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Trials
Published in: Trials 1/2022

Open Access 01-12-2022 | Addiction | Study protocol

G-CuP: the effect of a forced oral glucose intake on alcohol craving and mesolimbic cue reactivity in alcohol dependence—study protocol of a randomized, double-blind, placebo-controlled crossover study

Authors: Lea Wetzel, Madeleine Pourbaix, Alisa Riegler, Anna-Maria Pfeifer, Iris Reinhard, Sabine Hoffmann, Sabine Vollstädt-Klein, Falk Kiefer, Wolfgang Sommer, Jan Malte Bumb, Patrick Bach, Anne Koopmann

Published in: Trials | Issue 1/2022

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Abstract

Background

Multiple studies indicate that a lower plasma level of the acetylated form of the appetite-regulating hormone ghrelin and higher plasma levels of insulin lead to a reduction in subjective alcohol craving and a reduced mesolimbic cue reactivity in functional magnetic resonance imaging (fMRI) when being exposed to alcohol-associated stimuli. The ghrelin level can physiologically be reduced by the induction of stomach distension and the ingestion of glucose or lipids.

Methods

A total of 108 alcohol-dependent patients aged between 18 and 65 years are examined in the randomized, double-blind, placebo-controlled crossover study. After collecting demographic and psychometric data, participants take part in an alcohol exposure session. Afterwards, the participants go through the intervention condition (oral glucose intake) and the control condition (placebo intake) in a randomized order on two examination days. Blood samples are taken repeatedly (every 10 min) during the study course on both measuring days to determine changes in acetylated and total ghrelin and insulin plasma levels. In parallel, subjective alcohol craving after the glucose or placebo intake as the primary outcome is assessed using the Alcohol Urge Questionnaire (AUQ) and a visual analog scale (VAS). To examine the mesolimbic cue reactivity as the secondary outcome, a fMRI measurement is conducted while being exposed to alcohol-related stimuli. Appropriate statistical analysis will be used for the evaluation of the outcomes.

Discussion

If successful, the results of this study could offer alcohol-dependent patients a new potential option for acute short-term reduction of alcohol craving and thus prevent relapses and prolong periods of abstinence in the long term.

Trial registration

German Clinical Trials Register DRKS00022419 (UTN: U1111-1278-9428). Retrospectively registered on September 15, 2020.
Literature
1.
World Health Organization. International statistical classification of diseases and related health problems. 10th ed. Geneva: World Health Organization; 2016.
2.
Glantz MD, Bharat C, Degenhardt L, Sampson NA, Scott KM, Lim CCW, et al. The epidemiology of alcohol use disorders cross-nationally: findings from the World Mental Health Surveys. Addict Behav. 2020;102:106128.PubMedCrossRef
3.
Addolorato G, Capristo E, Leggio L, Ferrulli A, Abenavoli L, Malandrino N, et al. Relationship between ghrelin levels, alcohol craving, and nutritional status in current alcoholic patients. Alcohol Clin Exp Res. 2006;30(11):1933–7.PubMedCrossRef
4.
Leggio L, Ray LA, Kenna GA, Swift RM. Blood glucose level, alcohol heavy drinking, and alcohol craving during treatment for alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study. Alcohol Clin Exp Res. 2009;33(9):1539–44.PubMedPubMedCentralCrossRef
5.
Alarcon R, Tiberghien M, Trouillet R, Pelletier S, Luquiens A, Ahmed SH, et al. Sugar intake and craving during alcohol withdrawal in alcohol use disorder inpatients. Addict Biol. 2021;26(2):e12907.PubMedCrossRef
6.
Sha L, Dey P, Khess CR, Khitiz KK. The association of plasma acyl ghrelin level with alcohol craving in early abstinent alcohol dependent patients. J Postgrad Med. 2021;67(1):12–7.PubMedPubMedCentralCrossRef
7.
Naef L, Seabrook L, Hsiao J, Li C, Borgland SL. Insulin in the ventral tegmental area reduces cocaine-evoked dopamine in the nucleus accumbens in vivo. Eur J Neurosci. 2019;50(3):2146–55.PubMedCrossRef
8.
Cummings DE, Frayo RS, Marmonier C, Aubert R, Chapelot D. Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. Am J Physiol Endocrinol Metab. 2004;287(2):E297–304.PubMedCrossRef
9.
Geisel O, Hellweg R, Wernecke KD, Wiedemann K, Müller CA. Total and acylated ghrelin plasma levels as potential long-term response markers in alcohol-dependent patients receiving high-dose of the GABA-B receptor agonist baclofen. Psychiatry Res. 2019;272:431–7.PubMedCrossRef
10.
Arora S, Anubhuti. Role of neuropeptides in appetite regulation and obesity--a review. Neuropeptides. 2006;40(6):375–401.PubMedCrossRef
11.
12.
Farias G, Netto BDM, Bettini SC, Damaso AR, de Freitas ACT. Neuroendocrine regulation of energy balance: implications on the development and surgical treatment of obesity. Nutr Health. 2017;23(3):131–46.PubMedCrossRef
13.
Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, et al. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest. 2006;116(12):3229–39.PubMedPubMedCentralCrossRef
14.
Salamone JD, Correa M. Insulin and ventral tegmental dopamine: what’s impaired and what’s intact? Cell Metab. 2013;17(4):469–70.PubMedCrossRef
15.
Kiefer F. Ghrelin in addictive behaviors: plenus venter non studet libenter. Biol Psychiatry. 2014;76(9):676–7.PubMedCrossRef
16.
Palmiter RD. Is dopamine a physiologically relevant mediator of feeding behavior? Trends Neurosci. 2007;30(8):375–81.PubMedCrossRef
17.
Koopmann A, Bach P, Schuster R, Bumb JM, Vollstadt-Klein S, Reinhard I, et al. Ghrelin modulates mesolimbic reactivity to alcohol cues in alcohol-addicted subjects: a functional imaging study. Addict Biol. 2019;24(5):1066–76.PubMedCrossRef
18.
Koopmann A, von der Goltz C, Grosshans M, Dinter C, Vitale M, Wiedemann K, et al. The association of the appetitive peptide acetylated ghrelin with alcohol craving in early abstinent alcohol dependent individuals. Psychoneuroendocrinology. 2012;37(7):980–6.PubMedCrossRef
19.
Leggio L, Zywiak WH, Fricchione SR, Edwards SM, de la Monte SM, Swift RM, et al. Intravenous ghrelin administration increases alcohol craving in alcohol-dependent heavy drinkers: a preliminary investigation. Biol Psychiatry. 2014;76(9):734–41.PubMedPubMedCentralCrossRef
20.
Gomez JL, Cunningham CL, Finn DA, Young EA, Helpenstell LK, Schuette LM, et al. Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence. Neuropharmacology. 2015;97:182–93.PubMedPubMedCentralCrossRef
21.
Stevenson JR, Francomacaro LM, Bohidar AE, Young KA, Pesarchick BF, Buirkle JM, et al. Ghrelin receptor (GHS-R1A) antagonism alters preference for ethanol and sucrose in a concentration-dependent manner in prairie voles. Physiol Behav. 2016;155:231–6.PubMedCrossRef
22.
Stevenson JR, Buirkle JM, Buckley LE, Young KA, Albertini KM, Bohidar AE. GHS-R1A antagonism reduces alcohol but not sucrose preference in prairie voles. Physiol Behav. 2015;147:23–9.PubMedCrossRef
23.
Suchankova P, Steensland P, Fredriksson I, Engel JA, Jerlhag E. Ghrelin receptor (GHS-R1A) antagonism suppresses both alcohol consumption and the alcohol deprivation effect in rats following long-term voluntary alcohol consumption. PLoS One. 2013;8(8):e71284.PubMedPubMedCentralCrossRef
24.
Lee MR, Tapocik JD, Ghareeb M, Schwandt ML, Dias AA, Le AN, et al. The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study. Mol Psychiatry. 2020;25(2):461–75.PubMedCrossRef
25.
Edvardsson CE, Vestlund J, Jerlhag E. 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. Eur J Pharmacol. 2021;899:174039.PubMedCrossRef
26.
Bach P, Bumb JM, Schuster R, Vollstadt-Klein S, Reinhard I, Rietschel M, et al. Effects of leptin and ghrelin on neural cue-reactivity in alcohol addiction: two streams merge to one river? Psychoneuroendocrinology. 2019;100:1–9.PubMedCrossRef
27.
Farokhnia M, Grodin EN, Lee MR, Oot EN, Blackburn AN, Stangl BL, et al. Exogenous ghrelin administration increases alcohol self-administration and modulates brain functional activity in heavy-drinking alcohol-dependent individuals. Mol Psychiatry. 2018;23(10):2029–38.PubMedCrossRef
28.
Purnell JQ, Weigle DS, Breen P, Cummings DE. Ghrelin levels correlate with insulin levels, insulin resistance, and high-density lipoprotein cholesterol, but not with gender, menopausal status, or cortisol levels in humans. J Clin Endocrinol Metab. 2003;88(12):5747–52.PubMedCrossRef
29.
Saad MF, Bernaba B, Hwu CM, Jinagouda S, Fahmi S, Kogosov E, et al. Insulin regulates plasma ghrelin concentration. J Clin Endocrinol Metab. 2002;87(8):3997–4000.PubMedCrossRef
30.
Meek TH, Nelson JT, Matsen ME, Dorfman MD, Guyenet SJ, Damian V, et al. Functional identification of a neurocircuit regulating blood glucose. Proc Natl Acad Sci U S A. 2016;113(14):E2073–82.PubMedPubMedCentralCrossRef
31.
32.
33.
Janak PH, Wolf FW, Heberlein U, Pandey SC, Logrip ML, Ron D. BIG news in alcohol addiction: new findings on growth factor pathways BDNF, insulin, and GDNF. Alcohol Clin Exp Res. 2006;30(2):214–21.PubMedCrossRef
34.
Hamidovic A, Khafaja M, Brandon V, Anderson J, Ray G, Allan AM, et al. Reduction of smoking urges with intranasal insulin: a randomized, crossover, placebo-controlled clinical trial. Mol Psychiatry. 2017;22(10):1413–21.PubMedCrossRef
35.
Funk D, Marinelli PW, Lê AD. Biological processes underlying co-use of alcohol and nicotine: neuronal mechanisms, cross-tolerance, and genetic factors. Alcohol Res Health. 2006;29(3):186–92.PubMedPubMedCentral
36.
Labouèbe G, Liu S, Dias C, Zou H, Wong JCY, Karunakaran S, et al. Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids. Nat Neurosci. 2013;16(3):300–8.PubMedPubMedCentralCrossRef
37.
38.
Hirth N, Meinhardt MW, Noori HR, Salgado H, Torres-Ramirez O, Uhrig S, et al. Convergent evidence from alcohol-dependent humans and rats for a hyperdopaminergic state in protracted abstinence. Proc Natl Acad Sci U S A. 2016;113(11):3024–9.PubMedPubMedCentralCrossRef
39.
Koopmann A, Lippmann K, Schuster R, Reinhard I, Bach P, Weil G, et al. Drinking water to reduce alcohol craving? A randomized controlled study on the impact of ghrelin in mediating the effects of forced water intake in alcohol addiction. Psychoneuroendocrinology. 2017;85:56–62.PubMedCrossRef
40.
Greenman Y, Golani N, Gilad S, Yaron M, Limor R, Stern N. Ghrelin secretion is modulated in a nutrient-and gender-specific manner. Clin Endocrinol (Oxf). 2004;60(3):382–8.CrossRef
41.
Chan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586.PubMedPubMedCentralCrossRef
42.
43.
Osório FL, Loureiro SR, Hallak JEC, Machado-de-Sousa JP, Ushirohira JM, Baes CVW, et al. Clinical validity and intrarater and test-retest reliability of the Structured Clinical Interview for DSM-5 - Clinician Version (SCID-5-CV). Psychiatry Clin Neurosci. 2019;73(12):754–60.PubMedCrossRef
44.
Koopmann A, Schuster R, Kiefer F. The impact of the appetite-regulating, orexigenic peptide ghrelin on alcohol use disorders: a systematic review of preclinical and clinical data. Biol Psychol. 2018;131:14–30.PubMedCrossRef
45.
Kwako LE, Schwandt ML, Sells JR, Ramchandani VA, Hommer DW, George DT, et al. Methods for inducing alcohol craving in individuals with co-morbid alcohol dependence and posttraumatic stress disorder: behavioral and physiological outcomes. Addict Biol. 2015;20(4):733–46.PubMedCrossRef
46.
Vollstadt-Klein S, Loeber S, Richter A, Kirsch M, Bach P, von der Goltz C, et al. Validating incentive salience with functional magnetic resonance imaging: association between mesolimbic cue reactivity and attentional bias in alcohol-dependent patients. Addict Biol. 2012;17(4):807–16.PubMedCrossRef
47.
Vollstadt-Klein S, Kobiella A, Buhler M, Graf C, Fehr C, Mann K, et al. Severity of dependence modulates smokers’ neuronal cue reactivity and cigarette craving elicited by tobacco advertisement. Addict Biol. 2011;16(1):166–75.PubMedCrossRef
48.
Diehl A, Scherbaum N. Nikotinabhängigkeit als komorbide Störung bei Alkoholabhängigkeit - Epidemiologie, Ätiologie und Therapie. Fortschr Neurol Psychiatr. 2008;76(01):14–8.PubMedCrossRef
49.
Skinner HA, Allen BA. Alcohol dependence syndrome: Measurement and validation. J Abnorm Psychol. 1982;91(3):199–209.
50.
Bohn MJ, Krahn DD, Staehler BA. Development and initial validation of a measure of drinking urges in abstinent alcoholics. Alcohol Clin Exp Res. 1995;19(3):600–6.
51.
Anton RF. The Obsessive Compulsive Drinking Scale. Arch Gen Psychiatry. 1996;53(3):225–10.
52.
Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström Test for Nicotine Dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict. 1991;86(9):1119–27.
53.
Tiffany ST, Drobes DJ. The development and initial validation of a questionnaire on smoking urges. Br J Addict. 1991;86(11):1467–76.
54.
Beck AT, Steer RA, Brown GK. Manual for the beck depression inventory-II. San Antonio: Psychological Corporation; 1996.
55.
Cohen S. Perceived stress in a probability sample of the United States. In S. Spacapan & S. Oskamp (Eds.), The social psychology of health. Sage Publications, Inc; 1988. pp. 31–67.
56.
Spielberger C, Gorsuch R, Lushene R, Vagg PR, Jacobs GA. Manual for the State-Trait Anxiety Inventory. Palo Alto: Consulting Psychologists Press; 1983.
57.
Rose EJ, Donohoe G. Brain vs behavior: an effect size comparison of neuroimaging and cognitive studies of genetic risk for schizophrenia. Schizophr Bull. 2013;39(3):518–26.PubMedCrossRef
Metadata
Title
G-CuP: the effect of a forced oral glucose intake on alcohol craving and mesolimbic cue reactivity in alcohol dependence—study protocol of a randomized, double-blind, placebo-controlled crossover study
Authors
Lea Wetzel
Madeleine Pourbaix
Alisa Riegler
Anna-Maria Pfeifer
Iris Reinhard
Sabine Hoffmann
Sabine Vollstädt-Klein
Falk Kiefer
Wolfgang Sommer
Jan Malte Bumb
Patrick Bach
Anne Koopmann
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Trials / Issue 1/2022
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-022-06626-w

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