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Neotame: The Dipeptide Sweetener Built From Aspartame — What It Is, How the Body Handles It, and What FDA Set as Its Limit

Neotame is a high-intensity sweetener made by attaching a dimethylbutyl group to aspartame, itself a dipeptide of aspartic acid and phenylalanine. FDA approved it in 2002 for foods generally (except meat and poultry), put its sweetness at 7,000–13,000 times sugar and set an acceptable daily intake of 18 mg per person.

Approved food additive (US, 2002)A modified dipeptideNot a drug or supplement

Caroline S · Published 2026-11-03

Length

Two amino acids — aspartic acid and phenylalanine — as a methyl ester, with a 3,3-dimethylbutyl group on the aspartic acid's nitrogen; C20H30N2O5, molecular weight 378.5 (PubChem CID 9810996)

Sequence

N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester (21 CFR 172.829) — that is, aspartame (Asp-Phe-OMe, C14H18N2O5) with one extra side group

Origin

Synthetic: made by reductive N-alkylation of aspartame (L-phenylalanine-L-α-aspartyl methyl ester) with 3,3-dimethylbutyraldehyde (FDA final rule, Federal Register, 2002-07-09). Petitioned by Monsanto (1998); the specification cites The NutraSweet Co.

Last reviewed

2026-11-03

What is it good for?

Sweetening food and drink without sugar's calories. It is used in tiny amounts because, per the petitioner's figures quoted by FDA, it is roughly 7,000 to 13,000 times as sweet as sucrose. It is a food additive, not a health product; no health benefit is claimed for it on its approval.

Illustration: A small glass bottle with white powder on a white surface, with green and copper reflections.
Illustration

What it is

Neotame is a sweetener made from a dipeptide. Its parent is aspartame — aspartic acid joined to phenylalanine, with a methyl ester on the end — and neotame is aspartame with one extra side group, a 3,3-dimethylbutyl chain, attached to the aspartic acid's nitrogen. The US regulation gives its full chemical name: N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester (21 CFR 172.829).

PubChem lists it as C20H30N2O5, molecular weight 378.5 (CID 9810996); aspartame is C14H18N2O5, 294.3 (CID 134601). The difference, C6H12, is the dimethylbutyl group.

It is in a peptide library because it is built on a peptide bond — the smallest kind of peptide, two amino acids long — not because it does anything a peptide hormone does.

Why one side group changes so much

FDA's 2002 final rule records what the added group does, citing the petitioner:

  • Sweetness: about 7,000 to 13,000 times that of sucrose, depending on the food.
  • Stability: "The peptidyl linkage in neotame is stabilized by the N-alkyl substituent and is resistant to hydrolysis under typical use and storage conditions."

Because it is so intense, the amounts eaten are tiny. FDA estimated intake at the 90th percentile of consumers at 0.10 mg/kg body weight per day (0.17 mg/kg in children aged 2–5).

How the body handles it

From FDA's review of the petitioner's studies in rats, dogs, rabbits and humans:

  1. De-esterification first. Esterases in the gut or blood remove the methyl ester, giving DMB-Asp-Phe (the de-esterified dipeptide). The step is "similar in all species studied, including humans," though faster in rats and rabbits.
  2. Clearance. That metabolite is "rapidly cleared from the plasma and excreted via the bile duct or in urine."
  3. A little further breakdown. "A small percentage" undergoes peptide-bond hydrolysis to smaller fragments.

In rats given about 150 times the human 90th-percentile intake, 18–38% of the dose was absorbed, almost entirely in the small intestine.

The limit FDA set

FDA reviewed four long-term animal studies, derived acceptable-daily-intake values from 36 down to 18 mg per person per day, and took the lowest: 18 mg per person per day, based on a no-observed-effect level of 30 mg/kg/day for body-weight gain in a 52-week rat study. That limit is three times the 90th-percentile estimated intake of 6 mg a day.

Spread over a 60 kg adult, 18 mg is 0.3 mg per kilogram — our arithmetic, for scale.

On phenylalanine, the concern for people with phenylketonuria, FDA compared neotame's contribution at the 90th-percentile intake with ordinary diets (2.5–10 g a day for healthy adults; 0.4–0.6 g for a 20 kg child with PKU) and called it "trivial." That is a regulator's comparison, not clinical advice; PKU diets are set by the person's own clinic.

What is still argued about

The newest papers are laboratory and computational work, not human trials: a 2026 network-toxicology study proposing liver effects of sweeteners, a 2026 zebrafish study reporting gut inflammation with "newer high-intensity" sweeteners, and reviews of sweeteners and gut microbes. None of them measured neotame's effect in people. Of 151 PubMed records on neotame, 58 are indexed to humans (2026-11-03).

Where it stands

  • United States: approved 2002-07-09 (67 FR 45310), permitted "in foods generally, except in meat and poultry" (21 CFR 172.829, amended 2016 and 2023).
  • Specification: 97.0–102.0% pure; free dipeptide acid ≤1.5%; lead ≤2.0 mg/kg.

What makes neotame a peptide at all is the single bond explained in the peptide bond entry; how short chains differ from proteins is in peptide vs protein. Other peptides people eat rather than inject are described in the collagen peptides entry and the casein phosphopeptide entry.

What the research shows

Is safe at the levels people eat

FDA's 2002 safety determination: a no-observed-effect level of 30 mg/kg/day in a 52-week rat study gave an acceptable daily intake of 18 mg per person per day, three times the 90th-percentile estimated intake of 6 mg (FDA final rule, 2002-07-09). Animal-derived limit applied to people

Does not affect blood sugar or insulin

FDA's 2002 review reports no significant effects on fasting plasma glucose or insulin in the human studies submitted by the petitioner; those studies are not individually published

Causes liver disease or gut-microbe changes

Raised in recent laboratory and bioinformatic papers (e.g. PubMed 2026 network-toxicology and zebrafish studies); no human trial has tested it. Reported as an open question, not a finding

Bars show how much of the evidence is in humans, not how well anything works.

Where it stands

United States

Approved food additive since 2002 (67 FR 45310, 2002-07-09; 21 CFR 172.829): permitted 'as a sweetening agent and flavor enhancer in foods generally, except in meat and poultry', at good-manufacturing-practice levels (eCFR, read 2026-11-03).

Specification

Not less than 97.0% and not more than 102.0% neotame on a dry basis; free dipeptide acid not more than 1.5%; lead not more than 2.0 mg/kg (21 CFR 172.829).

Published record

PubMed: 151 records for neotame, 58 indexed to humans (2026-11-03).

Frequently asked questions

Is neotame a peptide?

It is a modified dipeptide — two amino acids, aspartic acid and phenylalanine, joined by a peptide bond, with a methyl ester on one end and a dimethylbutyl group on the other. FDA's rule notes that the extra group stabilises the peptide link against breakdown during storage.

How is neotame related to aspartame?

Neotame is made from aspartame. Chemists attach a 3,3-dimethylbutyl group to aspartame's aspartic acid. That one change makes it far sweeter — FDA quotes 7,000 to 13,000 times sugar — so it is used in much smaller amounts.

What is the acceptable daily intake of neotame?

FDA set it at 18 mg per person per day in 2002, from a no-effect level in rats with a safety margin applied; that is about 0.3 mg per kilogram for a 60 kg adult. FDA estimated that even heavy consumers ate about 6 mg a day.

Is neotame safe for people with phenylketonuria (PKU)?

Neotame contains phenylalanine, but FDA's 2002 rule judged the amount released at high intake trivial against normal dietary phenylalanine. Anyone managing PKU follows the advice of their own metabolic clinic; this entry reports the regulator's finding only.

Where is neotame allowed?

In the US, in foods generally except meat and poultry, at the level needed for the intended effect, under 21 CFR 172.829 (in force since 2002, last amended 2023).