Ketone Supplement + Diet for Bipolar Disorder

(BIPO Trial)

Recruiting at 1 trial location

Overseen By Jeff Bohnen, BSc

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Michigan

Must be taking: Mood stabilizers, Antipsychotics

Must not be taking: Insulin, THC products

Disqualifiers: Pregnancy, Diabetes, Substance use, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 13 weeks

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Small exploratory open-label pilot study to assess supplementation of a ketone ester (Juvenescence) combined with a 'ketogenic-mimicking diet' as a potential therapy for persons with bipolar disorder.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must be on a stable regimen of psychiatric medications, meaning no changes in mood stabilizers or antipsychotics for at least 4 weeks before joining.

Is the ketone supplement safe for humans?

Research shows that ketone supplements, like ketone monoesters and diesters, are generally safe and well-tolerated in healthy adults. Some mild side effects, such as gastrointestinal discomfort, have been reported, but no significant safety concerns were found in studies lasting up to 28 days. ^{1 2 3 4 5}

How does the Ketone Ester Beverage treatment for bipolar disorder differ from other treatments?

The Ketone Ester Beverage is unique because it elevates blood ketone levels quickly and safely without the need for a strict ketogenic diet, which can be difficult to maintain. This approach may offer a novel way to manage bipolar disorder by potentially improving brain energy metabolism, unlike traditional medications that primarily target neurotransmitter imbalances. ^{1 2 4 6 7}

What data supports the effectiveness of the treatment Ketone Supplement + Diet for Bipolar Disorder?

Research suggests that the ketogenic diet, which increases ketone levels in the body, may help stabilize mood in bipolar disorder due to its effects on brain energy and sodium levels. Additionally, ketone supplements have shown potential benefits for psychiatric disorders by improving mitochondrial function and reducing inflammation. ^{1 2 8 9 10}

Who Is on the Research Team?

Nicolaas Bohnen, MD

Principal Investigator

University of Michigan

Are You a Good Fit for This Trial?

Inclusion Criteria

My psychiatric medication has not changed in the last 4 weeks.

Able to provide informed consent

Regular access to smart phone capable of syncing biometric wearable data collection

Exclusion Criteria

I am currently being treated with insulin.

Use of marijuana or THC products more than once monthly on average

Inability to adhere to dietary changes as specified in protocol (e.g., not in control of food selection)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants follow a ketogenic-mimicking diet and consume ketone ester supplements for 90 +/- 10 days

13 weeks

Baseline, mid-intervention, and post-intervention assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ketone Ester Beverage
• Low Glycemic Index Diet

How Is the Trial Designed?

Group I: Bipolar Disorder Experimental Treatment 2 Interventions

Participants will follow an intervention consisting of dietary changes and ketone ester supplementation for 90 +/- 10 days. The dietary changes are intended to reduce glycemic spiking and include: not consuming sweets, not consuming soda, replacing 'white' grains with whole grain alternatives, and reserving any fruit consumption for the end of meals. During the same time period, participants will consume the ketone ester supplement, consisting of 19 g Juvenescence Cognitive Switch™ (=12.5 g active C8-KE) diluted in water twice per day.

Ketone Ester Beverage is already approved in United States, European Union for the following indications:

Approved in United States as Ketone Ester Beverage for:

• Exercise performance enhancement
• Adjunctive therapy for Parkinson's disease

Approved in European Union as Ketone Ester Beverage for:

• Exercise performance enhancement
• Adjunctive therapy for Parkinson's disease

Who Is Running the Clinical Trial?

University of Michigan

Lead Sponsor

Trials

1,891

Recruited

6,458,000+

Published Research Related to This Trial

The ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate effectively elevates blood ketone levels in healthy volunteers, reaching maximum plasma concentrations of 3.30 mM for β-hydroxybutyrate within 1-2 hours after ingestion.

This ketone monoester was generally well-tolerated over a 5-day period, although some gastrointestinal side effects were noted at higher doses, indicating it is a safe alternative to traditional ketogenic diets for enhancing physical and cognitive performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Clarke, K., Tchabanenko, K., Pawlosky, R., et al.[2022]

The ketogenic diet has shown significant efficacy in reducing seizure frequency in children with refractory epilepsy, with about two-thirds of patients experiencing a notable decrease and one-third becoming nearly seizure-free.

There is potential for the ketogenic diet to act as a mood stabilizer in bipolar disorder, as it may improve brain energy metabolism and reduce intracellular sodium levels, which are common mechanisms of effective mood stabilizers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The ketogenic diet may have mood-stabilizing properties. El-Mallakh, RS., Paskitti, ME.[2008]

In a 28-day study involving 59 healthy adults, the novel exogenous ketone diester bis-hexanoyl-(R)-1,3-butanediol (BH-BD) was found to be well-tolerated and safe, with no significant differences in tolerability scores compared to a placebo.

BH-BD effectively increased blood ketone levels one hour after consumption, indicating its potential for promoting nutritional ketosis without adverse effects on vital signs or laboratory measures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults. Chen, O., Blonquist, TM., Mah, E., et al.[2021]

A 48-week study involving 82 participants with Bipolar Disorder showed that a high n-3 plus low n-6 dietary intervention (H3-L6) significantly reduced variability in mood symptoms compared to a control diet, suggesting potential benefits for mood stability.

While the H3-L6 diet did not show significant differences in average mood ratings or other symptoms, it effectively altered the levels of n-3 and n-6 fatty acids over time, indicating a possible mechanism for its impact on mood variability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive dietary intervention for bipolar disorder: a randomized, controlled, parallel-group, modified double-blinded trial of a high n-3 plus low n-6 diet. Saunders, EFH., Mukherjee, D., Myers, T., et al.[2023]

Emerging evidence suggests that exogenous ketone supplements can induce nutritional ketosis, which may have therapeutic effects on psychiatric disorders by improving mitochondrial function and reducing inflammation.

Ketone supplementation elevates levels of ketone bodies that positively influence various metabolic pathways and cellular mechanisms, potentially offering a new approach to treating conditions like anxiety, depression, and ADHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Potential of Exogenous Ketone Supplement Induced Ketosis in the Treatment of Psychiatric Disorders: Review of Current Literature. Kovács, Z., D'Agostino, DP., Diamond, D., et al.[2020]

A study involving 24 healthy adults showed that consuming a ketone monoester three times a day for 28 days safely elevated blood ketone levels without affecting body weight, blood glucose, cholesterol, or kidney function.

The only reported side effect was mild nausea in a small number of instances, indicating that the ketone monoester is well-tolerated for sustained use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. Soto-Mota, A., Vansant, H., Evans, RD., et al.[2020]

Exogenous ketone drinks, such as ketone esters and ketone salts, effectively raise blood D-β-hydroxybutyrate (D-βHB) levels, with significant increases observed in a study of 15 participants, indicating a practical alternative to traditional ketogenic diets.

Both types of ketone drinks lowered blood glucose and triglyceride levels without causing adverse effects on blood electrolytes, suggesting they are safe and beneficial for metabolic health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

On the Metabolism of Exogenous Ketones in Humans. Stubbs, BJ., Cox, PJ., Evans, RD., et al.[2022]

In a study involving 18 adults with prediabetes, ingestion of the ketone monoester β-hydroxybutyrate (KEβHB) significantly elevated blood ketone levels and resulted in lower levels of remnant cholesterol and triglycerides, indicating potential cardiovascular benefits.

The positive effects on lipid profile were more pronounced in individuals with higher habitual saturated fat intake, suggesting that KEβHB may be particularly beneficial for those at risk of cardiovascular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of acute ketosis on lipid profile in prediabetes: findings from a cross-over randomized controlled trial. Liu, Y., Bharmal, SH., Kimita, W., et al.[2022]

The natural ketone body d-β-hydroxybutyrate (βHB) can potentially improve metabolic function and help manage chronic diseases like diabetes and Alzheimer's, and a new ingestible βHB monoester allows for rapid elevation of blood ketone levels without the downsides of traditional high-fat diets.

The βHB monoester has been shown to be safe for human consumption in studies involving athletes and healthy volunteers, and it may have specific applications in treating various conditions, including neurodegenerative diseases and heart failure, although further research is needed to fully understand its limitations and potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Why a d-β-hydroxybutyrate monoester? Soto-Mota, A., Norwitz, NG., Clarke, K.[2020]

Both powdered and ready-to-drink (RTD) formulations of the novel ketone ester BH-BD effectively induce ketosis in healthy adults, increasing blood beta-hydroxybutyrate (BHB) levels within approximately 15 minutes after consumption.

The study found that a higher dose of the powdered formulation (25g) resulted in significantly greater BHB concentrations compared to lower doses and the RTD version, but both formulations were equally effective in raising BHB levels without affecting blood glucose concentrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Novel Powder Formulation of the Ketone Ester, Bis Hexanoyl (R)-1,3-Butanediol, Rapidly Increases Circulating ß-Hydroxybutyrate Concentrations in Healthy Adults. Nieman, KM., Anthony, JC., Stubbs, BJ.[2023]

Citations

1. Netherlands pubmed.ncbi.nlm.nih.gov

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

The ketogenic diet may have mood-stabilizing properties. [2008]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults. [2021]

4. Denmark pubmed.ncbi.nlm.nih.gov

Adjunctive dietary intervention for bipolar disorder: a randomized, controlled, parallel-group, modified double-blinded trial of a high n-3 plus low n-6 diet. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Therapeutic Potential of Exogenous Ketone Supplement Induced Ketosis in the Treatment of Psychiatric Disorders: Review of Current Literature. [2020]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. [2020]

7. Switzerland pubmed.ncbi.nlm.nih.gov

On the Metabolism of Exogenous Ketones in Humans. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Effect of acute ketosis on lipid profile in prediabetes: findings from a cross-over randomized controlled trial. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Why a d-β-hydroxybutyrate monoester? [2020]

10. United States pubmed.ncbi.nlm.nih.gov

A Novel Powder Formulation of the Ketone Ester, Bis Hexanoyl (R)-1,3-Butanediol, Rapidly Increases Circulating ß-Hydroxybutyrate Concentrations in Healthy Adults. [2023]