Tryp Therapeuatics (TRYPF) Coverage Report

Psychedelics vs. standard of care in depression. Researchers have described the overlapping benefits from SSRIs and psychedelics (increasing circulation levels of serotonin), while highlighting the different impacts on emotions (Carhart-Harris and Goodwin, 2017). As shown in Exhibit 10, SSRIs post-synaptic 5-HT1 A receptor signaling is believed to generate anti-stress, pro-coping properties, however SSRIs also generate moderate or ‘blunt’ emotional responsiveness. Also, while SSRIs are currently the standard of care for depression, they typically take six to eight weeks to begin to show beneficial effects (Am J Psychiatry. 2006 Nov;163(11):1905-17), which frustrates most patients and caregivers, especially since the depressed patient has sought professional medical care and is expecting to see some improvements. Also, SSRI’s and SNRI’s show only moderate rates of response as only one in four see a benefit after 10 to 14 weeks (J Clin Psychiatry. 2008 Jun;69(6):946-58). Today’s depression treatments produce side- effects such as weight gain, anorexia, sexual dysfunction, and many others (Prim Care Companion J Clin Psychiatry. 2001 Feb; 3(1): 22–27), with high discontinuation rates (Ann Fam Med. 2019 Jan; 17(1): 52–60). Exhibit 10: Complementary serotonergic actions of SSRIs and psychedelics Source: Neuropsychopharmacology (2017) 42, 2105–2113 Psilocybin’s mechanism of action. Psilocybin’s primary mechanism of action is by its activation of the 5-HT 2A receptor. These receptors are highly expressed in the cortex, with some regions within the cortex showing higher receptor expression. The layer V of the cortex (the internal pyramidal layer) shows expression of 5-HT 2A receptors on the cell bodies and apical dendrites of large pyramidal neurons (Cell. 2020;181(1): 24). Upon psilocybin administration, layer V pyramidal neurons are activated leading to cortical desynchronization and increased entropy (J Neurosci. 2013; 33(38): 15171, Cell. 2020; 181(1): 24; see Exhibit 11). The claustrum, which is a subcortical nucleus, also shows a high expression of the 5-HT 2A receptor and plays a role in the integration of cortical inputs. Under a non-psychedelic state, these layer V neurons assist with the “top down” processing and cognition. However, under the psychedelic state, brain network connectivity is increased (Exhibit 11) and the brain is freed of its connections, allowing for new connections and behaviors from past actions, memories, and feelings. This is the main driver of psilocybin’s therapeutic effect. Michael Higgins 212.409.2074 Tryp Therapeutics, Inc. (TRYPF) Page 18