Safety of Graded-Dose of Histidine in Humans

Safety of Graded-Dose of Histidine as Determined by Circulating Analytes, Sleep Records, Physical Activity, Anthropometric Measurements, and Mood

Histidine is an essential amino acid with health benefits that include anti-inflammatory, anti-oxidant, glucoregulatory, and weight management. The current expert opinion for histidine intake is 8 and 12 mg/(kg body weight per day), an estimate that was extrapolated from the infant requirement for histidine. Further, the clinical safety of histidine supplementation above the average dietary intake has not been determined.The overarching objectives are to 1) measure the safety of histidine supplementation and 2) measure the potential benefits of histidine at doses above the average intake and current recommendation in a healthy adult population.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Dietary supplement: Histidine

Detailed Description

Histidine is an essential amino acid with health benefits that include anti-inflammatory, anti-oxidant, glucoregulatory, and weight management. Because of the extended period of time (>35 days) that is required to deplete body histidine pools in adults, it has not been possible to fully determine histidine requirements. The current expert opinion for histidine intake is 8 and 12 mg/(kg body weight per day), an estimate that was extrapolated from the infant requirement for histidine. The average intake of histidine from a normal adult diet in the U.S., Europe, and Japan was reported between 2.12 and 2.40 g/day with the 99th percentile intake in men at 50-70 years of age consuming 5.20 g/day. The clinical safety of histidine supplementation above the average dietary intake has not been determined. Therefore, this study will utilize graded doses of histidine that are at are moderately above the average intake to identify safety and benefits of histidine in a healthy human population. Further, the clinical safety of histidine supplementation above the average dietary intake has not been determined.The overarching objectives are to 1) measure the safety of histidine supplementation and 2) measure the potential benefits of histidine at doses above the average intake and current recommendation in a healthy adult population. Following the completion and review of a health history questionnaire, vitals, and a biochemical panel, participants will be deemed healthy by a nurse practitioner and able to participate. After baseline measures are obtained, supplements (encapsulated histidine) will be provided at three graded doses (4 g/day, 8 g/day and 12 g/day) a forth dose (16 g/day) will be consumed if no adverse effects are observed at the three graded doses. Each dose will be for 28 days followed by a three week recovery period. At baseline, weeks 2 and 4 of supplement, and recovery a basic biochemical panel, anthropometric, urinary and serum zinc, will be conducted. Additionally, body composition will be conducted at baseline and week 4 of each dose. Changes in dietary intake and physical activity will be measured with 4-day food records and Actigraph activity monitors, respectively. Changes in sleep patterns will be measured with the Pittsburgh sleep questionnaire.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • Ithaca, New York, United States, 14853
      • Human Metabolic Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• healthy young males and females aged 21-50 y.

Exclusion Criteria:

• A body-mass index (BMI) <19.9 kg/m2 or > 29.9 kg/m2
• taking/on immunosuppressive medications or prescription anti-coagulation therapy
• pregnancy
• breastfeeding
• musculoskeletal disorder
• diabetes
• alcoholism (>11 drinks per week for women, >14 drinks per week for men) or other drug addiction
• acute illness
• inability to travel to Cornell University campus
• A blood pressure at or above 140/90
• For individuals desiring to participate in the optional biopsy, a history of a negative or allergic reaction to local anesthetic is an exclusion criteria

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 4 g / day histidine; subjects ingest encapsulated high quality histidine for four continuous weeks at 4 g/day.	Dietary supplement: Histidine; ingestion of encapsulated high quality histidine for four continuous weeks followed by a washout period of 3 weeks
Experimental: 8 g / day histidine; subjects ingest encapsulated high quality histidine for four continuous weeks at 8 g/day	Dietary supplement: Histidine; ingestion of encapsulated high quality histidine for four continuous weeks followed by a washout period of 3 weeks
Experimental: 12 g /day histidine; subjects ingest encapsulated high quality histidine for four continuous weeks at 12 g/day	Dietary supplement: Histidine; ingestion of encapsulated high quality histidine for four continuous weeks followed by a washout period of 3 weeks
Experimental: 16 g /day histidine; subjects ingest encapsulated high quality histidine for four continuous weeks at 16 g/day. The 16 g /day dose will be administered if no adverse effects are observed for doses 4-12 g/day	Dietary supplement: Histidine; ingestion of encapsulated high quality histidine for four continuous weeks followed by a washout period of 3 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in concentration of zinc in mg/ml	The safety of histidine supplementation at each dose is monitored through blood markers of zinc	at week 0 and 4 of each dose
Change in concentration of liver enzymes (ALT, ALP, and AST) in Units per Liter	The safety of histidine supplementation at each dose is monitored through circulating liver enzymes	at weeks 0 (washout), 2 and 4 of each dose
Change in body weight in kilograms	The safety of histidine supplementation at each dose is monitored through changes in weight	at weeks 0 (washout), 2 and 4 of each dose
Change in concentration of total protein and albumin in g/dl	The safety of histidine supplementation at each dose is monitored through circulating total protein and albumin	at weeks 2 and 4 of each dose
Change in concentration of blood urea nitrogen, Creatinine, bilirubin and glucose each in mg/gL	The safety of histidine supplementation at each dose is monitored through circulating blood urea nitrogen, Creatinine, bilirubin and glucose	at weeks 0 (washout), 2 and 4 of each dose
Change in concentration of C-reactive protein mg/L	The safety of histidine supplementation at each dose is monitored through circulating CRP	at weeks 0 (washout), 2 and 4 of each dose
HgbA1c in %	The safety of histidine supplementation at each dose is monitored through circulating HgbA1c	at week 4 of each dose
Change in heart rate in beats per minute	The safety of histidine supplementation at each dose is monitored through heart rate	weeks 0 (baseline and washout), 1, 2, 3, and 4 of each dose
Change in systolic and diastolic blood pressures in mmHG	The safety of histidine supplementation at each dose is monitored through blood pressure	weeks 0 (baseline and washout), 1, 2, 3, and 4 of each dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in hours of sleep	The effects of histidine will be assessed with changes in sleep pattern as determined using a subjective measurement tool	week 0 to 4 of each dose
Change in dietary intake of energy, macronutrients, and amino acids measured in kcals and g/day with 4 day food record	The effects of histidine will be assessed with changes dietary intake as determined with 4 day food records	week 0 to 4 of each dose
Change in physical activity measured in steps per day	The effects of histidine will be assessed with changes in physical activity patterns using an Actigraph	week 0 to 4 of each dose
Change in subjective mood measured in arbitrary units	The effects of histidine will be assessed with changes in mood as determined using a subjective visual analog scale. 100 mm line is anchored by two opposing statements. The higher number the greater the mood.	week 0 to 4 of each dose
Change in subjective desire to eat measured in arbitrary units	The effects of histidine will be assessed with changes in desire to eat will be determined using a visual analog scale. 100 mm line is anchored by two opposing statements. The greater the number the stronger the desire.	week 0 to 4 of each dose

Collaborators and Investigators

• Sponsor: Cornell University

Publications and helpful links

General Publications

• Gheller ME, Vermeylen F, Handzlik MK, Gheller BJ, Bender E, Metallo C, Aydemir TB, Smriga M, Thalacker-Mercer AE. Tolerance to graded dosages of histidine supplementation in healthy human adults. Am J Clin Nutr. 2020 Nov 11;112(5):1358-1367. doi: 10.1093/ajcn/nqaa210.

Study record dates

Study Major Dates

• Study Start (Actual): September 21, 2017
• Primary Completion (Actual): August 31, 2019
• Study Completion (Actual): August 31, 2019

Study Registration Dates

• First Submitted: October 30, 2018
• First Submitted That Met QC Criteria: October 25, 2019
• First Posted (Actual): October 29, 2019

Study Record Updates

• Last Update Posted (Actual): February 7, 2022
• Last Update Submitted That Met QC Criteria: January 24, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: 83676/A001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No