By Yoon Hang "John" Kim, MD, MPH Board-Certified in Preventive Medicine | Integrative & Functional Medicine Physician |Root Cause Medicine

www.directintegrativecare.com

Chronic Fatigue Syndrome (CFS) and Myalgic Encephalomyelitis (ME) remain among the most misunderstood, underdiagnosed, and poorly managed conditions in modern medicine. Patients suffering from this debilitating illness often endure years of medical visits, inconclusive testing, and dismissive encounters before receiving a diagnosis — if they receive one at all. In this article, we will examine the current state of CFS/ME diagnosis, clarify the relationship between the two terms, explore the SHINE framework as a practical clinical starting point, and discuss why Low-Dose Naltrexone (LDN) may serve as a cornerstone treatment.

CFS and ME: One Condition or Two?

One of the most common questions patients and clinicians encounter is whether Chronic Fatigue Syndrome and Myalgic Encephalomyelitis are the same condition. The short answer is that they are largely used interchangeably in contemporary clinical practice, but the terms carry different historical and conceptual baggage.

Myalgic Encephalomyelitis (ME) was first described in the medical literature in the 1950s, following outbreaks of a polio-like illness characterized by profound fatigue, neurological symptoms, muscle pain, and post-exertional malaise. The term itself — meaning inflammation of the brain and spinal cord with associated muscle pain — implies a neuroinflammatory pathology. The World Health Organization (WHO) has classified ME as a neurological disease under ICD-10 code G93.3 since 1969.

Chronic Fatigue Syndrome (CFS) emerged as a term in the late 1980s, largely through the work of the Centers for Disease Control and Prevention (CDC), following an outbreak of unexplained fatiguing illness in Incline Village, Nevada. The CDC established formal diagnostic criteria (the Fukuda criteria, 1994) that defined CFS primarily by the presence of unexplained, persistent fatigue lasting six months or more, accompanied by at least four of eight specified symptoms. Critics have long argued that the name "Chronic Fatigue Syndrome" trivializes the condition, reducing a complex, multi-system illness to its most superficial symptom.

Today, the combined term ME/CFS is widely used in research and clinical settings to acknowledge both traditions. The 2015 Institute of Medicine (now the National Academy of Medicine) report proposed the alternative name Systemic Exertion Intolerance Disease (SEID), emphasizing the hallmark feature of post-exertional malaise, though this term has not achieved widespread adoption.

For practical clinical purposes, ME and CFS refer to the same clinical entity — a chronic, multi-system illness characterized by profound fatigue that is not substantially alleviated by rest, post-exertional malaise, unrefreshing sleep, and cognitive impairment (commonly referred to as "brain fog"), often accompanied by orthostatic intolerance, pain, and immune dysfunction.

CFS/ME as a Diagnosis of Exclusion

It is important to recognize that CFS/ME remains primarily a diagnosis of exclusion. There is, at present, no single definitive biomarker, laboratory test, or imaging study that can confirm the diagnosis. Instead, clinicians arrive at a diagnosis of CFS/ME by systematically ruling out other conditions that could explain the patient's symptoms.

This diagnostic process requires excluding conditions such as hypothyroidism, adrenal insufficiency, anemia, sleep disorders (including obstructive sleep apnea), autoimmune diseases (such as lupus or multiple sclerosis), chronic infections (including Lyme disease, hepatitis, and HIV), primary psychiatric disorders (particularly major depressive disorder), malignancies, and other chronic illnesses that present with fatigue as a prominent feature.

The major diagnostic criteria currently in use include:

• Fukuda Criteria (1994): Requires six months of unexplained fatigue plus four of eight specified symptoms. Widely used but criticized for being overly broad and not requiring post-exertional malaise as a mandatory criterion.
• Canadian Consensus Criteria (CCC, 2003): More clinically specific, requiring post-exertional malaise, sleep dysfunction, pain, and neurological/cognitive manifestations. Generally considered more accurate in identifying true ME/CFS patients.
• Institute of Medicine (IOM) Criteria (2015): Requires substantial reduction in activity lasting more than six months, post-exertional malaise, unrefreshing sleep, plus either cognitive impairment or orthostatic intolerance. Designed to be more accessible for general practitioners.

The exclusionary nature of the diagnosis creates significant challenges. Patients often undergo extensive and expensive workups over many months or even years. Many are told their symptoms are psychosomatic or are given diagnoses of depression or anxiety before CFS/ME is considered. This diagnostic odyssey contributes to patient frustration, delayed treatment, and worsening of the condition.

From an integrative medicine perspective, however, the exclusionary workup should not be viewed as an obstacle but rather as an opportunity. The process of ruling out other diagnoses allows us to identify and address co-existing conditions — hormonal imbalances, hidden infections, nutritional deficiencies, and autoimmune processes — that may be contributing to or exacerbating the patient's symptoms. This is precisely where the SHINE approach becomes invaluable.

The SHINE Approach: A Practical Framework for CFS/ME

When faced with the complexity of CFS/ME, clinicians need a structured framework to guide evaluation and treatment. The SHINE protocol provides exactly that — a systematic, integrative approach that addresses the major physiological domains commonly disrupted in CFS/ME patients. SHINE stands for:

• S — Sleep
• H — Hormones
• I — (Hidden) Infections
• N — Nutrition
• E — Endocrine/Autoimmune

S — Sleep

Unrefreshing sleep is one of the cardinal features of CFS/ME and is present in virtually all patients. Sleep dysfunction in CFS/ME is not simply insomnia; rather, it involves disrupted sleep architecture, including reduced slow-wave (deep) sleep, frequent awakenings, and a failure of sleep to restore normal function.

Addressing sleep is foundational because without restorative sleep, the body cannot repair tissues, consolidate memory, regulate immune function, or balance hormones. A thorough sleep evaluation should include screening for primary sleep disorders (obstructive sleep apnea, restless leg syndrome, upper airway resistance syndrome), assessing sleep hygiene, and considering both pharmacological and non-pharmacological interventions.

Clinicians should remember that sleep in CFS/ME patients is qualitatively different from typical insomnia, and standard sleep hygiene advice alone is rarely sufficient. A multimodal approach — potentially including low-dose sleep medications, melatonin, magnesium, and cognitive behavioral therapy for insomnia (CBT-I) — is often necessary.

H — Hormones

Hormonal dysregulation is frequently encountered in CFS/ME patients, even when standard laboratory values fall within "normal" reference ranges. The hypothalamic-pituitary-adrenal (HPA) axis is often blunted, leading to suboptimal cortisol responses. Thyroid function may appear normal on basic screening (TSH) but reveal subclinical dysfunction when a full thyroid panel (free T3, free T4, reverse T3, thyroid antibodies) is obtained.

Sex hormone imbalances — including low testosterone in both men and women, estrogen dominance, and progesterone deficiency — are also common and contribute to fatigue, cognitive dysfunction, mood disturbances, and pain. DHEA-S, pregnenolone, and growth hormone levels may also be suboptimal.

The integrative approach involves looking beyond conventional reference ranges and considering whether a patient's hormonal levels are optimal for their individual physiology, not merely "within normal limits."

I — (Hidden) Infections

Chronic, occult infections are a significant and often overlooked driver of CFS/ME. These "hidden" infections may include reactivated herpesviruses (EBV, HHV-6, CMV), chronic Lyme disease and co-infections (Babesia, Bartonella, Anaplasma), mycoplasma, chronic sinusitis with biofilm-forming organisms, small intestinal bacterial overgrowth (SIBO), candidal overgrowth, and other stealth pathogens.

These infections may not cause dramatic acute illness but instead maintain a state of chronic immune activation and inflammation that perpetuates the CFS/ME disease process. Identifying and appropriately treating these infections — whether with targeted antimicrobials, antivirals, antifungals, or immune-modulating therapies — can be a turning point in a patient's recovery.

N — Nutrition

Nutritional deficiencies are exceedingly common in CFS/ME patients and contribute significantly to symptom burden. Key nutrients to evaluate include B vitamins (especially B12 and folate, with attention to MTHFR polymorphisms), vitamin D, magnesium, iron (including ferritin), zinc, coenzyme Q10, omega-3 fatty acids, and amino acids.

Mitochondrial dysfunction is increasingly recognized as a central feature of CFS/ME pathophysiology. Supporting mitochondrial function through targeted supplementation — including CoQ10, D-ribose, L-carnitine, and B vitamins — can improve cellular energy production and reduce fatigue.

Equally important is addressing dietary factors: food sensitivities, gut permeability ("leaky gut"), and the gut microbiome all play significant roles in CFS/ME and should be evaluated as part of a comprehensive nutritional assessment.

E — Endocrine/Autoimmune

The final component of SHINE addresses the growing recognition that autoimmune and endocrine dysfunction plays a central role in CFS/ME pathophysiology. Emerging research has identified autoantibodies against various cellular receptors (including adrenergic and muscarinic receptors) in subsets of CFS/ME patients, suggesting an autoimmune etiology in at least some cases.

Autoimmune thyroiditis (Hashimoto's), adrenal autoimmunity, and other autoimmune processes may be present either as primary drivers or as co-existing conditions that compound the patient's illness. Additionally, mast cell activation syndrome (MCAS) — which sits at the intersection of immune and endocrine dysfunction — is increasingly recognized as a common comorbidity in CFS/ME and should be evaluated.

Screening for autoimmune markers (ANA, thyroid antibodies, celiac antibodies, inflammatory markers including CRP and ESR) and maintaining a high index of suspicion for autoimmune processes is essential in the comprehensive evaluation of CFS/ME patients.

Low-Dose Naltrexone (LDN): A Cornerstone Treatment for CFS/ME

While the SHINE framework provides a comprehensive approach to evaluation and treatment, Low-Dose Naltrexone (LDN) deserves special attention as a potential cornerstone treatment for CFS/ME. LDN — naltrexone prescribed at doses typically between 0.5 mg and 4.5 mg, far below the standard 50 mg dose used for addiction medicine — has emerged as a uniquely valuable therapeutic tool for this patient population.

Mechanism of Action

LDN works through several complementary mechanisms that are directly relevant to CFS/ME pathophysiology:

Anti-inflammatory effects: LDN has been shown to modulate microglial activation in the central nervous system. Microglia are the brain's resident immune cells, and their chronic activation is believed to be a key driver of neuroinflammation in CFS/ME. By reducing microglial activation, LDN can decrease neuroinflammation and its downstream effects on fatigue, pain, and cognitive dysfunction. LDN also modulates Toll-like receptor 4 (TLR4) signaling, a critical pathway in innate immune activation and systemic inflammation.

Immune system optimization: Rather than simply suppressing immune function (as conventional immunosuppressants do), LDN works to optimize and modulate immune function. Through its transient blockade of opioid receptors, LDN triggers an upregulation of endogenous endorphin and enkephalin production — a phenomenon known as the "rebound effect." These endogenous opioids, particularly OGF (opioid growth factor/met-enkephalin), play important roles in immune regulation, promoting a balanced immune response rather than the dysregulated, chronically activated state seen in CFS/ME.

Endorphin modulation: The upregulation of endogenous endorphins has broad systemic effects, including improved pain modulation, enhanced mood, better sleep quality, and improved stress resilience — all of which are compromised in CFS/ME patients.

Clinical Evidence and Application

While large-scale randomized controlled trials specifically for CFS/ME are still needed, the existing evidence base is encouraging. Studies in closely related conditions — including fibromyalgia, multiple sclerosis, Crohn's disease, and complex regional pain syndrome — have consistently demonstrated LDN's efficacy in reducing pain, fatigue, and inflammation while improving quality of life with minimal side effects.

Clinical experience with LDN in CFS/ME patients has shown improvements in energy levels, pain reduction, cognitive clarity, sleep quality, and overall functional capacity. LDN is particularly attractive as a treatment option because of its favorable safety profile, low cost, minimal drug interactions, and the ability to address multiple pathological mechanisms simultaneously.

Practical Considerations

LDN is typically initiated at a low dose (0.5–1.5 mg at bedtime) and gradually titrated upward to the therapeutic range (typically 1.5–4.5 mg) over several weeks. Some patients, particularly those who are highly sensitive or have co-existing mast cell activation syndrome, may benefit from starting at ultra-low doses (as low as 0.1 mg) and titrating even more slowly.

It is important to note that LDN should be compounded by a reputable compounding pharmacy, as commercial naltrexone tablets (50 mg) cannot be reliably split into the low doses required. Patients should be counseled that the full therapeutic effect may take 2–3 months to manifest and that vivid dreams — a common initial side effect — typically resolve within the first few weeks of treatment.

Conclusion

CFS/ME remains a challenging diagnosis — one that is often reached only after an exhaustive process of exclusion, leaving patients feeling dismissed and providers feeling uncertain. However, by embracing a structured, integrative framework like SHINE and incorporating evidence-informed treatments like Low-Dose Naltrexone, we can offer these patients a coherent and hopeful path forward.

The SHINE approach ensures that no major physiological domain is overlooked, while LDN provides a uniquely well-suited therapeutic intervention that addresses the core pathophysiological features of CFS/ME — chronic inflammation, immune dysregulation, and neuroinflammation — with remarkable safety and tolerability.

As our understanding of CFS/ME continues to evolve, integrative medicine is well-positioned to lead the way in providing comprehensive, patient-centered care for this underserved population.

Dr. Yoon Hang "John" Kim, MD, MPH is a board-certified integrative medicine physician and the founder of Direct Integrative Care. He leads the LDN Support Group with over 8,000 members and is the author of three books on Low-Dose Naltrexone therapy. For more information, visit www.directintegrativecare.com.

Disclaimer: This article is for educational purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider before starting any new treatment.