Xylazine Abuse, The Growing Risk: A Review of Its Effects, Upsurge Use and Associated Fatalities in the USA and Puerto Rico

Abstract

In the last decade, the opioid overdose epidemic has been exacerbated by the emerging drug of abuse, xylazine. This veterinary anesthetic, an alpha-2 agonist, not only potentiates the fatal effects of opioids but also causes toxic endothelial effects. This review aims to assess the impact of xylazine use and overdoses within the context of the opioid crisis as a public health issue. The research used data from scientific publications, state health reports, and analyses from the Institute of Forensic Sciences of Puerto Rico. The databases PubMed, Google Scholar, and Scopus were searched for relevant publications. The search strategy employed two groups of terms: the drug of interest (xylazine) and types of exposure (drug use, overdose, substance abuse, etc.). The initial search in PubMed was then extrapolated, and the search terms were adjusted for appropriate database syntax. According to the most recent publications and CDC data in the USA, approximately 95% of fentanyl overdose cases involve xylazine, while the other 5% of overdose cases are attributed solely to xylazine, predominantly administered intravenously. In the last four years, more than 4,000 overdose deaths have been related to xylazine use; the northeastern United States had reported the most significant number of deaths. This number changes daily as reanalysis results and new data are published. Less than 50% of states perform tests for xylazine detection or maintain statistical monitoring of overdoses related to this drug. The absence of testing impedes emergency room physicians from making accurate diagnoses, increasing the likelihood of fatal overdoses. This review highlights five major concerns: (1) The recognition of intoxication as a primary concern and the unavailability of alpha-2 antagonists for treatment. (2) The challenges in the clinical setting linked to xylazine abuse and its co-administration with substances like fentanyl and its analogs. (3) The necessity for robust government statistical resources for the unification and dissemination of critical overdose and emerging drug abuse detection information. (4) The need for effective rehabilitation programs, including psychosocial support and treatment interventions, to respond to this public health crisis. (5) The urgency for further research to understand the prevalence, toxic effects of chronic or acute use, and the clinical implications in xylazine users, including the development of alpha-2 antagonists for treatment. We conclude that addressing these concerns is crucial to working with the xylazine abuse situation.

INTRODUCTION:

Xylazine is a potent alpha-2 adrenergic agonist approved for animal use as a veterinary sedative and analgesic drug. Its illegal use has spread among intravenous drug abusers around the world. The growing use of this substance outside of its intended setting has created the need for better understanding and the development of detection and management strategies to help mitigate its damaging societal effects. Since 2000, the Puerto Rico Institute of Forensic Sciences (ICF) has identified xylazine as a drug of abuse, where it is often used in combination with heroin or cocaine to enhance its effects. The mistreatment of xylazine has led to severe physiological and psychological consequences, notably causing significant endothelial vascular damage among its users. The endothelial damage caused by xylazine abuse leads to severe complications. The sequelae of endothelial damage include the development of limb ulcers and, in some cases, necessitate amputation. Previous investigation work by our group identified a specific apoptotic pathway linked to endothelial cell death induced by xylazine¹. This identified pathway involves the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are known to cause cellular stress and DNA ^2,3. In excessive amounts, the levels of ROS and RNS lead to oxidative stress, a condition where the balance between antioxidants and oxidants in the body is disrupted. The oxidative stress triggered by ROS and RNS results in significant DNA damage within endothelial cells. This damage occurs through various mechanisms, such as DNA strand breaks and the formation of DNA adducts. Our research indicates that this DNA damage activates the intrinsic apoptotic pathway in endothelial human cells. The intrinsic pathway, often initiated by internal cell stress, leads to the activation of pro-apoptotic proteins like Bax and Bak, which in turn trigger the release of cytochrome c from mitochondria and activate caspases, leading to programmed cell death. This apoptotic death of endothelial cells exacerbates vascular dysfunction. The loss of endothelial cells impairs vascular integrity and contributes to the development of ulcers. The skin ulcers often require medical interventions, such as amputation in severe cases. This work underscores the broader impacts of xylazine on vascular health beyond endothelial dysfunction and ulceration. The endothelial dysfunction induced by xylazine not only predisposes individuals to peripheral vascular diseases but also to systemic vascular complications. These may include increased risks of thrombosis, hypertension, and, potentially, cardiovascular events.

MECHANISM OF ACTION

As an alpha-2 adrenergic receptor agonist, xylazine produces sedation, analgesia, and muscle relaxation. Its cardiovascular effects include bradycardia, hypotension, decreased cardiac output, and respiratory depression. When combined with other depressants, such as fentanyl and heroin, these effects are potentiated, leading to enhance respiratory depression, bradycardia, hypotension, and depression of the central nervous system ^4–6. The alpha-2 (α2) receptors, which have similar affinities for all subtypes, are a family of G-protein–coupled receptors involving pharmacological subtypes (α2A, α2B, and α2C). The subtypes α2A and α2C are primarily located in the central nervous system (CNS), interact with norepinephrine and epinephrine, mediating sedation, analgesia, and reduced sympathetic nervous activity ⁷. The α2B receptors, predominantly found in vascular smooth muscle, has and mediates vasopressor effects. The activation if these receptors initiate a negative feedback loop, resulting in reduce sympathetic stress reaction, decreased heart rate, and lower blood pressure.

Xylazine toxicity symptoms in an acute setting is often inappropriately managed due to delayed diagnosis and improper treatment protocols for polysubstance ingestion, frequently resulting in fatalities. This issue arises from the lack of immediate medical recognition, as xylazine is not detected through standard toxicological analyses. Consequently, xylazine must be considered a potential opioid adulterant in overdoses, especially when other clinical characteristics of its abuse, such as skin ulcerations, are present. Illicit xylazine abuse has been implicated in several pathological sequelae, including cardiovascular and renal impairment. The endothelial dysfunction it causes, leading to the development of ulcers and, in some cases, subsequent amputations, has been a significant contributor to morbidity ^8–11.

METHODOLOGY

Literature search strategy

This review was conducted using data available in scientific publications, state health, and Institute of Forensic Sciences of Puerto Rico reports. We searched three databases (PubMed, Google Scholar, and Scopus) for relevant publications over the past 15 years. Our search strategy comprised two groups of search terms: the drug of interest (xylazine) and types of exposure (drug use, fatal overdose, substance abuse, etc.). The initial search was executed in PubMed, followed by an extrapolation of the search terms, adjusted for the appropriate database syntax within each platform. The primary criterion for selection was the growing use of xylazine, either alone or in combination with other drugs, in the United States over the last decade. We repeatedly tested terms during each search process to optimize the database results.

INCLUSION AND EXCLUSION CRITERIA

For this literature review, we considered only original articles published in English, focusing on those with comprehensive methodology sections. Excluded were non-English articles, reviews, letters, and notes. The inclusion criteria were strictly associated with the study’s objective to provide a thorough review.

RESULTS

In the United States, the first detection of xylazine by the ICF occurred in 2000, in the commonwealth of Puerto Rico, where it is colloquially known as “anesthesia de Caballo” [horse anesthesia] ^5,10,12. By 2007, its presence was documented in Philadelphia, Pennsylvania, where it is often called “tranq” ^9,13. Literature on xylazine detection has primarily focused on postmortem blood samples of overdose victims and drug administration syringes ¹⁰. In Puerto Rico, the problem of xylazine abuse, often in conjunction with heroin or cocaine, and more recently with fentanyl or its analogs, is becoming increasingly. The number of associated fatalities rose from 12 in 2014 to 81 in 2017. In a more recent update from 2022, the Puerto Rico Institute of Forensic Sciences (ICF) reported detecting xylazine in 281 out of 654 drug-use-related deaths, sampled from a total of 2,571 cases. Notably, xylazine was the sole substance detected in 16.51% of these 654 drug-use-related deaths cases. Additionally, 10.70% involved a combination of xylazine with fentanyl and cocaine (or its metabolite benzoylecgonine), and 15.74% involved a combination of xylazine with fentanyl, as depicted in Figure 1.

Figure 1:

Xylazine Detection in Drug-Use-Related Deaths in Puerto Rico (2022)

Illustrates the breakdown of Xylazine detection in 654 drug-use-related deaths as reported by the Institute of Forensic Sciences of Puerto Rico in 2022 from a sample of 2,571 cases. In these cases, Xylazine was detected in 42.96% of the total drug-related death cases. The substance, Xylazine, was the sole substance detected in 16.51%, in combination with other drugs: 15.74% combined with fentanyl, 10.70% with cocaine (or its metabolite benzoylecgonine), and fentanyl. The figure highlights the polydrug use involving Xylazine and underscores the significant role of fentanyl in these fatalities.

In the last five years, reports from California, Colorado, Connecticut, Delaware, Illinois, Massachusetts, New York, North Carolina, and Pennsylvania ^12–17, as well as in British Columbia. Canada and Toronto have indicated the presence of xylazine in overdose cases ^{18, 19}. Between 5 to 11% of overdose-related deaths are reported as involve xylazine, primarily in combination with fentanyl, including its analogs ^20,21. The Fentanyl-associated deaths involving xylazine increased during the study period; with approximately 95% of xylazine-involved overdose deaths also testing positive for fentanyl or its analogs.

In 2019, Connecticut, one of the most affected states, reported 1,200 drug overdose deaths, of which 5.8% were xylazine-positive. The first half of 2020 showed an increasing trend, with 76 drug overdose deaths involving xylazine, which represents 11.4% of overdose deaths (Unintentional Drug Overdose Deaths in Connecticut Rate of Unintentional Drug Overdose Mortality by Sex, Connecticut, 2021 Data Source: Office of the Chief Medical Examiner (OCME) and C.T. State Unintentional Drug Overdose Reporting System (SUDORS).) Of these xylazine-positive cases in 2019 and 2020, 99.3% were also positive for fentanyl. Other affected states have recognized rising trends in xylazine related mortality; however, the prevalence of xylazine in fatal overdoses within the United States has not been widely measured.

Moreover, those states that report the presence of xylazine do not cover all counties within the state. Less than half of the states conduct screenings for xylazine in both fatal and non-fatal overdose cases. The Centers for Disease Control (CDC) and Prevention are making a significant effort to analyze data on unintentional and undetermined intent fatalities from the State Unintentional Drug Overdose Reporting System (SUDORS) across 38 states and Washington, D.C., scrutinizing xylazine-positive fatal overdoses since 2019. Data analysis is ongoing and subject to monthly updates. However, it still requires data from states that are not currently conducting xylazine detection tests. A recent study from ten jurisdictions representing all four U.S. Census regions reported that xylazine is present in overdose deaths with higher frequency. The most significant xylazine prevalence was observed in the eastern region, with Philadelphia reporting an increment in overdose deaths involving xylazine to 25.8%, Maryland at 19.3%, and Connecticut at 10.2%. The 98.4% of these xylazine positive cases, illicitly manufactured fentanyl was also detected ^9,13,16.

The information provided by the Department of Justice (DOJ) and Drug Enforcement Administration (DEA) reports from 2020 and 2021 offers insight into the advancements in testing development and the tools required for urgent scientific intervention²¹. The report categorizes the 50 states into four regions (not all states in the region report data) as defined by the U.S. Census Bureau:

Region 1: Northeast, which includes Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, Vermont, New Jersey, New York, and Pennsylvania.

Region 2: Midwest, comprising Illinois, Indiana, Michigan, Ohio, Wisconsin, Iowa, Kansas, Minnesota, Missouri, Nebraska, North Dakota, and South Dakota.

Region 3: South, encompassing Delaware, Florida, Georgia, Maryland, North Carolina, South Carolina, Virginia, Washington, D.C., West Virginia, Alabama, Kentucky, Mississippi, Tennessee, Arkansas, Louisiana, Oklahoma, and Texas.

Region 4: West covers Arizona, Colorado, Idaho, Montana, Nevada, New Mexico, Utah, Wyoming, Alaska, California, Hawaii, Oregon, and Washington.

This regional division facilitates a comprehensive understanding of the geographic distribution and impact of xylazine use, guiding targeted public health interventions. The findings described in the report are compiled in the subsequent figures.

The U.S. Centers for Disease Control and Prevention (CDC) reports that xylazine-associated deaths primarily occurred in males, making up more than 70% of these cases. The report established that most of these individuals were non-Hispanic whites, accounting for approximately more than 65% of the reported deaths. They identified that the highest risk age group is 25 to 44 years, comprising approximately more significant than 55% of cases, a demographic representing the most productive years of life. Individuals aged 55 and older are the next most vulnerable group, accounting for more than 20%, though data on elderly populations are limited. Notably, more than 20% of these deaths occurred in hospitals, where naloxone was administered in more than 18% of cases. This trend indicates that non-Hispanic white males, particularly in their most socially productive years, are at the most significant risk of fatal overdoses involving fentanyl and xylazine¹⁶.

DISCUSSION

The current analysis is based on available data, but it’s essential to acknowledge an information gap. Additional data is needed to establish a comprehensive understanding of the true prevalence for accurately assessing the full impact of xylazine abuse and its concomitant use with opioids ³⁶. Alarmingly, xylazine-related fatalities often occur in environments equipped to offer lifesaving medical interventions. The concomitant use of xylazine and fentanyl significantly increases the risk of cardiovascular and respiratory depression, a situation made worse by the unavailability of alpha-2 antagonists, often necessitating ventilatory support in overdose management. Healthcare professionals should be aware that cases of suspected fentanyl intoxication unresponsive to naloxone may involve xylazine as part of a polydrug use pattern. Administering naloxone remains advisable, given the frequent co-administration of these substances^22–26.

In veterinary medicine, alpha-2 antagonists like atipamezole have been approved to reverse xylazine induced sedation. Used to reverse dexmedetomidine sedation in dogs, providing rapid reversal of both sedative and sympatholytic effects. However, its use in humans is not FDA-approved despite promising results ^27–29. Another alternative to reverse xylazine effects is Idazoxan, an experimental alpha-2 adrenergic receptor antagonist that has shown potential in studies but is also not FDA-approved for human use. Research in animals and preliminary human case reports suggest it could be beneficial for treating xylazine overdose, though it is currently only authorized for investigational research. Further research is needed for considering Idazoxan as a potential FDA-approved one-time treatment for a xylazine user’s overdose ^28,30–32. The attention to this issue is critical, especially considering the lack of specific antagonist drugs to counteract overdoses effectively. As stated by the CDC, xylazine-related cases are considered xylazine-positive; however, a xylazine-positive case does not necessarily denote xylazine as the cause of death (xylazine-involved). These findings should be regarded as potential underestimation due to xylazine detection challenges. Reviews revealed instances where xylazine was present at overdose scenes but not captured in postmortem analysis. The lack of appropriate standard testing protocols, as routine toxicology panels may omit xylazine, can result in missed diagnoses. Due to xylazine not being included in the general screening in most of the forensic and clinical toxicology laboratories, the available information is far from the reality. Enhancing analytical methods in forensic toxicology laboratories will improve monitoring and understanding of polydrug use. In this context, we propose gas or liquid chromatography coupled with mass spectrometry to perform blood-related drug analyses. The actual prevalence of xylazine abuse is not adequately reflected in the existing data ^31–36. Enhanced laboratory resources would facilitate more accurate detection and reporting, contributing to a more precise understanding of this problem.

A recent review confirms the patterns of polydrug use observed in Puerto Rico, highlighting the concurrent xylazine abuse with fentanyl, heroin, cocaine, benzodiazepines, barbiturates, antihistamines, cannabinoids, antidepressants, ethanol, and stimulants, sampled from over 3,000 cases, each in varying proportions. Additionally, the review reports that the average concentration of xylazine detected in these cases was 17 ng/mL²⁴. The toxic effects of xylazine vary significantly depending on its combination with other drugs. The use of xylazine only has a distinct toxicity profile, but when combined with substances, the resultant effects can be more severe, such as opioids (e.g., fentanyl, Heroin), stimulants (e.g., cocaine), or depressants (e.g., benzodiazepines, barbiturates). Therefore, understanding the specific toxicology of xylazine in polydrug scenarios is crucial for effective medical intervention and prevention strategies. Further adverse interaction research is needed to understand when xylazine is concomitant and used with fentanyl, heroin, cocaine, or other drugs to establish effective treatment protocols. Clinical laboratories also play a crucial role in an effective surveillance network, contributing to informed medical responses and potentially reducing xylazine-related fatalities. Approximately 95% of xylazine-related overdose deaths have also tested positive for fentanyl or its analogs in most reported data. This percentage fluctuates as reanalysis results and new data are continuously published.

CONCLUSION

This review highlights a gap in the diagnosis and detection of xylazine in cases of concomitant drug use. We address five major concerns regarding the management of xylazine abuse, including the lack of consistent data from clinical settings, medical examiners’ offices, and other agencies. The scientific community lacks accurate case numbers related to xylazine abuse. The health professionals are not adequately equipped with the necessary tools to address this issue effectively. Especially when xylazine is mixed with opioids and other substances. Additionally, there is an ineffective government response and a lack of comprehensive research.

Limited detection and diagnostic capabilities:

The accessibility of tools for detecting emerging drugs in the blood, such as xylazine, fentanyl, its analogs, and others, is limited. The recognition of intoxication as a primary concern, along with the unavailability of alpha-2 antagonists for treatment, presents significant challenges, complicated by xylazine abuse and its combination with fentanyl, which hinder prompt treatment. The off-label use of alpha-2 antagonists for overdose treatment in humans shows potential, but it requires FDA approval and is currently limited to clinical research, despite no significant adverse effects being reported.

Absence of effective countermeasures:

It is necessary to change the analytical approach used in clinical laboratories to expand their blood tests to determine the presence of these emerging drugs accurately. The increasing detection of xylazine in overdose deaths underscores the urgent need for ongoing surveillance to improve strategies and prevent further overdoses. We believe the issue of xylazine abuse began over a decade ago but has largely gone unnoticed due to the lack of tests designed to detect emerging drugs. Currently, nearly 40% of states report data that fails to fully represent the magnitude of this problem.

Lack of comprehensive research:

It’s crucial to recognize that postmortem autopsy findings are key in identifying damage caused by xylazine. This includes endothelial injury, vascular thrombosis, and other conditions reported in various studies. The scant research available indicates that vital organs may also incur damage stemming. This approach will facilitate a deeper understanding of the extensive physiological and pathological impacts of widespread xylazine abuse. It should also include the development of alpha-2 agonists for rehabilitation treatment. This concerning trend among young men suggests a potential future public health crisis. This demographic shift poses a threat to societal well-being, as a reduced young workforce could severely impact labor availability and productivity.

Ineffective government response:

The necessity for strong government statistical resources to consolidate and share vital data on overdose incidents and emerging drug abuse trends cannot be overstated. Presently, numerous initiatives and data sources exist, but not all provide current, cohesive, or comprehensive coverage of all U.S. states and territories, including Puerto Rico. Moreover, it is imperative to update the International Classification of Diseases (ICD-10) to include specific codes for intoxications with xylazine, for more effective monitoring and addressing this burgeoning public health concern.

Data deficiency and inaccuracy:

A considerable disparity persists in data interlinking across various agencies and states. Although the SUDORS32 (State Unintentional Drug Overdose Reporting System) is a commendable platform for consolidating information, enhancements are necessary to ensure more comprehensive data collection and timely updates. This will facilitate coordinated assistance, precisely directed, and proportioned to the identified population size, ensuring that resources and interventions are optimally assigned and impactful. For example, the Census page fails to include data on overdose fatalities from Puerto Rico despite the availability of this information in the demographic registry.

Addressing these challenges is essential for effectively managing xylazine abuse and reducing its negative effects on public health.

Figure 2.

illustrates the correlation between the percentage increase in overdose deaths and the detection of xylazine in seized drugs, categorized by region. Ratios range from 1.68 to 6.69 across most regions, although the Midwest shows a notable disparity, likely due to insufficient testing in that area. Data from each year related to the number of overdose cases is presented in Figure 3.

Figure 3.

This illustrates the DEA-reported number of xylazine-positive overdose deaths in combination with the seized drug cases by region. This figure shows that the South and Northeast regions report the highest incidence of xylazine presence. The data indicate significant regional variations in the impact of xylazine abuse, with these two regions being the most affected. Caution is warranted in interpreting data from the West and Midwest, as potential misreporting may arise from inadequate testing.

HIGHLIGHTS:

• Xylazine abuse, an startling additive to the opioid crisis, often co-occurs with fentanyl.

• Approximately 95% of fentanyl overdose cases involve the presence of xylazine, primarily administered intravenously.

• Over 1,800 xylazine-associated overdose deaths registered in the last four years.

• Limited xylazine detection delays diagnoses, increasing fatal risks.

• Urgent actions are needed to alpha-2 antagonist development and government controls.