Abstract The parent award is to develop novel medications for alcohol and nicotine use disorders. These disorders have increased during COVID19 [e.g. Clay and Parker 2020] and are associated with increased susceptibility to, and severity of, infection. This supplemental proposal is focused on how mechanisms of COVID-19 infection and neurotoxicity are influenced by alcohol and nicotine, and how these novel medications interact with these mechanisms. The applicants have previously used organotypic hippocampal neuronal cultures to study interactions between nicotine, alcohol withdrawal and viral protein neurotoxicity, and these cultures will be used here. First, nicotine has been reported to up-regulate the viral “receptor” angiotensin converting enzyme 2 (ACE2) on neurons, providing a mechanism for increased SARS CoV2 infectivity and neurotoxicity in smokers and “vapers” [see Kabbani & Olds 2020]. The nicotinic receptor partial agonists (lobinaline N-oxides) from the parent award should inhibit this effect of nicotine, and this will be tested in the first specific aim using immunohistochemistry to evaluate ACE2 expression in organotypic cultures. Once CNS infection has occurred, coronaviruses cause “excitotoxicity” that is inhibited by inhibitors of neuronal glutamate /NMDA receptors (NMDARs) [Hasanagic & Serdeveric, 2020]. This is similar to alcohol withdrawal (AWD) [Stepanyan et al, 2008] and so should be ameliorated by drugs that prevent neurotoxicity in AWD. Once again, the nicotinic activity of lobinaline N-oxides may be valuable, but another medication under development by the company for alcohol use disorder, the aryliminoguanidine, JR220, is even more directly relevant because it is an inhibitory modulator of the NMDAR [Barron et al, 2012], The neuroprotective possibilities for these drugs will be evaluated against viral protein neurotoxicity in organotypic cultures in specific aim 2. The hypothesis is therefore that coronavirus infectivity and neurotoxicity are enhanced in patients with nicotine and alcohol use disorders, and that both the disorders and the COVID19 consequences should be inhibited by the medications under development. These novel therapeutic targets for lobinaline N-oxides and JR220 in COVID-19 infection will strongly support the therapeutic and commercial value of products from the parent award.