COVID-19 Disease as an Acute Angiotensin 1-7 Deficiency: A Preliminary Phase 2 Study with Angiotensin 1-7 in Association with Melatonin and Cannabidiol in Symptomatic COVID19 -Infected Subjects

COVID-19 disease is characterized by severe and acute immune alterations, consisting of an abnormal secretion of inflammatory cytokines, mainly IL-17, IL-6 and TNF-alpha, in association with decline in lymphocyte and increase in monocyte counts. ACE2 is the key for COVID19 entry into the cells. However, the link of viral spike protein to ACE2 receptor on cell surface would also block the ACE2 enzymatic activity itself, with a consequent diminished production of angiotensin 1-7 (Ang 1-7), which is provided by fundamental anti-inflammatory and anti-coagulant properties. Then, the severe and acute Ang 1-7 deficiency would allow an exaggerated cytokine-induced inflammatory response, endothelial damage, leak capillary syndrome and acute respiratory distress syndrome (ARDS). Moreover, because of the documented connections occurring among ACE2, cannabinoid system and melatonin (MLT) secretion from the pineal gland, the block of ACE2 activity would also allow a concomitant deficiency of pineal-cannabinoid system axis, which plays a fundamental antiinflammatory role by inhibiting IL-17 secretion, one of the main cytokine involved in COVID19 infection. Therefore, COVID19-induced exaggerated inflammatory response could be controlled at least in part by correcting Ang 1-7, MLT and cannabinoid deficiency through their exogenous administration. On these bases, a study was planned in 30 COVID19-infected patients with initial or important symptomatology, 16 of whom orally treated by MLT (20 mg/day in the evening) plus cannabidiol (CBD) (10 mg x 2/day) only, while the other 14 patients received also Ang 1-7 (0.5 mg 2/day orally). The results were compared to those observed in a control group of 30 COVID-19 infected patient, who received the only supportive therapy. No hospitalisation for initial respiratory failure was required in the group of patients treated by the neuroimmune regimen. In addition, most patients referred a rapid disappearance of fever and myalgia, as well as a relief of asthenia, particularly in those concomitantly treated with Ang 1-7. On the contrary, 5/30 (17%) control patients required hospitalisation. The difference was statistically significant (0/30 vs 5/30, P< 0.05). This preliminary study would suggest that a neuroimmune approach consisting of MLT and CBD in association with Ang 1-7 is an effective and nontoxic regimen in the therapy of COVID19-related symptoms, which could also control the clinical evolution of disease and reduce the need of hospitalisation.