Ketogenic Diet Suppresses Alcohol Withdrawal Syndrome in Rats
Ditte Dencker
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Shared first authorship.Search for more papers by this authorAnna Molander
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Shared first authorship.Search for more papers by this authorMorgane Thomsen
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Search for more papers by this authorChantal Schlumberger
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Search for more papers by this authorGitta Wortwein
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Search for more papers by this authorPia Weikop
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Search for more papers by this authorHelene Benveniste
Department of Anesthesiology, Yale University, New Haven, Connecticut
Search for more papers by this authorNora D. Volkow
Laboratory for Neuroimaging, National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, Maryland
Search for more papers by this authorCorresponding Author
Anders Fink-Jensen
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Reprint requests: Anders Fink-Jensen, Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, Edel Sauntes Allé 10, DK-2100 Copenhagen, Denmark. Tel.: +45 38647072 / +45 22755843; Fax: +45 38647077;
E-mail: [email protected]
Search for more papers by this authorDitte Dencker
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Shared first authorship.Search for more papers by this authorAnna Molander
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Shared first authorship.Search for more papers by this authorMorgane Thomsen
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Search for more papers by this authorChantal Schlumberger
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Search for more papers by this authorGitta Wortwein
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Search for more papers by this authorPia Weikop
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Search for more papers by this authorHelene Benveniste
Department of Anesthesiology, Yale University, New Haven, Connecticut
Search for more papers by this authorNora D. Volkow
Laboratory for Neuroimaging, National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, Maryland
Search for more papers by this authorCorresponding Author
Anders Fink-Jensen
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
Reprint requests: Anders Fink-Jensen, Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, Edel Sauntes Allé 10, DK-2100 Copenhagen, Denmark. Tel.: +45 38647072 / +45 22755843; Fax: +45 38647077;
E-mail: [email protected]
Search for more papers by this authorAbstract
Background
Alcohol use disorder is underdiagnosed and undertreated, and up to 50% of alcohol-abstinent patients diagnosed with alcohol dependence relapse within the first year of treatment. Current treatments for the maintenance of alcohol abstinence in patients with alcohol use disorder have limited efficacy, and there is an urgent need for novel treatment strategies. Decreased cerebral glucose metabolism and increased brain uptake of acetate were recently reported in heavy drinkers, relative to controls. Given the switch of metabolic fuel from glucose to acetate in the alcohol-dependent brain, we investigated the potential therapeutic benefit of a ketogenic diet in managing alcohol withdrawal symptoms during detoxification.
Methods
Male Sprague Dawley rats fed either ketogenic or regular diet were administered ethanol or water orally, twice daily for 6 days while the diet conditions were maintained. Abstinence symptoms were rated 6, 24, 48, and 72 hours after the last alcohol administration.
Results
Maintenance on a ketogenic diet caused a significant decrease in the alcohol withdrawal symptoms' “rigidity” and “irritability.”
Conclusions
Our preclinical pilot study suggests that a ketogenic diet may be a novel approach for treating alcohol withdrawal symptoms in humans.
Graphical Abstract
The potential therapeutic benefit of a ketogenic diet in managing alcohol withdrawal symptoms during detoxification was investigated. Rats fed either ketogenic or regular diets were administered ethanol or water orally, and abstinence symptoms were rated after the last alcohol administration. Maintenance on a ketogenic diet caused a significant decrease in the alcohol withdrawal symptoms ‘rigidity’ and ‘irritability’, suggesting that a ketogenic diet may be a novel approach for treating alcohol withdrawal symptoms in humans.
References
- American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Publishing, Arlington, VA.
10.1176/appi.books.9780890425596 Google Scholar
- Barrick C, Connors GJ (2002) Relapse prevention and maintaining abstinence in older adults with alcohol-use disorders. Drugs Aging 19: 583–594.
- Becker HC (2000) Animal models of alcohol withdrawal. Alcohol Res Health 24: 105–113.
- Brower KJ (2015) Assessment and treatment of insomnia in adult patients with alcohol use disorders. Alcohol 49: 417–427.
- Bueno NB, de Melo ISV, de Oliveira SL, da Rocha Ataide T (2013) Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr 110: 1178–1187.
- Centers for Disease Control and Prevention (2016) Fact Sheets - Alcohol Use and Your Health. Available at: http://www.cdc.gov/alcohol/fact-sheets/alcohol-use.htm. Accessed September 25, 2017.
- Connor JP, Haber PS, Hall WD (2016) Alcohol use disorders. Lancet 387: 988–998.
- Cruz NF, Lasater A, Zielke HR, Dienel GA (2005) Activation of astrocytes in brain of conscious rats during acoustic stimulation: acetate utilization in working brain. J Neurochem 92: 934–947.
- De Feyter HM, Behar KL, Rao JU, Madden-Hennessey K, Ip KL, Hyder F, Drewes LR, Geschwind JF, de Graaf RA, Rothman DL (2016) A ketogenic diet increases transport and oxidation of ketone bodies in RG2 and 9L gliomas without affecting tumor growth. Neuro Oncol 18: 1079–1087.
- Derr RF (1983) Suppression of an ethanol withdrawal syndrome in rats by butyrate, lactate and beta-hydroxybutyrate. Life Sci 32: 2551–2554.
10.1016/0024-3205(83)90237-0 Google Scholar
- Derr RF (1984) The ethanol withdrawal syndrome: a consequence of lack of substrate for a cerebral Krebs-cycle. J Theor Biol 106: 375–381.
10.1016/0022-5193(84)90036-5 Google Scholar
- Gibson AA, Seimon RV, Lee CM, Ayre J, Franklin J, Markovic TP, Caterson ID, Sainsbury A (2015) Do ketogenic diets really suppress appetite? A systematic review and meta-analysis. Obes Rev 16: 64–76.
- Glickman ME, Sowmya RR, Schultz MR (2014) False discovery rate control is a recommended alternative to Bonferroni-type adjustments in health studies. J Clin Epidemiol 67: 850–857.
- Hall W, Zador D (1997) The alcohol withdrawal syndrome. Lancet 349: 1897–1900.
- Hogg S (1996) A review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacol Biochem Behav 54: 21–30.
- Jiang L, Gulanski BI, De Feyter HM, Weinzimer SA, Pittman B, Guidone E, Koretski J, Harman S, Petrakis IL, Krystal JH, Mason GF (2013) Increased brain uptake and oxidation of acetate in heavy drinkers. J Clin Invest 123: 1605–1614.
- Jiang L, Mason GF, Rothman DL, de Graaf RA, Behar KL (2011) Cortical substrate oxidation during hyperketonemia in the fasted anesthetized rat in vivo. J Cereb Blood Flow Metab 31: 2313–2323.
- Jiang Y, Yang Y, Wang S, Ding Y, Guo Y, Zhang MM, Wen SQ, Ding MP (2012) Ketogenic diet protects against epileptogenesis as well as neuronal loss in amygdaloid-kindling seizures. Neurosci Lett 508: 22–26.
- Jin H, Rourke SB, Patterson TL, Taylor MJ, Grant I (1998) Predictors of relapse in long-term abstinent alcoholics. J Stud Alcohol 59: 640–646.
- Laramée P, Kusel J, Leonard S, Aubin HJ, François C, Daeppen JB (2013) The economic burden of alcohol dependence in Europe. Alcohol Alcohol 48: 259–269.
- Litten RZ, Egli M, Heilig M, Cui C, Fertig JB, Ryan ML, Falk DE, Moss H, Huebner R, Noronha A (2012) Medications development to treat alcohol dependence: a vision for the next decade. Addict Biol 17: 513–527.
- Little HJ, Stephens DN, Ripley TL, Borlikova G, Duka T, Schubert M, Albrecht D, Becker HC, Lopez MF, Weiss F, Drummond C, Peoples M, Cunningham C (2005) Alcohol withdrawal and conditioning. Alcohol Clin Exp Res 29: 453–464.
- Majchrowicz E, Hunt WA (1976) Temporal relationship of the induction of tolerance and physical dependence after continuous intoxication with maximum tolerable doses of ethanol in rats. Psychopharmacology (Berl) 50: 107–112.
- Nutt DJ, King LA, Phillips LD (2010) Drug harms in the UK: a multicriteria decision analysis. Lancet 376: 1558–1565.
- Parry CD, Patra J, Rehm J (2011) Alcohol consumption and non-communicable diseases: epidemiology and policy implications. Addiction 106: 1718–1724.
- Probst C, Roerecke M, Behrendt S, Rehm J (2014) Socioeconomic differences in alcohol-attributable mortality compared with all-cause mortality: a systematic review and meta-analysis. Int J Epidemiol 43: 1314–1327.
- Puchalska P, Crawford PA (2017) Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab 25: 262–284.
- Rho JM, Kim DW, Robbins CA, Anderson GD, Schwartzkroin PA (1999) Age-dependent differences in flurothyl seizure sensitivity in mice treated with a ketogenic diet. Epilepsy Res 37: 233–240.
- Ribeiro LC, Chittó AL, Müller AP, Rocha JK, Castro da Silva M, Quincozes-Santos A, Nardin P, Rotta LN, Ziegler DR, Gonçalves CA, Da Silva RS, Perry ML, Gottfried C (2008) Ketogenic diet-fed rats have increased fat mass and phosphoenolpyruvate carboxykinase activity. Mol Nutr Food Res 52: 1365–1371.
- Riihioja P, Jaatinen P, Oksanen H, Haapalinna A, Heinonen E, Hervonen A (1997) Dexmedetomidine alleviates ethanol withdrawal symptoms in the rat. Alcohol 14: 537–544.
- Sarkola T, Iles MR, Kohlenberg-Mueller K, Eriksson CJP (2002) Ethanol, acetaldehyde, acetate, and lactate levels after alcohol intake in white men and women: effect of 4-methylpyrazole. Alcohol Clin Exp Res 26: 239–245.
- Schreckenberger M, Lange-Asschenfeldt C, Lochmann M, Mann K, Siessmeier T, Buchholz HG, Bartenstein P, Gründer G (2004) The thalamus as the generator and modulator of EEG alpha rhythm: a combined PET/EEG study with lorazepam challenge in humans. NeuroImage 22: 637–644.
- Sinha R (2007) The role of stress in addiction relapse. Curr Psychiatry Rep 9: 388–395.
- Stafford P, Abdelwahab MG, Kim DY, Preul MC, Rho JM, Scheck AC (2010) The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutr Metab 7: 74.
- Stubbs BJ, Cox PJ, Evans RD, Cyranka M, Clarke K, de Wet HA (2017) A ketone ester drink lowers human ghrelin and appetite. Obesity doi: 10.1002/oby.22051 [Epub ahead of print].
10.1002/oby.22051 Google Scholar
- Substance Abuse and Mental Health Services Administration (2014) Behavioral Health Trends in the United States: Results from the 2014 National Survey on Drug Use and Health. Available at: www.samhsa.gov/data/sites/default/files/NSDUH-FRR1-2014/NSDUH-FRR1-2014.pdf. Accessed September 25, 2017.
- Ulrichsen J, Clemmesen L, Flachs H, Hemmingsen R (1986) The effect of phenobarbital and carbamazepine on the ethanol withdrawal reaction in the rat. Psychopharmacology 89: 162–166.
- Volkow ND, Hitzemann R, Wolf AP, Logan J, Fowler JS, Christman D, Dewey SL, Schlyer D, Burr G, Vitkun S, Hirschowitz J (1990) Acute effects of ethanol on regional brain glucose metabolism and transport. Psychiatry Res 35: 39–48.
- Volkow ND, Kim SW, Wang GJ, Alexoff D, Logan J, Muench L, Shea C, Telang F, Fowler JS, Wong C, Benveniste H, Tomasi D (2013) Acute alcohol intoxication decreases glucose metabolism but increases acetate uptake in the human brain. NeuroImage 64: 277–283.
- Volkow ND, Wang GJ, Franceschi D, Fowler JS, Thanos PP, Maynard L, Gatley SJ, Wong C, Veech RL, Kunos G, Kai Li T (2006) Low doses of alcohol substantially decrease glucose metabolism in the human brain. NeuroImage 29: 295–301.
- Volkow ND, Wang GJ, Hitzemann R, Fowler JS, Wolf AP, Pappas N, Biegon A, Dewey SL (1993) Decreased cerebral response to inhibitory neurotransmission in alcoholics. Am J Psychiatry 150: 417–422.
- Volkow ND, Wang GJ, Shokri Kojori E, Fowler JS, Benveniste H, Tomasi D (2015) Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases. J Neurosci 35: 3248–3255.
- Wang GJ, Volkow ND, Franceschi D, Fowler JS, Thanos PK, Scherbaum N, Pappas N, Wong CT, Hitzemann RJ, Felder CA (2000) Regional brain metabolism during alcohol intoxication. Alcohol Clin Exp Res 24: 822–829.
- WHO (World Health Organization) (2014) Global status report on alcohol and health 2014. Available at: who.int/iris/bitstream/10665/112736/1/9789240692763_eng.pdf?ua=1&ua=1 Accessed September 25, 2017.
- Wibisono C, Rowe N, Beavis E, Kepreotes H, Mackie FE, Lawson JA, Cardamone M (2015) Ten-year single-center experience of the ketogenic diet: factors influencing efficacy, tolerability, and compliance. J Pediatr 166: 1030–1036.
- Williams D, Lewis J, McBride A (2001) A comparison of rating scales for the alcohol withdrawal syndrome. Alcohol Alcohol 26: 104–108.
- de Wit H, Metz J, Wagner N, Cooper M (1990) Behavioral and subjective effects of ethanol: relationship to cerebral metabolism using PET. Alcohol Clin Exp Res 14: 482–489.
- World Health Organization (2011) International Statistical Classification of Diseases and Related Health Problems. 10th revision. World Health Organization, Geneva, Switzerland.
