and immune regulation, rather than being a purely psychosomatic or isolated syndrome [6, 7].

What is Chronic Fatigue Syndrome? (And why it’s not “just fatigue”)

Chronic Fatigue Syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a debilitating multisystem disorder characterized by persistent, unexplained fatigue that lasts for at least six months and is accompanied by a constellation of symptoms including post-exertional malaise, cognitive dysfunction, sleep disturbances, and orthostatic intolerance [8, 9].

It affects an estimated 67 million people worldwide and as many as 3.3 million adults in the United States, yet remains underdiagnosed and frequently misunderstood [3, 10]. The lack of definitive biomarkers and the variability of symptom presentation have contributed to difficulties in both diagnosis and treatment within conventional medical frameworks [11].

Common Symptoms of Chronic Fatigue Syndrome

• Crushing fatigue that isn’t fixed by sleep
• PEM (post-exertional “crash”) after activity
• Brain fog, word-finding trouble, headaches
• Dizziness/lightheadedness, palpitations (often with standing)
• Muscle/joint pain, temperature dysregulation
• Sleep that doesn’t restore energy
• GI issues (bloating, nausea, food sensitivities)

Post-exertional malaise (PEM) is a common symptom presentation of this condition. It is characterized by intense and disproportionate fatigue following physical, mental, or emotional exertion. Often, sleep doesn’t feel refreshing and doesn’t offer the usual “reset and repair” that occurs during sleep.

Research indicates that abnormalities in cellular energy metabolism, immune signaling, autonomic regulation, and exercise physiology are at the root of CFS; it is not merely a motivational problem [12, 13, 14].

Functional Medicine for Chronic Fatigue Syndrome: Mitochondria and Chronic Fatigue

The Energy Engines of the Body

Mitochondria are the cell’s powerhouses, responsible for producing the vast majority of cellular energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation [15, 16]. ATP fuels virtually every physiological process: nerve conduction, muscle contraction, detoxification, hormone synthesis, and immune responses [5].

Under healthy conditions, mitochondria can convert carbohydrates and fats from food into energy (ATP), allowing our cells to run their normal processes [17]. Carbs enter the citric acid cycle (also called the Krebs cycle) to produce 32–38 units of ATP energy [18, 19], and fats enter the electron transport chain (ETC) to make over 100 ATP per fat molecule [17, 20].

Electron donors produced in the citric acid cycle then drive the mitochondrial electron transport chain [21]. A balance of nutrients is required to produce energy effectively, as well as oxygen, and to provide sufficient micronutrients (vitamins and minerals) to shuttle carbs and fats through these cycles [22, 23]. This efficient process depends on intact mitochondrial membranes, properly functioning complexes, and an adequate supply of oxygen and nutrients [16, 24].

For context, every single second, about 47 million trillion metabolic reactions take place in our bodies [25]. This outstanding feat is driven by ATP energy [26].

This matters for people with this condition because mitochondrial energy metabolism is consistently impaired in Chronic Fatigue Syndrome (CFS) [27]. Studies have found reduced ATP production rates, altered oxygen consumption, and abnormalities in mitochondrial structure and gene expression [28, 29]. These defects translate clinically into profound fatigue and post-exertional malaise (PEM)—the hallmark worsening of CFS symptoms after even mild activity [6, 7, 29].

How Mitochondria Become Impaired in Chronic Fatigue Syndrome

Mitochondrial dysfunction in CFS can result from several converging mechanisms:

1. Reduced ATP synthesis capacity – Studies have reported slower ATP production and delayed recovery following exertion in CFS patients compared with healthy controls [8, 26, 28, 29].
2. Shift toward anaerobic metabolism – Impaired ATP production forces cells to rely more heavily on a process called glycolysis for energy. This process occurs outside of the mitochondria and is significantly less efficient than using carbohydrates or fats as fuel. This results in the accumulation of lactate, a compound that causes muscle pain and fatigue following physical activity [26, 27, 28].
3. Excess oxidative and nitrosative stress – Elevated reactive oxygen and nitrogen species (free radicals) can damage mitochondrial DNA (mtDNA), respiratory enzymes, and membranes, perpetuating dysfunction [8, 26].
4. Mitochondrial membrane potential disruption – The mitochondria require an electrical gradient for the electron transport chain to function. This gradient is characterized by a more positive electrical charge on the outside and a more negative charge on the inside. This gradient facilitates the movement of electrons down the chain. It works kind of like an assembly line, with electrons being handed off to the next “station” to ultimately produce energy molecules at the end. Oxidative stress damages the mitochondrial membranes and reduces the electrochemical gradient required for ATP production [8, 24, 26].
5. Altered mitochondrial gene expression – Downregulation of genes involved in oxidative phosphorylation and biogenesis has also been observed in muscle biopsies and immune cells from patients with CSF [8, 27, 28].

This results in a metabolic trap: low energy availability reduces cellular repair and detoxification capacity, which, in turn, allows further mitochondrial injury [8, 27, 28].

Functional Medicine for Chronic Fatigue Syndrome: Environmental Toxins

Hidden Saboteurs of Mitochondria in Chronic Fatigue Syndrome

Mitochondria are particularly susceptible to environmental toxicants due to their high oxygen consumption and proximity to sites of reactive oxygen and nitrogen species (ROS and RNS, respectively) production. Heavy metals, pesticides, solvents, and biotoxins, such as mold from water-damaged buildings, can all impair mitochondrial enzymes and damage mtDNA [30].

• Heavy metals, such as mercury, lead, and arsenic, inhibit key enzymes of the ETC, displace iron and copper from their biological “stations” in the electron “assembly line,” and deplete intracellular glutathione [31].
• Pesticides and organophosphates short-circuit ATP production and “hand off” down the ETC. They also increase oxidative stress, leading to ATP depletion [32].
• Solvents and VOCs disrupt mitochondrial membranes and interfere with fatty acid oxidation, contributing to neurological and systemic symptoms [33].
• Mycotoxins from mold, such as ochratoxin A and trichothecenes, inhibit ATP synthase and induce oxidative damage [34].

Chronic, low-level exposure to these toxins can go unnoticed for years, gradually impairing energy metabolism and immune regulation. Functional medicine emphasizes identifying and removing these exposures as an essential step in recovery. 

Urinary toxin testing can provide insights into chronic environmental toxicant exposure and offer a look into mitochondrial health and energy-producing capacity.

Functional Medicine for Chronic Fatigue Syndrome: Infectious Triggers

Viruses, Mold Colonization, and Lyme Disease

Many CFS cases follow an acute viral or bacterial infection after which patients never fully recover. Post-infectious fatigue syndromes have been documented for decades following outbreaks of Epstein–Barr virus (EBV), human herpesvirus-6 (HHV-6), enteroviruses, and, more recently, the COVID-19 virus [1].

• Viral latency and reactivation — EBV and HHV-6 can persist in tissues and periodically reactivate, damaging mitochondria by increasing ROS production and interfering with mitochondrial gene expression [35, 36, 37].
• Mycotoxin colonization — Beyond environmental exposure, mold can colonize the sinuses and/or gut, producing persistent biotoxins that inhibit ATP production and perpetuate immune dysregulation [38].
• Lyme disease and co-infections — Borrelia burgdorferi and tick-borne co-infections can disrupt mitochondrial structure, impair nutrient utilization, and provoke chronic immune activation, contributing to fatigue and neurological symptoms [39, 40].

Moreover, these infectious triggers can overlap with toxin exposures, nutrient deficiencies, and genetic vulnerabilities, creating a multifactorial cascade that overwhelms mitochondrial resilience and further impairs energy production.

Functional Medicine for Chronic Fatigue Syndrome: The Critical Role of Nutrients

Copper and Iron for Functional Chronic Fatigue Syndrome Care

Copper and iron are essential cofactors in mitochondrial energy metabolism. Think of these nutrients as the workers employed at each “station” along the ETC assembly line.

Iron is integral to proteins called cytochromes that shuttle electrons through the respiratory chain. At the same time, copper is required for a critical complex of the ETC, cytochrome c oxidase (Complex IV), which is the final step in oxidative phosphorylation that allows for ATP production [15].

• Disruptions in iron metabolism impair oxygen transport and cytochrome function, thereby decreasing ATP production [15]. Iron issues extend far beyond simple iron deficiency.
• Copper deficiency reduces Complex IV activity and increases oxidative stress [41]. It can also cause anemia because copper is a key cofactor required for proper iron metabolism. Copper deficiency (and subsequently copper-deficiency anemia) can be caused by excessive zinc supplementation.
• Iron overload can lead to iron-induced mitochondrial and cellular death via the Fenton reaction. This leads to an overproduction of harmful free radicals, specifically hydroxyl radicals, which damage mitochondrial membranes [42].

Therefore, a balanced iron and copper status is critical for mitochondrial function. Functional medicine often evaluates serum ferritin, iron, transferrin saturation, and other key biomarkers to assess these dynamics. Iron status should not be determined solely based on ferritin levels. A skilled functional medicine provider, trained in mineral metabolism and cofactor dynamics, can effectively guide mineral optimization.

B Vitamins for a Functional Medicine Approach to Chronic Fatigue Syndrome

The B vitamin family—particularly B1 (thiamine), B2 (riboflavin), B3 (niacin), B5 (pantothenic acid), and B12—act as coenzymes in carbohydrate, fat, and protein metabolism. They support glycolysis, the citric acid cycle, β-oxidation, and electron transport [15–20]. 

Deficiencies lead to metabolic bottlenecks and impaired ATP synthesis, manifesting as fatigue, neuropathy, and cognitive dysfunction [26]. For example, thiamine and riboflavin are indispensable for two key enzymes: pyruvate dehydrogenase and succinate dehydrogenase. These enzymes are key to the citric acid cycle “assembly line”—though this process of energy production works more like a traffic circle [15–17].

B vitamins are essential for the production of NAD and FAD molecules. These are necessary cofactors at several steps of the citric acid cycle and the ETC for shuttling substrates to produce energy [15–20].

Additional Nutrients for Mitochondrial Health in Chronic Fatigue Syndrome

Several other key nutrients play critical roles in supporting mitochondrial structure, energy production, and resilience against oxidative stress.:

Magnesium for Chronic Fatigue Syndrome

• Acts as a cofactor for over 300 enzymatic reactions, including those involved in ATP synthesis.
• Stabilizes mitochondrial membranes and is required for the activity of ATP synthase—the enzyme that actually produces ATP.
• Deficiency is associated with fatigue, muscle weakness, and impaired energy metabolism [42]

Coenzyme Q10 (CoQ10) for Chronic Fatigue Syndrome

• A vital component of the electron transport chain that shuttles electrons between complexes I/II and III.
• Also functions as an antioxidant within mitochondrial membranes, protecting against oxidative damage.
• Low levels of CoQ10 have been documented in CFS and are correlated with fatigue severity [43]

L-Carnitine for Chronic Fatigue Syndrome

• Transports long-chain fatty acids into mitochondria for β-oxidation, a critical step for energy production, especially in the heart and skeletal muscle.
• Deficiency can impair fatty acid metabolism and contribute to fatigue.
• Supplementation has shown promise in improving energy levels and exercise tolerance in some CFS patients [44]

Alpha-Lipoic Acid (ALA) for Chronic Fatigue Syndrome

• Functions as both a mitochondrial cofactor and a potent antioxidant.
• Supports regeneration of other antioxidants (e.g., vitamins C and E, glutathione) and improves mitochondrial enzyme activity [45]

Selenium for Chronic Fatigue Syndrome

• Integral to the function of glutathione peroxidases and thioredoxin reductases—key enzymes that protect mitochondria from oxidative stress.
• Adequate selenium status supports immune regulation and mitochondrial integrity [46]

Zinc for Chronic Fatigue Syndrome

• plays a structural and regulatory role in numerous mitochondrial enzymes.
• Supports antioxidant defenses via superoxide dismutase (SOD) and is essential for immune modulation.
• Zinc deficiency can exacerbate fatigue, inflammation, and oxidative damage [47]

Vitamin C & Vitamin E for Chronic Fatigue Syndrome

• These antioxidants protect mitochondrial membranes and mtDNA from ROS-mediated damage.
  Vitamin C can regenerate oxidized vitamin E, creating a synergistic antioxidant defense network [48]

Polyphenols (e.g., resveratrol, quercetin) for Chronic Fatigue Syndrome

• These plant compounds can stimulate mitochondrial biogenesis through pathways such as SIRT1 and PGC-1α.
• They also modulate inflammatory signaling and protect mitochondria from oxidative stress [49]

Functional Medicine for Chronic Fatigue Syndrome: The Gut–Mitochondria–Immune Axis 

Emerging research links gut dysbiosis and intestinal permeability (leaky gut) to mitochondrial dysfunction. Bacterial lipopolysaccharides (LPS) can enter systemic circulation through a “leaky gut,” triggering inflammation and directly inhibiting mitochondrial oxidative phosphorylation [50].

CFS patients often exhibit altered gut microbiome composition, reduced diversity, and elevated markers of permeability [51]. LPS exposure contributes to systemic fatigue by decreasing mitochondrial membrane potential and ATP production in immune cells [52]. As such, addressing gut health through antimicrobial therapies, probiotics, and barrier repair is a cornerstone of functional medicine protocols.

Functional Medicine Strategies for Chronic Fatigue Syndrome

A functional medicine approach to chronic fatigue syndrome is personalized and multi-layered. It targets the root causes rather than just the symptoms. Common strategies include:

• Reducing toxic load: Testing for and remediating mold, heavy metals, and chemical exposures; supporting detoxification with antioxidants and liver nutrients.
• Treating latent infections: Using antiviral, antimicrobial, or immune-modulating protocols tailored to EBV, Lyme, or fungal colonization.
• Mitochondrial support: Supplementing B vitamins, magnesium, CoQ10, acetyl-L-carnitine, alpha-lipoic acid, and glutathione precursors to enhance oxidative phosphorylation.
• Nutrient repletion: Correcting iron, copper, and zinc imbalances to optimize oxygen delivery and mitochondrial enzyme function.
• Restoring gut integrity: Addressing dysbiosis, SIBO/SIFO, and permeability to reduce systemic inflammation.
• Lifestyle interventions: Emphasizing pacing to prevent PEM, improving sleep hygiene, reducing psychological stressors, and implementing an anti-inflammatory diet.

Each case is different, and every patient presents with unique triggers, mediators, and symptoms. A skilled functional medicine provider specializing in CFS can help identify the key areas to address in each case. 

When applied systematically, these interventions aim to restore mitochondrial function, reduce the inflammatory burden, and rebuild resilience. This leads to meaningful improvements in energy, cognition, and quality of life.

Practical Applications for Chronic Fatigue Syndrome Patients

In conclusion, for individuals living with CFS, recovery often involves incremental progress rather than quick fixes. Practical steps may include:

1. Identifying and remediating environmental exposures (e.g., testing for mold, using air filtration, reducing chemical load).
2. Testing for and correcting nutrient deficiencies.
3. Supporting mitochondrial health with evidence-based supplementation.
   Investigating infectious triggers through appropriate laboratory diagnostics.
4. Addressing gut health to reduce systemic inflammation.
5. Working with a qualified functional medicine practitioner to tailor interventions.

Take the Next Step to Address Chronic Fatigue with Functional Medicine

Are you struggling with persistent fatigue, brain fog, or unexplained health issues? Then it’s time to look deeper than lab results. Mitochondrial dysfunction is often the missing piece in chronic fatigue. But with the proper testing, nutrient support, and environmental interventions, recovery is possible.

Schedule your free discovery call. And uncover the root of your symptoms and begin a personalized functional medicine approach to chronic fatigue syndrome.