Problem identification

The primary question of this study was: “What evidence links orexinergic and hypothalamic dysfunction to ME/CFS pathophysiology?”. Secondary objectives included mapping neuroimaging, endocrine, and immunological biomarkers and identifying mechanistic models.

Literature search strategy

Following the integrative-review framework of Whittemore and Knafl [32], comprehensive searches were conducted in PubMed, Scopus, Web of Science, and OpenAlex, with records retrieved up to April 2025. Search strings combined “chronic fatigue syndrome” OR “myalgic encephalomyelitis” AND (orexin OR hypocretin OR hypothalamus OR HPA axis OR cytokine OR neuroimaging OR biomarker) and were adapted to the specific syntax of each database. Terms were applied to title and abstract fields when available, without language restrictions. After de-duplication, records were screened against predefined inclusion and exclusion criteria to select relevant studies for synthesis. Reference lists of included studies and key reviews were examined to capture gray literature.

Eligibility and study selection

Eligible studies comprised peer-reviewed quantitative, qualitative, mixed-methods, and theoretical reports involving participants diagnosed with ME/CFS by recognized criteria that assessed orexin/hypothalamic parameters, HPA axis metrics, or inflammatory markers. We excluded non-English publications, conference abstracts, editorials, and narrative reviews, as well as any study in which comorbid conditions (e.g., fibromyalgia, major depressive disorder) were likely to confound neuroendocrine outcomes. All identified records were imported into a reference manager and duplicates removed prior to screening. A single reviewer then assessed titles, abstracts, and full texts against these predefined eligibility criteria (Table 1).

Data evaluation

Methodological quality of included studies was appraised using an adapted Joanna Briggs Institute tool [33], tailored for diverse designs (quantitative, qualitative, mixed-methods, and theoretical). Each article was scored on domains such as sample selection, measurement validity (e.g., orexin assays, HPA axis markers), data analysis rigor, and clarity of theoretical exposition. Studies deemed at high risk of bias—such as studies utilizing unvalidated biomarkers or providing insufficient methodological detail—were excluded from the synthesis to preserve interpretative integrity.

Data analysis and synthesis

Data extraction and analysis were conducted by a single reviewer who organized key study characteristics and findings into standardized matrices. Quantitative measures—such as orexin concentrations, HPA axis hormones (e.g., cortisol), cytokine profiles, and relevant neuroimaging parameters—were tabulated, while mechanistic and theoretical insights were summarized narratively. The phases of data reduction, display, comparison, conclusion drawing, and verification—the core steps of constant comparison—were applied to integrate evidence across diverse designs. An audit trail documented all analytical decisions and rationale to ensure transparency and reproducibility, in line with integrative-review standards.

Presentation of results

Results are synthesized both narratively and through a conceptual model to depict orexin-hypothalamic interactions in ME/CFS. Key quantitative findings (e.g., orexin-A concentrations, cortisol levels, cytokine profiles, and neuroimaging metrics) are presented in summary tables, while theoretical and mechanistic insights are mapped in a diagram illustrating feedback loops and modulatory pathways. Each conclusion is explicitly anchored to supporting primary sources to demonstrate a logical chain of evidence, ensuring that interpretations do not exceed the data. The presentation captures the depth and breadth of the literature and highlights implications for clinical practice, precision-medicine research, and health policy initiatives. Methodological limitations—such as heterogeneity of designs, potential publication bias, and reliance on single-reviewer selection—are acknowledged to contextualize the findings.

Neuroimaging findings, structural alterations, neuroendocrine abnormalities, proinflammatory profile, and potential biomarkers in CFS

Neuroimaging in ME/CFS reveals cortical volume reduction in frontal and temporal lobes, prefrontal gray matter hypodensity, and hypothalamic atrophy—linked to HPA axis dysregulation and fatigue [9, 34, 35]. Reduced fractional anisotropy in white matter tracts and disrupted default-mode-network (DMN) connectivity indicate impaired attention, executive function, and autonomic control [36, 37]. Additionally, altered hypothalamic and brainstem connectivity in orexinergic regions, visualized via magnetic resonance imaging (MRI) and positron emission tomography (PET), may serve as biomarkers [13, 34]. Voxel-based morphometry (VBM) shows gray- and white-matter alterations in sleep- and energy-related areas [38]. Pro-inflammatory cytokines correlate with hypothalamic dysfunction, but lack consistency as biomarkers [39, 40].

ME/CFS is linked to HPA axis hypoactivity, diminished corticotropin-releasing hormone (CRH) secretion, and blunted cortisol responses that impair stress regulation in ME/CFS [19, 41]. Autonomic dysfunction manifests through reduced catecholamine levels and postural orthostatic tachycardia syndrome (POTS)-like features, suggesting sympathetic dysregulation as a core component of the disorder [42]. Thyroid axis disruption (low T₃ without hypothyroidism) and growth hormone/insulin-like growth factor-1 (IGF-1) changes, prominent in fibromyalgia, are inconsistently seen in ME/CFS [43, 44]. Ghrelin-leptin imbalance may contribute to appetite and energy dysregulation [45].

Orexin-A in ME/CFS has been explored as a biomarker, but findings remain inconclusive [46, 47]. Since orexin neurons modulate the HPA axis, observed hypocortisolism may signal hypothalamic dysfunction [41]. Reliable biomarkers are crucial for elucidating orexinergic roles. Cerebrospinal fluid (CSF), imaging, and endocrine data indicate orexin dysregulation may underlie fatigue and cognitive deficits in ME/CFS [19, 20, 48, 49].

Chronic inflammation likely suppresses orexin signaling. Elevated interleukin-1 beta (IL-1β), IL-6, TNF-α, interferon-gamma (IFN-γ), IL-10, and IL-5 levels associate with poor sleep and immune dysfunction, though cytokine signatures lack uniformity [11, 50, 51]. Beyond molecular markers, sleep disruption and autonomic dysfunction—both modulated by the hypothalamus—further implicate orexin involvement [52, 53]. Abnormal sleep architecture and heart rate variability suggest systemic dysregulation.

Emerging digital technologies, including wearables and mobile apps, enable real-time monitoring of symptoms and physiological changes [54]. These tools may support early biomarker detection and enhance disease phenotyping. Refining biomarker panels—including orexin, cortisol dynamics, imaging data, and inflammatory mediators—will improve diagnostic precision and illuminate mechanisms underlying hypothalamic and orexinergic dysfunction in ME/CFS. All qualitative and quantitative findings from this Results section are synthesized in Tables 2 and 3.

Integrative mechanistic frameworks: synthesis from neuroendocrine, immune, and imaging data

Orexin, inflammation, and HPA axis interactions

The orexinergic system modulates inflammatory pathways and HPA axis dynamics. Pro-inflammatory cytokines may impair orexin signaling, sustaining fatigue and immune dysregulation [39, 72]. Orexin receptors, especially orexin receptor type 2 (OX2R), influence stress-related HPA responses, linking stress physiology and fatigue [79, 80]. This triadic interaction—orexin, inflammation, and HPA axis—may represent a central feedback mechanism in the pathophysiology of ME/CFS.

A hypothetical model of the positive feedback loop involving hypothalamic dysfunction, HPA axis dysregulation, inflammatory activity, and clinical symptomatology is presented in Figure 2.

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Figure 2. Conceptual model of hypothalamic-orexinergic dysfunction in ME/CFS. This diagram integrates empirical and theoretical findings into six key components. Orexin-producing neurons in the LH, which normally project to arousal and autonomic centers, are inhibited by physical or mental stress (systemic exertion). Resulting orexin deficiency or desensitization of orexin receptors leads to dysregulation of the HPA axis and hypocortisolism, conditioning a hyperimmune response characterized by elevated pro-inflammatory cytokines (IL-6, TNF-α). These cytokines further prevent CRH release and inhibit orexin neuron activity via neuroinflammation, creating a positive feedback loop that perpetuates an aberrant stress response. CRH: corticotropin-releasing hormone; HPA: hypothalamic-pituitary-adrenal; IL-6: interleukin-6; LH: lateral hypothalamus; ME/CFS: myalgic encephalomyelitis/chronic fatigue syndrome. Figure created by the author under a CC-BY-4.0 license. Icons were generated with DALL·E 3 (OpenAI)

Summary of key findings

The present review outlines how hypothalamic and orexinergic dysfunction may underlie crucial facets of CFS, including sleep disturbances, metabolic dysregulation, and autonomic instability. Specifically, the evidence suggests that: (1) neuroimaging abnormalities (e.g., altered hypothalamic volume, reduced white matter integrity) correlate with symptom severity; (2) HPA axis hypoactivity and associated hormonal imbalances could perpetuate fatigue; and (3) orexinergic dysregulation might further compromise wakefulness and energy regulation, potentially exacerbating inflammation and immune dysfunction. These interlinked processes reinforce the complexity of ME/CFS, highlighting a multifactorial etiology that demands integrated diagnostic and therapeutic frameworks [19, 41].

While the studies reviewed collectively suggest that hypothalamic orexinergic dysfunction may contribute to ME/CFS pathophysiology, methodological limitations (see Limitations of the current evidence base) preclude definitive conclusions. Further longitudinal and interventional research is required to clarify the temporal relationship between orexin signaling alterations and symptom severity in ME/CFS.

Although no clinical trials to date have directly tested orexin modulators in ME/CFS patients, data from recent insomnia studies illustrate the translational potential of this approach. In a phase 3 randomized, double-blind, placebo-controlled trial (NCT02952820), lemborexant 5 mg and 10 mg nightly significantly improved Insomnia Severity Index (ISI) scores and daytime functioning versus placebo at both 1 and 6 months [81, 82]. Similarly, a 12-month subgroup analysis of midlife women in the SUNRISE-2 study demonstrated sustained improvements in sleep-onset latency, wake-after-sleep-onset, and fatigue measures with lemborexant [83]. These findings suggest that dual orexin receptor antagonists (DORAs) may ameliorate sleep-wake and fatigue symptoms common to ME/CFS, supporting the rationale for targeted clinical trials in this population.

Critical appraisal and mechanistic implications

A major strength of the reviewed literature is its broad scope, addressing immune function, neuroendocrine pathways, and the neural underpinnings of fatigue [39, 48]. Yet critical appraisal reveals ongoing challenges.

Limitations of the current evidence base

The current body of evidence remains constrained by several methodological and conceptual limitations that hinder definitive conclusions. Despite frequent reports of cytokine imbalances and cortisol dysregulation in ME/CFS, no single biomarker has emerged as reliably specific, often overlapping with profiles observed in other inflammatory or fatigue-related disorders [11, 51]. Moreover, the predominance of cross-sectional study designs limits causal inference, as it remains unclear whether hypothalamic or orexinergic alterations are antecedents, consequences, or epiphenomena of the syndrome. Longitudinal studies are essential to clarify the temporal dynamics and directionality of these associations [38, 94]. A further complication arises from the high prevalence of comorbid conditions such as depression and fibromyalgia, which can confound neuroendocrine and immune measurements, making it difficult to isolate dysfunctions that are specific to ME/CFS pathophysiology [43].

While this integrative review adheres to rigorous methodological principles, several limitations must be acknowledged. First, the conduct of literature screening, quality appraisal and data extraction by a single reviewer increases the risk of systematic error and undermines inter-rater reliability [32, 95]. Second, the inclusion of both empirical and theoretical sources enhances conceptual breadth but may reduce analytic consistency and the generalizability of conclusions [32]. Third, despite comprehensive hand-searching of reference lists, the potential for publication bias and incomplete retrieval of grey literature persists in evidence syntheses [96]. Finally, the absence of a universally accepted critical-appraisal tool for reviews encompassing diverse study designs complicates consistent quality evaluation in mixed-method integrative reviews [97].

Research opportunities and perspectives

Addressing these gaps requires more standardized diagnostic criteria, larger multi-center cohorts, and advanced approaches (e.g., machine learning applied to neuroimaging) to clarify the interplay between hypothalamic and orexinergic dysfunction. Longitudinal studies tracking shifts in HPA hormones, orexin levels, and inflammatory markers could identify prognostic indicators and reveal windows for therapeutic intervention [39, 98]. Additionally, controlled trials of orexin receptor modulators, in combination with behavioral approaches (e.g., CBT, pacing), hold promise for improving both daytime function and sleep quality in ME/CFS [81, 99].

Clinical implications and therapeutic perspectives

Modulating orexin receptors emerges as a promising pharmacological avenue for managing the multifactorial symptomatology of ME/CFS. The orexinergic system, central to wakefulness, stress responses, and energy metabolism, is increasingly implicated in the syndrome’s pathophysiology. DORAs such as daridorexant and lemborexant have demonstrated efficacy in improving sleep quality and attenuating fatigue in insomnia—a frequent comorbidity in ME/CFS—without the adverse profiles associated with traditional sedatives [81, 99, 100]. Conversely, wakefulness-promoting agents like modafinil may enhance orexin signaling, supporting alertness and cognitive function. This agent activates specific hypothalamic circuits and may promote adaptive stress responses, offering therapeutic potential in ME/CFS by simultaneously alleviating fatigue and addressing underlying orexinergic deficits [63, 101]. Clinical observations indicate that low-dose modafinil, particularly when combined with non-pharmacologic strategies such as CBT, anti-inflammatory diets, graded exercise, and antioxidant supplementation, may reduce post-exertional malaise and improve metabolic and motivational parameters [9, 102].

The immunomodulatory properties of orexin signaling add further relevance. Orexin pathways may exert anti-inflammatory effects, suggesting their therapeutic utility in mitigating neuroinflammation associated with ME/CFS [72, 103]. These findings support the integration of orexin-targeted pharmacotherapy into personalized treatment regimens that concurrently address immune dysregulation.

Behavioral and lifestyle interventions targeting sleep regulation and energy conservation are also foundational in ME/CFS management. CBT has been shown to improve fatigue and support healthier behavioral patterns in chronic inflammatory diseases, indicating its relevance in ME/CFS [104]. Similarly, moderate physical activity tailored to individual tolerance has shown benefits for fatigue, sleep, and overall functioning in comparable syndromes [105]. Sleep hygiene—through consistent schedules and environmental optimization—can significantly reduce daytime fatigue, as disturbances in sleep architecture are strongly associated with symptom exacerbation [106]. The Energy Envelope Theory further emphasizes activity pacing to avoid overexertion and reduce the risk of post-exertional symptom exacerbation [107].

Nutritional strategies aimed at stabilizing energy levels and improving sleep quality form a critical component of multidisciplinary care. Integrative programs combining chronobiological regulation, tailored exercise, and dietary counseling, as exemplified by the SYNCHRONIZE study, underscore the value of holistic interventions in this context [108]. Taken together, behavioral and lifestyle strategies represent indispensable tools in enhancing quality of life and symptom control for individuals with ME/CFS.

Personalized medicine, guided by biomarker and metabolic profiling, holds transformative potential in tailoring interventions to the heterogeneity of ME/CFS. Neuroendocrine markers, including HPA axis functionality and mood-related biomarkers, may predict responsiveness to CBT and other targeted therapies [50]. Metabolic phenotyping, such as the detection of impaired pyruvate dehydrogenase activity, has emerged as a possible basis for individualized metabolic therapies [109]. Given the consistent evidence of hypocortisolism and hormonal imbalance, interventions restoring endocrine homeostasis could be particularly beneficial [19, 41]. Furthermore, the orexinergic system—by modulating both neuroendocrine and arousal pathways—represents a viable target for precision therapeutics, especially in patients with prominent sleep disturbances [99]. By integrating neurobiological, metabolic, and behavioral insights, personalized strategies may significantly improve outcomes and move beyond the limitations of one-size-fits-all treatment paradigms [110, 111].