ME/CFS Treatment Archetypes: Quick Reference Map

For educational, journalistic, and advocacy use. Full AI simulation, escalation sequences, and dosing logic require CYNAERA license.)

Why This Reference Matters

Treatment conversations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) have often been limited to a handful of recycled agents, discussed without mechanistic context.

Meanwhile, recent biomedical research confirms the illness is a multi-system, terrain-driven condition involving mitochondrial dysfunction, immune dysregulation, autonomic instability, and neuroinflammation (Komaroff & Bateman, 2023; Proal & VanElzakker, 2021; Esfandyarpour et al., 2019).

CYNAERA’s AI simulations analyze 120+ therapeutic candidates across 6 mechanisms, weighting them by patient endotype, Pathos™ severity score, and predicted remission probability. This map provides the first public-facing mechanism reference, while full dosing logic, contraindication overlays, and trial-ready protocols remain licensed.

CYNAERA ME/CFS Mechanism Map (Quick Reference)

1. Mitochondrial Support Axis

• Primary: Oxaloacetate (AEO), CoQ10, NADH, Metformin

• Secondary: Creatine, D-Ribose, Alpha-lipoic acid

• Rationale: Mitochondrial stress and impaired oxidative phosphorylation are documented in ME/CFS (Naviaux et al., 2016). These agents support ATP generation and reduce oxidative stress.

• CYNAERA Insight: Viral-triggered subtypes showed 1.8× greater recovery probability with mitochondrial + anti-inflammatory combinations vs. monotherapy.

2. Neuroimmune Modulation Axis

• Primary: Low-Dose Naltrexone (LDN), Ketamine, Statins, SSRIs

• Secondary: Minocycline, Dimethyl fumarate (DMF), Palmitoylethanolamide (PEA)

• Rationale: Microglial activation and kynurenine-pathway neurotoxicity drive sensory hypersensitivity and “brain fog” (Nakatomi et al., 2014; Younger et al., 2020). Agents here reduce neuroinflammation and stabilize cognition.

• CYNAERA Insight: Microglial-targeting therapies outperform broad systemic anti-inflammatories in sensory-dominant endotypes.

3. Autonomic Regulation Axis

• Primary: Pyridostigmine, Beta-blockers

• Secondary: Ivabradine, Low-dose Midodrine

• Rationale: Autonomic instability (e.g., POTS, OI) affects up to 60% of ME/CFS patients (Rowe et al., 2014). Interventions here stabilize tone and improve perfusion.

• CYNAERA Insight: Autonomic regulation emerged as a recovery “rate-limiter” in 42% of modeled cases.

4. Viral Reactivation Control Axis

• Primary: Valganciclovir, Acyclovir

• Secondary: Leflunomide, Maribavir

• Rationale: EBV, HHV-6, and CMV reactivation sustain immune dysregulation (Loebel et al., 2014; Proal & VanElzakker, 2021). Antivirals target these persistence loops.

• CYNAERA Insight: Antiviral benefit scores increased significantly when paired with mitochondrial support therapy.

5. Immune Reset Axis

• Primary: JAK inhibitors (Baricitinib, Tofacitinib), Rapamycin

• Secondary: BC007 aptamers, Colchicine, selective IVIG

• Rationale: T-cell exhaustion and chronic inflammatory signaling are core immune features (Mandarano et al., 2020; Ciccone et al., 2023). These agents rebalance immune signaling and restore Treg function.

• CYNAERA Insight: Combined targeting of inflammasome activity + T-cell exhaustion yielded the highest modeled remission gains.

6. Oxygenation & Recovery Axis

• Primary: Hyperbaric Oxygen Therapy (HBOT)

• Secondary: Erythropoietin, high-flow oxygen

• Rationale: Neurovascular hypoperfusion and impaired oxygen utilization are common in ME/CFS (Miller et al., 2014). Oxygenation strategies improve tissue perfusion and cognitive recovery in subsets.

Mechanism Performance (CYNAERA Simulated Reference Scores)

(Aggregate Pathos™-weighted scores; full simulation logic withheld)

Axis	Relative Benefit Score (0–10)
Mitochondrial Support	8.5
Neuroimmune Modulation	7.9
Autonomic Regulation	6.8
Viral Reactivation Control	6.3
Immune Reset	7.5
Oxygenation & Recovery	5.9

How to Use This Quick Reference

• As a mechanism-first lens for ME/CFS treatment exploration

• To guide grant proposals, clinical trial design, and advocacy documents

• As a public evidence map showing the breadth of therapeutic avenues under study

The full reference system includes 120+ therapies, escalation logic, contraindication overlays, and phased trial protocols — available under CYNAERA license.

Building Forward: Linking Treatment Archetypes to the Larger CYNAERA Library

This quick reference map is not a stand-alone document — it’s part of CYNAERA’s effort to create the most comprehensive ME/CFS research and clinical resource in the world. Understanding treatment archetypes is only the first step. To actually improve outcomes, they must be integrated with:

• SPARC™ (Smart Patient-Adaptive Research Clusters) — a framework for structuring ME/CFS and Long COVID trials with stratified arms, adaptive dosing, and pre-modeled flare safeguards.

• Phenotyping & Endotyping Papers — including the CYNAERA 25+ Phenotypes of ME/CFS reference, which defines how different subgroups present across immune, autonomic, cognitive, and metabolic domains.

• Best Practices for ME/CFS Trials — a white paper outlining stabilization-first protocols, digital monitoring, and multi-stage adaptive architectures.

• Diagnostic Frameworks — such as the Composite Diagnostic Fingerprint (CDF-ME) and CDF-Peds-ME/CFS™, which provide structured, multi-system tools for adult and pediatric diagnosis.

Together, these works form an interconnected library: diagnosis (CDF), phenotyping, trial logic (SPARC), and treatment archetypes. Each white paper connects to the others, offering a pathway from recognition → stratification → safe trial design → therapeutic exploration.

Readers are encouraged to explore the full CYNAERA ME/CFS Library for linked references, expanded models, and additional quick reference guides.

References

• Ciccone EJ, et al. (2023). T cell exhaustion and viral persistence in post-viral syndromes. Cell Reports Medicine, 4(1), 100870.

• Esfandyarpour R, et al. (2019). Molecular insights into ME/CFS pathophysiology. PNAS, 116(21), 10221–10227.

• Komaroff AL, Bateman L. (2023). Advances in understanding ME/CFS pathogenesis. Nature Reviews Immunology, 23(5), 327–340.

• Loebel M, et al. (2014). Antiviral treatment in ME/CFS associated with EBV reactivation. Antiviral Therapy, 19(5), 523–530.

• Mandarano AH, et al. (2020). T cell exhaustion in ME/CFS. Clinical Immunology, 210, 108263.

• Miller AH, et al. (2014). Neurovascular and metabolic abnormalities in fatigue syndromes. Brain, Behavior, and Immunity, 45, 180–192.

• Nakatomi Y, et al. (2014). Neuroinflammation in ME/CFS patients: PET study. Journal of Nuclear Medicine, 55(6), 945–950.

• Naviaux RK, et al. (2016). Metabolic features of chronic fatigue syndrome. PNAS, 113(37), E5472–E5480.

• Proal AD, VanElzakker MB. (2021). Biological factors sustaining Long COVID and ME/CFS. Frontiers in Microbiology, 12, 698169.

• Rowe PC, et al. (2014). Orthostatic intolerance in adolescents with ME/CFS. Pediatrics, 134(3), e903–e913.

• Younger J, et al. (2020). Neuroimmune drivers of ME/CFS and chronic pain. Frontiers in Neurology, 11, 826.

Author’s Note:

All insights, frameworks, and recommendations in this white paper reflect the author's independent analysis and synthesis. References to researchers, clinicians, and advocacy organizations acknowledge their contributions to the field but do not imply endorsement of the specific frameworks, conclusions, or policy models proposed herein. This information is not medical guidance.

Applied Infrastructure Models Supporting This Analysis

Several standardized diagnostic and forecasting models developed through CYNAERA were utilized or referenced in the construction of this white paper. These tools support real-time surveillance, economic forecasting, and symptom stabilization planning for infection-associated chronic conditions (IACCs).

Note: These models were developed to bridge critical infrastructure gaps in early diagnosis, stabilization tracking, and economic impact modeling. Select academic and public health partnerships may access these modules under non-commercial terms to accelerate independent research and system modernization efforts.

Licensing and Customization

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Learn More: https://www.cynaera.com/systems

About the Author 

Cynthia Adinig is an internationally recognized systems strategist, health policy advisor, and the founder of CYNAERA, an AI-powered intelligence platform advancing diagnostic reform, clinical trial simulation, and real-world modeling for infection-associated chronic conditions (IACCs). She has developed 400+ Core AI Frameworks, 1 Billion + Dynamic AI Modules. including the IACC Progression Continuum™, US-CCUC™, and RAEMI™, which reveal hidden prevalence, map disease pathways, and close gaps in access to early diagnosis and treatment.

Her clinical trial simulator, powered by over 675 million synthesized individual profiles, offers unmatched modeling of intervention outcomes for researchers and clinicians.

Cynthia has served as a trusted advisor to the U.S. Department of Health and Human Services, collaborated with experts at Yale and Mount Sinai, and influenced multiple pieces of federal legislation related to Long COVID and chronic illness. 

She has been featured in TIME, Bloomberg, USA Today, and other leading publications. Through CYNAERA, she develops modular AI platforms that operate across 32+ sectors and 180+ countries, with a local commitment to resilience in the Northern Virginia and Washington, D.C. region.