Transforming Health Care through Innovative and Impactful Research

Posted November 4, 2024

The Pharmacotherapies for Alcohol and Substance Use Disorders Alliance, a consortium funded by the Congressionally Directed Medical Research Programs Alcohol and Substance Use Disorders Research Program, recently funded five new studies to advance pharmacological treatments for alcohol and substance use disorders and reduce the number of opioid and other substance use-related deaths. Briefly, the new studies are as follows:

Planning Awards

Christian Hendershot, Ph.D., University of Southern California, and Dr. Lorenzo Leggio, National Institute on Drug Abuse/ National Institute on Alcohol Abuse and Alcoholism intramural research programs, will devise a clinical strategy targeting glucagon-like peptide-1 (GLP-1) receptor agonists as a treatment for alcohol use disorder (AUD). Semaglutide, and other glucagon-like peptide-1, GLP-1, receptor agonists demonstrate efficacy in reducing motivation and intake of alcohol and other drugs in animal models.1 The investigators, currently among the first conducting human trials of GLP-1 receptor agonists in AUD, will design a rigorous multisite clinical trial guided by a development plan to accelerate validation of one or more promising GLP-1 receptor agonists as candidate therapies for alcohol and other substance use disorders.

Dr. John Mendelson of Ria Health will design a clinical development plan for advancing xenon gas inhalation for the treatment for co-morbid alcohol use disorder and PTSD, conditions currently lacking efficacious pharmacotherapies. Rodent studies demonstrate potential for xenon gas to alleviate memory disturbances, negative emotions, and sympathetic nervous system hyperactivity associated with AUD and PTSD.2,3 If administered on-demand via an inhaler, xenon gas may offer real-time relief to individuals living with these conditions by blocking memory and alcohol withdrawal-related symptoms. Mendelson aims to establish a protocol for a Phase I proof-of-concept trial, evaluating the therapeutic potential of low-dose inhaled xenon gas as a treatment for comorbid AUD and PTSD.

Pre-clinical Research Awards

Howard Becker, Ph.D., and Marcelo Lopez, Ph.D., Charleston Alcohol Research Center, Medical University of South Carolina, will assess pharmacotherapies targeting heightened vulnerability to stress-induced alcohol relapse. Using a unique mouse model mimicking PTSD and alcohol-use disorder comorbidity, they will investigate the impact of aticaprant, a kappa opioid receptor antagonist, in combination with oxytocin on stress-induced alcohol relapse-like behavior. Signaling at kappa opiate receptors is thought to mediate dysphoria while oxytocin is known to possess stress-buffering properties. Based on evidence linking kappa opioid and oxytocin systems to stress-induced relapse and excessive alcohol consumption4-6, the investigators anticipate synergistic effects from this combination. The project will produce valuable data and insights to guide future clinical studies on the potential therapeutic effects of aticaprant and oxytocin treatment, both alone and in combination, for individuals with co-occurring PTSD and AUD.

Patrick Mulholland, Ph.D., Charleston Alcohol Research Center, Medical University of South Carolina, and Miao Zhang, Ph.D., Chapman University, will investigate novel pharmacological compounds with the potential to ameliorate symptoms of alcohol- and stress-related disorders, including excessive alcohol drinking and negative affective behaviors. With evidence indicating a critical role for KCa2 potassium channels in uncontrolled alcohol drinking and mood disorders7-8, the investigators will synthesize selective KCa2 channel positive allosteric modulators, PAMs, and test their efficacy in a mouse model of alcohol dependence and repeated stress co-exposure. PAMs that selectively target KCa2 channel subtypes may offer better therapeutic profiles than nonselective PAMs by minimizing potential side effects and yielding higher efficacy. Successful validation of these compounds may lead to promising breakthroughs including lead molecules for future development of pharmacotherapies for alcohol use and stress-related disorders.

Expansion Award

Dr. Colin Haile, Therese Kosten, Ph.D., and Gregory Cuny, Ph.D., of the University of Houston, and Elizabeth Norton, Ph.D., of Tulane University School of Medicine will advance their pioneering vaccine immunotherapy research targeting fentanyl use and overdose prevention. Their published findings demonstrate their anti-fentanyl vaccine creates durable antibodies that bind specifically to fentanyl.9,10 The vaccine prevents fentanyl from entering the brain, eliminates its analgesic effects, and safeguards against decreases in oxygen saturation, heart rate, and activity levels associated with fentanyl overdose. Importantly, combining the vaccine with buprenorphine, an FDA-approved medication for opioid use disorder, does not impact the vaccine's efficacy. The researchers now plan to explore the vaccine's efficacy on fentanyl-induced analgesia and adverse physiological effects in an animal model of overdose when it is combined with either methadone or naltrexone. Evaluation of the anti-fentanyl vaccine in conjunction with these pharmacotherapies is important, as individuals considering the vaccine may be on medications for opioid use disorders. A combination of the vaccine and medication presents a broader approach to addressing the opioid epidemic. The investigators will also conduct FDA-required toxicology testing and anticipate outcomes that will enable an Investigational New Drug application and future evaluation of the vaccine in a Phase I clinical trial.

References:

1. Klausen MK, Thomsen M, Wortwein G, Fink-Jensen A. The role of glucagon-like peptide 1 (GLP-1) in addictive disorders. Br J Pharmacol. 2022 Feb;179(4):625-641. doi: 10.1111/bph.15677. PMID: 34532853; PMCID: PMC8820218.


2. Vengeliene V, Bessiere B, Pype J, Spanagel R. The effects of xenon and nitrous oxide gases on alcohol relapse. Alcohol Clin Exp Res. 2014 Feb;38(2):557-63. doi: 10.1111/acer.12264. Epub 2013 Oct 7. PMID: 24118055.


3. Meloni EG, Gillis TE, Manoukian J, Kaufman MJ. Xenon impairs reconsolidation of fear memories in a rat model of post-traumatic stress disorder (PTSD). PLoS One. 2014 Aug 27;9(8):e106189. doi: 10.1371/journal.pone.0106189. PMID: 25162644; PMCID: PMC4146606.


4. Anderson RI, Lopez MF, Becker HC. Stress-Induced Enhancement of Ethanol Intake in C57BL/6J Mice with a History of Chronic Ethanol Exposure: Involvement of Kappa Opioid Receptors. Front Cell Neurosci. 2016 Feb 23;10:45. doi: 10.3389/fncel.2016.00045. PMID: 26941607; PMCID: PMC4763044.


5. Anderson RI, Becker HC. Role of the Dynorphin/Kappa Opioid Receptor System in the Motivational Effects of Ethanol. Alcohol Clin Exp Res. 2017 Aug;41(8):1402-1418. doi: 10.1111/acer.13406. Epub 2017 Jun 5. PMID: 28425121; PMCID: PMC5522623.


6. King CE, Becker HC. Oxytocin attenuates stress-induced reinstatement of alcohol seeking behavior in male and female mice. Psychopharmacology (Berl). 2019 Sep;236(9):2613-2622. doi: 10.1007/s00213-019-05233-z. Epub 2019 Mar 28. PMID: 30923836; PMCID: PMC6697557.


7. Mulholland PJ, Padula AE, Wilhelm LJ, Park B, Grant KA, Ferguson BM, Cervera-Juanes C. Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcripts by excessive ethanol drinking. Transl Psychiatry. 2023 Nov 27;13(1):365. PMID: 38012158; PMCID: In progress.


8. Padula AE, Rinker JA, Lopez MF, Mulligan MK, Williams RW, Becker HC, Mulholland PJ. Bioinformatics identification and pharmacological validation of Kcnn3/KCa2 channels as a mediator of negative affective behaviors and excessive alcohol drinking in mice. Transl Psychiatry. 2020 Nov 27;10(1):414. doi: 10.1038/s41398-020-01099-4. PMID: 33247097; PMCID: PMC7699620.


9. Haile CN, Baker MD, Sanchez SA, Lopez Arteaga CA, Duddupudi AL, Cuny GD, Norton EB, Kosten TR, Kosten TA. An Immunconjugate Vaccine Alters Distribution and Reduces the Antinociceptive, Behavioral and Physiological Effects of Fentanyl in Male and Female Rats. Pharmaceutics. 2022 Oct 26;14(11):2290. doi: 10.3390/pharmaceutics14112290. PMID: 36365109; PMCID: PMC9694531.


10. Stone AE, Scheuermann SE, Haile CN, Cuny GD, Velasquez ML, Linhuber JP, Duddupudi AL, Vigliaturo JR, Pravetoni M, Kosten TA, Kosten TR, Norton EB. Fentanyl conjugate vaccine by injected or mucosal delivery with dmLT or LTA1 adjuvants implicates IgA in protection from drug challenge. NPJ Vaccines. 2021 May 13;6(1):69. doi: 10.1038/s41541-021-00329-0. PMID: 33986280; PMCID: PMC8119695.

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