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POTS Treatment: Exploring the Role of MCAS and Infections

The rise of Postural Orthostatic Tachycardia Syndrome (POTS) has sharply increased since COVID. While it may have been underrecognized even a decade ago, COVID has made it better known now, even in mainstream medicine. POTS is associated with being infected with COVID and receiving the vaccine, though far more cases are associated with natural infection and can be seen in up to two-thirds of long-COVID patients.1-4 While long-COVID has been associated with multiple symptoms across multiple organ systems, this article will mainly focus on the POTS phenotype, its association with Mast Cell Activation Syndrome (MCAS ), and treatment approaches. The proposed treatment approaches may also help other long-COVID symptoms.

POTS Diagnosis and Management

POTS is an autonomic disorder characterized by orthostatic intolerance and excessive tachycardia. Symptoms can begin acutely with COVID infection, but a large percentage of COVID patients go on to develop POTS within 6 to 8 months of infection.3,5  Those affected with POTS from vaccination typically experience symptoms soon after vaccination.5,6 Symptoms may persist for years, but one study showed POTS resolved in 80% of hospitalized patients with severe COVID within 2 months of discharge.7,8 The duration of POTS from other causes and POTS from COVID may differ, and ultimately more research is needed to understand the differences.3,9

POTS symptoms include persistent fatigue, lightheadedness or dizziness when standing, palpitations, presyncope/syncope, sweating changes, chest pain, trouble breathing, exercise intolerance, cognitive dysfunction, anxiety, headaches, acrocyanosis, bladder issues, and gastrointestinal issues.3-5 Neurological symptoms tend to improve in a supine position. Symptoms range from mild to debilitating, with many patients requiring a reduction in work hours or disability.3

POTS diagnostic criteria include:3

  1. Chronic symptoms (>6 months) that occur with standing
  2. Sustained increase in heart rate of 30 bpm (≥40 bpm in those aged 12-19) or a heart rate of > 120 bpm when moving from a supine to a standing position
  3. Without orthostatic hypotension
  4. Absence of other tachycardia causes

The most common tests for diagnosis are the Head-Up Tilt Table Test or active standing test administered by cardiac electrophysiology departments. Holter monitoring can also be helpful. Specialized centers may also administer autonomic testing. Testing to rule out other causes of tachycardia may include complete blood count, albumin, renal function, electrolytes, B-type natriuretic peptide, thyroid-stimulating hormone, and morning cortisol.3

Treatment is focused on reducing pooled venous blood in the legs and abdomen by improving circulation and blood volume.

Supportive treatment includes:3,5

  • Increasing salt intake (8-12 g sodium chloride) and electrolytes (clinicians find that LMNT or similar electrolytes are effective due to high sodium content)10
  • Increasing fluid intake to 2-3 liters daily; drinking water before getting out of bed in the morning
  • Graduated compression stockings (30 to 40 mmHg)
  • Abdominal binders (10 mmHg)
  • Sleep in a head-up tilt position (>10°)
  • Avoiding exacerbating conditions including heat, sleep deprivation, alcohol intake, large meals, prolonged standing, anemia, dehydration
  • Standing up slowly
  • Small frequent meals lower in refined carbs to stabilize glycemic balance and avoid postprandial hypotension
  • Counterpressure maneuvers for patients experiencing syncope (crossing legs and squeezing thigh muscles, tightly folding arms, etc.)
  • Recumbent exercise to reduce the risk of falling; increasing physical activity of the lower extremities helps improve venous return

Depending on presentation, prescribed medications include beta-blockers, fludrocortisone, midodrine, ivabradine, and others. Reevaluating medications such as noradrenaline reuptake inhibitors and drugs that exacerbate orthostatic intolerance may be helpful.3,5

Conventional POTS and dysautonomia treatment focuses on symptom management, which is a necessary step for helping patients’ quality of life. There are no known cures for POTS, nor are there proposed treatments for the cause.

One post-COVID clinic noted recognizable phenotypes resembling post-infectious complex chronic diseases such as POTS, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and fibromyalgia and leveraged established treatment modalities to guide care. Treatment examples included propranolol for hyperadrenergic POTS or low-dose naltrexone (LDN) for ME/CFS. A multidisciplinary approach included physical therapy, supplements, prescription medications, and devices such as vagus nerve stimulators. The clinic reported significant improvements in symptoms, including dysautonomia, but complete recovery rates remained low even at 2 years out.8

These findings highlight the ongoing evolution of treatment strategies for post-COVID conditions, while underscoring the need for more effective interventions to achieve sustained recovery.

Treat the Cause: Can POTS Only Be Managed, or Can It Be Cured?

Beyond symptom management, functional medicine practitioners aim to identify and address root causes. But how realistic is this approach once a disease process is underway? Has the damage already been done, and can the resulting cascade be stopped or reversed? In long COVID, for example, the initial infection may have resolved, yet its effects persist. Do we target the original infection, the resulting autoimmune response, or ongoing inflammation? How far upstream can we intervene to meaningfully address the underlying cause?

Treating the cause warrants an understanding of disease pathophysiology. POTS development is thought to include virus- or immune-mediated damage to the autonomic nervous system, causing inadequate vasoconstriction. Proposed mechanisms include increased sympathetic nervous system activity, baroreceptor dysfunction, small nerve fiber dysfunction, volume depletion with an altered renin-angiotensin-aldosterone system, cerebral hypoperfusion, and autoimmunity.3-5 Autoimmunity due to molecular mimicry causing POTS can follow several infections, including Epstein-Barr virus (EBV), cytomegalovirus (CMV), Borrelia burgdorferi, and COVID.3,9

A study of POTS patients found significantly elevated inflammatory cytokines compared with healthy controls, including interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α), suggesting a proinflammatory signature underlying the condition. These cytokines may contribute to endothelial activation, microvascular permeability, and impaired endothelium-dependent vasoreactivity, leading to orthostatic tachycardia.4 Mast cell degranulation can release IL-8, TNF-α, and other mediators that play a role in allergic, inflammatory, and autoimmune diseases.11

Viral persistence and ongoing viral replication may also contribute to chronic post-infectious illnesses, including long-COVID. Therefore, it would seem that treating the infectious trigger could be curative. However, studies have reported mixed results regarding the effectiveness of prescription antivirals for treating long-COVID. Researchers continue to investigate whether earlier antiviral treatment, longer treatment durations, or specific combinations of antivirals may improve outcomes.12,13

In the absence of standardized treatment protocols for long-COVID, nutraceuticals are being studied. A novel protocol using 500 mg bromelain daily, 2,000 FU nattokinase twice daily, and 500 mg curcumin twice daily is proposed to reduce inflammation and promote spike protein metabolism, although clinical trials have not yet been conducted.14 Early in the pandemic, the Institute for Functional Medicine recommended several nutraceuticals and botanicals with antiviral, anti-inflammatory, and immune-enhancing properties, including curcumin, quercetin, epigallocatechin gallate (EGCG), resveratrol, and several others.15 Note: a document online has been recently updated and includes doses.

Fasting-induced autophagy is being explored as an intervention to treat spike proteins.16

A case study of a patient who developed POTS days after receiving the COVID vaccine reported success with increased salt consumption, fluid intake, 20 mmHg compression stockings, ivabradine 5 mg BID, and a supplement regimen to support autonomic balance, minimize fatigue, and reduce pain and neuropathy. Supplements included 2000 mg turmeric, 200 mg vitamin C, 2,000 IU vitamin D3, 400 mg vitamin B2, 1200 mg pine bark extract (Enzogenol), 800 mg resveratrol with quercetin, 1,200 mg boswellia, and 4,800 mg aged garlic extract.6 Many of these supplements overlap with MCAS and long-COVID treatments and have anti-inflammatory effects.

In summary, a proposed approach to treating POTS (and long-COVID) involves attempting antiviral treatment despite the lack of established protocols, managing inflammation and mast cell degranulation, immunomodulation, and simultaneously addressing patients’ symptoms.

The MCAS, POTS, and COVID Connection

Mast cell activation syndrome (MCAS) may be a root cause of a high percentage of POTS cases. In the general population alone, its prevalence is around 17%, yet, like POTS, it’s often under-recognized.17,18 MCAS is a broad spectrum of disorders associated with oversensitive or inappropriately activated mast cells. COVID infection can trigger mast cell activation and could exacerbate existing diagnosed or undiagnosed MCAS.19-24  COVID can also activate normal mast cells, causing viral particles to persist.20

MCAS triggers include foods, environmental toxins (perfumes, mycotoxins, heavy metals, chemicals, etc.), stress, exercise, medications, implants, amalgams, sleep deprivation, hormones, light, temperature changes, alcohol, venom, physical stimulation (pressure, friction), acute or chronic infections (Lyme, EBV, tuberculosis, COVID, SIBO), medications such as opiates, nonsteroidal anti-inflammatory drugs, muscle relaxants, antibiotics such as quinolones, and others.17,20,22,25  With MCAS, multiple systems are typically affected, including neurologic, dermatologic, respiratory, cardiovascular, digestive, and musculoskeletal, with many symptoms overlapping with POTS and long COVID symptoms.20,22

POTS is divided into hyperadrenergic, neuropathic, and hypovolemic POTS. Hyperadrenergic POTS is characterized by elevated serum norepinephrine levels (>600pg/mL) and has been associated with MCAS. The more the mast cell is activated, the more sympathetic hyperactivity is generated, and vice versa, creating a vicious cycle. The sympathetic overactivity and histamine effects are responsible for the hemodynamics seen in POTS. The figure below from Gonzalez-Alvarez et. al. demonstrates the positive feedback loop seen with this condition.26

It’s important to recognize the frequently described triad of POTS, MCAS, and hypermobile Ehlers-Danlos syndrome (hEDS), a connective tissue disorder characterized by joint hypermobility and increased tissue elasticity that may affect vascular function.27-29 Although hEDS is beyond the scope of this article, awareness of its association with POTS is important. Patients presenting with this constellation of conditions may experience symptoms for decades before receiving an accurate diagnosis, in part due to limited awareness and recognition of these disorders.17

Interrupting the Cycle of Inflammation: A Focus on Mast Cells

Treating POTS and other long-COVID symptoms with therapies that help patients with MCAS may be beneficial. Although mast cell activation may contribute to the pathophysiology of long COVID, it’s unlikely to account for all underlying mechanisms, and treatments targeting mast cells alone may not benefit all patients.20,30 However, if it has been overlooked, it may be worth considering for patients who are struggling and not finding relief otherwise.

Minimizing inflammatory mediators is the goal. In addition to mast cells releasing histamine, they also release prostaglandins, leukotrienes, proteases, heparin, and various cytokines and chemokines (i.e., TNF-α, etc.). While the inflammatory cascade can be helpful in certain situations, aberrant mast cell degranulation in chronic states can be detrimental.31 Identifying and avoiding mast cell triggers (mentioned above), including dietary histamine and other trigger foods, may be helpful. H1 and H2 antagonists and natural mast cell stabilizers can be very helpful.

Different classes of medications are used to address MCAS: mast cell stabilizers (ketotifen, cromolyn sodium), medications that mitigate effects of mast cell mediators (antihistamines, anti-leukotrienes, anti-prostaglandins), and anti-inflammatories (corticosteroids, immunosuppressives).20

H1 receptor blockers are the cornerstone of MCAS treatment.22 Trials using antihistamines for POTS are mostly positive. A small trial of 14 long-COVID patients who did not respond to other therapies all had significant improvement with H1 blocker fexofenadine (180 mg/day) and H2 blocker famotidine (40 mg/day) compared with controls. Patients struggled with fatigue, increased heart rate, brain fog, and/or gastrointestinal symptoms.30 A retrospective study showed that 72% of long-COVID patients who received histamine receptor antagonists reported clinical improvement in a wide variety of symptoms, except dysautonomia.32  A case study showed resolution of long-COVID POTS symptoms after starting H1-blocker loratadine 10 mg/12 h daily.26

Although beta-blockers are sometimes prescribed for POTS to reduce tachycardia, they do not act on the mechanisms by which mast cell activation increases heart rate. This may cause blood pressure to decrease, activating baroreceptors, and subsequently increasing heart rate. Whereas histamine receptor blockers help reduce heart rate and increase blood pressure, which may reduce POTS symptoms.30

In addition to the above-mentioned standard pharmaceutical treatments for MCAS, there are several natural or nutritional considerations. Commonly used supplements include:

  • Vitamin C: 500-1000 mg/daily; breaks down histamine, stabilizes mast cells20,25,33
  • Quercetin: 1-2 g/daily; stabilizes mast cells;11,20,25,33 antiviral against COVID15,34-36
  • Luteolin and other flavonoids: stabilizes mast cells20,25,37
  • Vitamin D: stabilizes mast cells20,25
  • Magnesium: controls mast cell division and histamine production20
  • Curcumin: stabilizes mast cells;38,39 immunomodulatory40
  • Nettles (Urtica dioica): antihistamine; stabilizes mast cells; reduces cytokine/chemokine production41
  • Omega-3 fatty acids: stabilizes mast cells; reduces cytokine/chemokine production; immunomodulatory42

Some clinicians also treat MCAS with 4.5 mg (low-dose naltrexone) LDN, which acts as a toll-like 4 receptor blocker, mast cell and T-cell stabilizer, and enhances endorphin production.17,25,33 LDN is being studied as a treatment for long-COVID symptoms, including POTS and fatigue.8,43-45

A case study described a patient with MCAS and hyperadrenergic POTS who experienced improvements in dysautonomia and mood symptoms following treatment with low-dose naltrexone (LDN), intravenous immunoglobulin (IVIg), and rifaximin for small intestinal bacterial overgrowth (SIBO). Because conventional POTS treatments (discussed earlier) may be less effective for the hyperadrenergic subtype, a more targeted treatment approach may be necessary. IVIg can regulate mast cell activation through multiple immune-mediated mechanisms.18

The same gastroenterology clinic reported that, among 15 patients with SIBO, 10 experienced improvement in GI symptoms following antibiotic treatment, while 4 also reported improvement in POTS symptoms.18 Although research is limited, a low-histamine diet and diamine oxidase (DAO) supplementation before meals may help reduce the inflammatory burden. DAO helps break down dietary histamine.46-48 Certain probiotics may also help metabolize histamine, and studies are beginning to show benefit for symptoms including dysautonomia in long-COVID.49 GI involvement is common in patients with POTS and MCAS, and concurrent treatment may help improve overall symptoms.

Finally, several nutrients help support the various enzymes that are involved in histamine metabolism and clearance, including: vitamin B5 for N-acetyltransferase (NAT); vitamins B12 and folate, along with other nutrients that support methylation for histamine N-methyltransferase (HNMT), vitamins C, B6, magnesium, and copper for DAO; vitamin B2 for monoamine oxidase (MAO); and vitamin B3 for aldehyde dehydrogenase (ALDH).48,50-55 A good multivitamin should cover the bases.

Other Treatment Considerations for POTS

Without standardized treatment guidelines, managing these complex conditions requires both the science and art of medicine, integrating clinical judgment, emerging evidence, and patient preferences to develop individualized treatment strategies.

Several additional therapies for long COVID, POTS, and MCAS are under investigation, including guanfacine, N-acetylcysteine (NAC), L-arginine, and others.8,56 Complementary approaches, including limbic system retraining, neurofeedback, acupuncture, and interventions aimed at improving vagal tone, may also support autonomic nervous system regulation.33,57-59

Functional medicine practitioners emphasize the interconnected influences of environmental exposures, psychological trauma, and chronic or hidden infections on health, recognizing that these factors may have cumulative effects and that effective care often requires a whole-person approach. A comprehensive strategy that addresses diet and lifestyle, mental health, potential environmental and infectious exposures, and targeted supplements may help reduce overall burden and support physiological resilience.

References:

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