Objective Understanding public discourse on emergency use of unproven therapeutics is essential to monitor safe use and combat misinformation. We developed a natural language processing (NLP)-based pipeline to understand public perceptions of and stances on COVID-19-related drugs on Twitter across time. Methods This retrospective study included 609,189 US-based tweets between January 29th, 2020 and November 30th, 2021 on four drugs that gained wide public attention during the COVID-19 pandemic: 1) Hydroxychloroquine and Ivermectin, drug therapies with anecdotal evidence; and 2) Molnupiravir and Remdesivir, FDA-approved treatment options for eligible patients. Time-trend analysis was used to understand the popularity and related events. Content and demographic analyses were conducted to explore potential rationales of people’s stances on each drug. Results Time-trend analysis revealed that Hydroxychloroquine and Ivermectin received much more discussion than Molnupiravir and Remdesivir, particularly during COVID-19 surges. Hydroxychloroquine and Ivermectin were highly politicized, related to conspiracy theories, hearsay, celebrity effects, etc. The distribution of stance between the two major US political parties was significantly different (p < 0.001); Republicans were much more likely to support Hydroxychloroquine (+55%) and Ivermectin (+30%) than Democrats. People with healthcare backgrounds tended to oppose Hydroxychloroquine (+7%) more than the general population; in contrast, the general population was more likely to support Ivermectin (+14%). Conclusion Our study found that social media users with have different perceptions and stances on off-label versus FDA-authorized drug use across different stages of COVID-19, indicating that health systems, regulatory agencies, and policymakers should design “targeted” strategies to monitor and reduce misinformation for promoting safe drug use. Our analysis pipeline and stance detection models are made public at https://github.com/ningkko/COVID-drug.

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