ABSTRACT The Administrative Supplement requests support for costs arising from unanticipated expenses to conduct preclinical studies required by the FDA and to be able to continue our Phase 1 single-ascending dose clinical trial of the novel smoking cessation pharmacotherapy on our current active U01 grant U01DA054882. The required preclinical studies were not expected and thus not planned for but are now necessary to preserve the overall impact of the project consistent with its originally approved Specific Aims and overall objectives. Our current grant aims to advance the clinical development of a novel smoking cessation pharmacotherapy into first-in-human (FIH) Phase 1 and early Phase 2A efficacy clinical trials, subsequent to obtaining FDA approval of the IND for these clinical trials. This novel small-molecule drug candidate is a new chemical entity with a first-in-class pharmacological mechanism targeting the α3β4 nicotinic acetylcholine receptor (nAChR) subtype. The objectives of our currently funded grant U01DA054882 are to conduct a Phase 1 single- and multiple-ascending dose (SAD/MAD) FIH trial to assess the safety, tolerability and pharmacokinetic (PK) profile in humans, and to conduct an efficient Early Phase 2 trial using a crossover procedure that will provide an early readout of medication efficacy for smoking cessation and a Go/No-go decision to advance this novel first-in-class candidate to subsequent larger randomized Phase 2 trials. As required by the FDA, our experienced drug development team has designed preclinical studies in rat to address the FDA questions and obtained FDA feedback on the proposed studies to be conducted. The Administrative supplement requests additional funding for these unanticipated studies, which will allow us to continue our clinical trial and meet the overall objectives of our grant.