Melatonin, angiotensin 1-7, and cannabidiol in refractory autoimmune disease: clinical case series

Introduction: Dysregulation of the TH17/T regulatory (Treg) axis represents a frequently implicated pathway that may contribute to immune imbalance in selected autoimmune diseases, and experimental and clinical evidence suggests that several neuroendocrine systems—including melatonin, the endocannabinoid system, and the ACE2/angiotensin 1-7 axis—inhibit interleukin 17 (IL-17) signaling and physiologically modulate immune homeostasis. Materials and methods: This retrospective, observational case series evaluated 70 consecutive patients with refractory autoimmune diseases who were nonresponsive to or declined conventional immunosuppressive therapies. Patients received an integrative neuroendocrine regimen consisting of oral melatonin (10–50 mg nightly), gastro-protected angiotensin 1-7 (0.5 mg twice daily), and cannabidiol (20 mg twice daily). Outcomes included changes in disease-specific autoantibody titers (anti-thyroglobulin antibodies and antinuclear antibodies), lymphocyte-to-monocyte ratio (LMR) as an exploratory biomarker of systemic inflammation, and clinical or radiological disease stability, particularly in multiple sclerosis. Results: After 3 months, patients with Hashimoto’s thyroiditis showed a significant reduction in anti-thyroglobulin antibody levels (−49%), while patients with other systemic autoimmune diseases exhibited a significant decline in antinuclear antibody titers (−60%). In the multiple sclerosis subgroup, 62% of patients achieved radiological disease stabilization, with a median follow-up of 46 months. Abnormally low baseline LMR values were normalized in 67% of patients experiencing disease flares at enrollment. The regimen was well tolerated, and no clinically significant adverse events requiring treatment discontinuation were observed. Conclusions: In this heterogeneous cohort of patients with refractory autoimmune diseases, modulation of the neuroendocrine immune axis using melatonin, angiotensin 1-7, and cannabidiol was feasible, well tolerated, and associated with favorable serological and clinical trends. Given the retrospective, non-controlled design, these findings should be interpreted as hypothesis-generating. Controlled, randomized trials incorporating standardized immunological endpoints are warranted to validate the therapeutic potential of this integrative neuroimmune approach.