Guanfacine and Cromolyn Sodium for POTS: The DBPOTS Trial

Postural Orthostatic Tachycardia Syndrome (POTS) is a chronic disorder of the autonomic nervous system characterized by an excessive increase in heart rate upon standing, accompanied by symptoms such as dizziness, lightheadedness, palpitations, fatigue, cognitive impairment ("brain fog"), gastrointestinal disturbances, exercise intolerance, and reduced quality of life. POTS affects up to 1% of the population, disproportionately impacts women, and has become increasingly recognized following viral illnesses, including COVID-19. Current treatment options consist primarily of lifestyle modifications and off-label medications, yet many patients continue to experience persistent symptoms, highlighting the need for more effective therapies.

Emerging evidence suggests that POTS is a heterogeneous disorder involving both autonomic nervous system dysfunction and immune dysregulation. Recent genetic studies have identified variants in voltage-gated sodium channel genes among patients with dysautonomia, suggesting that abnormal neuronal excitability may contribute to disease pathophysiology. In addition, increasing evidence supports a role for immune activation and mast cell dysfunction in subsets of patients with POTS. These findings provide a biologic rationale for evaluating therapies that target these complementary mechanisms.

This study is a randomized, double-blind, placebo-controlled, three-period crossover clinical trial designed to evaluate the efficacy and safety of guanfacine and cromolyn sodium in adults with POTS. Both medications are approved by the U.S. Food and Drug Administration (FDA) for other indications but are investigational for the treatment of POTS.

Guanfacine is an α2A-adrenergic receptor agonist that reduces sympathetic nervous system activity and has demonstrated additional effects on voltage-gated sodium channels in preclinical studies. Cromolyn sodium is a mast cell stabilizer that reduces mast cell activation and inflammation and has demonstrated potential effects on ion channel function in laboratory studies. Together, these therapies target two proposed contributors to POTS pathophysiology: autonomic hyperexcitability and immune-mediated inflammation.

Approximately 25 adults meeting established diagnostic criteria for POTS will be enrolled. Following screening and baseline evaluations, participants will be randomly assigned to one of six treatment sequences. Each participant will receive guanfacine, cromolyn sodium, and placebo during separate 4-week treatment periods, with each treatment period separated by a 2-week washout interval. The crossover design allows each participant to serve as own control, reducing variability associated with the heterogeneous clinical presentation of POTS.

Throughout the study, participants will continue standardized non-pharmacologic management of POTS, including recommendations for increased fluid and sodium intake, compression garments, exercise, and lifestyle modifications. During each treatment period, participants will complete validated patient-reported outcome assessments measuring physical function, fatigue, cognitive function, gastrointestinal symptoms, and overall symptom severity. The primary endpoint is improvement in physical functioning as measured by the PROMIS® Physical Function scale. Secondary endpoints include changes in fatigue, cognitive symptoms, gastrointestinal symptom burden, global impression of change, and POTS symptom severity.

The study will also investigate biological mechanisms that may contribute to treatment response. Blood, urine, and sputum samples will be collected at specified study visits. Urine samples will be analyzed for biomarkers of mast cell activation, while blood and sputum specimens will be stored in a research biorepository for future analyses of immunologic, genetic, transcriptomic, and other molecular biomarkers related to autonomic dysfunction and POTS pathophysiology.

Safety will be closely monitored throughout the trial through scheduled study visits, adverse event assessments, protocol-defined dose adjustments, and oversight by the study investigators and an independent Data and Safety Monitoring Board, when applicable. Participants may have study medication doses increased according to predefined criteria if adequate clinical improvement is not observed and no significant safety concerns are identified.

This exploratory trial seeks to provide the first rigorous comparative evaluation of guanfacine and cromolyn sodium in a randomized, double-blind, placebo-controlled crossover study of adults with POTS. By integrating clinical outcomes with biomarker analyses, the study aims not only to determine whether these therapies improve symptoms and physical functioning but also to better understand the biological mechanisms underlying treatment response. The findings may help identify novel therapeutic strategies and support future precision medicine approaches for patients living with POTS.

Inclusion criteria

• Documented diagnosis of POTS per current consensus guidelines:
• a heart rate increase of ≥30 bpm within the first 10 minutes of standing or tilt-table testing, without orthostatic hypotension (systolic BP drop ≥20 mmHg)
• Frequent symptoms of orthostatic intolerance (e.g., dizziness, palpitations, GI complaints) persisting ≥3 months
• Symptom onset within 3 months of a recognized POTS trigger (e.g., infection, vaccination, injury, surgery, pregnancy, or puberty)
• Symptomatic response to mediator-targeting medications (e.g., antihistamines, mast cell stabilizers) - also eligible
• Presence of flushing, pruritis, urticaria, or angioedema - also eligible
• Alternative diagnoses must be excluded via prior clinical workup and laboratory assessment

Exclusion criteria

• Alternative medical causes for symptoms, including:
• Anemia,
• Active infection,
• Dehydration,
• Hyperthyroidism,
• Pheochromocytoma,
• Adrenal insufficiency,
• Paraneoplastic conditions
• Active neurologic disease (including stroke and epilepsy)
• Prolonged immobilization
• Current use of medications that cannot be safely discontinued during study enrollment (safety-based exclusion)
• Pregnancy or breastfeeding