The EDS-POTS-MCAS Trifecta: What's Actually Connecting Your Symptoms
If you've been diagnosed with hypermobile Ehlers-Danlos syndrome (hEDS), postural orthostatic tachycardia syndrome (POTS), or mast cell activation syndrome (MCAS), you've probably noticed these conditions are often discussed together. Many people eventually come across the term EDS–POTS–MCAS trifecta and wonder whether there's a single explanation for everything they're experiencing.
The answer isn't quite that simple.
As a naturopathic physician, I frequently meet patients who have spent years trying to piece together symptoms that never seemed to fit into one diagnosis. Some have been told they're simply anxious. Others have been reassured that their lab work is "normal," despite feeling anything but normal. By the time they arrive in my office, many are exhausted, not just physically, but emotionally, from trying to connect the dots themselves.
The encouraging news is that these symptoms are real. Even more importantly, they often begin to make much more sense when we step back and look at the body as an interconnected system.
Why Are EDS, POTS, and MCAS So Often Linked?
One of the moments that stays with me most isn't when a patient finally receives a diagnosis, it's when they realize their seemingly unrelated symptoms may actually be connected.
Imagine someone who has spent their entire life thinking they were simply "double-jointed." They rolled their ankles repeatedly as a child, dislocated a shoulder reaching into the back seat of the car, and have always lived with nagging aches that everyone dismissed as normal.
Then, sometime in their twenties or thirties, something changes.
They begin feeling lightheaded every time they stand up. Walking through the grocery store becomes exhausting. Their heart races after climbing a single flight of stairs, and brain fog starts interfering with work. Around the same time, foods they once tolerated suddenly cause flushing, itching, stomach upset, or hives. Heat becomes unbearable. Perfumes trigger headaches. It feels like their body is reacting to everything.
Eventually they discover the phrase EDS–POTS–MCAS trifecta and wonder:
"Could all of this actually be connected?"
In many cases, the answer is yes - but perhaps not in the way the internet often suggests.
Researchers continue to investigate why these conditions overlap so frequently. While there isn't evidence that they share one single root cause, we do know that connective tissue, the autonomic nervous system, blood vessels, and the immune system constantly communicate with one another. When one system becomes dysregulated, it can influence the others, creating the pattern of symptoms many people recognize as the EDS–POTS–MCAS trifecta.
Understanding those relationships is often the first step toward finding meaningful answers.
What Does EDS, POTS, and MCAS Actually Feel Like?
Medical definitions are important, but they rarely capture what people experience day to day. Here's how these conditions commonly present in my practice.
Many people think hypermobile Ehlers-Danlos syndrome simply means being unusually flexible.
In reality, it's much more than that.
Patients often tell me they've always been "accident-prone." They sprained ankles repeatedly as children. Their knees unexpectedly give out. They live with chronic neck or back pain despite normal imaging. Some experience frequent subluxations or joint dislocations from activities that shouldn't cause injury.
Because connective tissue exists throughout the body, not just in the joints, people with hEDS may also experience digestive issues, pelvic floor dysfunction, chronic fatigue, headaches, easy bruising, or slower recovery after injuries. No two people present exactly the same way, which is one reason diagnosis is often delayed.
One misconception I frequently hear is that someone can't have hEDS if they are no longer extremely flexible.
In reality, years of injuries, chronic pain, muscle guarding, or arthritis can reduce flexibility over time. A careful history often reveals that hypermobility was much more obvious earlier in life.
Postural Orthostatic Tachycardia Syndrome (POTS): "I Feel Fine Until I Stand Up"
POTS is a form of dysautonomia, meaning the autonomic nervous system isn't regulating body functions appropriately when someone changes position.
Patients rarely describe it by saying, "My heart rate increases when I stand."
Instead, they say things like:
"I feel like I'm going to pass out the moment the hot shower starts."
"Standing in line at the grocery store is harder than walking through it."
"After running a few errands, I feel completely wiped out."
"Once I've been on my feet too long, I can't think clearly or find the right words."
These symptoms often develop because the body struggles to maintain blood flow to the brain while standing. Blood pools in the lower body, the heart compensates by beating faster, and patients experience dizziness, palpitations, fatigue, brain fog, headaches, exercise intolerance, or significant relief after sitting or lying down.
Symptoms often fluctuate. Some days patients function relatively well, while on others even routine activities feel overwhelming.
Mast Cell Activation Syndrome (MCAS): When Your Body Seems to React to Everything
Mast cells are normal immune cells found throughout the body. They help defend against infections, participate in wound healing, and coordinate allergic responses by releasing chemical messengers such as histamine.
When mast cells become activated inappropriately, they may release these chemicals too readily, producing symptoms that can affect multiple organ systems.
Patients often describe experiences such as:
Sudden flushing, hives, or unexplained itching
Abdominal pain, bloating, nausea, or diarrhea after eating
Sensitivity to fragrances, heat, seasonal pollen, or environmental triggers
Episodes that feel like severe allergic reactions despite negative allergy testing
Headaches, fatigue, or a general sense that their body overreacts to everyday exposures
Not everyone experiencing these symptoms has mast cell activation syndrome.
Some have histamine intolerance. Others have allergies, autoimmune conditions, gastrointestinal disorders, or entirely different causes of immune activation. Some may have increased mast cell activity without meeting the formal diagnostic criteria for MCAS.
That's an important distinction, and one I spend a great deal of time discussing with patients.
Whether symptoms ultimately stem from confirmed MCAS or another condition, they deserve careful evaluation rather than dismissal.
Why Do EDS, POTS, and MCAS Often Occur Together?
This is usually the point where patients lean forward and ask,
"Okay...but why?"
The short answer is that we don't fully know.
Researchers continue to investigate why hypermobile Ehlers-Danlos syndrome, POTS, and mast-cell-related disorders overlap so frequently. While there isn't evidence that they all stem from one underlying cause, there are several biologically plausible ways these systems may influence one another.
The body doesn't function as isolated parts. Your connective tissue, blood vessels, nervous system, immune system, hormones, and digestive tract are constantly communicating. When one system becomes dysregulated, the effects can ripple through others, creating a pattern of symptoms that appears surprisingly connected.
Can Hypermobile EDS Contribute to POTS?
One of the leading theories involves connective tissue itself. When people hear the phrase connective tissue disorder, they naturally think about ligaments and joints. But connective tissue also provides structural support to blood vessels.
Researchers have proposed that, in some people with hypermobile Ehlers-Danlos syndrome, blood vessels may be more compliant, or stretchier, than average. If blood vessels don't constrict as efficiently when someone stands, more blood may pool in the lower body. The heart compensates by beating faster in an effort to maintain blood flow to the brain, potentially contributing to symptoms of orthostatic intolerance or POTS.
This almost certainly isn't the whole story, but it may be one important piece of the puzzle.
How Are the Nervous System and Immune System Connected?
Another area of active research involves communication between the autonomic nervous system and the immune system.
I often explain it to patients this way:
Think of your nervous system as the body's communication network and your immune system as its security team. When the communication network becomes dysregulated, the security team can get confused or miscommunicate.
Stress, infections, poor sleep, hormonal fluctuations, and chronic inflammation can all influence autonomic function and immune signaling. Likewise, inflammatory chemicals released by mast cells may affect blood vessel tone and nerve signaling, potentially contributing to symptoms such as flushing, rapid heart rate, dizziness, or feeling unwell after eating.
Researchers are actively studying these interactions, but we still have much to learn.
Is Histamine Intolerance the Same as MCAS?
Another common source of confusion is the relationship between histamine intolerance and mast cell activation syndrome.
Although they can produce similar symptoms, they are not the same condition.
Histamine naturally widens blood vessels. In some people, that may contribute to flushing, lower blood pressure, dizziness, or a faster heart rate. Histamine intolerance can therefore overlap with some POTS symptoms without someone having mast cell activation syndrome.
Likewise, not everyone with POTS has histamine intolerance or MCAS.
This is one reason I encourage patients not to assume that dizziness, flushing, or food sensitivities automatically point to mast cell disease. Similar symptoms can occur with iron deficiency, thyroid disorders, nutritional deficiencies, medication side effects, chronic illness, dehydration, or other medical conditions that deserve careful evaluation.
Why Diagnosing EDS, POTS, and MCAS Isn't Always Straightforward
Over the past several years, awareness of the EDS-POTS-MCAS trifecta has grown tremendously. That's encouraging because more people are finally recognizing patterns that may have been overlooked for years.
At the same time, increased awareness has also created confusion. Patients often arrive convinced they have all three conditions because their symptoms closely match what they've read online. Sometimes they're absolutely right.
Other times, they have one condition alongside something entirely different that's producing remarkably similar symptoms.
My goal isn't to fit someone into a diagnosis. It's to understand what's actually driving their symptoms.
Not Every Histamine Symptom Is MCAS
Mast cells release many different chemical messengers, including histamine, that help coordinate immune responses. When those chemicals are released inappropriately, people may experience flushing, itching, hives, abdominal pain, diarrhea, headaches, rapid heart rate, or episodes that resemble allergic reactions.
Those symptoms alone, however, are not enough to diagnose MCAS.
Current international consensus criteria require all three of the following:
Typical symptoms involving two or more organ systems.
Objective evidence of elevated mast cell mediators obtained during an episode (such as serum tryptase or specific urine metabolites).
Improvement with medications that block mast cell mediators, including H1 or H2 antihistamines or mast cell stabilizers.
Recent research suggests that many people who believe they have MCAS don't actually meet these criteria. That doesn't mean their symptoms aren't real. It simply means another explanation may be responsible, and deserves to be investigated just as carefully.
What Other Conditions Can Mimic POTS or MCAS?
One of the biggest lessons I've learned in practice is that different conditions can produce remarkably similar symptoms. I've cared for patients whose dizziness, flushing, fatigue, or rapid heart rate ultimately turned out to be related to:
Iron deficiency
Low blood volume or dehydration
Certain medications
Chronic infections
Nutritional deficiencies
Adrenal disorders affecting blood pressure regulation
This is why I avoid making assumptions based on symptoms alone. A thorough history, physical examination, and appropriate laboratory evaluation often reveal important contributors that would otherwise be missed.
Why We Sometimes Evaluate Adrenal Function
One area I think deserves more attention is adrenal function. Patients sometimes come to my office convinced they have POTS because they experience dizziness, fatigue, brain fog, exercise intolerance, and feel dramatically worse when they're under stress.
Sometimes they truly do have POTS.
Sometimes they have POTS and another condition that's making it significantly worse.
And occasionally, the underlying issue turns out to be something different altogether.
The adrenal glands produce hormones, including cortisol and aldosterone, that play important roles in regulating blood pressure, fluid balance, energy production, and the body's response to stress. When these systems aren't functioning normally, symptoms can overlap substantially with dysautonomia.
It's important to be clear that primary adrenal insufficiency (Addison's Disease) is uncommon and requires medical evaluation, and the popular term "adrenal fatigue" is not yet a recognized medical diagnosis.
That said, evaluating adrenal function can still be clinically appropriate in the right patient, and point us to the right treatment that finally helps. Depending on someone's history, symptoms, and examination, I may recommend laboratory testing to assess cortisol production or refer to an endocrinologist when a more significant endocrine disorder is suspected.
I've also found that some patients who arrive convinced they have POTS improve substantially once contributing factors, such as hormonal imbalances, iron deficiency, nutritional deficiencies, or inadequate blood volume, are identified and addressed. That's one reason I believe it's so important to evaluate the whole person and to always start with the basics for healthy organ and cellular function.
Looking Beyond the Diagnosis: Why Individualized Care Matters
Sometimes patients truly have hypermobile Ehlers-Danlos syndrome, POTS, and mast cell activation syndrome.
Sometimes they have hEDS and POTS, along with seasonal allergies.
Sometimes POTS develops after a viral illness.
Sometimes symptoms overlap with mast cell activation but never meet the diagnostic criteria for MCAS.
Each of those situations deserves an individualized evaluation and treatment plan.
That's one of the reasons I enjoy practicing naturopathic medicine. It gives me the opportunity to step back, ask why, and consider how multiple body systems may be contributing to the bigger picture rather than viewing each symptom in isolation.
If you're living with unexplained dizziness, hypermobility, flushing, food sensitivities, or other symptoms that seem connected but no one has been able to explain, I'd love to help. Together we can determine what testing is appropriate, identify contributing factors, and develop a personalized treatment plan while collaborating with the specialists involved in your care.
Tessaundra Steinhebel, ND
Frequently Asked Questions
Is the EDS–POTS–MCAS trifecta a real medical diagnosis?
No. The EDS–POTS–MCAS trifecta is not an official medical diagnosis. It's a term commonly used to describe the frequent overlap of hypermobile Ehlers-Danlos syndrome, postural orthostatic tachycardia syndrome, and mast-cell-related symptoms. Researchers recognize that these conditions often occur together, but they're still working to understand why.
Can you have POTS and MCAS without EDS?
Yes. Although many people discuss these conditions together, both POTS and mast cell activation syndrome can occur in individuals who do not have hypermobile Ehlers-Danlos syndrome. Likewise, many people with hEDS never develop either condition.
What tests actually confirm MCAS?
Diagnosing mast cell activation syndrome requires more than symptoms alone. Current consensus criteria include symptoms involving multiple organ systems, laboratory evidence of mast cell mediator release obtained during or shortly after an episode, and improvement with medications that block mast cell mediators. Because testing can be challenging, evaluation is often coordinated with an allergist or immunologist.
Can naturopathic treatment help all three at once?
A naturopathic approach doesn't "treat the trifecta" as a single disease. Instead, it focuses on identifying the factors contributing to each person's symptoms. That may include supporting connective tissue health, improving autonomic nervous system function, reducing inflammation, optimizing nutrition, addressing gut health, and coordinating care with specialists when additional evaluation or prescription therapies are needed.
References
Afrin LB, Weinstock LB, Molderings GJ. Diagnosis of Mast Cell Activation Syndrome: A Global "Consensus-2". Diagnosis (Berl). 2021;8(1):5-16.
Celletti C, Castori M, Morlino S, et al. Orthostatic Intolerance and Postural Orthostatic Tachycardia Syndrome in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome, Hypermobility Type. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2015;169C(1):84-96.
Husebye ES, Pearce SH, Krone NP, Kämpe O. Adrenal insufficiency. The Lancet. 2021;397(10274):613-629.
Malfait F, Francomano C, Byers P, et al. The 2017 International Classification of the Ehlers-Danlos Syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):8-26.
Raj SR, Guzman JC, Harvey P, et al. Canadian Cardiovascular Society Position Statement on Postural Orthostatic Tachycardia Syndrome (POTS) and Related Disorders. Canadian Journal of Cardiology. 2020;36(3):357-372.
Roma M, Marden CL, De Wandele I, et al. Postural Tachycardia Syndrome and Other Forms of Orthostatic Intolerance in Ehlers-Danlos Syndrome. Autonomic Neuroscience. 2018;215:89-96.
Valent P, Akin C, Bonadonna P, et al. Using the Right Criteria for Mast Cell Activation Syndrome (MCAS). Journal of Allergy and Clinical Immunology: In Practice. 2019;7(4):1125-1133.e1.
Wang E, Ganti T, Vaou E, Hohler A. The Relationship Between Mast Cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome, and Ehlers-Danlos Syndrome. Allergy and Asthma Proceedings. 2021;42(3):243-246. This retrospective study found a significantly higher prevalence of MCAS among patients with both POTS and hypermobile EDS, while emphasizing that the association does not establish causation.
The Ehlers-Danlos Society. Healthcare Professional Resources and Clinical Guidance. This organization provides evidence-based educational resources, the 2017 hEDS diagnostic criteria, and clinical guidance for healthcare professionals.
The Mast Cell Disease Society (TMS). Mast Cell Activation Syndrome (MCAS): Diagnostic Criteria and Clinical Resources.
Disclaimer: The entire contents of this website are based upon the opinions of physicians at Pacific Clinic of Natural Medicine, unless otherwise noted. Individual articles are based upon the opinions of the respective author, who retains copyright as marked. The information on this website is not intended to replace a one-on-one relationship with a qualified health care professional and is not intended as medical advice. It is intended as a sharing of knowledge and information from the research and experience of our physicians and their community. PCNM encourages you to make your own health care decisions based upon your research and in partnership with a qualified healthcare professional. If you are pregnant, nursing, taking medication, or have a medical condition, consult your health care professional before using products based on this content.
If you want to use an article on your site please direct to and cite the original article page. This content may be copied in full, with copyright, contact, creation and information intact, without specific permission, when used only in a not-for-profit format. If any other use is desired, permission in writing from PCNM and the original author is required.
Comments