Amphetamines Exacerbate then Ameliorate Respiratory Effects of Fentanyl
as Their Dose Increases
Neil B. Varshneya, PhD
Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA, Center for Drug Evaluation and Research, Food and Drug Administration, United States Department of Health and Human Services, Silver Spring, MD, USA
Author ProfilePatrick M. Beardsley, PhD
Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA, Center for Biomarker Research & Precision Medicine, Virginia Commonwealth University School of Pharmacy, Richmond, VA, USA
Author ProfileAbstract
Background and Purpose: The opioid epidemic remains one of the most
pressing public health crises facing the United States. Rising rates of
opioid-involved overdose deaths are presently driven primarily by
fentanyl and related synthetic opioid agonists that are resistant to
reversal by naloxone and increasingly used as adulterants or clandestine
substitutes in illicitly produced opioids, sedatives, and
psychostimulants. Deaths involving opioids typically result from lethal
respiratory depression and it is currently unknown whether co-use of
psychostimulants with opioids affects respiratory toxicity. Considering
psychostimulant overdoses have increased over 3-fold since 2013, and
half of those co-involved opioids, this is a cardinal question.
Experimental Approach: Naloxone, d-amphetamine (AMPH), and
(+/-)-methamphetamine (METH), were evaluated for their effects on basal
and fentanyl-depressed respiration. Minute volume (MVb) was measured in
awake, freely moving mice via whole-body plethysmography to quantify
fentanyl-induced respiratory depression and its modulation by dose
ranges of each test drug. Key Results: Naloxone reversed respiratory
depression induced by fentanyl only at the highest dose tested (10
mg•kg-1). Both AMPH and METH exhibited bidirectional effects on MVb
under basal conditions, producing depressions then elevations of
respiration as dose increased. Under depressed conditions the
bidirectional effects of AMPH and METH on respiration were exaggerated,
exacerbating and then reversing fentanyl-induced depression as dose
increased. Conclusions and Implications: These results indicate that
co-use of amphetamines with fentanyl may worsen respiratory depression,
but conversely, monoaminergic components of the amphetamines may
possibly be exploited to mitigate fentanyl overdose.