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Introduction Vasomotor symptoms (hot flashes) are the most common symptom of menopause, affecting about 75% of menopausal women and about 40% of perimenopausal women. PH80, an investigational neuroactive nasal spray, is hypothesized to be a potential treatment for moderate to severe hot flashes due to menopause given that it rapidly activates olfactory to limbic-hypothalamic neural circuits that control autonomic activity, including body temperature and sweating. The primary objective of this Phase 2A clinical study was to explore the efficacy, safety, and tolerability of intranasal administration of PH80 for the acute management of hot flashes due to menopause. Methods The study was a randomized, double-blind, placebo-controlled, exploratory Phase 2A clinical study. PH80 nasal spray containing epoxyestrenolone 0.8 μg per 50 μL was self-administered intranasally; two sprays in each nostril (total dose = 3.2 μg) up to four times daily as needed for 4 consecutive weeks. One additional dose was allowed at night if subjects were awakened by hot flashes. During the study period, subjects recorded the number and severity of hot flashes, disruption in function, and sweating related to hot flashes. Patient global impression of change (PGI-C) and clinician global impression of severity (CGI-S) were also assessed. Results At baseline, subjects reported a daily mean of 7.7 hot flashes in the PH80 group (n = 18) and 8.0 in the placebo group (n = 18). After 1 week of treatment, the number of hot flashes dropped to 2.8 for PH80 and 6.4 for placebo ( P <.001), and after 4 weeks of treatment, the number of hot flashes dropped to 1.5 for PH80 and 5.1 for placebo ( P <.001). Treatment with PH80 significantly reduced the severity, disruption in function, and sweating associated with hot flashes during the treatment period as compared with subjects in the placebo group. There was a significant improvement in PGI-C for PH80 vs placebo at endpoint ( P = .015) and a strong trend for improvement on CGI-S ( P = .053). PH80 was well-tolerated with no serious adverse events (AEs); the AE profiles of PH80 and placebo were comparable. All 36 subjects completed 4 weeks of treatment and with no study discontinuations due to AEs. Conclusions The rapid onset, significant reduction in symptoms, and improved function induced by intranasal PH80 in menopausal women with hot flashes compared with placebo, observed as early as the end of week 1 of treatment, provide a strong signal for continued development of PH80 for the acute treatment of hot flashes due to menopause. The safety data further suggest that, if approved, PH80 will provide a substantial safety benefit over all currently available agents. Funding Vistagen Therapeutics, Inc. Editorial assistance was provided by Peloton Advantage, an OPEN Health company, funded by Vistagen Therapeutics, Inc.