A Dose Response Investigation of Docosahexaenoic Acid (DHA)

NCT06294067 | Completed Phase 1 DMC

• 1 other identifier: 43261
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 1

Brief Summary

Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (n-3 PUFA), commonly consumed from fish, that regulates many critical functions within the body including the brain, eye, and heart. While the metabolic precursor to DHA, alpha-linolenic acid (ALA) is considered nutritionally essential and has a set Dietary Reference Intake (DRI), DHA has not yet been deemed essential and does not have a set DRI. Currently, research suggests an intake range of dietary DHA to be anywhere from 0 to over 500mg/d. The aim of our study is to further investigate a feedback mechanism or accumulation that occurs with eicosapentaenoic acid (EPA) as a result of increased dietary DHA to provide insight for potential Recommended Dietary Intake (RDI) values. Hypothesis: The dietary DHA dose at which blood EPA levels increase is the point at which elongation slows, indicating a significant negative feedback pathway is present. Objectives: 1: To determine the dose-response for DHA to increase blood EPA levels in a mixed vegetarian and vegan population. 2: Investigate the DHA dose and time at dose that increases EPA using natural abundance delta carbon-13 (δ13C) as a tracer. 3: To measure DHA turnover and loss rates. 4: Provide data for exploratory analyses related to PUFA metabolism and the effect of DHA on disease related biomarkers. Method: During an 8-week trial, 72 healthy vegan or vegetarian males and females (18-50 years) will be supplemented with 1 of 6 algal-oil based DHA doses: 0, 100, 200, 400, 800 or 1000 mg/d. Blood will be collected at days 0, 3, 7, 14, 28 and 56 and will be analyzed for changes in blood EPA levels as the primary outcome and plasma δ13C EPA signature as the secondary outcome. Significance: Investigating this negative feedback pathway is of great importance in providing evidence to support n-3 PUFA DRIs. EPA and DHA are ecologically sensitive with their major source coming from unsustainably farmed fish stocks and having a set DRI may help to limit the overconsumption of these nutrients.

Conditions

Nutrition, Healthy

Keywords

docosahexaenoic acid; eicosapentaenoic acid; dietary reference intakes; retroconversion

Outcome Measures

Primary Outcomes (1)

• Changes in omega-3 polyunsaturated fatty acid (n-3 PUFA) blood levels

  Changes in blood n-3 PUFA levels within the various groups and at what day a rise in EPA occurs at.

  8 weeks

Secondary Outcomes (3)

• Changes in the delta carbon 13 (δ13C) n-3 PUFA signatures

  8 weeks

• Measure of n-3 LC PUFA turnover rates

  8 weeks

• Measure of n-3 LC PUFA half-lives

  8 weeks

Other Outcomes (11)

• Increased intake of dietary α-Linolenic acid (ALA) and the inhibition of long chained omega-3 polyunsaturated fatty acids (LC n-3 PUFA) synthesis

  8 weeks

• Comparing the potential change in omega-3 long chained polyunsaturated fatty acids (n-3 LC PUFA) levels between male and female participants

  8 weeks

• Comparing the potential change in n-3 LC PUFA δ13C signatures between male and female participants

  8 weeks

Study Arms (6)

DHA0 - 0mg of DHA/d

PLACEBO COMPARATOR

DHA0 participants are in the placebo group and will take 5 soybean oil based capsules per day and will not receive any DHA. Every group takes 5 capsules per day to maintain blinding.

Dietary Supplement: soybean oil placebo

DHA1 - 100mg of DHA/d

ACTIVE COMPARATOR

DHA1 participants will take 100mg/d of DHA. As the DHA supplements are 200mg of DHA per capsule the participants here will take one 200mg capsule every other day and the rest of the capsules will be placebos.

Dietary Supplement: docosahexaenoic acid (DHA)

DHA2 - 200mg of DHA/d

ACTIVE COMPARATOR

DHA2 participants will take one 200mg capsule of DHA and 4 placebos per day.

Dietary Supplement: docosahexaenoic acid (DHA)

DHA3 - 400mg of DHA/d

ACTIVE COMPARATOR

DHA3 participants will take two 200mg capsules of DHA and 3 placebos per day.

Dietary Supplement: docosahexaenoic acid (DHA)

DHA4 - 800mg of DHA/d

ACTIVE COMPARATOR

DHA4 participants will take four 200mg capsules of DHA and 1 placebo per day.

Dietary Supplement: docosahexaenoic acid (DHA)

DHA5 - 1000mg of DHA/d

ACTIVE COMPARATOR

DHA5 participants will take five 200mg capsules of DHA and no placebos per day.

Dietary Supplement: docosahexaenoic acid (DHA)

Interventions

docosahexaenoic acid (DHA) DIETARY_SUPPLEMENT

72 healthy participants will be divided into 6 groups and receive varying amounts of DHA (0mg, 100mg, 200mg, 400mg, 800mg and 1000mg) over the course of 8 weeks.

DHA1 - 100mg of DHA/d; DHA2 - 200mg of DHA/d; DHA3 - 400mg of DHA/d; DHA4 - 800mg of DHA/d; DHA5 - 1000mg of DHA/d

soybean oil placebo DIETARY_SUPPLEMENT

72 healthy participants will be divided into 6 groups and receive varying amounts of DHA (0mg, 100mg, 200mg, 400mg, 800mg and 1000mg) over the course of 8 weeks. The 0mg group will receive only placebos.

DHA0 - 0mg of DHA/d

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy vegans or vegetarians who do not consume meat or fish.

You may not qualify if:

• Has regularly consumed EPA and/or DHA supplements within the past six months
• Having 3% or higher of DHA in their total plasma lipids
• BMI \<18 kg/m2 or \>30 kg/m2
• Menopausal or post-menopausal
• Pregnant or breastfeeding
• Has a chronic or communicable diseases (like multiple sclerosis, kidney and inflammatory bowel disease, Type 2 diabetes, cancer or heart disease)
• Suffers from acute or chronic infections, use of chronic anti-inflammatory medication, use of lipid-controlling medication, hypertriglyceridemia (\>4 mmol/l) or hypercholesterolemia (LDL-C \>5 mmol/l)
• Anticipates major changes in lifestyle
• Is a smoker
• Is a heavy alcohol user (\>3 drinks/day)
• Has had a major surgery involving organs like open heart surgery or organ transplants in the last six months
• Is or has participated in an intervention trial in the last six months

Sponsors & Collaborators

• University of Toronto: lead
• Unity Health Toronto: collaborator

Study Sites (1)

Clinical Nutrition and Risk Factor Modification Centre

Toronto, Ontario, M5C 2T2, Canada

Location

Related Publications (7)

• Li J, Pora BLR, Dong K, Hasjim J. Health benefits of docosahexaenoic acid and its bioavailability: A review. Food Sci Nutr. 2021 Jul 23;9(9):5229-5243. doi: 10.1002/fsn3.2299. eCollection 2021 Sep.

  PMID: 34532031 BACKGROUND

• Abdelhamid AS, Brown TJ, Brainard JS, Biswas P, Thorpe GC, Moore HJ, Deane KH, Summerbell CD, Worthington HV, Song F, Hooper L. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2020 Feb 29;3(3):CD003177. doi: 10.1002/14651858.CD003177.pub5.

  PMID: 32114706 BACKGROUND

• Metherel AH, Irfan M, Klingel SL, Mutch DM, Bazinet RP. Compound-specific isotope analysis reveals no retroconversion of DHA to EPA but substantial conversion of EPA to DHA following supplementation: a randomized control trial. Am J Clin Nutr. 2019 Oct 1;110(4):823-831. doi: 10.1093/ajcn/nqz097.

  PMID: 31204771 BACKGROUND

• Metherel AH, Chouinard-Watkins R, Trepanier MO, Lacombe RJS, Bazinet RP. Retroconversion is a minor contributor to increases in eicosapentaenoic acid following docosahexaenoic acid feeding as determined by compound specific isotope analysis in rat liver. Nutr Metab (Lond). 2017 Nov 28;14:75. doi: 10.1186/s12986-017-0230-2. eCollection 2017.

  PMID: 29209405 BACKGROUND

• Schuchardt JP, Ostermann AI, Stork L, Kutzner L, Kohrs H, Greupner T, Hahn A, Schebb NH. Effects of docosahexaenoic acid supplementation on PUFA levels in red blood cells and plasma. Prostaglandins Leukot Essent Fatty Acids. 2016 Dec;115:12-23. doi: 10.1016/j.plefa.2016.10.005. Epub 2016 Oct 12.

  PMID: 27914509 BACKGROUND

• Sanders TA. DHA status of vegetarians. Prostaglandins Leukot Essent Fatty Acids. 2009 Aug-Sep;81(2-3):137-41. doi: 10.1016/j.plefa.2009.05.013. Epub 2009 Jun 4.

  PMID: 19500961 BACKGROUND

• Jenkins DJ, Sievenpiper JL, Pauly D, Sumaila UR, Kendall CW, Mowat FM. Are dietary recommendations for the use of fish oils sustainable? CMAJ. 2009 Mar 17;180(6):633-7. doi: 10.1503/cmaj.081274. No abstract available.

  PMID: 19289808 BACKGROUND

MeSH Terms

Interventions

Docosahexaenoic Acids

Intervention Hierarchy (Ancestors)

Fatty Acids, Omega-3; Dietary Fats, Unsaturated; Dietary Fats; Fats; Lipids; Fatty Acids, Unsaturated; Fatty Acids; Fish Oils; Oils

Study Officials

• Richard P Bazinet, PhD

  University of Toronto

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Block Randomization was used to ensure that sample sizes remain balanced throughout the study. Following successful completion of informed consent, the questionnaire and anthropometric assessment participants will be randomized into groups, of a possible six, using a blocked (Latin squares) randomization. These groups will represent DHA0 (0mg/d), DHA1 (100mg/d), DHA2 (200mg/d), DHA3 (400mg/d), DHA4 (800mg/d), and DHA5 (1000mg/d) groups. The Latin square sequences will be randomly allocated to participants with a similar number of participants allocated to each treatment sequence. The participants will only be randomized once all information is collected, informed consent has been obtained and questionnaires have been filled out following the first study call/zoom meeting. Then following their first study in person visit and post blood sample extraction they will be given their DHA capsules, which have been organized by a lab member not directly involved in the study.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle Investigator

Model Details: Double blinded, randomized, control, dose-response supplementation trial

Study Record Dates

• First Submitted: September 25, 2023
• First Posted: March 5, 2024
• Study Start: February 26, 2024
• Primary Completion: February 26, 2025
• Study Completion: March 26, 2025
• Last Updated: October 3, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)