Medetomidine

"One emerging substance of concern is medetomidine, a racemic mixture of levo- and dex-medetomidine [10]. First identified in the unregulated supply in Maryland in mid-2022 [11], medetomidine, like xylazine, is a potent veterinary tranquilliser; unlike xylazine, its active enantiomer (dexmedetomidine, commonly delivered as injectable Precedex, Pfizer, New York, USA) is an FDA-approved α2-adrenergic agonist used as a sedative, analgesic and anxiolytic in humans. Dexmedetomidine is widely used in hospital settings because it is not a controlled substance and is also used in veterinary medicine and biopharmaceutical research in animal models. Sublingual dexmedetomidine (Igalmi, BioXcel Therapeutics, New Haven, CT, USA) is additionally used in humans for management of agitation among adult patients with agitation due to schizophrenia or bipolar disorder.

"Dexmedetomidine was developed to be a safer human sedative due to its purported lack of respiratory depressive effect and increased selectivity for the alpha-adrenergic receptors. Interestingly, dexmedetomidine and xylazine were both developed in a cascade of medicinal chemistry attempts to improve on the sedative and addiction therapy potential of clonidine, an earlier α2-adrenergic agonist [12]. Xylazine and dexmedetomidine have both been touted as selective α2-adrenergic agonists, but this has recently been refuted for xylazine [13, 14]. In fact, xylazine has now been reported to have agonist activity at the kappa opioid receptor, 5-HT7 serotonin receptor, sigma 1 and 2 receptors, as well as the 3 α2-adrenergic receptor subtypes [13, 14]. Current literature does not report any indications that dexmedetomidine is not selective for the alpha-adrenergic system."

"Xylazine is a non-opiate sedative, analgesic, and muscle relaxant that shares its drug class (α2-adrenoreceptor agonists) with medications such as clonidine, lofexidine, tizanidine, and dexmedetomidine [6]. It was initially developed as an antihypertensive agent by Farbenfabriken Bayer AG in 1962; however, subsequent testing revealed severe adverse events related to hypotension and central nervous system (CNS) depression [6, 7]. Consequently, xylazine never gained approval for human use; however, it was approved by the US Food and Drug Administration (FDA) in 1972 exclusively for use in veterinary medicine [6, 7]. At present, xylazine remains unregulated under both the Controlled Substances Act (CSA) in the USA [8] and the Controlled Drugs and Substances Act (CDSA) in Canada [9].

"Fatal xylazine-positive overdoses, often co-occurring with synthetic compounds such as IMF and its analogs, surged dramatically in the past decade in North America. These overdoses have increased approximately 12-fold between 2018 and 2021 in the USA [6]. Importantly, naloxone—an opioid antagonist medication that is safe and effective for reversing opioid-induced respiratory depression during overdose—does not directly address the effects of xylazine as it is not an opioid, thereby introducing new challenges regarding overdose response best practices within clinical- and community-based settings [8, 10]. Altogether, this pressing issue has prompted The White House Office of National Drug Control Policy (ONDCP) to designate fentanyl associated or adulterated with xylazine (FAAX) as an emergent health threat to the USA in April 2023 and issue a comprehensive response plan in July 2023 [11, 12]. Similar cases are also on the rise in Canada and other countries such as the UK, marking the first xylazine-involved overdose outside of North America [9, 13]. Against the backdrop of this global health crisis, it is imperative to renew efforts in delivering evidence-based public health and harm reduction programs to facilitate secondary and tertiary prevention of adverse health outcomes following xylazine exposure."

"Medetomidine was identified in primary abundance in seven US states during the analysis period (New York, Pennsylvania, North Carolina, Michigan, Ohio, Florida, Virginia) (Appendix B). Medetomidine-containing samples were most often white and in powder form (Table 1). Commonly endorsed sensations included ‘sedating’ (32.4%), ‘stronger’ (25.0%), ‘unpleasant’ (16.9%), ‘weird’ (13.2%) and ‘more down’ (11.0%). Sample donors most often expected samples to contain fentanyl (86.9%), xylazine (42.3%) and/or heroin (23.1%).

"Most medetomidine-positive samples also contained fentanyl (58.8%) and/or xylazine (55.9%) (Table 2). Including trace substances, GCMS identified a median of eight substances in medetomidine-containing samples (range: 2–17) compared with a median of three substances in all other samples (range: 1–19) (Table 3).

"Hallucinations were reported in 17.6% of samples containing medetomidine overall (n = 24) and 25.0% of such samples with recorded sensation data, as compared with 1.2% and 2.3% in the overall dataset. Adjusting for covariates, samples containing medetomidine were significantly more likely to be associated with hallucinations compared with other samples, with an aPR of 11.95 (95% confidence interval [CI] 6.36, 22.44) (Table 4). Among covariates, selected nonpsychoactive fillers (aPR 0.41, 95% CI 0.24, 0.70) and fentanyl precursors and impurities (aPR 0.46, 95% CI 0.22, 0.96) were associated with lower prevalence of hallucinations. Hallucinations were significantly more common overall in the Northeast, South and Midwest compared with the West during the study period. Model results were robust to sensitivity analysis, though attenuated (aPR 9.11, 95% CI 4.81, 17.23) (Appendix C). In free response, participants described medetomidine-related hallucinations as ‘intense’, ‘trippie [sic] like DMT’, ‘psychedelic’ and ‘dissociative seeming’ (Appendix D)."

"The ongoing adulteration of pharmaceutical products in the illegal drug supply poses significant public health and safety risks in many communities. Recently, the incorporation of medetomidine—a potent, nonopioid sedative—transformed the fentanyl supply in Philadelphia, leading to severe medical complications from a novel withdrawal syndrome [1]. Drug checking programs and forensic laboratories first detected medetomidine in street opioid samples in 2022 [2]. By 2023–2024, medetomidine was identified in multiple U.S. states and Canada as a co-contaminant in fentanyl or heroin preparations [3]. One of Pennsylvania’s drug checking programs, PAGroundhogs (PAG), confirmed that 61% of the total dope samples tested since April 2024 (169 samples) showed positivity for medetomidine and had surpassed xylazine, which was the previous most prevalent adulterant (present in up to 99% of fentanyl samples in 2023) [4]. Many medetomidine-positive samples in Philadelphia also contained xylazine and fentanyl, indicating that medetomidine is entering the street supply as part of the evolving mixture often referred to as tranq (traditionally associated with xylazine–fentanyl combinations) and now referred to as demon (fentanyl–medetomidine ± xylazine combination) [5]. Similar findings were reported in alerts and media reports of overdose clusters outside of Philadelphia, spreading west in 2024, prompting public health warnings about an “emergent adulterant” driving a new wave of overdoses [3]."

"The syndrome described in this report is similar to that described among ICU patients with days-long exposure to dexmedetomidine, an enantiomer of medetomidine, who experience an autonomic withdrawal syndrome with vomiting and agitation when dexmedetomidine is discontinued (4,5). In the patients described in this report, these signs and symptoms were not resolved by increasing doses of medications previously effective in managing fentanyl and xylazine withdrawal; however, they were responsive to dexmedetomidine, as described in the management of dexmedetomidine withdrawal (4,5). Health care providers and public health agencies need to be aware of this life-threatening withdrawal syndrome because it can require substantial escalations in care compared with the typical opioid and xylazine withdrawal syndromes. Public health agencies should consider testing for medetomidine in their regional drug supplies."

"Medetomidine, a veterinary non-selective alpha-2-agonist like xylazine, has also been gaining recognition as an adulterant across the recreational opioid drug supply in the US. It is yet to be identified in the UK illicit supply (as of July 2024), yet it has been reported to be rapidly proliferating across the USA and Canada in samples also containing heroin, fentanyl, xylazine, and cocaine [11,12]. Medetomidine’s increasing prevalence is concerning due to it being a more potent, selective, and specific a-2-agonist, exhibiting increased sedation compared with xylazine [13]. Alongside medetomidine, two other veterinary medications—acepromazine (a phenothiazine) and phenylbutazone (a non-steroidal anti-inflammatory drug (NSAID))—were identified as potential toxic adulterants and predicted to be the “next xylazine” [14]. Although acepromazine reports remain relatively low, phenylbutazone has been identified in 116 seized drug samples between 2016 and 2021, alongside heroin, fentanyl, xylazine, tramadol, and cocaine [15]. Pentobarbital, a veterinary euthanasia agent, has also been detected in seized samples across the US [15,16], although it is classified as a Class B Schedule 3 drug. These five drugs’ pharmacological profiles have made them valuable tools in veterinary medicine, yet it is these same properties that influence the dangerous outcomes in humans. The lack of control or scheduling of these drugs may contribute to their increased availability and prevalence, leading to their rise as adulterants in the illicit opioid supply."

"Reports on the detection of medetomidine in biospecimens and drug supplies have emerged much more recently. In July 2022, the first identification of medetomidine in illicit drug packaging was reported in Maryland [16]. Medetomidine occurs in two enantiomeric forms: dexmedetomidine and levomedetomidine. Dexmedetomidine is approved for human medical use in procedural or general sedation, but racemic medetomidine (which includes the less active levomedetomidine enantiomer) is only approved for veterinary use [17].

"In May 2024, 38 confirmed or probable cases of medetomidine-involved overdose were reported in Chicago, with patients experiencing hypertension, bradycardia, and most showing no improvement in symptoms with naloxone administration [18]. Medetomidine most frequently co-occurs with IMF (and sometimes xylazine) but has also been detected in the absence of these drugs [3,4,16,19]. The geographical prevalence of medetomidine in the illicit drug supply appears to coincide with areas where xylazine is more prevalent. The prevalence of both medetomidine and xylazine is likely underestimated overall due to limited awareness and availability of testing for these drugs [7]."

"Both xylazine and medetomidine bind to alpha-2 adrenergic receptors and inhibit the release of norepinephrine, leading to profound sedation and analgesia. Addition of these adulterants to IMF may be intended to prolong or enhance the euphoric effects of IMF, but they can also cause central nervous system depression, hypotension, and bradycardia [20]. Both drugs pose a risk for individuals exposed to IMF since naloxone, an opioid antidote, does not reverse their effects. There are known antidotes for these drugs in veterinary medicine, but no approved antidotes in humans [21]. Acute overdose treatment primarily focuses on addressing sedative and cardiovascular effects, including supportive airway management [21,22]. Repeated exposure to xylazine has also been linked to severe skin ulcerations that have the potential to progress to bone involvement and amputation, and these have become recognized as a distinct clinical entity [23]. Concurrent use of xylazine and/or medetomidine with IMF potentially complicates longer term treatment but much remains unknown regarding the effects of these drugs and their potential interactions with fentanyl, or other opioids [24–26]."

"Based on the observed half-life of xylazine in plasma (12 hours), a reasonable estimate for window of detection is several days after last use, but this can also be affected by assay limit of detection, dosing and mode of administration, hepatic and/or renal function, and potentially pharmacogenetic differences, and/or drug–drug interactions [34]. Particularly for xylazine, unavailability of commercial standards for major metabolites presents a challenge to their routine inclusion in clinical and/or forensic assays, and it is currently unknown whether their detection might improve the sensitivity or window of detection for exposure. The short half-life of dexmedetomidine suggests an even shorter window of detection for medetomidine, and this is consistent with the detection of medetomidine metabolites in the absence of medetomidine in urine.

"Both xylazine and medetomidine are lipophilic with large volumes of distribution which could potentially result in prolonged elimination kinetics in a setting of chronic dosing. For example, in patients chronically exposed to fentanyl, the major norfentanyl metabolite may be detectable in urine for 3–4 weeks post-cessation, reflecting an elimination phase which is significantly longer than the 2–4 days that norfentanyl is generally detectable in urine after short term medical administration during clinical anesthesia [42,43]."

"Medetomidine, a nonopioid sedative not approved for use in humans, has periodically been detected in illegally manufactured opioids across North America since 2022. On May 11, 2024, the Chicago Department of Public Health (CDPH) and the Illinois Department of Public Health were alerted by hospitals and the Illinois Poison Center to an increase in emergency medical services responses for suspected opioid-involved overdoses with atypical symptoms, mostly clustered on Chicago’s West Side. CDPH and CDC investigated and identified 12 confirmed, 26 probable, and 140 suspected overdoses involving medetomidine mixed with opioids among patients treated at three hospitals in Chicago’s West Side during May 11–17, 2024. Medetomidine had not been previously identified in Chicago’s illegal drug supply. Fentanyl was identified in all drug samples and blood specimens containing medetomidine. Most patients were male, non-Hispanic Black or African American, and aged 45–64 years; most patients with confirmed cases experienced bradycardia and had no or only a partial response to naloxone. This cluster is the largest reported for confirmed medetomidine-involved overdoses. Multisector surveillance, including by health care providers, toxicology laboratories, and public health personnel, was essential for quickly identifying and responding to new adulterants in the illegal drug supply. Because all specimens and samples in this investigation that contained medetomidine also contained natural or synthetic opioids, administering naloxone for all suspected opioid-involved overdoses remains crucial."