Background: Xylazine is an animal tranquilizer without approved medical use in humans that is increasingly being misused as an adulterant in illicit drugs. This study aimed to characterize national trends and adverse outcomes associated with the emerging misuse of xylazine using digital surveillance data. Methods: We examined online search trends and social media discussions related to xylazine misuse in the U.S. from 2019 to 2023 using Google Searches data and conducted Joinpoint regression to assess trends. We also examined social media attention using Almetric attention score and analyzed reports on xylazine in the FDA Adverse Event Reporting System (FAERS) through September 2023 using logistic regression. Results: Our analysis revealed an overall increasing trend in online searches for XYLAZINE nationally, with an average monthly percentage change of 4.6% (95% CI: 3.9 to 5.1, P trend <0.001), indicating growing awareness. On social media, mentions of xylazine rose exponentially starting in late 2021. Analysis of the FAERS data identified 94 reports of adverse events related to xylazine, most of which involved men (70.2%), with a mean age of 36.5 (SD: 14.3) years. Alarmingly, these xylazine-linked adverse events had an 87.2% fatality rate, which increased over 40-fold with concurrent fentanyl use (reported OR: 40.5, 95% CI: 4.0 to 407.4, P = 0.002). Conclusions: These findings underscore the urgent need for greater public health awareness, harm reduction strategies, and enhanced surveillance targeting the worsening xylazine addiction and overdose crisis.

The authors have declared no competing interest.

This study did not receive any funding

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors