Does a Ketogenic Dietary Supplement Reduce Alcohol Withdrawal Symptoms in Humans?

Inclusion Criteria KME trial

1. Between 18 and 70 years of age.

2. Ability to provide written informed consent as determined by the physical examination and verbal communication. The capacity to consent will be determined by study personnel.

3. Alcohol-dependent individuals must meet alcohol dependency syndrome criteria according to ICD-10 and alcohol use disorder according to DSM-5, have a score >15 on the Alcohol Use Disorder Identification Test (AUDIT) and a history of previous treatment for alcohol withdrawal syndrome following cessation of alcohol use.

Inclusion Criteria Healthy Volunteers for MRS sub-study

1. Between 18 and 70 years of age.

2. Ability to provide written informed consent as determined by the physical examination and verbal communication. The capacity to consent will be determined by study personnel.

3. Light drinkers (LD): Alcohol consumption less than 7 drinks per week typically over the past year and no more than three drinks per occasion. AUDIT score below 7 in the Alcohol Use Disorder Identification Test.

4. Heavy drinkers (HD): Not treatment-seeking and not fulfilling criteria for alcohol dependence syndrome according to ICD-10 or alcohol use disorder according to DSM-5. For at least one-year consuming alcohol at a typical rate of above a level of 14 drinks per week for men and consume at least 4 drinks per day at least once per week. For females, consume alcohol in excess of 11 drinks per week and exceed 3 drinks per day at least once per week.

5. Long term sober (LTS): For the long-term sober group, a previous diagnosis of alcohol dependence, consumed no alcohol in the previous 6 months.

Exclusion Criteria KME trial and MRS sub-study

1. Diagnosis of current psychiatric disorder that is deemed not stable by the study physician, except for the following:

• Diagnosis of nicotine dependence

• Alcohol withdrawal patients may have a diagnosis of alcohol dependence

• HD may have a diagnosis of alcohol abuse

2. Lifetime diagnosis of bipolar disorder, schizophrenia, paranoid psychosis or mental retardation.

3. Incapable of understanding and/or speaking Danish.

4. Head trauma with loss of consciousness for more than 60 minutes (self-report, medical history).

5. Lifetime diagnosis of epilepsy.

6. Alcohol withdrawal seizures within the previous 3 months.

7. Use of any medication that could interfere with study assessments, including anticonvulsants, benzodiazepines and non-benzodiazepine hypnotics (Zopiclone and/or Zolpidem). Use of medications will be reviewed by a study physician on a case by case basis.

8. Body Mass Index, BMI, < 18.5 kg/m2 or body weight <60 kg or >120kg.

9. Urine positive for cocaine, amphetamines, methadone, opioids or benzodiazepines.

10. Blood glucose >12.2 mmol/L on finger-prick measurement (>7.0 if over-night fasted).

11. Known kidney disease, pancreatic disease, porphyria or other mitochondrial diseases, type 1 diabetes, type 2 diabetes or any other history of severe somatic illness that the investigator believes would interfere with trial participation.

12. Known cirrhosis or clinical evidence of significant liver disease, such as ascites or hepatosplenomegaly.

13. Following a low-carbohydrate diet, intermittent fasting diet or consuming nutritional ketone supplements.

14. Other substance use dependency than alcohol and/or nicotine and/or cannabis within the previous 1 month.

15. Benzodiazepine dependence within the previous 1 month and/or use of benzodiazepines within the previous 14 days.

16. Females of childbearing potential who are pregnant, breast-feeding or have intention of becoming pregnant within the next 4 months, or are not using contraceptives (during the whole study period) considered as highly effective (combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) intrauterine device - IUD, IUS, bilateral tubal occlusion, vasectomized partner, sexual abstinence) (HMA - Clinical Trials Facilitation and Coordination Group, 2014).

17. Participated in a clinical trial with investigational medication or weight reduction within the previous three months.

18. Use of Disulfiram (Antabus) in the previous 14 days prior to any planned KME ingestion or MRS procedure.

19. For HD and LD groups in MRS sub-study only: Inability to abstain from alcohol for 24 hours, to reduce risks and to avoid confounding results with alcohol withdrawal.

20. For HD and LD in MRS sub-study only: History of alcohol use disorder or alcohol withdrawal symptoms requiring medication

21. For participants undergoing MRS (all HD, LD, and LTS, some KME patients): Implanted metallic devices or objects that could potentially prove harmful when exposed to the MRS environment or procedures. Patients in the alcohol withdrawal group can still participate in the KME study if meeting this criterion, but cannot undergo subsequent MRS.

22. Any condition that the investigator estimates would interfere with trial participation and/or the safety of the participant.