Metabolic Ketosis As a Potential Treatment for Alcohol Use Disorder

Metabolic ketosis as a potential treatment for alcohol use disorder

Corinde E. Wiers, PhD Assistant Professor of Psychiatry

BSc PsychoBiology, BSc MSc Psychology (2010) University of Amsterdam, Sussex University Mentors: Dr. Duka, Dr. Stephens

PhD Psychology (2014) Berlin School of Mind and Brain Mentors: Dr. Bermpohl, Dr. Heinz

Postdoctoral Fellow (2014-2020) NIH/NIAAA Bethesda Mentor: Dr. Volkow Alcohol Use Disorder

• Worldwide, 3 million deaths every year result from harmful alcohol use (5.3 %) WHO, 2018 • Over 1 in 7 Americans are estimated to develop an AUD in their life Grant, 2015 JAMA • 31.4% increase in alcohol sales during COVID19 lockdown in UK The Lancet Gastroenterology Hepatology, July 2020 • There is an urgent need for interventions that can promote long-term abstinence and reduce alcohol craving Research Objectives

• Study neurobiological basis of AUD using neuroimaging to explore targets for treatment

• Utilize neuroimaging to capture treatment effects in AUD Research Overview

Dopaminergic system Neuroinflammation TSPO: PET 11C PBR28 Alcohol Cue reactivity, fMRI

Dopamine D2/D3: PET 11C Raclopride Metabolism Neurogenetics Glucose metabolism (FDG)

DAT1 methylation, PET 11C Cocaine

Genetic ancestry 11C Acetate, MRS Talk Outline

Part 1: K99 Brain metabolism and alcohol withdrawal Part 2: R00 Brain metabolism and alcohol consumption

Part 3: B2B proposal Brain metabolism and alcohol tolerance

Part 4: Future Directions

6 Talk Outline

Part 1: K99 Brain metabolism and alcohol withdrawal Part 2: R00 Brain metabolism and alcohol consumption

Part 3: B2B proposal Brain metabolism and alcohol tolerance

Part 4: Future Directions

7 Talk Outline

Part 1: K99 Brain metabolism and alcohol withdrawal Part 2: R00 Brain metabolism and alcohol consumption

Part 3: B2B proposal Brain metabolism and alcohol tolerance

Part 4: Future Directions

8 Talk Outline

Part 1: K99 Brain metabolism and alcohol withdrawal Part 2: R00 Brain metabolism and alcohol consumption

Part 3: B2B proposal Brain metabolism and alcohol tolerance

Part 4: Future Directions

9 1. Brain metabolism and alcohol withdrawal

Effects of a ketogenic diet on alcohol withdrawal in AUD - K99

Wiers, Vendruscolo …. Koob, Volkow, under review Effects of acute alcohol on brain glucose metabolism and brain acetate uptake Placebo Alcohol

Brain Glucose Metabolism (FDG)

Brain Acetate Uptake (11C Acetate) • Alcohol decreases glucose metabolism, increases acetate • Acetate metabolism was higher in heavy drinkers than controls

Volkow et al., NeuroImage 2013; Shokri-Kojori et al., 2019 During sobriety, heavy drinkers During sobriety, heavy show higher acetate uptake drinkers show lower brain compared to social drinkers glucose metabolism

13C acetate

AUD < Control

Volkow, Wiers et al, 2017 Jiang L, et al, 2013 J Clin Investigation Tomasi, Wiers et al, 2019 Relevance to AUD treatment

During prolonged detoxification, decrease in acetate may result in an energy-deficient state in the brain that could contribute to neurotoxicity and enhanced neuronal excitability in AUD

Low acetate High acetate Detox

Low glucose High glucose Ketogenic Diet • High fat, low carbohydrate diet • Frequently used for reducing seizures in epilepsy • Metabolic Ketosis: cells are using ketone bodies for fuel rather than glucose: aceto-acetate, β-hydroxybutyrate and acetone

Diet compositions Grams of fat: protein+carbohydrates Ketogenic diet and alcohol withdrawal • KD reduces withdrawal in rats Derr, 1981 • KD lowers body rigidity and irritability during detox:

Dencker, Fink-Jenssen et al ACER, 2018 n=48, 12 per group Aims and Hypotheses

• To assess effects of KD in human AUD on:

Aim 1 Withdrawal symptoms (CIWA), benzodiazepine use and alcohol craving H: KD reduces withdrawal symptoms, need for benzodiazepines, and craving

Aim 2 Ketone bodies in brain using 1H-MRS H: Ketones in brain mediate effects of KD on withdrawal and craving Methods • Patients with AUD undergoing detoxification and inpatient treatment (N=33) • Within 2 days: randomly assigned to KD or Standard American (double blind) for 3 weeks • Daily withdrawal and craving ratings • Weekly 1H-MRS scans, fMRI Alcohol Cue Reactivity

Anterior Cingulate Cortex Frontal White Matter Methods: KD/SA diet (isocaloric) • Shakes: chocolate, blueberry, raspberry, strawberry, and peanut butter • Snacks: o Avocado Dip with Veggies o Beef Broth o Cauliflower and Cheese (low carb version of mac and cheese) o Buffalo Chicken Dip o Chicken Broth o Chocolate Mousse o Salad o Scrambled Eggs o Tuna and Celery o Vegetable Broth o Yogurt and Pecans Current sample

Randomized n=53 (3:2 KD:SA ratio) Excluded/ withdrawn n=20 Completed 3 weeks of diet Ongoing n=0 n=33

KD n=19 SA n=14 Sample characteristics KD n=19 SA n=14 p-value Age 39.3 ± 11 44.2 ± 16 .31 Sex 7 F, 12 M 3 F, 11 M .34 BMI 24.5 ± 3 27.5 ± 5 .051 Weight loss during 3- 1.4 ± 3 1.8 ± 2 0.69 week study (kg) Max CIWA withdrawal at 9.9 ± 6 7.9 ± 4 .23 admission Drinks/day 15.2 ± (8) 17.0 ± (10) .58 Heavy Drinking years 12.5 ± 8 15.9 ± 8 .24 Days since last drink at 0.2 ± 0.2 0.4 ± 0.3 .49 admission Urine and blood ketones

160 6 KD (n=19) 140 SA (n=14) 120

100 4

60 KD (n=19) 2 40 *** SA (n=14) Urinary AcAc (mg/dL) 20 * * * * BHB serum (mM) 0 0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 BL Week 1 Week 2 Week 3 Days of detoxification 1H-MRS brain ketones

KD (n=19) 0.15 0.08 KD (n=19) SA (n=14)

SA (n=14) 0.06 0.10 * 0.04

0.05 * * * 0.02

0.00 0.00

Week 1 Week 2 Week 3 AcAc/Cre concentration Week 1 Week 2 Week 3 Acetone/Cre concentration

However, no reliable measures of BHB with standard PRESS sequence End of diet evaluation

No effect of diet expectation X2=0.14, p=0.71

Pleasant (0-10) Improve Health (0-10)

10 10 Expect SA * Expect SA Expect KD 8 Expect KD

6 5 4

0 0

KD SA KD SA * Interaction diet x diet expectation for pleasantness (F=7.6, p=0.01)

1 2 1 2 Benzodiazepine intake: dose Diazepam: Oxazepam 1:3 cumulative dose 800 before diet start diet 100 600 KD (n=19) 400 80 SA (n=14) 200

60 oxazepam (mg) 0 KD SA 40 ^ * cumulative dose after 20 800 diet intiation KD Oxazepam (mg) ^ SA 0 600 adm 1 2 3 4 5 6 400

Significant effect of diet x time (F=2.6, p=0.01), 200 with KD showing lower benzodiazepine use oxazepam (mg) 0 after diet initiation KD SA Benzodiazepine intake

Admission Day 2

Benzo No Benzo Benzo No Benzo ^ 100 100 % % 50 50

84 % 79 % 262626 % %% 6457 % 0 0 KD SA KD SA After diet initiation, there was a trend effect of fewer AUD inpatients needing benzodiazepines in the KD group compared to SA (X2=3.2, p=0.073)

1 2 1 2 Alcohol withdrawal: CIWA score before diet 30 initiation

start diet 20 15 KD (n=19) 10

SA (n=14) CIWA max 10 0 KD SA after diet 5 30 intiation KD SA Daily Max CIWA 0 20 initial1 2 3 4 5 6 7 8 9 10 CIWA max

0 KD SA Benzodiazepines are prescribed when CIWA is =>8, which may explain lack of effect of KD on withdrawal Desire for Alcohol Questionnaire (craving)

KD (n=19) 25 SA (n=14)

DAQ craving ^ 15 Week 1 Week 2 Week 3

^ Self-reported alcohol craving on the Desire for Alcohol Questionnaire reduced in KD at trend level (t=1.9, p=0.07) but not in the SA group (t=.9, p=0.4) Alcohol cue-induced brain reactivity

3T fMRI Subjective ratings: How much do you want this right now? (-3 – 3)

40 alcohol 40 food cues cues

KD KD 0.5 3.0 SA SA 0.0 2.5

-0.5 2.0 -1.0 * 1.5 -1.5 Week 1 Week 2 Week 3 Week 1 Week 2 Week 3

-2.0 “Wanting” food cues 1.0 “Wanting” alcohol cues

* “Wanting” ratings of alcohol > neutral cues used in the fMRI cue reactivity task reduced in the KD group (t=3.4, p=0.003) but not in SA (t=.84, p=0.42), and the interaction effect of time x group was significant (F=4.9, p=0.048). No effects for food cues. Group x time interaction in dorsal ACC

Alcohol > Neutral cues KD (n=18) 4 SA (n=14)

-2 dACC (A>N) Week 1 Week 2 Week 3

-4 Food > Neutral cues KD (n=18) 4 SA (n=14)

-2 dACC (F>N) Week 1 Week 2 Week 3

-4 dACC responses to both alcohol and food cues increased in KD versus SA. Region implicated in self-control and processing salience attribution. A B

KD’s effect on other metabolites

C 0.15 D 0.08 KD SA 0.06 0.10 0.04 * 0.05 AcAc/Cr KD Acetone/Cr 0.02 * * SA 0.00 * 0.00 Week 1 Week 2 Week 3 Week 1 Week 2 Week 3 E F 1.5 KD 1.9 KD SA SA 1.7 KD increased Glutamate 1.3 and Glutamine – 1.5 Glx/Cr Glu/Cr 1.1 * * # alternative energy source? 1 * 1.3 0 0.0 Week 1 Week 2 Week 3 Week 1 Week 2 Week 3 G H 0.9 0.30 KD decreased myo- * * # # inosytol and Choline – * 0.25 0.7 markers of mI/Cr KD Cho/Cr 0.20 KD neuroinflammation? 0.5 SA 0.2 SA 0.0 0.0 Week 1 Week 2 Week 3 Week 1 Week 2 Week 3 Summary

• First KD intervention study in human AUD: 4:1 KD diet well tolerated • KD lowers benzodiazepine intake and (hence) no effect on withdrawal • KD reduced “wanting” of alcohol cues, and alcohol craving at trend level • KD increased Acetone and AcAc in dACC, and elevated reactivity to alcohol cues may indicate enhanced control over alcohol Many thanks to:

Nora Volkow Michele Yonga Nancy Diazgranados Gene-Jack Wang Dani Kroll Kimberly Herman Ehsan Shokri-Kojori Dana Feldman Ted George Pete Manza Erin Biesecker Yvonne Horneffer Rui Zhang Katherine McPherson Mackenzie Cervenka Dardo Tomasi Sara Turner Melanie Schwandt Sukru Baris Demiral Shanna Yang George Koob Jan-Willem vd Veen Richard Veech Leandro Vendruscolo Talk Outline

Part 1: K99 Brain metabolism and alcohol withdrawal Part 2: R00 Brain metabolism and alcohol consumption

Part 3: B2B proposal Brain metabolism and alcohol tolerance

Part 4: Future Directions

34 Does ketosis influence alcohol consumption? A

B C 60 # n=36200 Wistar rats 80 150 45 * 40 100 30 0 50 15

Reinforcers/30min Alcohol vapor - Chow 0 0 Alcohol vapor - KD 2 3 4 5 6 7 1 2 3 4 5 6 7 8 9 1011 121314 Blood alcohol levels (mg/dL) Air - Chow Weeks of vapor Self-administration session Air - KD

Wiers, Vendruscolo …. Koob, Volkow, under review Does ketosis influence alcohol consumption? A

B C n=18 KD # 200 n=1860 Chow 80 for 2 months 150 45 * 40 100 30 0 50 15

Reinforcers/30min Alcohol vapor - Chow 0 0 Alcohol vapor - KD 2 3 4 5 6 7 1 2 3 4 5 6 7 8 9 1011 121314 Blood alcohol levels (mg/dL) Air - Chow Weeks of vapor Self-administration session Air - KD

Wiers, Vendruscolo …. Koob, Volkow, under review Does ketosis influence alcohol consumption? A

B C # 200 60 80

150 45 * 40 100 30 Alcohol or air for 7 0 50 weeks 15

Reinforcers/30min Alcohol vapor - Chow 0 0 Alcohol vapor - KD 2 3 4 5 6 7 1 2 3 4 5 6 7 8 9 1011 121314 Blood alcohol levels (mg/dL) Air - Chow Weeks of vapor Self-administration session Air - KD

Wiers, Vendruscolo …. Koob, Volkow, under review Does ketosis influence alcohol consumption? A

B C # 200 60 80

150 45 * 40 100 30 0 50 15

Reinforcers/30min Alcohol vapor - Chow 0 0 Alcohol vapor - KD 2 3 4 5 6 7 1 2 3 4 5 6 7 8 9 1011 121314 Blood alcohol levels (mg/dL) Air - Chow Weeks of vapor Self-administration session Air - KD

History of KD lowers alcohol consumption

Wiers, Vendruscolo …. Koob, Volkow, under review R00 proposal

Aim 1: to test whether metabolic ketosis decreases alcohol consumption in AUD outpatients H: ketosis lowers alcohol consumption

Aim 2: to measure effects of metabolic ketosis on brain ketone bodies H: Ketones in brain mediate effects of ketosis on alcohol consumption

Blood ketones in KD vs Ketone Ester

K99: Ketogenic Diet in AUD N=1 Ketone Ester “pilot” data

6 KD (n=19) 6 SA (n=14)

4 4

2 2 BHB serum (mM) BHB serum (mM) 0 0 BL Week 1 Week 2 Week 3 Baseline 30 min 120 min

Comparable BHB levels 2-weeks diet versus 30 mins after HVMN ketone ester Proposed R00 Design at Penn n = 20 AUD patients (non-treatment seeking) n = 20 Healthy volunteers

Visit 1 Ketone Ester Random order: 2-way crossover Visit 2 Placebo R00 Design: study visits

Curve from Stubbs et al, 2018 1-hr MRI scan (3T Prisma - Hup6)

• T1/T2 • fMRI Alcohol Cue Reactivity H: Ketone Ester normalizes cue-induced craving and brain reactivity • MRS: BHB edited sequence • H: Faster elevation of BHB in AUD patients than controls Alcohol self administration: Bar lab

Priming drink Each participant received 16$ with which they could purchase 8 alcoholic BrAC to 0.02- mini-drinks (2$ each) over the course of 0.03 g/dL 2 hours (max BrAC .1g/dL) OR keep the money

O’Malley, 2002 Talk Outline

Part 1: K99 Brain metabolism and alcohol withdrawal Part 2: R00 Brain metabolism and alcohol consumption

Part 3: B2B proposal Brain metabolism and alcohol tolerance

Part 4: Future Directions

46 Bench to Bedside proposal (pending)

To test the effect of metabolic ketosis on (1) brain Acetoacetate ([11C]AcAc) in AUD H: KE-induced uptake of [11C]AcAc will be faster in AUD than controls, reflecting enhanced brain uptake of AcAc as an alternative to glucose as an energy source in alcohol dependence (2): alcohol tolerance in AUD H: Individuals with AUD will be more sensitive to the effects of alcohol PET scan design

AcAc FDG Pre KE

Post KE

Courchesne-Loyer 2017 Talk Outline

Part 1: K99 Brain metabolism and alcohol withdrawal Part 2: R00 Brain metabolism and alcohol consumption

Part 3: B2B proposal Brain metabolism and alcohol tolerance

Part 4: Future Directions

49 Future Directions

• Collaboration with Paco Bravo: effects of Ketone Ester on Glucose/AcAc metabolism in heart and liver etc (whole body PET scan) • Larger clinical trial of KD or KE on alcohol consumption in AUD patients • Effects of metabolic ketosis on NAD+/NADH (brain energy) in AUD (31P-MRS) Thank you!

Hank Kranzler Nora Volkow David Mankoff Leandro Vendruscolo Reagan Wetherill George Koob Anna Rose Childress Todd King Jacob Dubroff Robert Mach Robert Doot Erin Schubert Zhenhao Shi Tim Pond