Efficacy and Mechanisms of Guanfacine and Cromolyn Sodium in Adults With Postural Orthostatic Tachycardia Syndrome (POTS): A Randomized, Double-Blind, Placebo-Controlled Crossover Clinical Trial. Acronym is DBPOTS (Double Blind POTS)

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.