Leucine for Depression

Overseen By Diana Beltran, BS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Emory University

Must not be taking: Psychotropics, Sedatives, Benzodiazepines, others

Disqualifiers: Psychotic disorders, Mania, Substance use, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

75 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how the amino acid leucine affects brain function and behavior in individuals with moderate to severe depression. Researchers compare leucine with another amino acid, lysine, over a 6-week period to determine which has a more positive impact on depression symptoms. Individuals diagnosed with major depression and experiencing significant symptoms might be suitable candidates for this study. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as immune-active medications, antibiotics, steroids, supplements affecting the immune system, and psychotropic medications, before participating. Stabilized medications for general medical conditions are allowed if the dose remains the same during the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that L-leucine, a type of amino acid, has been tested in clinical trials to assess its effects on depression. One study examined its potential to reduce symptoms in people with major depressive disorder. Although the study did not provide detailed safety information, amino acids like leucine are generally safe for humans.

Some studies have found that large amounts of leucine can alter eating and growth patterns in animals, but this primarily occurs with diets very low in protein. For humans, leucine is a common component of food and supplements, suggesting it is usually safe when used correctly.

Lysine, another amino acid being compared in this trial, is also generally safe for humans. Both leucine and lysine are essential amino acids, meaning the body needs them to stay healthy, and they are usually well-tolerated.

In this trial, researchers are studying how leucine and lysine affect depression, and existing evidence supports their safety for human use. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for depression, like SSRIs and SNRIs, work by altering neurotransmitter levels in the brain. But L-leucine works differently, targeting metabolic pathways that may influence mood by affecting brain function directly. Unlike traditional antidepressants, which can take weeks to show effects, L-leucine has the potential to offer quicker relief due to its unique action on these pathways. Researchers are excited because this approach could provide an alternative for those who don’t respond well to existing medications. Additionally, the use of an amino acid like L-leucine suggests a novel and potentially safer treatment option with fewer side effects.

What evidence suggests that this trial's treatments could be effective for depression?

Research has shown that leucine, which participants in this trial may receive, might help reduce depression symptoms. One study found that people with major depressive disorder (MDD) experienced less severe depression when taking leucine compared to a placebo. Another study discovered that mice on a diet without leucine showed signs of improved mood, suggesting a possible connection between leucine levels and mood. Additionally, older women with moderate depression often lacked essential amino acids like leucine. These findings suggest that leucine might help improve mood and reduce depression. Meanwhile, researchers are studying L-lysine, another treatment option in this trial, as an active comparator. ^{1 2 3 6 7}

Who Is on the Research Team?

Ebrahim Haroon, MD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for adults with midlife depression who can consent, have a certain level of inflammation (CRP >1 mg/L), and are diagnosed with major depression. They must experience moderate to severe symptoms, be within a specific weight range (BMI 20-35), and have no issues that prevent MRI scans. Participants need support for post-procedure transport and should not have significant EKG findings.

Inclusion Criteria

I have been diagnosed with major depression.

Able and willing to provide informed consent

SHAPS score >30 on the 0-56 scale

Exclusion Criteria

I haven't taken immune-affecting drugs, steroids, certain supplements, or specific psychiatric meds recently.

My medications for other conditions are stable and won't change during the trial.

Cognitive: Cognitive impairment (MMSE score <28)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either leucine or lysine supplements for 6 weeks to assess changes in brain chemistry and behavior

6 weeks

Weekly visits for assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• L-leucine
• L-lysine

Trial Overview The study examines the impact of leucine on brain function and mood in people with midlife depression over six weeks, comparing it against lysine as an active comparator. It aims to understand how leucine affects brain chemistry, connectivity, and depressive behavior.

How Is the Trial Designed?

Group I: L-leucine Experimental Treatment 1 Intervention

Group II: L-lysine Active Control 1 Intervention

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

L-tryptophan, as a precursor to serotonin, may be beneficial in treating mild depression and bipolar disorder that does not respond to standard treatments, based on its biochemical role and clinical trial evidence.

It has potential as a natural hypnotic and may improve mood in Parkinson's patients, while also enhancing the effects of certain antidepressants like monoamine oxidase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-tryptophan: a rational anti-depressant and a natural hypnotic? Boman, B.[2017]

Leucine administration in mice effectively blocked the entry of kynurenine into the brain, which is linked to inflammation-induced depression, demonstrating its potential as an antidepressant.

In experiments, leucine not only reduced brain kynurenine levels but also prevented depression-like behaviors induced by inflammation, suggesting a novel mechanism for its antidepressant effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice. Walker, AK., Wing, EE., Banks, WA., et al.[2022]

Women with a history of major depression showed impaired regulation of brain serotonin (5-HT) function when subjected to dieting-induced tryptophan depletion, indicating a potential vulnerability during dietary changes.

While dieting lowered plasma tryptophan levels in both groups, only women without a history of depression exhibited an increased prolactin response to tryptophan, suggesting that their serotonin regulation is more intact compared to those with a history of depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impaired regulation of brain serotonin function during dieting in women recovered from depression. Smith, KA., Williams, C., Cowen, PJ.[2019]

In a 4-week study involving about 40 in-patients, adding a tailored amino acid mixture to the antidepressant Remeron significantly improved depression symptoms compared to a placebo.

The amino acid treatment showed no side effects, which may enhance patient compliance and improve the overall benefit/risk ratio of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

"Add-On"-therapy with an individualized preparation consisting of free amino acids for patients with a major depression. Ille, R., Spona, J., Zickl, M., et al.[2018]

In a study of 58 patients with major depressive disorder, those receiving L-Carnosine in addition to citalopram showed significantly greater improvements in depression symptoms compared to the placebo group over six weeks, as measured by the Hamilton Depression Rating Scale.

L-Carnosine not only improved overall depression scores but also resulted in higher response and remission rates without increasing side effects, suggesting it is a safe and effective adjunct therapy for MDD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-Carnosine combination therapy for major depressive disorder: A randomized, double-blind, placebo-controlled trial. Araminia, B., Shalbafan, M., Mortezaei, A., et al.[2021]

In a double-blind placebo-controlled study involving hospitalized depressed patients, large doses of amino acid precursors levodopa and L-tryptophan did not lead to significant clinical improvement, as patients were unable to leave the hospital.

The study highlights the inconsistency in previous research regarding the effectiveness of amino acid precursors in treating depression, suggesting that these compounds may not be reliable treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amine precursors and depression. Mendels, J., Stinnett, JL., Burns, D., et al.[2019]

A systematic review and meta-analysis of various nutritional supplements as adjuncts to antidepressants found that omega-3 polyunsaturated fatty acids (n-3 PUFAs) and zinc showed significant efficacy in improving depression symptoms, based on multiple studies.

In contrast, the evidence for folic acid was not supportive of its efficacy, and while some positive results were noted for vitamin D, vitamin B12, and S-adenosyl-L-methionine (SAMe), the overall data for most supplements remains inconclusive or insufficient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of adding nutritional supplements in unipolar depression: A systematic review and meta-analysis. Schefft, C., Kilarski, LL., Bschor, T., et al.[2022]

In a double-blind study involving 16 depressive patients, L-tryptophan showed some antidepressant efficacy, with responses noted in 1 out of 10 unipolar patients and 3 out of 6 bipolar patients.

The study suggests that L-tryptophan, a precursor to serotonin, may interact with electrolyte systems, which could play a role in the development of mood disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-tryptophan in depression. Farkas, T., Dunner, DL., Fieve, RR.[2013]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03079297

NCT03079297 | Rapid Antidepressant Effects of Leucine Investigators hypothesize that MDD subjects will have greater reduction in depression severity on leucine as compared to placebo.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06580145?term=LEUCINE&viewType=Table&rank=1

Study Details | NCT06580145 | Leucine in Midlife Depression The study will use brain scans and symptom assessments to see if leucine improves brain function and reduces depression. If successful, this research could ...

3. news-medical.net news-medical.net/news/20230303/Leucine-deprivation-results-in-antidepressant-effects-study-shows.aspx

Leucine deprivation results in antidepressant effects, study ... In this study, leucine deficient diet was found to have antidepressant effects on chronic restraint stress-induced depression-related behaviors ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8623361/

Deficiency in the Essential Amino Acids l-Isoleucine, l-Leucine ... These findings suggest that elderly women classified as having moderate depressive symptoms displayed a deficiency in essential amino acids.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11748975/

Leucine deprivation results in antidepressant effects via GCN2 ... We demonstrate that although deprivation of the EAA leucine has no effect in unstressed mice, it remarkably reverses the depression-like behaviors.

6. sciencedirect.com sciencedirect.com/science/article/pii/S0022316623028535

The Nature of Human Hazards Associated with Excessive ... In studies on animals fed low-protein diets, excess leucine was shown to cause depression of food intake and growth (reviewed in ref. 1). However, this was ...

7. carlroth.com carlroth.com/downloads/sdb/en/3/SDB_3984_GB_EN.pdf

Safety Data Sheet: L-Leucine Uses advised against: Do not use for private purposes (household). Food, drink and animal feedingstuffs. 1.3. Details of the supplier of the safety data sheet.