Exploring the promise of human iPSC-heart cells in understanding fentanyl abuse
Stanford Cardiovascular Institute
image:
Representative figure of the study and its main findings published in the journal Circulation [https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.068560.]
view moreCredit: GEMA MONDEJAR PARREÑO/Stanford Cardiovascular Institute
In recent years, fentanyl, a synthetic opioid that is 50 to 100 times stronger than morphine, has been a main contributor to the opioid crisis. One of the worst adverse effects of fentanyl abuse is opioid-induced cardiac arrest. Although it is well known that opioid abuse can induce arrhythmias; the effects of fentanyl abuse on heart rhythms have not yet been thoroughly investigated.
In a recent study published in Circulation, first-author Gema Mondéjar-Parreño, PhD and senior author Joseph C. Wu, MD, PhD, director of Stanford Cardiovascular Institute, found that human induced pluripotent stem cells provide an unparalleled opportunity to study patient-specific response to opioid abuse. The investigators studied the consequences of fentanyl abuse, specifically those relating to the electrical activity of the heart that determine how the heart controls its rhythm and pumping. The scientists analyzed 19 toxicology studies between 1994 and 2022 in which the mean estimate of fentanyl concentration was three times higher than patients with chronic pain. Using the data, the investigators exposed human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to doses of fentanyl that mimicked circumstances of overdose. They found that this caused changes in calcium signaling homeostasis in heart muscle cells and slowed down preparation for the next heartbeat that contributed to beating irregularities. Additionally, since arrhythmias are often more evident when the heart rate increases, the researchers found the combination of fentanyl and isoproterenol, a stimulant used to increase heart rate, can worsen fentanyl-induced arrhythmias.
This study offers groundbreaking evidence that fentanyl abuse can impair the function of cardiac cells, leading to rhythm defects. Together with respiratory depression, fentanyl-induced effects on electrophysiology significantly contribute to cardiac arrest. Further studies will help us better understand fentanyl abuse and its relationship to arrhythmias.
Additional authors include Shane Rui Zhao, Xu Cao, Yu Liu, Johnson Y. Yang, James Jahng, David Wu, and Nazish Sayed from the Stanford Cardiovascular Institute; José Jalife from Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; and Jeremy Leitz from Greenstone Biosciences.
This project was supported by Leducq Foundation Grant 18CVD05, Gootter-Jensen Foundation, and National Institutes of Health (NIH) R01 HL130020, R01 HL145676, R01 HL146690, R01 HL163680, and R01 HL176822 (JCW); R01 HL158641 and R01 HL161002 (NS); R01 HL163943 and PI20/01220 Instituto de Salud Carlos III (JJ); and American Heart Association Postdoctoral Award #872244 (GMP).
Journal
Circulation
Article Title
Investigating the Risk of Arrhythmogenesis Associated With Fentanyl Abuse Using Human and Mouse Cardiomyocytes
Study proposes new, more personalized
methadone restart approach for opioid use
disorder
First-of-its-kind study considered gamechanger in supporting patients in their recovery
AURORA, Colo. (August 28, 2025) – A new study from University of Colorado Anschutz and Denver Health researchers, published today in JAMA Network Open, introduces a more individualized approach to restarting methadone treatment for people with opioid use disorder. The findings suggest that tailoring methadone doses to each patient’s unique circumstances can improve care without compromising safety.
Methadone is a proven medication that can cut the risk of death from opioid use disorder by about 50%. The researchers considered that current treatment protocols often overlook individual patient needs, especially when restarting methadone after missed doses. Standard guidelines typically require large dose reductions, even if patients have maintained their opioid tolerance through use of non-prescribed opioids.
CU Anschutz assistant professor of internal medicine, Paul Christine, MD, PhD, was part of the team that developed and tested a new protocol that allows for more personalized methadone restart decisions. The study found that patients who restarted methadone after the new protocol was introduced received higher doses safely, with no increase in adverse events compared to traditional methods.
“This study shows that we can safely tailor methadone treatment to better meet patients where they are,” said Christine, who is also a physician at Denver Health. “It’s a step toward more responsive, effective care.”
The research also reflects the changing landscape of opioid use. As the supply has shifted from heroin to more potent synthetic opioids like fentanyl, many patients enter treatment with higher tolerance levels, making individualized dosing even more critical.
Nearly 200 patients were part of the study, which was supported by Denver Health’s Center for Addiction Medicine. The study reviewed nearly 500 restart episodes before and after the new protocol was introduced.
The team shared initial findings at a conference in 2024 where some methadone clinics in other states promptly adopted the protocols in the study. The full study, funded by the National Institutes of Health and Denver Health’s Center for Addiction Medicine, is available in the JAMA Network Open, a peer-reviewed, open-access journal from the American Medical Association.
About the University of Colorado Anschutz Medical Campus
The University of Colorado Anschutz Medical Campus is a world-class medical destination at the forefront of transformative science, medicine, education and patient care. The campus encompasses the University of Colorado health professional schools, more than 60 centers and institutes and two nationally ranked independent hospitals - UCHealth University of Colorado Hospital and Children's Hospital Colorado – which see more than two million adult and pediatric patient visits yearly. Innovative, interconnected and highly collaborative, the CU Anschutz Medical Campus delivers life-changing treatments, patient care and professional training and conducts world-renowned research fueled by $910 million in annual research funding, including $757 million in sponsored awards and $153 million in philanthropic gifts.
Journal
JAMA Network Open
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