Tryp Therapeuatics (TRYPF) Coverage Report

Dissociatives: This class of psychedelics produces a temporary disconnect with reality but does not necessarily involve a loss of consciousness. There are various dissociatives with different neurological activities.  Phencyclidine (PCP), ketamine, dextromethorphan (DXM) and nitrous oxide (NO) act as antagonists at the N-methyl-Daspartate (NMDA) glutamate receptor, which may help explain rapid euphoric effects from ketamine and NO. Atypical hallucinogens: These affect multiple neurotransmitter systems. While unrelated, atypicals are pharmacologically distinct substances with some hallucinogenic properties, exhibiting diverse mechanisms, legal status, and therapeutic potentials.  Ibogaine is a Schedule I serotonin 2A agonist, as well as a mu opioid receptor agonist, kappa opioid receptor antagonist, and an NMDA antagonist. Ibogaine has demonstrated potential as an anti-addiction agent, particularly for opioids. (Am J Addict. Summer 1999;8(3):234-42; J Psychopharmacol. 2014 Nov;28(11):993-1000)  Salvia divinorum , and one of its major compounds salvinorin A, activate kappa opioid receptors more than mu receptors yet it is a potent hallucinogen as researchers describe this unscheduled drug having “frequent non-medical use” (Front Pharmacol. 2015; 6: 190). However, salvinorin A has shown preclinical evidence for potential in treating addiction (Psychopharmacology volume 210, pages253–262 (2010).  Tetrahydrocannabinol (THC) is a Schedule I drug and the most hallucinogenic component in the cannabis plant. It has established evidence in treating nausea and vomiting due to chemotherapy, chronic neuropathic or cancer pain, and spasticity due to multiple sclerosis (JAMA. 2015 Jun 23-30;313(24):2456-73). When most people think of psychedelics, we believe they are thinking of the "classic psychedelics” because they have had the largest scientific and cultural influence. While these hallucinogens exert their primary mechanism of action via activation of 5-HT 2A serotonin receptors they have also been shown to activate other serotonin receptors (5- HT 2B , 5-HT 2C , 5-HT 1 , 5-HT 6 , and 5-HT 7 ). LSD and other ergolines also act upon D1 and D2 dopamine receptors and adrenergic receptors. Psychedelics mediate their behavioral and psychological effects via the 5-HT 2A receptors located in the brain (Trends Pharmacol Sci. 2017 Nov;38(11):992-1005. doi: 10.1016/j.tips.2017.08.003; Nat Rev Neurosci. 2020 Nov;21(11):611-624). The 5-HT 2A receptor is a G-protein-coupled receptor, the most widely expressed serotonin receptor in mammals and found in nearly every tissue including muscle, endothelial, immune, and endocrine. In the brain, it is primarily found in regions that are responsible for perception, learning, memory, emotional processing, and self-awareness. Exhibit 7: Hallucinogen's routes of administration Sources: April 2019 publ- National Institute on Drug Abuse; National Institutes of Health; Department of Health & Human Services Psilocybin LSD Peyote DMT Ketamine PCP DXM Salvia Swallowing as tablets or pills X X X X Swallowing as liquid X X X X Consuming raw or dried X X X Brewing into tea X X X X Snorting X X Injecting X Inhaling, vaporizing, or smoking X X X Drug-soaked paper X Routes of administration Classic DMT = N,N-dimethyltryptamine; DXM= Dextromethorphan; LSD = D-lysergic acid diethylamide; PCP = Phencyclidine Dissociative Michael Higgins 212.409.2074 Tryp Therapeutics, Inc. (TRYPF) Page 14