Guanfacine and Cromolyn Sodium for POTS: The DBPOTS Trial

The goal of this clinical trial is to learn whether guanfacine or cromolyn sodium can improve symptoms and physical functioning in adults with Postural Orthostatic Tachycardia Syndrome (POTS). Both medications are FDA-approved for other conditions but are investigational for the treatment of POTS. The main questions this study aims to answer are: Does treatment with guanfacine or cromolyn sodium improve physical functioning in adults with POTS compared with placebo? Does treatment with guanfacine or cromolyn sodium improve fatigue, cognitive function ("brain fog"), gastrointestinal symptoms, and overall symptom burden in adults with POTS? Researchers will compare guanfacine, cromolyn sodium, and placebo to determine whether either active treatment provides greater improvement in symptoms and physical functioning than placebo. Participants will: Be randomly assigned to receive guanfacine, cromolyn sodium, and placebo during separate 4-week treatment periods in a randomized, double-blind crossover study. Continue standard non-drug POTS management, including recommendations for fluid and salt intake, exercise, compression garments, and other lifestyle measures. Complete questionnaires that measure physical function, fatigue, cognitive symptoms, gastrointestinal symptoms, and overall health throughout the study. Attend scheduled study visits for safety monitoring and assessment of study outcomes. Provide blood, urine, and sputum samples so researchers can evaluate biomarkers related to POTS and better understand how these treatments may work.

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