Linaclotide
A 14-amino-acid peptide taken by mouth that works inside the bowel and is barely absorbed at all
Linaclotide is one of the few peptides people swallow. It activates guanylate cyclase-C on the gut lining, pulling fluid into the intestine and easing both constipation and the pain of IBS. Because it stays in the gut, its boxed warning is about dehydration in young children rather than anything systemic.
What is it?
Linaclotide acts where it lands. Swallowed as a capsule, it binds guanylate cyclase-C on the cells lining the intestine, raising cyclic GMP inside them; that pushes fluid into the bowel and speeds transit, and the cyclic GMP leaking the other way appears to dampen pain-sensing nerves. Almost none reaches the bloodstream. The label says plasma levels of linaclotide and its active metabolite stayed below the limit of quantitation at every approved dose.
Its trials are large and consistent. In 804 adults with IBS with constipation, 33.7% met the FDA's composite responder definition on 290 mcg against 13.9% on placebo. In two 12-week trials in 1,276 adults with chronic constipation, the primary endpoint was reached by roughly one in five on either dose against 3% to 6% on placebo. A second IBS-C trial in 800 adults, with a four-week randomised withdrawal, gave the same picture: 33.6% met the FDA endpoint on linaclotide against 21.0% on placebo, a number needed to treat of 8.
The lowest dose was tested on its own. In a 12-week trial in 1,223 adults with chronic idiopathic constipation, 13.4% on 72 mcg met the primary endpoint against 4.7% on placebo, which is why the label offers 72 mcg as an alternative to 145 mcg based on presentation or tolerability.
The label has since grown into childhood. Linzess now covers IBS-C in adults and children of 7 and over, chronic idiopathic constipation in adults, and functional constipation from age 2 — the last on the strength of a phase 3 trial in 6- to 17-year-olds given 72 mcg. The adult doses are 290 mcg for IBS-C and 145 or 72 mcg for chronic constipation. The capsule is taken on an empty stomach at least 30 minutes before a meal, at about the same time each day, and is not crushed or chewed.
The boxed warning runs the other way: linaclotide is contraindicated under the age of 2, because in neonatal mice a single adult-sized dose caused deaths from dehydration. Diarrhoea, the common adverse effect at every age, is the mechanism at work.
Diarrhoea is the price of the mechanism, and the pooled data put a number on it. Across 3,853 patients in the phase 3 programme, diarrhoea was the most common adverse event, mild or moderate in 90.5% of cases in the randomised trials; 4.0% of linaclotide patients stopped because of it against 0.3% on placebo, and there were no serious adverse events of diarrhoea. The label says to suspend dosing and rehydrate if diarrhoea becomes severe.
Mechanism of Action
Linaclotide activates guanylate cyclase-C on the intestinal lining, raising cyclic GMP, which drives fluid into the bowel; it is barely absorbed.
Fluid secretion
Raised cyclic GMP in intestinal cells pushes fluid into the bowel and speeds transit, which is also why diarrhoea is its common side effect.
Pain signalling
Cyclic GMP released from the cells appears to dampen pain-sensing nerves, the proposed reason abdominal pain improves in IBS-C.
Stays in the gut
Plasma levels are below the limit of quantitation at approved doses (label).
Age-dependent risk
In neonatal mice it caused fatal dehydration, the basis of the contraindication under age 2 (label).
Published Research
The studies behind linaclotide, read from their PubMed abstracts: the IBS-C and constipation trials at each dose, children, pooled safety, and its action in the colon lining.
IBS-C over 26 weeks
804 adults took 290 mcg or placebo daily. Over the first 12 weeks, 33.7% met the FDA's composite responder definition against 13.9% on placebo, a number needed to treat of about five. Abdominal pain and complete spontaneous bowel movements both improved.
IBS-C with a randomised withdrawal
In 800 adults, the FDA responder endpoint was met by 33.6% on linaclotide and 21.0% on placebo (number needed to treat 8); abdominal pain fell by at least 30% in 50.1% against 37.5%.
Two chronic constipation trials
1,276 adults took 145 mcg, 290 mcg or placebo for 12 weeks. The primary endpoint — three or more complete spontaneous bowel movements a week plus an increase of at least one — was met by 16% to 21% on either dose against 3.3% and 6.0% on placebo. Every secondary endpoint favoured linaclotide.
The 72 mcg dose for chronic constipation
In 1,223 adults over 12 weeks, the primary endpoint was met by 13.4% on 72 mcg and 12.4% on 145 mcg against 4.7% on placebo; diarrhoea was the most common adverse event.
Children aged 6 to 17
A phase 3 trial at 64 sites in seven countries randomised children with functional constipation to 72 mcg or placebo for 12 weeks, measuring spontaneous bowel movements and stool consistency. This is the evidence behind the paediatric part of the label.
Japan, with a 40-week extension
500 adults with IBS-C took 0.5 mg or placebo for 12 weeks, then 324 continued open-label for 40 more. Global improvement and complete bowel movement responder rates were both higher than placebo, and patients switched from placebo matched them in the extension.
What it does to the colon lining
Healthy volunteers took 0.87 mg daily for seven days after a colonoscopy preparation. Cyclic GMP accumulated in cells of the cecum, transverse colon and rectum, with reduced Ki67 staining — evidence the drug reaches the large bowel's lining.
Pooled safety across the phase 3 programme
Among 3,853 patients treated for up to 104 weeks, diarrhoea was the most common adverse event (90.5% mild or moderate in the randomised trials); 4.0% stopped for diarrhoea against 0.3% on placebo, with no serious diarrhoea events.
Dosing Data
Linzess is a once-daily capsule taken on an empty stomach; the dose depends on the condition and age.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
From the trials above and the Linzess prescribing information (AbbVie; DailyMed set 09beda19, version 39, effective May 21, 2026).
Contraindications & Cautions
Set by the label, which carries a boxed warning.
Legal Status
Linaclotide is approved in the US as Linzess.
Frequently Asked Questions
?What is linaclotide?
A 14-amino-acid peptide taken as a capsule. It activates guanylate cyclase-C on the gut lining, drawing fluid into the bowel and easing constipation and IBS pain.
?What is it approved for?
IBS with constipation in adults and children of 7 and over, chronic idiopathic constipation in adults, and functional constipation in children from age 2.
?Why does a gut drug have a boxed warning?
Because of the very young. It is contraindicated under 2 years: in neonatal mice a single adult-sized dose caused deaths from dehydration.
?Is it absorbed into the blood?
Barely. It acts on the surface of the intestinal lining and is broken down in the gut, which is why its effects and its risks are local.
?What dose is used?
For adults, 290 mcg once daily for IBS-C and 145 or 72 mcg for chronic idiopathic constipation; for children, 145 mcg for IBS-C from age 7 and 72 mcg for functional constipation from age 2 (label).
?How should it be taken?
On an empty stomach at least 30 minutes before a meal, at about the same time each day, without crushing or chewing the capsule (label).
?How often does diarrhoea make people stop?
In pooled phase 3 data, 4.0% of patients stopped linaclotide because of diarrhoea against 0.3% on placebo; most cases were mild or moderate.
References
- [fda-pi] Linzess (linaclotide) capsules Prescribing Information, boxed warning and sections 1 and 2. AbbVie (DailyMed version 39, effective May 21, 2026; read September 30, 2026).
- [pubmed] Chey WD, et al. "Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety." Am J Gastroenterol, 2012;107(11):1702-12. PMID: 22986437.
- [pubmed] Rao S, et al. "A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation." Am J Gastroenterol, 2012;107(11):1714-24; quiz p.1725. PMID: 22986440.
- [pubmed] Lembo AJ, et al. "Two randomized trials of linaclotide for chronic constipation." N Engl J Med, 2011;365(6):527-36. PMID: 21830967.
- [pubmed] Schoenfeld P, et al. "Low-Dose Linaclotide (72 μg) for Chronic Idiopathic Constipation: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial." Am J Gastroenterol, 2018;113(1):105-114. PMID: 29091082.
- [pubmed] Di Lorenzo C, et al. "Efficacy and safety of linaclotide in treating functional constipation in paediatric patients: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial." Lancet Gastroenterol Hepatol, 2024;9(3):238-250. PMID: 38211604.
- [pubmed] Fukudo S, et al. "A randomized controlled and long-term linaclotide study of irritable bowel syndrome with constipation patients in Japan." Neurogastroenterol Motil, 2018;30(12):e13444. PMID: 30136447.
- [pubmed] Weinberg DS, et al. "Bioactivity of Oral Linaclotide in Human Colorectum for Cancer Chemoprevention." Cancer Prev Res (Phila), 2017;10(6):345-354. PMID: 28396341.
- [pubmed] Nee JW, et al. "Safety and tolerability of linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled Phase 3 analysis." Expert Rev Gastroenterol Hepatol, 2019;13(4):397-406. PMID: 30791771.
- [other] US FDA, Drugs@FDA (openFDA): LINZESS (linaclotide), NDA 202811, AbbVie, prescription. Read September 30, 2026.
Sources & Citations
Studies were read from their PubMed records (October 5, 2026); the label and Drugs@FDA are listed below with their read dates.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.