{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T08:26:09Z","timestamp":1765182369470,"version":"3.46.0"},"reference-count":49,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T00:00:00Z","timestamp":1764979200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 DA056646","U18 DA052319","U01 DA051079","UH2\/UH3 DA041115","UG3\/UH3 NS134920","R01 DA035552","R01 DA032910","R01 DA013930"],"award-info":[{"award-number":["R01 DA056646","U18 DA052319","U01 DA051079","UH2\/UH3 DA041115","UG3\/UH3 NS134920","R01 DA035552","R01 DA032910","R01 DA013930"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The appetite hormone ghrelin influences biological processes that are responsible for substance use disorder, which is related to alcohol and most abused drugs including cocaine, methamphetamine, nicotine, etc. In general, upregulation of the ghrelin system enhances drug cravings and substance use. Studies reported in the literature consistently demonstrated that the ghrelin system is associated with stimulants. However, research on opioids in combination with methamphetamine has not been reported. In this study, we examined the relationship of circulating ghrelin with the polydrug use of fentanyl and methamphetamine in male Sprague-Dawley rats, demonstrating for the first time that concurrent use of fentanyl and methamphetamine significantly increased plasma acyl-ghrelin (the active form of ghrelin) and total ghrelin concentrations. Additionally, the data also demonstrated for the first time that the use of fentanyl alone also significantly increased the plasma ghrelin concentrations. These findings imply that the ghrelin system could be a potential pharmacological target for the treatment of substance use disorders caused by polydrug use involving fentanyl and methamphetamine as well as the fentanyl use alone.<\/jats:p>","DOI":"10.3390\/ijms262411806","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T08:21:43Z","timestamp":1765182103000},"page":"11806","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of Fentanyl-Adulterated Methamphetamine on Circulating Ghrelin in Rats"],"prefix":"10.3390","volume":"26","author":[{"given":"Huimei","family":"Wei","sequence":"first","affiliation":[{"name":"Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA"},{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elise C.","family":"Maul","sequence":"additional","affiliation":[{"name":"Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA"},{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shawn","family":"Park","sequence":"additional","affiliation":[{"name":"Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA"},{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaniz","family":"Fatema","sequence":"additional","affiliation":[{"name":"Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA"},{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7302-6375","authenticated-orcid":false,"given":"Daniel J.","family":"Peter","sequence":"additional","affiliation":[{"name":"Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA"},{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang-Guo","family":"Zhan","sequence":"additional","affiliation":[{"name":"Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA"},{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA"},{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,6]]},"reference":[{"key":"ref_1","unstructured":"(2025, February 16). Fentanyl, Available online: https:\/\/www.dea.gov\/factsheets\/fentanyl."},{"key":"ref_2","unstructured":"(2025, February 18). Facts About Fentanyl, Available online: https:\/\/www.dea.gov\/resources\/facts-about-fentanyl."},{"key":"ref_3","unstructured":"Klobucista, C., and Ferragamo, M. (2025, February 16). Fentanyl and the U.S. Opioid Epidemic, Council on Foreign Relations. Available online: https:\/\/www.cfr.org\/backgrounder\/fentanyl-and-us-opioid-epidemic."},{"key":"ref_4","unstructured":"Nodell, B. (2025, November 27). Co-Addiction of Meth and Opioids Hinders Treatment: Study Finds Meth Undermines Success in Treatment for Opioid-Use Disorder. Available online: https:\/\/newsroom.uw.edu\/news\/co-addiction-meth-and-opioids-hinders-treatment."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wei, H., Maul, E.C., Kyomuhangi, A., Park, S., Mutchler, M.L., Zhan, C.-G., and Zheng, F. (2025). Effects of Fentanyl-Laced Cocaine on Circulating Ghrelin, Insulin, and Glucose Levels in Rats. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26052341"},{"key":"ref_6","unstructured":"Weiland, N., and Sanger-Katz, M. (International New York Times, 2022). Overdose Deaths Continue Rising, with Fentanyl and Meth Key Culprits, International New York Times."},{"key":"ref_7","unstructured":"HealthDay (2025, February 16). U.S. Deaths Involving Meth Are Skyrocketing, Fentanyl a Big Factor. Available online: https:\/\/www.healthday.com\/methamphetamine-2659441796.html."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s12954-023-00782-1","article-title":"Attitudes and experiences with fentanyl contamination of methamphetamine: Exploring self-reports and urine toxicology among persons who use methamphetamine and other drugs","volume":"20","author":"Daniulaityte","year":"2023","journal-title":"Harm Reduct. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e1918514","DOI":"10.1001\/jamanetworkopen.2019.18514","article-title":"Evaluation of Trends of Near-Real-Time Urine Drug Test Results for Methamphetamine, Cocaine, Heroin, and Fentanyl","volume":"3","author":"Twillman","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"110985","DOI":"10.1016\/j.drugalcdep.2023.110985","article-title":"Prevalence of fentanyl in methamphetamine and cocaine samples collected by community-based drug checking services","volume":"252","author":"Wagner","year":"2023","journal-title":"Drug Alcohol Depend."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.drugalcdep.2018.08.029","article-title":"Twin epidemics: The surging rise of methamphetamine use in chronic opioid users","volume":"193","author":"Ellis","year":"2018","journal-title":"Drug Alcohol Depend."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2621","DOI":"10.1097\/00001756-200008210-00003","article-title":"Intravenous self-administration of methamphetamine-heroin (speedball) combinations under a progressive-ratio schedule of reinforcement in rats","volume":"11","author":"Ranaldi","year":"2000","journal-title":"NeuroReport"},{"key":"ref_13","unstructured":"Maucione, S. (2025, November 27). Fentanyl Mixed with Cocaine or Meth Is Driving the \u20184th Wave\u2018 of the Overdose Crisis, Health Reporting in the States, Available online: https:\/\/www.npr.org\/sections\/health-shots\/2023\/2009\/2014\/1199396794\/fentanyl-mixed-with-cocaine-or-meth-is-driving-the-1199396794th-wave-of-the-overdose-cris."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"761","DOI":"10.3390\/ijms23020761","article-title":"The role of ghrelin\/GHS-R1A signaling in nonalcohol drug addictions","volume":"23","author":"Charalambous","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16691","DOI":"10.1021\/ja8055326","article-title":"Modeling Differential Binding of \u03b14\u03b22 Nicotinic Acetylcholine Receptor with Agonists and Antagonists","volume":"130","author":"Huang","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/45230","article-title":"Ghrelin is a growth-hormone-releasing acylated peptide from stomach","volume":"402","author":"Kojima","year":"1999","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/bs.irn.2017.08.002","article-title":"Chapter Four\u2014The Role of the Ghrelin System in Drug Addiction","volume":"Volume 136","author":"Zallar","year":"2017","journal-title":"The Role of Neuropeptides in Addiction and Disorders of Excessive Consumption"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1523\/JNEUROSCI.1151-21.2021","article-title":"Complexes of ghrelin GHS-R1a, GHS-R1b, and dopamine D1 receptors localized in the ventral tegmental area as main mediators of the dopaminergic effects of ghrelin","volume":"42","author":"Navarro","year":"2022","journal-title":"J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1007\/s00213-010-1907-7","article-title":"Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference","volume":"211","author":"Jerlhag","year":"2010","journal-title":"Psychopharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1111\/adb.12197","article-title":"Adolescent pre-treatment with oxytocin protects against adult methamphetamine-seeking behavior in female rats","volume":"21","author":"Hicks","year":"2016","journal-title":"Addict. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Zhao, J., Du, X., Chen, M., and Zhu, S. (2021). Growth Hormone Secretagogue Receptor 1A Antagonist JMV2959 Effectively Prevents Morphine Memory Reconsolidation and Relapse. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.718615"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Sustkova-Fiserova, M., Puskina, N., Havlickova, T., Lapka, M., Syslova, K., Pohorala, V., and Charalambous, C. (2020). Ghrelin receptor antagonism of fentanyl-induced conditioned place preference, intravenous self-administration, and dopamine release in the nucleus accumbens in rats. Addict. Biol., 25.","DOI":"10.1111\/adb.12845"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"174039","DOI":"10.1016\/j.ejphar.2021.174039","article-title":"A ghrelin receptor antagonist reduces the ability of ghrelin, alcohol or amphetamine to induce a dopamine release in the ventral tegmental area and in nucleus accumbens shell in rats","volume":"899","author":"Edvardsson","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.neuroscience.2004.11.037","article-title":"Differential effects of methamphetamine on expression of neuropeptide Y mRNA in hypothalamus and on serum leptin and ghrelin concentrations in ad libitum-fed and schedule-fed rats","volume":"132","author":"Crowley","year":"2005","journal-title":"Neuroscience"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1111\/j.1369-1600.2007.00052.x","article-title":"Correlation between serum ghrelin levels and cocaine-seeking behaviour triggered by cocaine-associated conditioned stimuli in rats","volume":"12","author":"Tessari","year":"2007","journal-title":"Addict. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.pbb.2018.11.001","article-title":"Cocaine and cocaine expectancy increase growth hormone, ghrelin, GLP-1, IGF-1, adiponectin, and corticosterone while decreasing leptin, insulin, GIP, and prolactin","volume":"176","author":"You","year":"2019","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1038\/s41386-021-01249-2","article-title":"Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: A role of adrenergic action at peripheral \u03b21 receptors","volume":"47","author":"You","year":"2022","journal-title":"Neuropsychopharmacology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ejphar.2013.01.016","article-title":"Glial cell modulators attenuate methamphetamine self-administration in the rat","volume":"701","author":"Snider","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1007\/s00429-016-1322-x","article-title":"Methamphetamine self-administration modulates glutamate neurophysiology","volume":"222","author":"Mishra","year":"2017","journal-title":"Brain Struct. Funct."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1097\/FBP.0000000000000586","article-title":"Effects of the GluN2B antagonist, Ro 25-6981, on extinction consolidation following adolescent- or adult-onset methamphetamine self-administration in male and female rats","volume":"31","author":"Westbrook","year":"2020","journal-title":"Behav. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"112599","DOI":"10.1016\/j.drugalcdep.2025.112599","article-title":"Adolescent vulnerability to methamphetamine: Dose-related escalation of self-administration and cue extinction deficits","volume":"269","author":"Luikinga","year":"2025","journal-title":"Drug Alcohol Depend."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"12678","DOI":"10.1021\/acs.analchem.8b02909","article-title":"Detection and Quantitation of Trace Fentanyl in Heroin by Surface-Enhanced Raman Spectroscopy","volume":"90","author":"Haddad","year":"2018","journal-title":"Anal. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"13014","DOI":"10.1021\/acs.analchem.9b03083","article-title":"Separation and Detection of Trace Fentanyl from Complex Mixtures Using Gradient Elution Moving Boundary Electrophoresis","volume":"91","author":"Krauss","year":"2019","journal-title":"Anal. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"109110","DOI":"10.1016\/j.jneumeth.2021.109110","article-title":"A drug-vs-food \u201cchoice\u201d self-administration procedure in rats to investigate pharmacological and environmental mechanisms of substance use disorders","volume":"354","author":"Townsend","year":"2021","journal-title":"J. Neurosci. Methods"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1073\/pnas.1212137110","article-title":"Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons","volume":"110","author":"Schaeffer","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1124\/jpet.102.034827","article-title":"Extent and Direction of Ghrelin Transport Across the Blood-Brain Barrier Is Determined by Its Unique Primary Structure","volume":"302","author":"Banks","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"11318","DOI":"10.1073\/pnas.0812809106","article-title":"Requirement of central ghrelin signaling for alcohol reward","volume":"106","author":"Jerlhag","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.drugalcdep.2011.01.010","article-title":"Ghrelin receptor antagonism attenuates nicotine-induced locomotor stimulation, accumbal dopamine release and conditioned place preference in mice","volume":"117","author":"Jerlhag","year":"2011","journal-title":"Drug Alcohol Depend."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1016\/j.euroneuro.2015.10.004","article-title":"A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding properties of morphine and increases opioid peptide levels in reward areas in mice","volume":"25","author":"Engel","year":"2015","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.neuint.2017.09.013","article-title":"Ghrelin receptor antagonism of morphine-induced conditioned place preference and behavioral and accumbens dopaminergic sensitization in rats","volume":"110","author":"Jerabek","year":"2017","journal-title":"Neurochem. Int."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Havlickova, T., Charalambous, C., Lapka, M., Puskina, N., Jerabek, P., and Sustkova-Fiserova, M. (2018). Ghrelin Receptor Antagonism of Methamphetamine-Induced Conditioned Place Preference and Intravenous Self-Administration in Rats. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19102925"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2725","DOI":"10.1007\/s00213-014-3640-0","article-title":"The role of ghrelin in addiction: A review","volume":"231","author":"Panagopoulos","year":"2014","journal-title":"Psychopharmacology"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Shevchouk, O., Tufvesson-Alm, M., and Jerlhag, E. (2021). An Overview of Appetite-Regulatory Peptides in Addiction Processes; From Bench to Bed Side. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.774050"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.molmet.2018.09.007","article-title":"Ghrelin transport across the blood\u2013brain barrier can occur independently of the growth hormone secretagogue receptor","volume":"18","author":"Rhea","year":"2018","journal-title":"Mol. Metab."},{"key":"ref_45","first-page":"260","article-title":"Pharmacokinetics of fentanyl in male and female rats after intravenous administration","volume":"57","author":"Ohtsuka","year":"2007","journal-title":"Arzneimittelforschung"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1097\/ADM.0000000000001185","article-title":"Fentanyl Absorption, Distribution, Metabolism, and Excretion: Narrative Review and Clinical Significance Related to Illicitly Manufactured Fentanyl","volume":"17","author":"Bird","year":"2023","journal-title":"J. Addict. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3259","DOI":"10.1021\/acsptsci.5c00391","article-title":"Development of a Ghrelin Deacylase to Attenuate Drug Reward and Associated Effects of Methamphetamine","volume":"8","author":"Stewart","year":"2025","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1021\/acs.bioconjchem.2c00210","article-title":"Development of a Highly Efficient Long-Acting Cocaine Hydrolase Entity to Accelerate Cocaine Metabolism","volume":"33","author":"Zheng","year":"2022","journal-title":"Bioconjug. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"108128","DOI":"10.1016\/j.neuropharm.2020.108128","article-title":"Cebranopadol reduces cocaine self-administration in male rats: Dose, treatment and safety consideration","volume":"172","author":"Wei","year":"2020","journal-title":"Neuropharmacology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/11806\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T08:23:29Z","timestamp":1765182209000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/11806"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,6]]},"references-count":49,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262411806"],"URL":"https:\/\/doi.org\/10.3390\/ijms262411806","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,6]]}}}