AUTHOR=Budamkayala Madhuri , Yalakala Jyostna , Skeen Madison B. , Karuturi Surya , McPhillen Chelsey , Bailey Kristen , Davies Todd H. , Hambuchen Michael D. 
  
TITLE=Ketamine enhancement of dexmedetomidine attenuation of methamphetamine-induced agitation in rats
  
JOURNAL=Journal of Pharmacy & Pharmaceutical Sciences
  
VOLUME=Volume 29 - 2026
  
YEAR=2026
  
URL=https://www.frontierspartnerships.org/journals/journal-of-pharmacy-pharmaceutical-sciences/articles/10.3389/jpps.2026.16294
  
DOI=10.3389/jpps.2026.16294
  
ISSN=1482-1826
  
ABSTRACT=Methamphetamine (METH)-induced agitation, a major concern in acute METH intoxication, is currently treated with benzodiazepines. Due to current polysubstance use patterns in METH consumption, this treatment may fatally exacerbate respiratory depression produced by opioid adulterants or intentionally co-administered opioids. We previously showed that the α2-agonist dexmedetomidine (DEX), which does not potentiate opioid-induced respiratory depression in clinical practice, can be safely and effectively co-administered with naloxone to attenuate METH-induced agitation following naloxone reversal in METH-fentanyl co-intoxicated rats. While the unique arousability of DEX-induced sedation is clinically useful, the current study tested the safety and efficacy of DEX and adjunctive ketamine (KET) in producing deeper, less arousable sedation when needed (i.e., for severe agitation or to facilitate an intricate procedure). Fifteen minutes after 1 mg/kg METH administration in male rats (simulating treatment of naloxone-unmasked agitation with a delay), low-dose (0.032 mg/kg) DEX ± (56 mg/kg) KET, high-dose (0.18 mg/kg) DEX, or saline was administered. Key measurements included METH-induced locomotor activity (a rat model of agitation), the rat coma scale (a quantification of arousability), and α2-agonist class side effects. Both high-dose DEX and DEX-KET almost completely attenuated METH-induced locomotor activity for 90 min after administration, but with the combination the sedation was deeper during the most intense METH-induced stimulation, and the α2-agonist side effects were less intense and of shorter duration. These data provide proof-of-concept support for the potential use of DEX-KET in producing deeper sedation in METH-induced agitation.