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Medetomidine, a veterinary α2-adrenergic agonist, has recently emerged as an adulterant in the non-medical opioid supply, yet human exposure has remained poorly characterized. We conducted a pragmatic retrospective cohort analysis utilizing chart review and liquid chromatography–tandem mass spectrometry (LC-MS/MS) toxicology testing on available urine samples from patients presenting to two hospitals in Philadelphia, PA, who fit two clinical phenotypes, intoxication or withdrawal. Samples also underwent glucuronidase pre-treatment to assess impact on the yield of medetomidine and xylazine metabolite detection. Testing identified universal exposure to medetomidine (58/58 samples) via the 3-hydroxy-medetomidine (3-OH-M) metabolite, post glucuronidase treatment and variable xylazine exposure (40/58 samples). Importantly, 32% of medetomidine exposures would have been missed without enzymatic pre-treatment. Patients exhibited two distinct clinical phenotypes: intoxication, characterized primarily by sedation; bradycardia; and often hypotension, and withdrawal, presenting with life-threatening tachycardia; hypertension and often encephalopathy. Notably, clinical phenotype correlated with urinary concentrations of 3-OH-M but not xylazine. These findings underscore the critical need for heightened clinical awareness and need for contemporaneous toxicologic screening mechanisms for medetomidine exposure, emphasizing its distinct clinical presentations and the potential public health implications posed by its widespread adulteration in illicit opioids.

General anesthesia is characterized by reversible loss of consciousness accompanied by transient amnesia. Yet, long-term memory impairment is an undesirable side effect. How different types of general anesthetics (GAs) affect the hippocampus, a brain region central to memory formation and consolidation, is poorly understood. Using extracellular recordings, chronic 2-photon imaging, and behavioral analysis, we monitor the effects of isoflurane (Iso), medetomidine/midazolam/fentanyl (MMF), and ketamine/xylazine (Keta/Xyl) on network activity and structural spine dynamics in the hippocampal CA1 area of adult mice. GAs robustly reduced spiking activity, decorrelated cellular ensembles, albeit with distinct activity signatures, and altered spine dynamics. CA1 network activity under all 3 anesthetics was different to natural sleep. Iso anesthesia most closely resembled unperturbed activity during wakefulness and sleep, and network alterations recovered more readily than with Keta/Xyl and MMF. Correspondingly, memory consolidation was impaired after exposure to Keta/Xyl and MMF, but not Iso. Thus, different anesthetics distinctly alter hippocampal network dynamics, synaptic connectivity, and memory consolidation, with implications for GA strategy appraisal in animal research and clinical settings.

Medetomidine is a non-opioid sedative with an increasing presence as an adulterant in the North American illicit drug supply. This study’s purpose was to characterize the prevalence of medetomidine-positive cases in both ante- and post-mortem samples across Michigan. Post-mortem blood samples were submitted to the Swift Toxicology of Overdose-Related Mortalities (STORM) project between March 1, 2024, and May 16, 2025. Ante-mortem oral fluid samples were submitted to Forensic Fluids Laboratories Inc. between August 6, 2024, and May 27, 2025. All ante- and post-mortem samples were screened for common drugs of abuse. Medetomidine was qualitatively identified in both matrices using liquid chromatography-tandem mass spectrometry. 4290 post-mortem blood samples were tested with medetomidine detection in 17 (0.4 %) specimens. Fentanyl was co-detected with medetomidine in 16/17 (94.1 %) cases while xylazine was co-detected in 8/17 (47.1 %) cases. Positive co-detection of both xylazine and fentanyl occurred in 8/17 cases (47.1 %) cases. 20,736 ante-mortem oral fluid samples were tested with medetomidine detection occurring in 129 (0.6 %) specimens. Fentanyl was detected in 126/129 (97.7 %) cases while 59/129 (45.7 %) samples involved co-detection of both fentanyl and xylazine. Our findings support recent evidence of frequent co-detection of medetomidine in mixtures containing fentanyl and xylazine. Post-mortem blood and ante-mortem oral fluid data may reflect different inflection points related to market saturation of emerging drugs and adulterants. The prevalence of medetomidine in street-level opioids highlights the significance of increasing awareness and education directed to people who use drugs and health information exchange across health sector entities to mitigate morbidity and mortality. •Medetomidine detected in 0.4 % of post-mortem and 0.6 % of ante-mortem samples.•Fentanyl co-detected in 94.1 % of medetomidine-positive post-mortem blood samples.•Medetomidine-fentanyl-xylazine co-detected in 8/4290 post-mortem blood samples.•Fentanyl detected in 126/129 medetomidine-positive ante-mortem oral fluid samples.•Medetomidine-fentanyl-xylazine co-detected in 59/20,736 ante-mortem oral samples.

BACKGROUND: This study investigated effects on cardiovascular parameters during anaesthesia with isoflurane (ISO, 2–3 Vol%), ketamine-xylazine (KX, 100 mg•kg⁻¹ + 5 mg•kg⁻¹) or a combination of medetomidine-midazolam-fentanyl (MMF, 0.15 mg•kg⁻¹ + 2.0 mg•kg⁻¹ + 0.005 mg•kg⁻¹) in rats throughout induction, maintenance and recovery from anaesthesia. Rats were instrumented with a telemetric system for the measurement of systolic, diastolic and mean arterial pressure (SAP, DAP, MAP), pulse pressure (PP), heart rate (HR) and core body temperature (BT). The parameters were continuously measured before, during and after each type of anaesthesia. Forty minutes after induction, ISO delivery was terminated and MMF was antagonized with atipamezole-flumazenil-naloxone (AFN, 0.75 mg•kg⁻¹ + 0.2 mg•kg⁻¹ + 0.12 mg•kg⁻¹) whereas KX was not antagonized. RESULTS: Differences were observed between anaesthesias with KX (301 min) lasting much longer than MMF (45 min) and ISO (43 min). HR in ISO ([Formula: see text] = 404 ± 25 bpm) increased during the time of surgical tolerance whereas a HR decrease was observed in KX ([Formula: see text] = 255 ± 26 bpm) and MMF ([Formula: see text] = 209 ± 24 bpm). In ISO (MAP during time of surgical tolerance: [Formula: see text] = 89 ± 12.3 mmHg) and KX (MAP during wake-up period: [Formula: see text] = 84 ± 8.5 mmHg) mild hypotensive values were observed, whereas blood pressure (BP) in MMF (MAP during time of surgical tolerance: [Formula: see text] = 138 ± 9.9 mmHg) increased. Despite keeping animals on a warming pad, a loss of BT of about 1°C was seen in all groups. Additionally, we observed a peaked increase of HR ([Formula: see text] = 445 ± 20 bpm) during the wake-up period with ISO and an increase of PP ([Formula: see text] = 59 ± 8.5 mmHg) in MMF during the time of surgical tolerance. CONCLUSION: The anaesthesias influenced very differently the cardiovascular parameters measured in Wistar rats. ISO caused mild hypotension and increased HR whereas MMF produced a marked hypertension and a significant decrease of HR. The slightest alterations of BP, HR and BT were observed using KX, but the long wake-up and recovery period suggest the need for prolonged monitoring.

Anesthesia is essential, but not selective, in resting-state functional magnetic resonance imaging (fMRI) for pre-clinical studies. To mitigate stress and minimize head-movement artifacts, animals should be anesthetized during resting-state fMRI. Although the type, dosage, and timing of anesthesia can influence fMRI outcomes, responses to stimulation, and functional connectivity, the appropriate dosage of anesthesia is among the most important considerations. However, little is known about the effects of anesthetic dosage on innate fear responses induced by electrical stimulation. Therefore, we aimed to investigate the effects of medetomidine dosage on electrical stimulation and functional connectivity in fear-related regions. We conducted a graph-based network analysis of functional connectivity before and after electrical stimulation, based on different medetomidine dosages. We observed increased functional connectivity post-stimulation in the high-dose condition, but not in the low-dose condition. The high-dose condition showed increased global network properties post-stimulation compared to those observed pre-stimulation. In contrast, the low-dose condition showed no significant difference in global network properties between pre- and post-stimulation. The results suggest that high-dose medetomidine suppresses functional connectivity in fear-related regions in the brain; however, this suppressed functional connectivity can be recovered by electrical stimulation.

Background Standing sedation is frequently required in donkeys for minor surgical and diagnostic procedures, yet information on the cardiac safety of α2-adrenoceptor agonists and opioid combinations in this species is limited. This study evaluated the echocardiographic effects of intravenous medetomidine, butorphanol, and their combination in clinically healthy donkeys. Materials and methods Sixty donkeys were randomly assigned to four groups ( n  = 15/group) to receive intravenous saline (control group, CG), medetomidine group (10 µg/kg, MG), butorphanol group (50 µg/kg, BG), or medetomidine–butorphanol group (10 µg/kg + 50 µg/kg, MBG). Butorphanol was administered 5 min after medetomidine in the MBG. M-mode echocardiography was performed from a right parasternal short-axis view at baseline and at 5, 15, 30, 45, 60, 90, and 120 min after treatment. Left ventricular internal diameter (LVID), interventricular septal thickness (IVST), and left ventricular posterior wall thickness (LVPW) were measured at end-diastole (d) and end-systole (s). Left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), stroke volume (SV), ejection fraction (EF%), and fractional shortening (FS%) were calculated. Data were analyzed using a repeated-measures general linear model. Results Medetomidine alone was associated with significant reductions in EF% and FS%, together with significant changes in LVIDs and LVIDd. SV was also significantly lower in the medetomidine group than in the control group during the main post-treatment period; however, SV and the calculated LV volumes were interpreted cautiously because they are load-dependent variables derived from linear M-mode measurements. These changes were accompanied by an increase in LVIDs and a reduction in IVSs, indicating transient depression of conventional left ventricular systolic indices and altered loading conditions. Butorphanol alone produced only minor, parameter-specific changes in LVID, IVST, and most echocardiographic indices, with no consistent clinically relevant deterioration compared with baseline or the CG. In contrast, the MBG showed marked changes in ventricular dimensions and calculated indices from 15 to 60 min; however, these findings were interpreted cautiously because the calculated systolic indices are load-dependent. Conclusions Intravenous medetomidine, butorphanol, and their combination exert distinct and protocol-dependent effects on left ventricular dimensions and systolic function in donkeys. Medetomidine alone substantially and transiently depresses systolic performance, whereas butorphanol alone is comparatively cardiovascular-sparing. The medetomidine–butorphanol combination may be considered for standing sedation in clinically healthy donkeys; however, its echocardiographic effects should be interpreted cautiously as load-dependent changes, and cardiovascular monitoring remains advisable.

Background Medetomidine-vatinoxan is a relatively new medicinal product indicated for sedation of healthy dogs. Vatinoxan alleviates medetomidine-induced bradycardia and peripheral vasoconstriction in dogs, but when used as a preanaesthetic medication, it has been shown to cause more hypotension during general anaesthesia compared to medetomidine alone. Our aim was to compare medetomidine-vatinoxan to acepromazine when used as a preanaesthetic medication in a randomised, blinded, clinical study. Healthy client-owned dogs ( n  = 25) scheduled for elective ovariectomy were randomly assigned to receive 0.2 mg/kg intramuscular methadone combined with either 0.01 mg/kg medetomidine and 0.2 mg/kg vatinoxan (group MV, n  = 13) or 0.02 mg/kg acepromazine (group A, n  = 12). A sedation scale (SS, range 0–12) and visual analogue scale (VAS, range 0–100 mm) were applied to assess sedation every 5 min until one of the following endpoints was reached: the SS was ≥ 6 or30 min from treatment had passed. After this, general anaesthesia was induced with propofol and maintained with sevoflurane vaporised in oxygen. The need for cardiovascular interventions according to current guidelines was recorded. Statistical comparisons were performed with Student’s t test, the Mann‒Whitney U test and Fisher’s exact test. P-values < 0.05 were considered statistically significant. Results The median (range) time to achieve an SS ≥ 6 was 5 (5–10) minutes in the MV group and 20 (10–25) minutes in the A group (P-value < 0.001). The number of dogs needing interventions for hypotension, bradycardia and/or bradyarrhytmias (7 in group MV, 8 in group A) did not significantly differ between the groups. Conclusions When used as a preanaesthetic medication in combination with methadone, medetomidine-vatinoxan causes faster onset of sedation, without statistically significant differences in cardiovascular interventions, compared to acepromazine.

Background This study evaluated the influence of repeated anaesthesia using isoflurane (ISO, 2–3 Vol%), ketamine-xylazine (KX, 100 mg·kg −1  + 5 mg·kg −1 , i.m.) or a combination of medetomidine-midazolam-fentanyl (MMF, 0.15 mg·kg −1  + 2.0 mg·kg −1  + 0.005 mg·kg −1 , i.m.) on heart rate (HR), arterial blood pressure (BP), body temperature (BT), duration of anaesthetic intervals and body weight (BW) in Wistar rats. Rats were instrumented with a telemetric system for the measurement of systolic, diastolic and mean arterial pressure (SAP, DAP, MAP), pulse pressure (PP), HR and BT during induction, maintenance and recovery of anaesthesia. Each anaesthesia was performed six times within three weeks. KX was not antagonized, but ISO delivery was terminated 40 minutes after induction and MMF was reversed with atipamezole-flumazenil-naloxone (AFN, 0.75 mg·kg −1  + 0.2 mg·kg −1  + 0.12 mg·kg −1 , s.c.). Results With repeated anaesthesia, ISO showed a decrease of HR and BP. A significant decrease of PP could be observed with repeated anaesthesia using MMF. HR and BP were not affected by repeated KX anaesthesia, but we noted a reduction of sleeping time and BW. Neither MMF nor ISO showed significant differences in the duration of anaesthetic intervals and BW. With KX we observed tissue necrosis at the injection site and surgical tolerance was not achieved in 25% of the anaesthesias performed. Conclusion HR, BP values, BT, duration of anaesthetic intervals and BW were affected differently by repeated anaesthesia performed with ISO, KX or MMF. ISO produced a reproducible anaesthesia, thereby being suitable for repeated use, but with a decrease of HR and BP throughout the six anaesthesias. The use of ISO in cases where these parameters should be unaffected is therefore not advised. The inability to produce a surgical tolerance, the reduction of sleeping time and BW, as well as the tissue necrosis are significant contraindications for a repeated use of KX. Only mild changes of BP were found with repeated MMF anaesthesia, so it seems suitable for serial use, unless the high BP and the low HR during the surgical plane of anaesthesia are undesirable for a special procedure.

Background Alpha2-adrenoceptor agonists (α 2 -agonists) are widely used in animals as sedatives and for pre-anaesthetic medication. Medetomidine has often been given subcutaneously (SC) to rats, although its absorption rate is slow and the individual variation in serum drug concentrations is high via this route. In addition, α 2 -agonists have various effects on metabolic and endocrine functions such as hypoinsulinaemia, hyperglycaemia and diuresis. Vatinoxan is a peripherally acting α 2 -adrenoceptor antagonist that, as a hydrophilic molecule, does not cross the blood-brain barrier in significant quantities and thus alleviates peripheral cardiovascular effects and adverse metabolic effects of α 2 -agonists. Aim of this study was to evaluate the effects of vatinoxan on sedation, blood glucose concentration, voiding and heart and respiratory rates and arterial oxygen saturation in rats sedated with subcutaneous medetomidine, midazolam and fentanyl. Results Onset of sedation and loss of righting reflex occurred significantly faster with vatinoxan [5.35 ± 1.08 (mean ± SD) versus 12.97 ± 6.18 min and 6.53 ± 2.18 versus 14.47 ± 7.28 min, respectively]. No significant differences were detected in heart and respiratory rates and arterial oxygen saturation between treatments. Blood glucose concentration (18.3 ± 3.6 versus 11.8 ± 1.2 mmol/L) and spontaneous urinary voiding [35.9 (15.1–41.6), range (median) versus 0.9 (0–8.0) mL /kg/min] were significantly higher without vatinoxan. Conclusions Acceleration of induction of sedation, alleviation of hyperglycaemia and prevention of profuse diuresis by vatinoxan may be beneficial when sedating rats for clinical and experimental purposes with subcutaneous medetomidine, midazolam and fentanyl.

Background Alpha2-adrenoceptor agonists, such as medetomidine, are pivotal drugs in laboratory rodent sedation and anesthesia. However, they induce marked systemic cardiovascular adverse effects, which can be mitigated with vatinoxan, a peripherally acting alpha2-adrenoceptor antagonist. We investigated the impact of vatinoxan (5 mg/kg) and fentanyl (0.010 mg/kg), an opioid-receptor agonist, on cutaneous microcirculation in male Wistar rats sedated with medetomidine (0.25 mg/kg) and midazolam (2.0 mg/kg). Mean arterial blood pressure (MAP) and pulse rate (PR) were measured. Cutaneous microcirculation was assessed with simultaneous quantification of laser-Doppler flow (LDF) and tissue hemoglobin saturation (T-HbO2). Data were analyzed with Dunn’s tests, Student’s t-tests and Spearman’s correlation tests with Bonferroni-adjusted alpha-levels when appropriate. Results Overall median [range] LDF (139 [95–561] vs. 120 [72–201] perfusion units) and T-HbO2 (57 [39–75] vs. 41 [18–75] %) from pooled data including all time points were significantly higher ( p  < 0.001) for the treatments with vatinoxan. Similarily, pooled MAP was lower with vatinoxan (92 ± 14 mmHg [mean ± SD]) than without it (139 ± 18 mmHg) ( p  < 0.001). Furthermore, MAP was moderately negatively correlated with LDF (Spearman’s rho = − 0.439, p  < 0.001). Pooled pulse rates were also significantly higher with the addition of vatinoxan (323 ± 33 bpm) compared with treatments without it (281 ± 29 bpm) ( p  < 0.001). Fentanyl did not significantly alter any of the outcomes. Conclusions The addition of vatinoxan alleviated the hypertension and improved pulse rate, cutaneous microcirculation and tissue oxygenation in male Wistar rats sedated with these medetomidine-based protocols. By reducing the peripheral adverse effects attributed to medetomidine, vatinoxan may contribute to refinement of laboratory rodent sedation.