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Published in final edited form as: Subst Use Misuse. 2025 Apr 12;60(8):1164–1172. doi: 10.1080/10826084.2025.2491768 Search in PMC Search in PubMed View in NLM Catalog Add to search “All you can do is what you know to do”: Naloxone knowledge and uncertainty among people who use drugs in Maryland amid a volatile drug market Laura N Sisson Laura N Sisson a Department of Health, Behavior, and Society, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA b Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Find articles by Laura N Sisson a, b , Abigail K Winiker Abigail K Winiker a Department of Health, Behavior, and Society, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Find articles by Abigail K Winiker a , Tricia Triece Tricia Triece a Department of Health, Behavior, and Society, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Find articles by Tricia Triece a , Richard S Rousch Richard S Rousch a Department of Health, Behavior, and Society, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Find articles by Richard S Rousch a , Saba Rouhani Saba Rouhani c Department of Epidemiology, New York University School of Global Public Health, New York, NY, USA Find articles by Saba Rouhani c , Jill Owczarzak Jill Owczarzak a Department of Health, Behavior, and Society, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Find articles by Jill Owczarzak a , Susan G Sherman Susan G Sherman a Department of Health, Behavior, and Society, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Find articles by Susan G Sherman a , Kristin E Schneider Kristin E Schneider a Department of Health, Behavior, and Society, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Find articles by Kristin E Schneider a Author information Article notes Copyright and License information a Department of Health, Behavior, and Society, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA b Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA c Department of Epidemiology, New York University School of Global Public Health, New York, NY, USA ✉ Corresponding Author: Laura Nicole Sisson, [email protected] Issue date 2025. PMC Copyright notice PMCID: PMC12199276 NIHMSID: NIHMS2074745 PMID: 40219904 The publisher's version of this article is available at Subst Use Misuse Abstract Community-based distribution of naloxone has continued to serve as an important strategy in combatting the U.S. opioid overdose crisis. People who use drugs are first responders in this crisis, administering and disseminating knowledge about naloxone among their social networks. However, it is unclear how knowledge of naloxone evolves over time and across individuals, especially amid a volatile, unregulated drug market. We conducted 22 qualitative interviews with people who use drugs in rural, suburban, and urban regions of Maryland. Interviews focused on respondents’ experiences witnessing and experiencing overdose, reversing overdoses with naloxone, and sources of uncertainty in overdose response. Participants demonstrated high willingness and capacity to respond to overdose using naloxone. However, limited technical knowledge about naloxone contributed to riskier overdose reversal strategies, especially among individuals who had not received formal training. Non-naloxone reversal strategies, such as rescue breathing, were not widely used by participants. Finally, perceived volatility within local drug markets, specifically fentanyl analogues and xylazine, undermined participants’ confidence in the effectiveness of naloxone. People who use drugs serve an important role in community-based overdose reversal. Leveraging their experiential knowledge of overdose with technical knowledge of naloxone is foundational to effective community-based naloxone dissemination. Harm reduction programs should ensure that educational materials describe technical aspects of overdose response in ways that are intuitive to the experiences of people who use drugs, as well as ensure materials are responsive to an evolving drug supply. Keywords: naloxone, overdose, xylazine, fentanyl, qualitative Introduction Overdose deaths have continued to rise in the United States, escalating substantially during the COVID-19 pandemic. In 2022, 107,941 individuals died of a drug overdose, a rate of 32.6 deaths per 100,000 people ( Spencer et al., 2023 ). Since 2013, these deaths have largely been driven by the increasing presence of synthetic opioids, including fentanyl and its many analogues, in the drug supply ( Ciccarone, 2019 ). To reduce opioid overdose deaths, state and local health departments have invested resources into the community distribution of naloxone, a medication that reverses the effects of an opioid overdose. Often referred to as overdose education and naloxone distribution (OEND), these programs strive to teach those without medical training to effectively intervene in a suspected opioid overdose ( Clark et al., 2014 ). These programs have been supported by the widespread enactment of policies decriminalizing the possession and administration of naloxone by lay responders ( Lambdin et al., 2018 ). Across jurisdictions, promoting community-based naloxone distribution and overdose education has emerged as a core public health strategy to combat the opioid overdose crisis ( Lambdin et al., 2020 ). People who use drugs (PWUD) are among the most common bystanders to overdoses ( Clark et al., 2014 ; Latkin et al., 2018 ; Song et al., 2023 ). For this reason, many OEND programs are implemented by local syringe service programs and focus their distribution to this population ( Lambdin et al., 2020 ). One 2014 survey of 136 OEND program managers found that approximately 82% of naloxone kits dispensed by these programs had been given to PWUD, compared to 12% to friends and family members and 3% to service providers ( Wheeler et al., 2012 ). This highlights the “social logic” that underlies overdose reversal, which relies on social connections and expertise among PWUD as much as it does on the pharmacological effectiveness of naloxone. ( Faulkner-Gurstein, 2017 ). OEND programs focus on promoting the self-efficacy, knowledge, and capacity of PWUD to respond to overdoses, with the goal of reducing the rate of fatal overdose in a community ( Farrugia et al., 2019 ; Marshall et al., 2017 ). However, such programs tend to emphasize technical aspects of naloxone and its function, often overlooking the experiential and embodied forms of knowledge developed by individuals with first-hand experience of overdose and its reversal. Such experiential knowledge is key to naloxone’s function as a “technology of solidarity,” galvanizing PWUD, harm reduction advocates’ and communities’ efforts to demand increased public investment in resources to prevent overdose deaths ( Campbell, 2019 ). These efforts are undergirded by the broader “culture of care” documented among social networks of PWUD, with an emphasis on reciprocity and mutual aid among peers ( Bathje et al., 2020 ; Greenhough et al., 2023 ; Kolla & Strike, 2020 ). The social logic of naloxone underlies the diffusion of naloxone kits and knowledge about overdose response beyond the primary recipients of OEND programs. These programs often intentionally capitalize on the common practice of resource dissemination among social networks of PWUD ( De et al., 2007 ; Latkin et al., 2010 ). Prior research has suggested that secondary transmission of information and resources to facilitate overdose response extends the reach of OEND programs beyond those who are directly trained ( Sherman et al., 2009 ). While these diffusive practices mean that individuals who may not otherwise be engaged with services are reached, it is unclear how they may result in alterations or aberrations to training content. It is also unclear how adaptive and responsive the information conveyed directly by OEND trainings and secondarily via social diffusion is to changes in the drug market. In many states, including Maryland, this has been compounded by the emergence of xylazine, a veterinary tranquilizer, into the street opioid supply ( Friedman et al., 2022 ; Russell et al., 2023 ). The proliferation of this adulterant has raised concerns that the presentation of overdoses may be shifting, due in large part to the sedating qualities of xylazine ( Alexander et al., 2022 ; Zhu, 2023 ). While guidance for emergency medical staff have been developed, whether and how lay responders should differentiate between xylazine and non-xylazine-involved overdoses remains an ongoing point of discussion for policymakers and harm reduction advocates alike ( Kariisa et al., 2021 ; Sue & Hawk, 2024 ). Existing evidence on the effects of OEND training on PWUD’s capacity for overdose response has focused on short-term effects on participants’ knowledge and self-efficacy and been largely quantitative ( Heavey et al., 2018 ; Lewis et al., 2016 ; Pauly et al., 2018 ). Other quantitative studies have focused on PWUD’s willingness to carry naloxone and the longer-term psychological effects of witnessing and responding to overdose ( Kesich et al., 2023 ; Shearer et al., 2019 ; Song et al., 2023 ). However, qualitative research on how PWUD cultivate and retain knowledge about naloxone administration has been more limited. One study focused on the role of embodied and experiential knowledge in reversal practices at an overdose prevention center in Vancouver, Canada ( Olding et al., 2023 ). Another study of OEND training recipients in New York City highlighted the practical and social competencies required to effectively respond to an overdose ( Neale et al., 2019 ). Using qualitative data, the present study examines how PWUD’s knowledge of overdose response is influenced by their training source and identifies areas of uncertainty, with special consideration of how the emergence of xylazine into the local drug supply may influence overdose response strategies and uncertainties. Methods Data for this analysis were part of a larger qualitative study designed to explore the perceptions and experiences of overdose and naloxone administration among people who use drugs (PWUD) amid a rapidly changing drug supply. A total of 22 in-depth interviews were conducted with PWUD in three distinct counties in Maryland representing urban, suburban, and rural communities. Interviews were conducted by research assistants who had received training in qualitative interviewing techniques and trauma-informed interviewing strategies before being scheduled to conduct interviews. Data collection took place between April and November 2023 with participants recruitment being supported by partnering harm reduction programs in each locale. All interested participants were screened for eligibility, which included: 1) being at least 18 years old, 2) having used non-prescribed opioids in the past 3 months, and 3) having responded to an overdose using naloxone in the past 3 months. Eligible participants were then invited to participate in an in-depth interview. In urban and suburban areas, interviews were conducted on the study team’s mobile van, while in rural areas interviews were conducted at the offices of the local partnering program. All participants provided verbal informed consent, including permission to audio record and transcribe the interview. Interviews lasted approximately 45 minutes and participants were remunerated with a $40 gift card. All study procedures were reviewed and approved by the Johns Hopkins Bloomberg School of Public Health and Maryland Department of Health Institutional Review Boards. The interview guide included questions about participants’ beliefs, attitudes and experiences about naloxone administration, their perceptions of changes to the local drug supply, and their engagement with harm reduction programming, including OEND programming. Audio recordings were professionally transcribed and uploaded into MAXQDA, a qualitative data management software ( VERBI Software, 2019 ). Demographic characteristics of participants, captured with a brief survey, were encoded along with participants’ responses. The principal investigators and research team met to develop a preliminary codebook based on the interview guide, including deductive codes derived from the interview guide and inductive codes emerging from preliminary data analysis. Two randomly selected interviews were then coded by each member of the research team and compared to refine the codebook and review discrepancies in codebook application. This process was repeated until a satisfactory level of convergence was achieved as assessed by the principal investigator. Once the codebook was finalized, each interview was coded by an individual member of the research team. This analysis focused specifically on respondents’ self-reported experiences with overdose response, identified via the application of codes such as “overdose response knowledge/experiences”, “naloxone knowledge”, and “uncertainty”. Specifically, we reviewed all relevant excerpts to identify where knowledge about overdose response and naloxone administration diverged across participants. To investigate how the diffusion of information through social networks potentially influences knowledge about overdose response, we identified participants’ initial source of naloxone training. This enabled us to compare the responses of those who had and had not received first-hand training from an OEND program. This process was supported by MAXQDA’s MaxMaps feature, a tool that allows for the visual and spatial organization of data. Data analysis took a critical realist approach to analyze and interpret participants’ experiences with overdose and naloxone administration, grounded in the understanding that there are specific physiological mechanisms at play that are understood and interpreted differently in practice ( Fletcher, 2017 ). Results Eleven interviews were conducted in suburban neighborhoods, 6 in urban neighborhoods, and 5 in a rural region of Maryland. The majority of participants were cisgender men (n=16). Fourteen participants identified as White or European American (e.g., German, Italian), 7 as Black or African American, and 1 participant was American Indian/Alaskan Native. The majority of participants described having reversed an overdose with naloxone multiple times, including both sporadic reversals and reversals on a weekly or monthly basis. Participants had predominantly used intranasal formulations of naloxone and expressed greater comfort in administering this formulation as opposed to intravenous or intramuscular. During the course of the interview, 14 participants indicated that they had received training via an Overdose Response Program (ORP) certified by the Maryland Department of Health to disseminate naloxone and provide overdose response trainings. The remaining 8 participants indicated that they had never received a formalized training to use naloxone but had either been told how to use it by a friend or family member, had learned through observation, or had taught themselves. We identified three key areas where individuals’ technical and experiential knowledge of overdose and naloxone merged and diverged: recognizing the signs of overdose and responding using naloxone, identifying the need to provide additional naloxone doses, and understanding the mechanisms through which naloxone reverses overdoses. Additionally, we examined how this knowledge had become further complicated by recent changes to the drug market. Recognizing and responding to overdose Participants were confident in their ability to recognize an opioid-involved overdose. The most frequently identified sign of an overdose reported was a change in breathing usually described in terms of a depressed breathing rate as well as signs of oxygen deprivation, such as an individual’s skin and lips turning blue, purple, or gray. Several individuals also referred to the sounds that individuals might make when they are struggling to breathe, sometimes referred to as a “death gurgle” or “last breath”: If they’re changing their colors and they’re not breathing. You know you have to administrate it, you know, because you’ll know. You’ll hear that last breath. You hear someone take their last breath. (53-year-old Black woman, non-ORP trained) While the role of breathing in overdose was widely recognized, ORP-trained participants emphasized the importance of ensuring that a person was not breathing before administering naloxone. Several of these individuals identified lack of breathing rather than non-responsiveness as the tell-tale sign that naloxone was needed. ORP-trained respondents highlighted that this step was imperative to distinguish between an overdose and a heavy nod, to avoid inadvertently giving naloxone to someone who didn’t need it. People give it to people that don’t need it. They don’t accurately… really know what is and isn’t-- if they just aren’t responding but they’re fully breathing, you’re not supposed to give it to them… if they’re just not waking up but they’re fully breathing, they’re not overdosing, they’re breathing. (25-year-old white woman, ORP trained) While participants’ confidence in administering intranasal naloxone was generally high, knowledge and utilization of supplemental overdose response strategies was more variable, especially CPR or rescue breathing. While a handful of individuals identified that they regularly used breathing techniques in addition to administering naloxone, it was often used as a last resort, for example if multiple doses had been provided with no response. Additionally, individuals were generally more willing to provide rescue breathing with friends or family members than with strangers. One woman who lived in a neighborhood with a large homeless encampment expressed hesitation regarding hygiene, especially in the wake of COVID-19. They were saying if you have like this thing, the barrier, the COVID person’s mouth, yeah, it would be nice, especially if they’re not breathing. But I’m going to tell you now, in this neighborhood, unless it was somebody I know, I’m not putting my mouth on them. (48-year-old Black woman, ORP trained) Identifying the need for multiple doses While participants were confident in recognizing the need for and administering an initial dose of naloxone, confidence in administering multiple doses of naloxone waned considerably. Certainty about when to give more than one dose, how long to wait between doses, and how many doses overall should be given varied considerably. There was a lack of consensus among participants about how long to wait before administering an additional dose, ranging from 20 seconds to 10 minutes. Several individuals explained that they sometimes gave an additional dose earlier than recommended because it is difficult to withstand the uncertainty of waiting. I’m not uncomfortable with giving the Narcan but uncomfortable with the situation in general because then you have an emotional attachment, you’re scared to lose the person, so you could mess up or you could just, your fear get in the way and you possibly give them too much because they’re not responding. (25-year-old White woman, ORP trained) The number of naloxone doses that should be given was another frequently cited source of uncertainty. Some believed that there was an upper limit to the number of doses that should be given without oversight by emergency medical services. The most frequently referenced “upper limit” was three doses, reported by both ORP-trained and non-ORP trained individuals. Concerns raised about going above this threshold ranged from complicating the ability of Emergency Medical Services (EMS) to respond to potentially causing an overdose from naloxone. Even without referencing an upper limit, needing to give multiple doses was often viewed as an indicator that EMS should be called, if they hadn’t been called already. I don’t know if I knew that you’re really not supposed to Narcan somebody so many times within so much time. I gave her three and then my boyfriend was like, “We got to call 911 because we can’t keep Narcaning her. You know, when she could overdose on Narcan.” (38-year-old white woman, non-ORP trained) Additionally, recognizing when someone had been successfully revived and naloxone was no longer needed was not considered as clear cut as recognizing an overdose in the first place. While many individuals recognized that a resumption of breathing was the most important indicator that naloxone had been effective, several individuals expressed that an overdose was only successfully reversed if the person was fully alert. For them to get up and start walking around or at least get up and start moving around, you know what I mean, be able to where you can understand things. (56-year old white man, non-ORP trained) Knowledge of naloxone mechanisms and product safety Individuals’ decision-making when administering naloxone was shaped by their perception of the safety of naloxone products and their understanding of the mechanisms by which naloxone works to reverse an overdose. Some individuals cited product safety concerns similar to those of other over-the-counter or prescription medications, including concerns about expiration dates and safe storage practices. While naloxone products were generally considered safe, a handful of individuals expressed concerns about potential long-term health effects of repeated naloxone administration, for example cardiac or respiratory conditions. The most common concern about naloxone safety was a potential allergic reaction, especially when administering naloxone to a stranger. I hope they ain’t allergic to it or whatnot, you know, and I might cause something even worser than what they want to, you know what I mean? That’s the only concern I have about it. (59-year old Black man, ORP trained) While individuals would generally provide naloxone even if they were concerned about allergic reactions, a few individuals expressed that these concerns would lead them to try alternative strategies and only use naloxone as a last resort. Many of these strategies, including “slapping around” a person or giving them another drug, such as a stimulant, carry their own host of risks of harm. There’s been times where I’ve taken a hit of crack and I’ve shot-gunned into somebody to bring them out of it because I heard that they were allergic to the Narcan. But if they don’t come out of it from that, I will Narcan. I try everything before I Narcan somebody. (38-year old white woman, non-ORP trained) The most widely known “side effect” of administering naloxone was withdrawal. While none of the participants expressed that concerns about causing withdrawal would prevent them from administering naloxone, it did increase hesitancy towards using additional doses. This was largely driven by concerns about doing more harm than good by giving someone more naloxone than was needed. Informed by first-hand experience administering or having been administered naloxone, most individuals believed that the more doses of naloxone administered, the more intense and long-lasting withdrawal effects would be. However, by and large respondents believed that the risk of withdrawal was far outweighed by the risk of death. Some individuals expressed the belief that no one was known to die from precipitated withdrawal, but others expressed concern that it could have a negative effect, especially among medically vulnerable individuals. I know if they’ve got a real high tolerance, they’re going to be, you know, as sick as hell when they wake up. At least they’re not dead. But I know that it’s just, it’s not good for their body, especially if they’re already, you know, weak and stuff like that and their organs and stuff like that. It’s just not good to administer it too soon and make the body go in shock. (28-year old Native American man, ORP-trained) Understanding of the mechanisms through which naloxone works to reverse an opioid-induced overdose and causes and symptoms of withdrawal varied considerably among participants. Clear differences emerged among participants who had and had not received ORP training regarding accurate knowledge of these mechanisms of action. Many individuals who were not directly trained by an ORP did not have accurate technical knowledge of how naloxone operated, for example describing naloxone’s effect as removing opioids from a person’s system. This was described in terms of “purging dope,” “sucking everything out,” or “eating up everything” in your system. Those who had less accurate knowledge of naloxone’s mechanisms of action often reported engaging other non-evidence-based approaches to responding to an overdose. For example, a handful of these individuals attempted to ease withdrawal effects by providing opioids and were not aware that this would be ineffective during naloxone’s half-life and could contribute to a subsequent overdose. One individual explained that she would wait until an individual had vomited, taking this as a sign that the naloxone had effectively taken everything out of their system. From my experience Narcaning people, the more opiates they do, the longer they go through that horrible feeling… So I’ll even go get them dope. But I tell them, ‘You can’t have dope until you throw up. You have to throw up a few times before I give you anything. That means you’ve got it out of your system.’ (38-year old white woman, non-ORP trained) Others believed that naloxone functioned similarly to adrenaline, supported by witnessing people “jumping up” or having a “manic reaction” after being administered naloxone. This led one individual to conclude that it was unsafe to administer naloxone to individuals who had used stimulants, due to concerns that giving naloxone could “blow their heart up.” So the paramedics, that’s the first thing they want to do, is Narcan you. Sometimes that ain’t the case. I’ve had people who have seizures and stuff like that, and they want to get out with Narcan and go Narcan them. It’s like ‘No you can’t Narcan him, he’s having a seizure.’ Or, ‘He’s high on meth. You can’t Narcan him. You’ll blow their heart up,’ or something like that. (45-year old white man, non-ORP trained) In contrast, those who had undergone an ORP-delivered training generally had a more accurate technical understanding of the mechanisms through which naloxone reverses overdose. These individuals described the role of naloxone as preventing opioids from binding with receptors in the brain, were cognizant of naloxone’s half-life and that the effects would wear off in approximately 30 minutes and were aware of the risk of an individual slipping back into an overdose. Perhaps most importantly, these participants were aware that providing the individual with more opioids would not ease withdrawal effects and would increase the risk of overdosing again once the naloxone had worn off. A lot of people don’t realize that dope is still in their system and then they’re adding more on top of it. And then they overdose again hours later. So I kept asking the one guy who was with him, I said don’t let him do any more dope. I said he’s going to be sick, I said, but you need to let him cool down for a little while. (45-year old white woman, ORP trained) Drug market volatility and perceived effectiveness of naloxone Uncertainties about administering naloxone were rooted in participants’ perceptions of volatility in the drug market, undermining the predictability of naloxone’s efficacy. While most participants acknowledged that there is always a level of uncertainty in overdose response, the introduction of new cuts and adulterants into the drug supply raised questions about whether naloxone would work at all. The unpredictability of an opioid market saturated with fentanyl analogues of varying potency, such as carfentanil, generated uncertainty about how many doses of naloxone should be given to reverse an overdose. One time, I had to call 911 because this person wouldn’t come out of it because they got a hold of that blue fentanyl. Narcan don’t help with that. And that’s the only time I had to call the paramedics was because I tried everything to bring them up. (37-year-old white man, ORP trained) The emergence of xylazine or “tranq” into Maryland’s illicit opioid market caused some individuals to question what they knew about overdose response. Those who were aware of tranq believed it was responsible for changes in the presentation of overdose, including a quicker onset, increased levels of sedation or sleepiness, and episodes of “blacking out”. While many people said that knowing or suspecting that tranq was involved in an overdose would not significantly alter their response strategy, several individuals expressed the belief that naloxone was completely ineffective against tranq, leading them to lean more heavily on alternative response strategies. I guess there’s some stuff out here now it’s a tranquilizer and this person this week took some of that stuff and the Narcan didn’t even work. I really had to shake her around and I even smacked her and I was really, really scared… It didn’t do anything, they didn’t even react. (58-year-old Black man, ORP trained) Generally, participants reported that they hadn’t specifically been trained to recognize and respond to a tranq-involved overdose. Therefore, many would simply default to the training they had already received if faced with an overdose suspected to involve tranq. No, I wouldn’t know what to do different, an overdose is an overdose. If someone’s not breathing no more I guess all you can do is what you know to do and what medicine you have to give them and honestly I really don’t know what would be different about [it]. (39-year-old white man, ORP trained) Many participants attributed the presence of xylazine in the drug supply to recent experiences where multiple doses of naloxone were needed to reverse an overdose. One participant expressed that if an overdose was reversed with a single dose of naloxone, it was unlikely that tranq was involved. However, a handful of individuals expressed concern that the increasingly complex presentation of overdose was making it more common for naloxone to be administered prematurely or in excessive amounts. Specifically, participants raised concerns that the sedating properties of xylazine were being misrecognized as an overdose and repeated doses of naloxone were administered without checking for a pulse or breathing rate. They see them with their eyes shutting and they’re back like this. They automatically think oh my God, he’s OD-ed, let me Narcan him, or something like that real quick. They don’t know to feel for a pulse because sometimes you might not be able to see somebody’s chest moving or something, so you got to feel around for a pulse. (45-year-old white man, non-ORP trained) Discussion PWUD are at the front-line of the opioid overdose crisis, often serving as first responders at the scene. Overdose education and naloxone distribution (OEND) initiatives have played a key role in empowering PWUD to respond to overdose before the arrival of emergency medical services. While concerns have been raised about the appropriateness of lay-administered naloxone, our findings confirm prior research that PWUD are highly capable of recognizing the signs of an opioid-involved overdose and responding appropriately with naloxone ( Bennett et al., 2018 ; Giglio et al., 2015 ). Perhaps most importantly, all participants expressed high levels of willingness and minimal hesitation to intervene in an overdose. However, our analysis revealed several knowledge gaps, especially among individuals who had not been trained directly by an OEND. Specifically, knowledge of the mechanisms through which naloxone reverses an opioid overdose and auxiliary response strategies, such as rescue breathing, varied depending on the source of an individual’s training. This highlights potential pitfalls to the “social logic” of naloxone dissemination among social networks of PWUD. Additionally, we found that the volatility of the drug market in Maryland generated uncertainty in how to properly respond to an overdose, undermining individuals’ confidence in their ability to respond effectively. These findings offer some suggestions for how OEND programs, such as those funded through Maryland’s ORP program, can further promote PWUD’s comfort and confidence responding to an overdose amid a volatile, unregulated drug supply. The logic underlying participants’ decision-making while responding to an overdose was guided by their understanding of the mechanisms through which naloxone works to reverse an opioid overdose. The most common misconception among participants was that naloxone removes opioids from a person’s system, rather than preventing those opioids from binding with receptors in the brain. This understanding was derived from participants’ first-hand experiences of withdrawal, generally experienced during delays in using opioids again as the effects of previous doses wear off. PWUD’s knowledge of naloxone cannot be understood simply in terms of their technical comprehension, but how it is interpreted via their embodied and social experiences. Deciphering how these technical and experiential aspects interact is essential to understanding how overdose response practices manifest and evolve among PWUD ( Campbell, 2021 ; Olding et al., 2023 ). Yet, individuals who were directly trained by an OEND program had greater technical knowledge about naloxone than those who had been trained via another source, contributing to differential use of riskier overdose response strategies. OEND programs are tasked with the challenging job of communicating an abstract, scientific concept in easily accessible language within a limited amount of time, often fewer than five minutes. Recent evaluations of OEND programming have highlighted the value and importance of incorporating the experiences and perspectives of PWUD when developing educational materials ( Enich et al., 2023 ; Olding et al., 2023 ). Soliciting input from PWUD regarding how technical information about naloxone should be communicated would leverage their experiential knowledge of opioid use, overdose, and reversal to identify language and metaphors that may promote comprehension ( Campbell, 2019 ; Olding et al., 2023 ). Additionally, distilling this information into a few key points, for example that opioids remain in a person’s system after naloxone administration, may also help reinforce more accurate baseline knowledge of how naloxone reverses overdoses. Study participants reported needing to administer an increasing number of naloxone doses to reverse an overdose, yet many also acknowledged that they did not always allow sufficient time for initial doses to take effect. Additionally, a limited number of participants expressed that they regularly engaged in supplementary practices, such as rescue breathing, in addition to administering naloxone. While many participants were empathetic about withdrawal effects, concerns about the person in front of them dying made waiting to administer further doses intolerable for many participants. The rapid administration of naloxone doses by medical personnel, including EMS and emergency department staff, has been cited as an example of “uncompassionate” overdose response, indicating a disregard for the discomfort of naloxone-induced precipitated withdrawal ( Ondocsin et al., 2020 ; Russell et al., 2024 ). However, among participants in our sample, many of whom have themselves been administered naloxone, this behavior was largely driven by fear that waiting too long to provide another dose could cause an avoidable death. This aligns with prior research highlighting the emotional toll that overdose response can take on the responder ( Enich et al., 2023 ; Kolla & Strike, 2019 ; McAuley et al., 2018 ). OEND programs can emphasize additional strategies responders can employ after administering an initial dose of naloxone. This might include active strategies, such as counting the number of breaths a person is taking, which may lengthen the amount of time lay responders can tolerate waiting before administering additional doses. To address hygienic concerns, harm reduction programs may consider more regular distribution of safety supplies, such as rescue breathing masks. A key factor undermining participants’ confidence in responding to overdose with naloxone were experiences of volatility within their local drug markets. Popular, but unvalidated, narratives that hyper-potent synthetic opioids, such as carfentanil, render naloxone ineffective may be shifting individuals’ expectations about what it takes to reverse an overdose ( Beletsky et al., 2020 ). Additionally, varying levels of awareness about the presence of xylazine in the local drug supply and how it alters the presentation of an overdose may be clouding the need for differential overdose reversal strategies. In the absence of greater technical knowledge of the composition of the drugs they are using, PWUD rely on their experiential knowledge to improvise adapted overdose response strategies. OEND programs that strive to provide PWUD with the resources and knowledge to respond to overdoses would be enhanced by expanded drug checking programming. These programs, in which PWUD submit samples of drugs or paraphernalia to be tested, can identify the presence of a broad range of substances, including fentanyl analogues and xylazine, in a timelier manner than existing surveillance sources, such as autopsy toxicologies ( Gozdzialski et al., 2023 ; Green et al., 2020 ; Sherman et al., 2019 ). Having up-to-date information regarding the presence of highly potent synthetic opioids and non-opioid adulterants, such as xylazine, would enable OEND programs to tailor educational materials and messaging to reflect anticipated changes in overdose presentation. Such messaging could be adapted from clinical guidance for emergency medical providers to identify specific strategies or considerations that are feasible in a community-based setting ( Sue & Hawk, 2024 ). For example, identifying strategies to promote oxygenation without access to oxygen machines or respirators. This could include reenforcing the importance of rescue breathing, providing community-based CPR trainings, and identifying alternative tools to promote oxygenation, such as single use oxygen cannisters. Implementation of strategies that benefit both fentanyl- and xylazine-involved overdoses may resolve some of the debate in dissemination of xylazine-specific overdose protocols within the community. This study is one of the first to examine how the emergence of xylazine into North America’s opioids supply generates may generate uncertainty in overdose response among PWUD. This research is not only timely, but is grounded in the experiences of individuals who use drugs in distinct geographies, including urban and rural environments .However, this study is also subject to several notable limitations. First, our sample was limited to three counties in Maryland with distinct local drug markets. Therefore, our findings may not be generalizable or representative of experiences in other regions, or even the entirety of the state of Maryland. Our sample is also likely not generalizable to all PWUD because participants were recruited in partnership with local harm reduction organizations, therefore our findings may be limited to service-engaged individuals and may not apply to PWUD with more limited-service access. Additionally, to be eligible for the study, participants needed to have administered naloxone in the past 3 months. Therefore, our findings do not represent the experiences and perspectives of those who have not administered naloxone, but may have responded to overdose in other ways, such as calling 911. PWUD are considered by many to be the true “first responders” in the opioid overdose crisis ( Mamdani et al., 2022 ). Our sample of 22 individuals who use drugs revealed that many PWUD feel an obligation to be prepared to respond to overdoses among their friends, family, and even strangers in their community. Regardless of how they learned to administer naloxone, participants were generally confident in both their ability to administer naloxone and naloxone’s effectiveness in reversing overdose. However, several knowledge gaps stemming from limited technical knowledge of overdose and how naloxone works to reverse them contributed to use of riskier overdose response practices. Additionally, volatility and unpredictability within local drug markets, especially the increasing prevalence of xylazine, were shown to undermine participants’ general level of confidence in overdose response. Increased dissemination of timely information about the drug supply, accompanied by tailored harm reduction strategies, would promote the capacity of OEND programs to ensure that PWUD are prepared to effectively respond to overdoses. Acknowledgements We would like to thank the participants in this research for sharing their time and knowledge with us. Additionally, we would like to thank the staff at our partnering organizations for their efforts to support this study. Funding This study was funded by a grant from the Bloomberg American Health Initiative. Dr. Sisson was supported by the National Institute of Mental Health ([T32MH122357]) and National Institute on Drug Abuse ([T32DA007292]). 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