Ghrelin

The 28-amino-acid stomach hormone that is the natural ligand for the GHS-R1a growth hormone secretagogue receptor, requiring an octanoyl group on serine 3 for activity — the modification that makes it chemically fragile and clinically impractical.

Also referenced as: Lenomorelin, Acyl ghrelin, Acylated ghrelin, Octanoyl ghrelin, Ghrelin (human), GHRL

Also appears in: Metabolic

What is Ghrelin?

Ghrelin is a 28-amino-acid peptide hormone released mainly by endocrine cells of the gastric oxyntic mucosa, and it is the natural ligand for GHS-R1a — the receptor that synthetic growth hormone secretagogues had been hitting for years before anyone knew what the body’s own agonist was. Its defining chemical feature is a post-translational modification: the hydroxyl group of serine 3 is esterified with octanoic acid, an eight-carbon fatty acid. Kojima and colleagues named it for growth hormone release rather than appetite, from ghre, the Proto-Indo-European root of “grow.”

That octanoyl ester is also why ghrelin itself is rare in commerce while its imitators are everywhere. The acyl group is required for receptor activity, it is installed by a dedicated enzyme the body keeps inside its own cells, and it is hydrolyzed quickly in plasma. The research-peptide market therefore stocks the receptor analogs — GHRP-2, GHRP-6, hexarelin, ipamorelin, MK-677 — which were engineered to do ghrelin’s job without ghrelin’s chemistry. Ghrelin appears mostly as a reference and comparator peptide rather than as a product with a use case of its own.

How it works

• Octanoylation at serine 3 gates all receptor activity. The purified peptide releases growth hormone in vivo and in vitro, and the original characterization established that O-n-octanoylation at Ser3 is essential for that activity — unacylated material does not activate GHS-R1a (Kojima et al., Nature, 1999)
• A single enzyme installs the acyl chain. Ghrelin O-acyltransferase (GOAT/MBOAT4), a membrane-bound O-acyltransferase, was identified independently by two groups as the enzyme responsible, making acylation an enzymatic step that a synthetic peptide has to be manufactured with rather than acquire in the body (Yang et al., Cell, 2008; Gutierrez et al., Proceedings of the National Academy of Sciences, 2008)
• Two separate downstream arms. Acting on pituitary somatotrophs, ghrelin drives growth hormone release; acting on hypothalamic NPY and AgRP neurons in the arcuate nucleus, it drives feeding — and intracerebroventricular ghrelin still increased feeding in rats genetically deficient in growth hormone, so the appetite effect is not merely downstream of GH (Nakazato et al., Nature, 2001)
• The system has a built-in brake. Liver-expressed antimicrobial peptide 2 (LEAP2) — produced in the liver and small intestine, and suppressed by fasting — was later identified as an endogenous antagonist of the same receptor. It fully inhibits GHS-R1a activation by ghrelin and blocks ghrelin’s major in vivo effects, including food intake and GH release, meaning GHS-R1a tone reflects a ratio between two hormones rather than ghrelin alone (Ge et al., Cell Metabolism, 2018)

Research status

Ghrelin is one of the best-characterized hormones in endocrinology and one of the least developed as a drug. The physiology is settled; the therapeutic program essentially does not exist.

• Discovery and physiology. Kojima et al. (1999) purified the peptide from rat stomach and identified the Ser3 octanoylation (Nature, 402(6762):656–660). Nakazato et al. (2001) established the central feeding role (Nature, 409(6817):194–198). Cummings et al. (2001) showed that plasma ghrelin rises before meals in humans, consistent with a role in meal initiation (Diabetes, 50(8):1714–1719).
• Human pharmacokinetics. The key human study remains a double-blind, placebo-controlled trial of intravenous ghrelin at 1 and 5 µg/kg in 18 healthy male volunteers. Acylated ghrelin cleared with an elimination half-life of 9–13 minutes and total ghrelin 27–31 minutes; both doses strongly stimulated growth hormone release; blood glucose and insulin shifted slightly. Notably, hunger increased in a dose-dependent pattern that did not reach statistical significance (Akamizu et al., European Journal of Endocrinology, 2004, 150(4):447–455).
• Clinical trials of ghrelin itself are small and largely negative on their primary endpoints. A multicenter, randomized, double-blind, placebo-controlled trial gave 33 cachectic COPD patients intravenous ghrelin (2 µg/kg) or placebo twice daily for three weeks alongside pulmonary rehabilitation. A single dose raised serum growth hormone by a mean of 46.5 ng/ml (between-group p<0.0001) and the treatment was well tolerated, but the co-primary six-minute walk distance showed no significant between-group difference — it improved within the ghrelin group (+40 m at Week 3, within-group p=0.033) without separating from placebo. Of the St George’s Respiratory Questionnaire, the other co-primary, the reported between-group gain at Week 7 was in the symptoms component (p=0.026) rather than the total score, alongside improvements in the MRC dyspnoea scale (p=0.030) and maximal expiratory pressure (p=0.015) (Miki et al., PLoS One, 2012, 7(5):e35708).
• The registry picture is wide but uniformly small. ClinicalTrials.gov lists roughly 40 interventional records that actually administer ghrelin (August 2026) — for example a completed Phase 2 study in frail older adults enrolling 16 participants (NCT01898611) and a Phase 1/2 heart-failure study enrolling 31 (NCT05277415). They are almost entirely single-site mechanistic studies, none enrolling more than about 100 participants, spread across appetite, glucose metabolism, alcohol craving, sleep, and post-bariatric physiology. Exactly one record carries a phase 3 label — a 30-participant academic appetite study in weight-losing cancer patients run at Göteborg University and completed in 2008 (NCT00681486) — and that label sits on an investigator-initiated trial, not a registrational program. No ghrelin product holds marketing authorization in any country.
• The molecules that did advance are receptor agonists, not ghrelin. Anamorelin, an orally active ghrelin-receptor agonist, ran two phase 3 trials in non-small-cell lung cancer cachexia enrolling 484 and 495 patients (ROMANA 1, NCT01387269; ROMANA 2, NCT01387282). It met the lean-body-mass co-primary endpoint in both (p<0.0001), and failed the handgrip-strength co-primary endpoint in both (p=0.15 and p=0.65); grade 3–4 treatment-related adverse events did not differ between groups, and the most common grade 3–4 event was hyperglycemia, in under 1% and 1% of anamorelin recipients respectively (Temel et al., Lancet Oncology, 2016, 17(4):519–531). It was approved in Japan on 22 January 2021 for cachexia in non-small-cell lung, gastric, pancreatic, and colorectal cancer, but the EMA’s CHMP adopted a negative opinion on 18 May 2017 — citing a marginal lean-body-mass effect, no proven effect on handgrip strength or quality of life, and inadequately recorded safety data — and confirmed the refusal on re-examination on 14 September 2017. Macimorelin, another ghrelin-receptor agonist, was approved by the FDA in December 2017, but only as an oral solution for the diagnosis of adult growth hormone deficiency, not as a therapy. MK-677, an oral ghrelin mimetic, raised growth hormone and IGF-1 into the young-adult range and increased fat-free mass in 65 healthy adults aged 60–81 over 12 months — but the added mass produced no change in strength or function, and fasting glucose rose while insulin sensitivity fell (Nass et al., Annals of Internal Medicine, 2008, 149(9):601–611).

Common dosage forms

Ghrelin is supplied by analytical-reagent and research-chemical vendors as a lyophilized powder in vials, usually as an acetate or trifluoroacetate salt, in milligram or sub-milligram quantities, stored frozen. It is a laboratory reagent format rather than a pharmaceutical one.

Two chemically distinct versions circulate under the same product name: acylated (octanoylated) ghrelin and des-acyl or unacylated ghrelin. Listings do not always specify which is being offered, and the two are not interchangeable at the receptor.

There is no oral, capsule, topical, or pharmacy-compounded ghrelin dosage form, because no ghrelin product is approved in any country. The orally active formats that do exist on the market — tablets and oral solutions — belong to the receptor agonists (anamorelin, macimorelin, MK-677), not to ghrelin.

Key considerations

• No approved product anywhere. Ghrelin holds no marketing authorization in any jurisdiction, and it does not appear on FDA’s 503A Category 1 list of bulk drug substances eligible for pharmacy compounding. The approved molecules in this receptor family are macimorelin, cleared only as a diagnostic agent, and anamorelin, approved in Japan and refused in the European Union.
• The acyl group is the entire compound, and it is easy to lose or omit. Des-acyl ghrelin differs from acyl ghrelin by 126 daltons and does not activate GHS-R1a. A certificate of analysis reporting HPLC purity alone cannot distinguish the two — a purity percentage describes how homogeneous a sample is, not which species it contains, and that requires mass confirmation. This is the single most consequential identity question for any material sold as “ghrelin,” and it is compounded by the ester’s tendency to hydrolyze in solution.
• The measured human half-life constrains what is plausible. Acylated ghrelin cleared with a 9–13 minute elimination half-life in the human pharmacokinetic study above. Any claim of a sustained effect from a peripheral dose has to be reconciled with that number.
• Documented metabolic signal. Ghrelin is counter-regulatory to insulin: the human PK study recorded slight shifts in blood glucose and insulin after dosing, and in the MK-677 trial fasting glucose rose by about 5 mg/dL with a measured fall in insulin sensitivity. In the anamorelin phase 3 program hyperglycemia was the most common grade 3–4 adverse event, though at low absolute rates and with no between-group difference in grade 3–4 treatment-related events overall. Glucose handling is the most consistently reported metabolic theme in the receptor-agonist literature rather than a high-frequency toxicity.
• Naming confusions are frequent. Ghrelin is not a GHRP — GHRP-2 and GHRP-6 are synthetic mimetics of ghrelin, not ghrelin itself. It is also not GHRH: sermorelin, CJC-1295, and tesamorelin act on the growth-hormone-releasing hormone receptor, a different receptor with different pharmacology. Des-acyl ghrelin and obestatin derive from the same preproghrelin precursor but are distinct entities. Separately, the enormous published literature that measures circulating ghrelin as a biomarker should not be read as evidence for administering it; the interventional literature is a small fraction of the total.