Functional Medicine Approaches to

EDS and Hypermobile EDS (hEDS)

A Clinician’s Deep Dive

Compiled September 2026 | Revised Edition | For Clinical Reference

by Yoon Hang Kim MD

Dr. Yoon Hang Kim is board-certified in Preventive Medicine and practices integrative & functional medicine. He completed a University of Arizona Osher Fellowship under Dr. Andrew Weil, holds a UCLA medical acupuncture certification, and is an IFM Scholarship recipient. With more than 20 years of clinical experience, he specializes in low-dose naltrexone (LDN), mast cell activation syndrome (MCAS), autoimmune conditions, chronic pain, integrative oncology, fibromyalgia, chronic fatigue, and mold toxicity. He is the author of 8 books — including MCAS: Epidemic in Plain Sight, LDN Primer, LDN for Clinicians, and Integrative Oncology: Evidence-Based Strategies to Support Cancer Treatment — with more than 25 peer-reviewed articles published. He is the founder of the LDN Support Group. Professional: www.yoonhangkim.com | Clinical: www.directintegrativecare.com

A Note on Evidence: This document discusses emerging biology, off-label therapeutics, nutritional status, and individualized phenotypes. That is exactly the territory functional medicine should occupy. But mechanistic plausibility, association, biomarker findings, and demonstrated treatment efficacy are not interchangeable. Throughout this document, we label claims by their evidence maturity so that clinical decisions stay grounded while the conversation stays intellectually open.

Evidence Framework Used in This Document

Each intervention and claim in this document is labeled by the following evidence tiers:

1. Where the Science Stands: 2024–2026 Developments

The past two years have produced genuinely important findings that reshape how we think about hEDS. Three lines of evidence deserve attention — but each needs to be understood at its actual level of maturity.

1.1 Proteomic Discoveries [Emerging]

A 2025 study in ImmunoHorizons (Griggs, Gensemer et al.) used mass spectrometry-based proteomic analysis of serum from women with hEDS versus age-matched controls, then validated results in an expanded cohort. They identified 35 differentially expressed proteins in hEDS, with approximately 43% involving the complement cascade and roughly 80% linked to immune, coagulation, or inflammatory pathways. The study also found dysregulation of profibrotic cytokines and complement system components.

What this means: It challenges the traditional view of hEDS as solely a structural problem and supports the concept that immune dysregulation may be a core feature. However, this is a discovery study. It does not yet establish whether these protein abnormalities are causal, secondary to disease burden, or useful as clinical biomarkers. It generates important hypotheses; it does not confirm them.

1.2 Genome-Wide Association Study [Emerging — Preprint]

A September 2025 GWAS meta-analysis (1,815 cases, 5,008 controls) — the first of its kind for hEDS — identified two genome-wide significant loci, including a regulatory region near the ACKR3 gene (atypical chemokine receptor 3) on chromosome 2. Functional annotation showed ACKR3 risk alleles colocalize with expression quantitative trait loci in tibial nerve, alter enhancer activity, and generate a de novo AHR transcription factor regulatory site, implicating neuroimmune and pain signaling pathways (Petrucci-Nelson et al., medRxiv, 2025).

Important: This study was available as a preprint as of September 2025 and had not yet undergone peer review. It demonstrates genetic associations, not therapeutic targets. Clinicians should watch for its peer-reviewed publication.

1.3 KLK15: A Separate Line of Evidence [Emerging]

Distinct from the GWAS, the KLK15 finding (Gensemer et al., iScience, 2025) used whole-exome sequencing, familial segregation analysis, biochemical work, and a knock-in mouse model to identify this kallikrein serine protease gene’s role in connective tissue remodeling, immune modulation, and neurovascular signaling. This is an impressive finding but represents a familial/subset mechanism, not necessarily a universal hEDS pathway. It should not be conflated with GWAS results.

1.4 Mitochondrial Dysfunction [Hypothesis-Generating]

A 2025 scoping review (Shirvani, Shirvani & Holick, Current Issues in Molecular Biology) highlighted mitochondrial dysfunction as a potential unifying mechanism in hEDS, noting impaired oxidative phosphorylation, elevated reactive oxygen species, and calcium dysregulation. However, the review itself acknowledges that only eight original studies directly addressed mitochondrial dysfunction in hEDS and describes much of the mechanistic framework as hypothetical. This provides a rationale for future research and a plausible substrate for fatigue and exercise intolerance, but mitochondrial causality in hEDS is not established.

1.5 Synthesis

Emerging genetic, proteomic, immune, neurologic, and metabolic observations suggest that hEDS may involve biology extending beyond structural connective tissue alone. The relative causal contributions of these pathways remain uncertain. This is entirely compatible with a functional medicine approach — it means there are multiple modifiable systems to address — but it does not yet justify calling hEDS a defined “neuroimmune-mitochondrial disease.”

2. The hEDS–POTS–MCAS Overlap: What We Know and Don’t Know

2.1 Clinical Co-occurrence [Supported Association]

The clinical overlap of hEDS, POTS, and MCAS is increasingly recognized. In one study, 31% of patients with both POTS and EDS also met criteria for MCAS. In another, 42% of POTS patients with allergic and GI symptoms showed mast-cell mediator abnormalities. These numbers are clinically meaningful.

2.2 The Definition Problem

However, definition matters enormously. A 2025 cohort found MCAS prevalence among young POTS patients ranging from 2% to 87% depending on the diagnostic definition used (PubMed, 2025). A separate 2025 systematic review using prespecified rigorous mast-cell criteria found no eligible studies capable of confirming the proposed MCAD/POTS/EDS relationship.

This tension is worth featuring, not suppressing. It is an excellent teaching point: the phenotype may be clinically meaningful even while the nosology and mechanism remain unsettled.

2.3 Unified Causal Mechanism [Hypothesis-Generating]

The hypothesis that defective connective tissue destabilizes mast cells and blood vessels, triggering both MCAS and POTS, is biologically plausible but not established. The 2025 AGA Clinical Practice Update explicitly acknowledges observed overlap while stating that the biological mechanisms remain limited and evolving.

2.4 The 2025 AGA Clinical Practice Update

The AGA published a landmark update in July 2025 (Aziz Q, Harris LA, Goodman BP, Simrén M, Shin A; Clinical Gastroenterology and Hepatology, 23(8):1291–1302). Key positions:

Screening: Gastroenterologists seeing patients with disorders of gut-brain interaction (DGBI) should inquire about joint hypermobility and consider the Beighton score as a screening tool.

Universal testing NOT recommended: The AGA advises against universal POTS or MCAS testing in hEDS/HSD. Test when there are episodic, multisystem symptoms consistent with mast cell mediator release — not for every patient with nonspecific food intolerance.

Mechanistic link: Changes in collagen structure or extracellular matrix molecules may lead to alterations in intestinal motility, tone, sensation, and permeability.

Prevalence: In a cross-sectional survey of over 600 individuals with hEDS/HSD, almost all (98%) met diagnostic criteria for DGBI.

2.5 A More Useful Framework: Phenotype-First

Rather than applying a single triad label to every patient, a more sophisticated approach asks which domain dominates: mechanical instability, dysautonomia, small-fiber or neuropathic features, nociplastic pain, mast-cell phenotype, GI motility disorder, pelvic-floor dysfunction, nutrient insufficiency, sleep disorder, restrictive eating, endocrine or menstrual amplification, post-infectious phenotype, or ME/CFS-like post-exertional symptom exacerbation. That is more useful than calling every hEDS patient “inflammatory” or “dysbiotic,” and it lets functional medicine go well beyond a conventional organ-by-organ approach without inventing a single root cause.

3. Targeted Nutritional Assessment

This is where functional medicine adds genuine value — if it stays disciplined. Studies show 61–81% of hEDS/HSD patients report taking supplements. The question is whether those supplements are indicated and at what evidence tier.

3.1 Vitamin C [Established Biology, Empiric/Integrative Dosing]

Vitamin C is an essential cofactor for prolyl and lysyl hydroxylases in collagen biosynthesis, contributes to histamine degradation, and has antioxidant properties relevant to inflammatory processes. A 2025 narrative review confirmed these roles and noted that clinical stressors including chronic inflammation and trauma may increase vitamin C turnover. Supplementation is biologically reasonable when dietary intake is inadequate — particularly in patients on low-histamine or low-salicylate diets where dietary vitamin C is often reduced. However, an optimal hEDS-specific dose has not been established. Assess dietary intake, restrictive diets, smoking or oxidative stress burden, and wound-healing demands. Doses in the range of 500–1000 mg daily are commonly used in integrative practice but should be understood as empiric rather than validated.

3.2 Magnesium [Established Physiology, Integrative Practice Preference]

Magnesium supports muscle relaxation, reduces cramps, may support sleep quality, and aids in reducing anxiety through GABA modulation. It also helps ease symptoms related to dysautonomia and chronic stress. Magnesium glycinate is commonly preferred in integrative practice for its bioavailability and GI tolerance, though this preference is based on clinical experience rather than hEDS-specific trials. Serum magnesium identifies overt abnormalities but incompletely reflects intracellular stores. RBC magnesium is sometimes used as an adjunct in integrative practice, although its clinical validation and analytical standardization remain limited.

3.3 Iron and Ferritin [Established Assessment, Integrative Thresholds]

Iron deficiency, even without anemia, is prevalent in hEDS/HSD due to malabsorption or chronic GI blood loss. Check CBC, ferritin, iron/TIBC or transferrin saturation, with CRP or inflammatory context when necessary — ferritin is an acute-phase reactant and can be falsely elevated in inflammatory states. There is no hEDS-specific ferritin repletion threshold, but integrative clinicians commonly consider repletion when ferritin is below 30–50 ng/mL, particularly in the setting of fatigue.

3.4 Vitamin D [Established Deficiency Correction; Integrative Target Range]

Deficiency is prevalent in this population and warrants correction. Check 25-OH vitamin D. There is an important conceptual difference between correcting deficiency and maintaining a specific concentration to improve hEDS. The former is established; the latter has not been demonstrated. The 40–60 ng/mL target commonly used in integrative practice represents an integrative preference, not an hEDS treatment threshold.

3.5 Folate and MTHFR [Hypothesis-Generating]

A review in Practical Gastroenterology (2024) postulates that hEDS/HSD might involve MTHFR polymorphisms preventing proper folate utilization, leading to elevated homocysteine, increased oxidative stress, and impaired collagen synthesis. However, this hypothesis was based on insufficiently described clinical experience, and there are no published hEDS/HSD trials of the proposed folate strategy. Checking folate, B12, and homocysteine may sometimes be useful clinically. Routine MTHFR genotyping should not be presented as central to hEDS management. File this under nutrigenomics worth watching, not yet ready for standard protocols.

3.6 Zinc [Established Biology, Empiric Application]

Zinc plays important roles in tissue repair and immune function, and it assists in regulating mast cell degranulation and cytokine production. This makes it relevant in the MCAS overlap population. Assess zinc status when clinically indicated rather than supplementing empirically.

3.7 Collagen Supplements [Not Supported]

No data suggests excess collagen from any source or type provides additional benefit for hEDS/HSD. The problem in hEDS is not insufficient collagen production but rather abnormal collagen structure or extracellular matrix processing. Supporting the cofactors for collagen synthesis (vitamin C, zinc, copper) is reasonable. Collagen supplements to “fix” connective tissue in hEDS are not supported and should not be recommended.

4. Gastrointestinal Dysfunction in hEDS

4.1 Prevalence [Supported Association]

The GI tract is one of the most affected systems in hEDS. In a Cleveland Clinic study of 218 hEDS patients, 62.3% had at least one GI symptom at EDS diagnosis. Among those who underwent motility testing (an important denominator — these were selected, symptomatic patients, not all hEDS patients), 42.8% had gastroparesis, 11.9% had esophageal dysmotility, 11.9% had altered small bowel/colon transit, and 9.5% had global dysmotility.

4.2 Celiac Disease [Supported Association]

Rates of celiac disease appear 2 to 5.5 times higher in EDS populations than in general population controls. Swedish patients with EDS/JHS had an odds ratio of 2.3 for subsequent celiac diagnosis. Celiac testing (TTG-IgA + total IgA) is prudent for hEDS patients with GI symptoms.

4.3 SIBO [Inconsistent Evidence]

Dysmotility provides a plausible substrate for microbial overgrowth in selected hEDS patients, and some patients with significant dysmotility do have documented SIBO. However, prevalence data are inconsistent. One large tertiary breath-testing study found none of the hEDS patients tested had a positive hydrogen breath test (Dervin et al., Neurogastroenterology & Motility, 2023). Test based on phenotype rather than assuming dysbiosis is present.

4.4 SIFO [Limited Evidence]

Small intestinal fungal overgrowth remains poorly standardized diagnostically. Small-intestinal aspirate fungal culture is currently the most direct method. Treatment response to antifungals does not prove SIFO and should not be used as a diagnostic criterion. Guard against the circular pattern of: symptoms → empiric antifungal → improvement → therefore SIFO.

4.5 Intestinal Permeability [Hypothesis Under Active Investigation]

The hypothesis that connective tissue weakness affects gut wall integrity, leading to increased permeability, altered microbiome composition, and systemic inflammatory consequences, is plausible and actively investigated. The Ehlers-Danlos Society has announced research programs examining whether permeability, mast-cell activity, and functional dyspepsia are mechanistically linked. However, this should be described as a hypothesis under investigation, not as an established pathophysiologic fact.

4.6 Dietary Approach [Empiric/Integrative]

An anti-inflammatory Mediterranean-style diet is the best-supported baseline. A 2024 feasibility study (Disability and Rehabilitation) evaluated a 9-week integrative medicine program using an anti-inflammatory Mediterranean diet with behavioral and psychosocial support in HSD/EDS adults, finding that dietary tracking through mobile apps might promote self-efficacy and adherence. The long-term goal should always be the most expansive diet that supports the best gut function. Low-histamine or elimination diets may help temporarily but should be time-limited with clear re-evaluation endpoints.

5. Low-Dose Naltrexone (LDN) for EDS

Evidence tier: Promising off-label option with encouraging preliminary evidence

5.1 Proposed Mechanism

At low doses (0.1–6.0 mg/day), naltrexone is proposed to act as an anti-inflammatory agent in the central nervous system via modulation of microglial cells. A review in Clinical Rheumatology described LDN as potentially one of the first glial cell modulators used for chronic pain management. These effects appear to be unique to low dosages and independent from naltrexone’s opioid receptor activity. The proposed mechanism — microglial modulation reducing neuroinflammation — is the leading hypothesis but has not been definitively confirmed in humans. It may be particularly relevant to the mixed pain phenotype seen in EDS (neuralgic, nociceptive, neuropathic, and pain secondary to immune dysfunction).

5.2 Evidence in EDS/HSD

A real-world effectiveness study published in the Journal of Pain Research (2025) was a retrospective cohort of 93 patients across 12 chronic-pain diagnostic groups. Subjective benefit was reported by 53.8% overall. Among the HSD/EDS subgroup, approximately 66.7% reported benefit, particularly with fatigue reduction. The study also found 71.4% response rates in MCAS patients. A 2024 observational dose-determination study (Marcus & Brock) of 41 patients with chronic musculoskeletal pain — including hEDS patients — found that individualized dosing could identify the minimal effective dose for nociplastic pain, with hEDS patients showing significantly more diffuse sensitized muscles. These are real signals, but they come from small observational studies, not randomized controlled trials specific to hEDS.

5.3 Dosing Considerations

Standard starting dose is typically 1.5 mg at bedtime, titrating up to 4.5 mg over 4–8 weeks. The 2024 study demonstrated that idiosyncratic dosing may matter — some patients respond below 4.5 mg, and forcing the standard target may overshoot the therapeutic window. EDS patients may be more sensitive to dose adjustments. LDN is increasingly being used as part of a multimodal strategy alongside MCAS management, POTS treatment, and ME/CFS symptom control.

5.4 Clinical Positioning

LDN offers a favorable safety profile, no addiction risk, and a plausible mechanism for the complex pain of hEDS. While opioids may lower pain sensation short-term, they may sensitize the nervous system and increase pain long-term (opioid-induced hyperalgesia). LDN deserves a place in the hEDS treatment conversation as a reasonable off-label option, particularly for patients with nociplastic or mixed pain phenotypes. Larger, controlled hEDS-specific studies are needed to move it from “promising” to “established.”

6. Mast Cell Activation Syndrome (MCAS) in hEDS

6.1 Diagnostic Criteria [Established Framework, Challenging Application]

MCAS diagnosis requires three elements: (1) recurrent systemic symptoms involving two or more organ systems consistent with mast cell mediator release; (2) objective evidence of mast cell mediator elevation — for tryptase, the accepted criterion is an event-related increase of baseline × 1.2 + 2 ng/mL; other mediators include urinary N-methylhistamine, leukotriene E4, and prostaglandin D2 metabolites; and (3) response to mast cell-directed therapy. Baseline tryptase is often normal in MCAS, making event-related testing (collected during or shortly after a flare) important. A 2024 prospective study found low prevalence of confirmed idiopathic MCAS among patients referred with suspected MCAS, underscoring the importance of rigorous criteria.

6.2 When to Test

Test when there are episodic, multisystem symptoms — flushing, urticaria, GI distress, tachycardia, brain fog, and in severe cases anaphylaxis-like reactions. Do not test every hEDS patient with nonspecific food intolerance. The AGA’s 2025 update was explicit that universal testing is not recommended.

6.3 Treatment: Separate by Evidence Tier

Better-established pharmacologic approaches: H1 antagonists (cetirizine, loratadine), H2 antagonists (famotidine), cromolyn sodium.

Integrative, biologically plausible agents: Quercetin, luteolin, vitamin C, diamine oxidase supplementation. These have mechanistic rationale and clinical use but should not be presented at the same evidence tier as H1/H2 blockade.

Dietary: Low-histamine dietary trial with defined duration and re-evaluation. Trigger identification and avoidance.

Response to H1/H2 blockade supports the diagnosis but is nonspecific — it does not confirm MCAS by itself.

6.4 Overlap Observations

A 2024 case report described complete remission of intractable hyperadrenergic POTS secondary to long COVID with histamine blocker therapy, illustrating the clinical overlap between mast cell-mediated and autonomic dysfunction. This is hypothesis-generating — interesting for clinical pattern recognition but not a basis for establishing the hEDS-POTS-MCAS mechanism.

7. Autonomic Dysfunction and POTS Management

7.1 Screening [Established]

Postural vital signs should be checked on every hEDS patient. If POTS is suspected, a 10-minute active standing test is the minimum screening; tilt-table testing provides confirmation.

7.2 Non-Pharmacologic Interventions [Established]

Salt loading (2–3 g sodium supplementation daily when appropriate and not contraindicated), compression garments (waist-high preferred over knee-high), adequate hydration (2–3 liters daily), and graded exercise protocols. Recumbent or semi-recumbent exercise initially, with gradual progression to upright exercise.

7.3 Referral

The AGA update recommends referral to cardiology or neurology for non-responders. Pharmacologic options (midodrine, fludrocortisone, ivabradine, pyridostigmine) fall outside typical functional medicine scope but should be available through specialist referral.

8. Mitochondrial and Metabolic Support

Evidence tier: Mechanistically plausible, clinically unproven in hEDS

The 2025 scoping review provides mechanistic rationale for considering cellular energetic support, particularly for patients with prominent fatigue and exercise intolerance. The biology of these nutrients is legitimate. What is not established is that supplementation at specific doses improves hEDS because hEDS involves clinically actionable mitochondrial deficiency.

8.1 Reasonable Considerations (Empiric)

CoQ10: Supports electron transport chain function. Commonly used at 100–300 mg daily, ubiquinol form for better absorption.

L-Carnitine: Facilitates fatty acid transport into mitochondria. Commonly used at 500–1500 mg daily.

B Vitamins: Riboflavin (B2) is a cofactor for complexes I and II of the electron transport chain. B12 and folate (methylated forms) support methylation and energy metabolism.

Alpha-Lipoic Acid: Antioxidant that regenerates other antioxidants and supports mitochondrial function. Commonly used at 300–600 mg daily.

8.2 Testing Considerations

Urine organic acid testing has legitimate clinical roles in inherited metabolic disorders and selected mitochondrial diseases. Using broad commercial OAT panels to diagnose nonspecific “mitochondrial dysfunction” is a different proposition and lacks comparable validation. OAT results may be exploratory and adjunctive rather than definitive documentation of mitochondrial pathology in hEDS.

9. Rehabilitation [Established]

Hypermobility-informed physical therapy is the single most important referral in hEDS management. A review supports therapeutic exercise and motor-function training, though evidence for specific protocols remains limited.

9.1 Core Principles

Graded isometric and eccentric strengthening of joint-supporting muscles. Proprioceptive training to compensate for impaired joint position sense. Joint stabilization work tailored to patient tolerance. Pelvic floor therapy for the significant subset with pelvic floor dysfunction. Activity-specific bracing and splints when useful.

On stretching: Avoid repetitive passive end-range stretching that increases instability. Mobility work should be individualized and paired with neuromuscular control and stabilization. The goal is functional range of motion with stability, not increased flexibility.

9.2 Hippotherapy [Very Low-Certainty Evidence; Promising]

A 2024 case report (Viruega et al., BMJ Case Reports) documented a patient with hEDS who underwent 30 hours of hippotherapy rehabilitation and transitioned from wheelchair reliance to walking with crutches, with improved postural balance, motor skills, proprioception, muscle function, and endurance. This is a promising rehabilitation modality but currently supported by a single case report.

9.3 Inspiratory Muscle Training [Emerging]

A clinical trial (NCT04972565) studied inspiratory muscle training for dyspnea in hEDS/HSD. Respiratory muscle weakness is an underappreciated contributor to exercise intolerance in this population.

10. Pain Management Beyond LDN

10.1 Central Sensitization and Nociplastic Pain [Supported Association]

The 2025 GWAS findings implicating neuroimmune pathways reinforce that pain in hEDS is not purely peripheral. The pain phenotype is typically mixed: nociceptive (joint instability), neuropathic (nerve compression), and nociplastic (central sensitization). Each component requires a different therapeutic approach.

10.2 Sleep and Psychological Dimensions [Established]

Pain severity correlates with low nocturnal sleep quality. Psychiatric symptoms were present in 56.1% of a pediatric EDS cohort, and adult rates are at least comparable. Depression and anxiety amplify central sensitization. Addressing sleep and screening for mood disorders is not optional — it is a core part of pain management in this population.

10.3 Acupuncture [Empiric/Integrative]

A 2020 systematic review in Pain Medicine found acupuncture effective for chronic musculoskeletal pain. Though not EDS-specific, many patients report symptom relief. Given concerns about tissue fragility in connective tissue disorders, clinical prudence suggests gentler needling technique and awareness of individual patient tissue characteristics. Note: tissue fragility and vascular risk differ substantially between hEDS and vascular EDS (vEDS), and recommendations should not inadvertently conflate the two.

10.4 Tracking Outcomes

Track meaningful functional outcomes — fewer injuries or symptom flares, better activity tolerance, improved daily function — rather than expecting biomarkers to show connective tissue has been “fixed.”

11. What NOT to Do: Functional Medicine Pitfalls

Over-labeling MCAS: Not every hEDS patient with food intolerance has MCAS. Apply rigorous diagnostic criteria. A 2024 prospective study found low prevalence of confirmed MCAS among referred suspected cases.

Running expensive untargeted panels on initial visit: Start with fundamentals (CBC, CMP, ferritin, iron studies, 25-OH vitamin D, celiac panel, inflammatory markers) and expand based on clinical findings.

Promising collagen repair: No supplement regimen treats the connective tissue defect in hEDS.

Framing hEDS as “caused by” toxins, mold, or diet: These may be comorbid triggers of symptom flares but are not the etiology.

Neglecting psychology: Psychiatric comorbidity is frequent, diverse, and strongly associated with pain and function in EDS. Ignoring this domain means incomplete care.

Blanket yoga or stretching programs: Increasing flexibility in someone who is already hypermobile increases instability and injury risk. Strengthening and neuromuscular control come first.

Assuming SIBO in every patient: Prevalence data are inconsistent. Test based on phenotype.

Using antifungal response as SIFO diagnosis: This circular reasoning is a common functional medicine error.

Treating OAT results as definitive: Exploratory, not validated documentation of hEDS-specific mitochondrial dysfunction.

12. The December 2026 Updated Classification

The Ehlers-Danlos Society has confirmed that updated global diagnostic criteria are scheduled for December 1, 2026, with management guidance expected in 2027. The update is expected to integrate emerging evidence from recent years. Until the new criteria are published, work with the 2017 framework. Avoid speculating about specific changes (such as proposed subtypes) that have not been formally announced by the classification project.

13. The Functional Medicine Value Proposition

The value of functional medicine for hEDS patients is in systematic identification and treatment of modifiable contributors to symptom burden: nutrient insufficiency, gut dysfunction, autonomic instability, mast cell overactivation, central sensitization, sleep disruption, and metabolic inefficiency. The key distinction is treating modifiable symptom burden versus claiming to treat the cause of hEDS. The former fits evidence-based multidisciplinary care. The latter damages credibility.

These patients are often desperate for comprehensive, individualized care and rarely find it in conventional settings. A functional medicine practice that approaches them with rigor, humility about what can and cannot be changed, and a commitment to measurable functional outcomes is exactly what this population needs.

Key References

Griggs M, Gensemer C, et al. Proteomic discoveries in hypermobile Ehlers–Danlos syndrome. ImmunoHorizons. 2025;9(10):vlaf044.

Petrucci-Nelson T, Guilhaumou S, et al. Complex Genetics and Regulatory Drivers of hEDS: Insights from GWAS Meta-analysis. medRxiv. 2025 Sep 21. [Preprint]

Gensemer C, et al. KLK15 Alters Connective Tissues in hEDS. iScience. 2025;28(9):113343.

Shirvani P, Shirvani A, Holick MF. Mitochondrial Dysfunction in hEDS: A Scoping Review. Curr Issues Mol Biol. 2025;47(2):134.

Aziz Q, Harris LA, Goodman BP, Simrén M, Shin A. AGA Clinical Practice Update on GI Manifestations in hEDS. Clin Gastroenterol Hepatol. 2025;23(8):1291–1302.

Aalto H, Paul S, McEwen V. Real World Effectiveness and Tolerability of Low Dose Naltrexone. J Pain Res. 2025.

Marcus N, Brock I. Effective Doses of LDN for Chronic Pain. PMC. 2024.

Viruega H, et al. Hippotherapy in hEDS management. BMJ Case Reports. 2024;17(11):e261605.

Shah ND. Nutritional Considerations for hEDS. Practical Gastroenterology. 2024.

Castells M, et al. Mast cell activation syndrome: Current understanding. J Allergy Clin Immunol. 2024;154(2):255–263.

Dervin A, et al. Low prevalence of positive hydrogen breath tests in hEDS. Neurogastroenterol Motil. 2023;35:e14570.

Demmler JC, et al. Diagnosed prevalence of EDS and HSD in Wales. BMJ Open. 2019;9(11):e031365.

Hakim A. Hypermobile Ehlers-Danlos Syndrome. GeneReviews. Updated Feb 22, 2024.

Integrative medicine for HSD and EDS: a feasibility study. Disabil Rehabil. 2024.

Ehlers-Danlos Society. New Global Diagnostic Criteria 2026. ehlers-danlos.com.