Ghrelin
lenomorelin (INN), acyl ghrelin, octanoyl ghrelin, growth hormone secretagogue receptor ligand, the hunger hormone
Ghrelin is a 28-amino-acid peptide made mainly by X/A-like cells in the stomach lining. It is the only known circulating hormone that increases appetite, rising before meals and falling after them. It is also the natural ligand for the growth hormone secretagogue receptor, which means it triggers growth hormone release. And that is why ghrelin and every ghrelin mimetic are banned in sport at all times.
Mechanism
Ghrelin is unique among human peptide hormones in requiring a fatty acid modification for activity. The enzyme ghrelin O-acyltransferase (GOAT, encoded by MBOAT4) attaches an eight-carbon octanoyl group to serine 3. Without that acylation the peptide cannot bind the growth hormone secretagogue receptor 1a (GHSR1a), a class A G-protein-coupled receptor. Most circulating ghrelin (often 80 to 90 per cent) is in fact des-acyl ghrelin, which does not activate GHSR1a and whose biology remains genuinely unsettled; it may have distinct actions through an unidentified receptor, or it may simply be an inactive reservoir.
Acyl ghrelin acts on GHSR1a in the pituitary to release growth hormone, and in the hypothalamic arcuate nucleus to activate orexigenic NPY/AgRP neurons and inhibit POMC neurons, the mirror image of what PYY 3-36 and GLP-1 do. Vagal afferent GHSR1a receptors provide a second route, with signals relayed via the nucleus tractus solitarius. Ghrelin also stimulates gastric motility and acid secretion (linking it to motilin, whose receptor is structurally related), suppresses insulin secretion, promotes fat storage in adipose tissue, and has reported cardiovascular effects including increased cardiac output and reduced systemic vascular resistance. Plasma concentrations rise sharply before habitual meal times and fall within an hour of eating, a pattern that led to the proposal that ghrelin is a meal-initiation signal. Concentrations are paradoxically low in obesity and high in anorexia nervosa and cachexia. Regulation appears to be a consequence of energy state rather than a cause of it.
What the research shows
Kojima and colleagues identified ghrelin in 1999 by reverse pharmacology, working back from the orphan growth hormone secretagogue receptor to its natural ligand in rat stomach, and discovered that O-n-octanoylation at serine 3 is essential for activity. Wren and colleagues then showed in 2001 that intravenous ghrelin produced a clear-cut increase in energy consumed from a free-choice buffet in every individual studied, with a mean increase of 28 per cent, the first demonstration of a circulating orexigenic hormone in humans. Cummings and colleagues showed that plasma ghrelin increased nearly twofold immediately before each meal and fell to trough levels within an hour of eating, supporting a meal-initiation role.
The therapeutic work has concentrated on cachexia, where ghrelin's combination of appetite stimulation, growth hormone release and anabolic signalling is attractive. Nagaya and colleagues showed ghrelin is elevated in cardiac cachexia, consistent with a compensatory anabolic response and providing the rationale for interventional work. Miki and colleagues then ran a multicentre randomised, double-blind, placebo-controlled trial in 33 cachectic COPD patients receiving intravenous ghrelin twice daily for three weeks, published in PLOS ONE in 2012, with improvements in food intake and body composition. These are genuine randomised data, but the sample is tiny and the follow-up measured in weeks.
Development then moved to orally active small-molecule GHSR agonists. Anamorelin was tested in the ROMANA 1 and ROMANA 2 phase 3 trials in non-small-cell lung cancer cachexia: it reliably increased lean body mass and body weight but failed to improve handgrip strength, its co-primary endpoint, and was not approved by either the FDA or the EMA, though it was approved in Japan in 2021. That pattern (reliable gains in body mass without demonstrated gains in function) is the central unresolved problem for the whole ghrelin-agonist field, and it is worth stating plainly rather than glossing. Separately, ghrelin's growth-promoting and insulin-suppressing actions have raised theoretical concerns about tumour promotion and glucose control that have never been resolved in long-term human studies.
Evidence assessment
Mixed evidence
The physiology is extremely well established, and a genuine multicentre randomised, double-blind, placebo-controlled trial of ghrelin administration exists in COPD cachexia. But it enrolled 33 patients for three weeks and reported intermediate outcomes rather than survival or durable function. Ghrelin is not licensed as a medicine anywhere, and the phase 3 programme for the oral ghrelin receptor agonist anamorelin increased body mass but failed its co-primary functional endpoint and was not approved by the FDA or EMA. Human trials exist but are small, short, and mixed on what matters.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Ghrelin is a growth-hormone-releasing acylated peptide from stomach Preclinical only
Identified ghrelin as the endogenous ligand for the growth hormone secretagogue receptor and established that O-n-octanoylation at serine 3 is essential for activity, the founding paper of the field.
Ghrelin enhances appetite and increases food intake in humans Preclinical only
Intravenous ghrelin produced a clear-cut increase in energy consumed from a free-choice buffet in every individual, mean increase 28 +/- 3.9 per cent (p<0.001), the first demonstration of a circulating appetite-stimulating hormone in humans.
A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans Preclinical only
Plasma ghrelin increased nearly twofold immediately before each meal and fell to trough levels within one hour of eating, establishing the preprandial pattern that underpins the meal-initiation hypothesis.
Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors Preclinical only
Plasma ghrelin was significantly higher in cachectic than non-cachectic heart failure patients (237 versus 147 fmol/mL), correlating positively with growth hormone and TNF-alpha and inversely with BMI, consistent with a compensatory anabolic response and providing the rationale for interventional trials.
Ghrelin treatment of cachectic patients with chronic obstructive pulmonary disease: a multicenter, randomized, double-blind, placebo-controlled trial Preclinical only
Improvements in food intake and body composition measures with ghrelin. Genuinely randomised and blinded, but with only 33 patients over three weeks it establishes proof of concept rather than clinical utility.
Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials Preclinical only
Anamorelin increased lean body mass and body weight but did not improve handgrip strength, its co-primary functional endpoint. Neither the FDA nor the EMA approved it. The clearest statement of the field's central problem: mass gain without demonstrated functional gain.
Safety
Ghrelin administration in human studies causes transient hunger, flushing, sweating and somnolence. It reliably raises growth hormone, and also ACTH, cortisol and prolactin, so it perturbs several endocrine axes at once. It suppresses insulin secretion and can raise blood glucose, which is a specific concern in anyone with impaired glucose tolerance or diabetes. Because ghrelin is a growth factor acting on a receptor expressed in several tumour types, there is a theoretical concern about promoting existing malignancy; this has not been demonstrated in humans but has never been adequately excluded either, and the studied population (cachectic cancer patients) is precisely the one where it matters. There is no long-term human safety data at all. For athletes the position is unambiguous: ghrelin is named on the WADA Prohibited List as lenomorelin and is banned at all times as a non-specified substance, so a positive test carries the maximum sanction. Ghrelin sold as a research chemical additionally carries the usual risks of unverified identity, purity and sterility, and the octanoyl modification that makes it active is chemically labile, so material sold as ghrelin may be substantially des-acylated and therefore inactive at the receptor it is supposedly bought for.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Ghrelin has no UK marketing authorisation and is not a licensed medicine. Anamorelin was not authorised by the EMA. Ghrelin sold to consumers in the UK is an unlicensed medicinal product. Products marketed as 'ghrelin boosters' or ghrelin mimetics fall into the same unlicensed category. |
| United States | Ghrelin is not an approved medicine in the United States. Anamorelin, an orally active small-molecule GHSR agonist, was not approved by the FDA for cancer cachexia. Ghrelin is available only as a research reagent. |
| WADA (sport) | Prohibited at all times, in and out of competition, under section S2.2 of the WADA Prohibited List (growth hormone secretagogues and their mimetics), where it is listed explicitly by its INN, lenomorelin. This is a non-specified substance, carrying the strictest sanctions. Related GHSR agonists including anamorelin, capromorelin, ibutamoren, ipamorelin, macimorelin and tabimorelin are prohibited under the same heading. |
Questions
Yes, unambiguously. Ghrelin is named on the WADA Prohibited List under its INN, lenomorelin, in section S2.2 covering growth hormone secretagogues and their mimetics. It is prohibited at all times, in and out of competition, and is a non-specified substance, meaning a positive test attracts the strictest sanctions. The same applies to anamorelin, ibutamoren, ipamorelin, capromorelin, macimorelin and tabimorelin.
Because the octanoyl group attached to serine 3 by the enzyme GOAT is required for binding the growth hormone secretagogue receptor. Without it, the peptide cannot activate the receptor at all. This is unusual among human peptide hormones and has practical consequences: the modification is chemically labile, so blood samples must be specially handled and synthetic material can deacylate in storage.
Because ghrelin appears to respond to energy state rather than drive it. Concentrations are suppressed in obesity and elevated in anorexia nervosa and cachexia, the opposite of what a simple causal model would predict. This is one reason blocking ghrelin has never worked as an obesity strategy despite decades of interest.
Partly, and the honest answer matters here. A small randomised trial in 33 COPD patients showed gains in food intake and body composition over three weeks. But the phase 3 programme for the oral ghrelin receptor agonist anamorelin reproduced gains in lean mass and weight while failing to improve handgrip strength, and was rejected by both the FDA and the EMA. Increasing body mass without improving function is not the same as treating cachexia.