To follow up on Psychedelics and 5HT2B cardiotoxicity, which mentioned Harmine is an effective therapeutic small molecule for the treatment of cardiac hypertrophy (2021):
5-HT2B receptor agonism can cause fibrosis in organs other than the heart. While cardiac valvulopathy is the most well-known adverse effect, 5-HT2B agonism has been implicated in fibrotic, proliferative, and remodeling diseases in the lungs, liver, skin, and retroperitoneal space.
Harmine is a promising agent here:
Implications for valvulopathy: in theory, since antifibrotic agents (especially 5-HT2B antagonists) block the fibrotic mechanisms driving 5-HT2B agonist-induced valvulopathy, preclinical data supports protection from progression. But that doesn't necessarily mean they can reverse valvulopathy.
5-HT2B receptor agonism can cause fibrosis in organs other than the heart. While cardiac valvulopathy is the most well-known adverse effect, 5-HT2B agonism has been implicated in fibrotic, proliferative, and remodeling diseases in the lungs, liver, skin, and retroperitoneal space.
Harmine is a promising agent here:
- A pulmonary fibrosis study: Harmine inhibits pulmonary fibrosis through regulating DNA damage repair-related genes and activation of TP53-Gadd45α pathway (2024) found that harmine inhibits pulmonary fibrosis by regulating DNA damage repair-related genes and activating the TP53-Gadd45α pathway. It reduced fibrosis in bleomycin-induced mouse models and suppressed fibroblast-to-myofibroblast transition in vitro, indicating reversal of established fibrosis. Harmine also reduced fibroblast viability and collagen deposition in vitro, with effects comparable to known antifibrotic agents.
- An intenstinal fibrosis study: TWIST1+FAP+ fibroblasts in the pathogenesis of intestinal fibrosis in Crohn’s disease (2024) identified TWIST1 as a key driver of fibroblast activation in Crohn’s disease. Harmine inhibited TWIST1, reducing collagen expression (COL3A1) and fibrosis in inflamed ileum tissue and in vitro models.
- Harmine suppresses collagen production in hepatic stellate cells by inhibiting DYRK1B (2022) found harmine suppresses collagen production in hepatic stellate cells (LX-2) by inhibiting DYRK1B, a kinase involved in fibrotic signaling, suggesting a mechanism for regression of liver fibrosis.
Implications for valvulopathy: in theory, since antifibrotic agents (especially 5-HT2B antagonists) block the fibrotic mechanisms driving 5-HT2B agonist-induced valvulopathy, preclinical data supports protection from progression. But that doesn't necessarily mean they can reverse valvulopathy.
