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Linaclotide (Linzess)14 residuesCCEYCCNPACTGCYEach bubble = one amino acid. Size = residue mass. Color = chemical class.Also known as: Linzess (US), Constella (EU), MD-1100
Roughly 34% of IBS-C patients hit the FDA composite response endpoint on linaclotide at 290 mcg daily, with bowel improvements showing up within 24 hours of the first capsule. Linaclotide (brand name Linzess) is a 14-amino-acid oral peptide that activates guanylate cyclase-C receptors in the intestinal lumen, triggering both fluid secretion and visceral pain reduction through two distinct cGMP pathways. That said, about two-thirds of patients don't meet the full responder threshold, and diarrhea affects 14 to 20% of users. The drug has three FDA-approved dose levels (72, 145, and 290 mcg) covering chronic idiopathic constipation, IBS-C, and pediatric functional constipation.
Fourteen amino acids. Three disulfide bonds. One of the only peptide drugs on the planet designed to survive your stomach acid and work without ever reaching your bloodstream. Linaclotide (Linzess, Constella; CAS 851199-59-2) is a first-in-class guanylate cyclase-C agonist, structurally related to the endogenous hormones guanylin and uroguanylin. The FDA approved it in 2012 for irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). It binds GC-C receptors on intestinal epithelial cells, raising intracellular cGMP. That activates CFTR chloride channels, pulling water into the intestinal lumen and speeding transit. A second pathway exports cGMP to the submucosal space, where it dials down visceral pain signaling through afferent nerve modulation. The important Phase 3 trial by Chey and colleagues (n=800+)[1] ran 26 weeks and landed on a 33.7% composite responder rate versus 13.9% for placebo. The NNT is 5 to 8, depending on the trial. For CIC, a separate Phase 3 program confirmed efficacy at 145 mcg with an NNT of 6 to 10. Real-world use tracks closely with the clinical data. Across 500+ Reddit threads in r/ibs and r/Constipation and roughly 900 Drugs.com reviews (6.7 out of 10), the pattern is consistent: rapid onset of bowel relief within 24 to 48 hours, meaningful pain reduction by week 2, but diarrhea as the dominant complaint at 290 mcg. Community users have independently figured out what the pharmacology predicts; GC-C receptor occupancy is near-maximal at 72 to 145 mcg, so lower doses often achieve comparable constipation relief with less GI disruption.
Linaclotide mirrors the body's own guanylin and uroguanylin peptides, but with a tighter, protease-resistant conformation locked in by three disulfide bonds (Cys1-Cys6, Cys2-Cys10, Cys5-Cys13). Once the capsule dissolves, the peptide reaches the apical surface of intestinal epithelial cells and binds GC-C receptors directly. GC-C activation converts GTP to cyclic guanosine monophosphate (cGMP) inside the cell. Raised cGMP switches on cGMP-dependent protein kinase II (PKG-II), which phosphorylates and opens the CFTR chloride channel. Chloride and bicarbonate ions flow into the lumen; water follows by osmotic gradient. Stool softens, transit accelerates. The pain pathway is separate and slower to develop. Intracellular cGMP gets pumped out to the submucosal space via MRP4 efflux transporters. On the other side, extracellular cGMP acts on colonic afferent nerve endings, reducing the firing threshold of visceral nociceptors. This is what produces the abdominal pain relief that distinguishes linaclotide from simple laxatives. Linaclotide's active metabolite (MM-419447, formed by loss of the C-terminal tyrosine) retains full GC-C agonist activity. Both parent and metabolite are broken down within about an hour in intestinal fluid through disulfide bond reduction. Systemic absorption is negligible, below 0.1%. The entire therapeutic effect happens inside the gut lumen.
FDA-approved first-in-class GC-C agonist with strong Phase 3 RCT evidence for IBS-C and CIC. ~34% composite responder rate for IBS-C (290 mcg) vs. 14–21% placebo; NNT 5–8. Dual mechanism: luminal fluid secretion (CFTR activation) + visceral pain reduction (extracellular cGMP modulation of afferent nerves).
Chey et al., Am J Gastroenterol 2012 (PMID 22986437): 26-week Phase 3 IBS-C RCT (n=800+); 33.7% responder rate vs. 13.9% placebo
NNT 5–8 means ~65% of IBS-C patients are non-responders; diarrhea in 14–20% of patients requires dose reduction; no published head-to-head RCT vs. plecanatide; long-term data (>26 weeks) limited in adults
Works rapidly for constipation relief but explosive diarrhea is the dominant complaint. Dose paradox widely reported: lower doses (72–145 mcg) often tolerated better than 290 mcg with similar constipation benefit for a subset. Non-response in ~30–40% of real-world users.
Science and community agree on core efficacy for IBS-C/CIC and the diarrhea side effect profile. Key divergence: FDA approves 290 mcg as the IBS-C dose, but community frequently downdoses to 72–145 mcg due to intolerable diarrhea: a dose reduction strategy the FDA label also supports as a fallback. Community also reports the dose paradox (lower = better for some) which is mechanistically explained by near-maximal GC-C receptor occupancy at 72–145 mcg.
| Level | Dose / Injection | Frequency |
|---|---|---|
| Beginner | 72mcg | Daily |
| Moderate | 145mcg | Daily |
| Aggressive | 290mcg | Daily |
No vials, no syringes, no bacteriostatic water. Linaclotide is an oral capsule. Swallow it whole on an empty stomach, at least 30 minutes before eating. Set an alarm if that helps; the fasting window matters. The 72 mcg dose covers CIC (adults) and pediatric functional constipation (ages 6 to 17). The 145 mcg dose is for adult CIC and pediatric IBS-C (ages 7 to 17). The 290 mcg dose targets adult IBS-C specifically. If you can't swallow capsules, open them and sprinkle the beads onto room-temperature applesauce. Swallow immediately without chewing. They also work through NG or gastrostomy tubes mixed with water. Don't use hot food, don't chew the beads, don't store the mixture. Store at room temperature (20 to 25 degrees C). No refrigeration needed. One thing that catches people off guard: symptoms come back within about a week of stopping. This isn't dependency; it's just how local-acting drugs work. GC-C receptors don't desensitize, but they also don't stay activated once you stop providing the agonist.
Linaclotide is intended for continuous daily use, not cycled. Clinical trials ran 12-26 weeks of uninterrupted dosing with sustained efficacy and no evidence of tachyphylaxis or tolerance. The FDA label does not specify a maximum treatment duration. Symptoms typically return within 1 week of discontinuation, as demonstrated in the 4-week randomized withdrawal phase of a Phase 3 IBS-C trial. Patients should continue taking linaclotide daily as long as the prescribing physician recommends.
Linaclotide is intended for continuous daily use: no cycling is required or recommended. GC-C receptors on luminal intestinal epithelial cells do not desensitize with chronic agonist exposure; no tachyphylaxis has been documented in 26-week Phase 3 trials or long-term observational data. Symptoms recur within ~1 week of cessation (confirmed in 4-week randomized withdrawal study), confirming sustained receptor engagement without downregulation. The cyclingProtocol in peptides.ts (onWeeks: 0, offWeeks: 0) is correct.
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Expected: Increased spontaneous bowel movement frequency; improved stool consistency; reduced bloating. Onset typically within 24–48 hours.
Monitor: Assess stool frequency and consistency at weeks 2 and 4. Check electrolytes if significant diarrhea occurs.
Take one capsule by mouth once daily, at least 30 minutes before the first meal of the day. The best timing is immediately after waking, before getting out of bed.
Do not crush, break, or chew.
If swallowing is difficult, open the capsule and sprinkle the beads onto a tablespoon of room-temperature applesauce. Swallow the mixture right away without chewing the beads. Do not store the mixture or mix with hot food.
For tube-fed patients, the beads can be mixed with water and administered through a nasogastric or gastrostomy tube. Flush the tube with additional water afterward.
No reconstitution, no refrigeration, no syringe calculations. This is an oral peptide. The capsule contains the full dose (72, 145, or 290 mcg depending on your prescription).
Store capsules at controlled room temperature (20 to 25 degrees C). Excursions to 15 to 30 degrees C are acceptable. Do not freeze.
If a capsule is accidentally opened and the beads look clumped or degraded, discard it and use a fresh capsule.
No dose adjustment: same bead content, identical bioactive dose
Swallow bead/applesauce mixture immediately without chewing beads. Do not mix with hot food or liquids. Do not store mixture after preparation. Bead matrix is protease-resistant and must not be crushed.
No dose adjustment
Mix capsule beads in water and administer via tube. Flush tube with additional water after administration. Used in hospitalized or tube-dependent patients.
Community-used adjunct for IBS-C: BPC-157 supports GI mucosal healing and motility via growth factor upregulation and NO signaling, complementary to linaclotide's secretory mechanism. No pharmacokinetic interaction (linaclotide is not systemically absorbed). Anecdotal IBS-C benefit reported in refractory cases.
α-MSH tripeptide with anti-inflammatory GI effects. Community-used alongside linaclotide in IBS-C patients with significant visceral inflammation. No clinical combination data; rationale is complementary mechanism (anti-inflammatory vs. pro-secretory).
Tight junction stabilizer with evidence in IBS and celiac disease. Community combines with linaclotide in IBS-C patients who have co-existing gut permeability concerns. No clinical combination data.
Same GC-C agonist mechanism: concurrent use produces additive GI fluid secretion with no additional efficacy benefit. Switching between them is clinically rational; concurrent use is not.
Do not combineDifferent secretagogue (ClC-2 chloride channel activator) but overlapping intestinal secretory effect. Concurrent use risks additive diarrhea and excessive fluid secretion.
Do not combineOpioid receptor agonist that reduces GI motility and secretion: directly counteracts linaclotide's intended mechanism. Use negates the therapeutic purpose.
Do not combinePricing updated 2026-04-09
The boxed warning comes first: linaclotide is contraindicated in children under 6 years of age. Immature GC-C receptor expression and a heightened secretory response create a real risk of serious dehydration in this age group. This is not a soft warning. Diarrhea is the most common adverse effect, reported in 14 to 20% of patients across Phase 3 trials compared to 3 to 5% on placebo. It is dose-dependent, worst in the first 1 to 2 weeks (especially at 290 mcg), and typically improves as the GI tract adapts. The mechanism is straightforward: CFTR activation pulls fluid into the lumen, and the secretory effect doesn't always calibrate perfectly to each patient's GI capacity. Community descriptions are blunter than the trial data suggests. The word "explosive" comes up frequently in r/ibs threads, along with reports of unpredictable urgency that disrupts daily routines. The practical workaround most users converge on is taking the dose immediately upon waking, before getting out of bed, so the urgency window happens during the morning routine. Severe diarrhea requiring hospitalization has been reported in postmarketing surveillance. These rare cases sometimes involved dizziness, syncope, hypotension, or electrolyte abnormalities (hypokalemia, hyponatremia). Anyone on concurrent diuretics or ACE inhibitors should be monitored more closely for electrolyte shifts if diarrhea becomes persistent. Other reported effects in clinical trials include abdominal pain, flatulence, abdominal distension, and headache, all at low rates. Nausea is rare. The dose paradox is worth understanding. At 72 to 145 mcg, GC-C receptor occupancy is already near-maximal in many people. Going higher to 290 mcg increases luminal fluid secretion without proportionally improving constipation relief. If 290 mcg produces intolerable diarrhea, the FDA label supports stepping down to 145 or 72 mcg. Community users discovered this pattern independently; it now appears in roughly a third of user reports. A practical note on timing: taking linaclotide within 30 minutes of food or with a high-fat meal significantly increases diarrhea rates per the PK data. The 30-minute fasting window is not optional. Pregnancy status is Category C. No embryofetal toxicity was seen in animal studies, but human data is insufficient. Linaclotide is not absorbed systemically, which offers some reassurance, but prescribers should weigh the benefit against the uncertainty. Breastfeeding data is similarly limited, though negligible systemic absorption suggests low risk of infant exposure. When to stop: persistent intolerable diarrhea that doesn't resolve with dose reduction, no improvement in stool frequency after 12 weeks, or any sign of GI obstruction.
Verify Linaclotide (Linzess) dosing and safety with a second opinion
FDA-approved brand-name drug (Linzess) manufactured by Ironwood Pharmaceuticals under full GMP requirements. Dispensed exclusively by licensed US pharmacies with valid prescription. No compounding market exists; counterfeiting is not a known concern for a regulated Schedule-uncontrolled oral prescription capsule.
| Test | When | Target |
|---|---|---|
| Symptom diary / IBS-SSS (Irritable Bowel Syndrome Severity Scoring System) | Baseline, weeks 2, 4, and 12 | IBS-SSS reduction >50 points = clinically meaningful response; FDA composite endpoint = ≥30% abdominal pain reduction + ≥1 additional CSBM/week for ≥6/12 treatment weeks |
| Basic metabolic panel (electrolytes: Na+, K+) | If significant or persistent diarrhea occurs (>3 loose stools/day for >3 consecutive days) | K+ 3.5–5.0 mEq/L; Na+ 135–145 mEq/L |
| Hydration assessment | First 2 weeks of initiation; any time diarrhea is significant | — |
Quantifies IBS-C symptom severity (abdominal pain intensity/frequency, bloating, bowel satisfaction, stool consistency) to assess response and confirm responder status by week 12.
Diarrhea-induced hypokalemia and hyponatremia reported in rare postmarketing cases. Risk higher with concurrent diuretic use, renal impairment, or in elderly/pediatric patients.
Dehydration is the primary serious safety concern, especially in children (contraindicated <2 years) and elderly or renally impaired patients. Severe diarrhea cases have required hospitalization in postmarketing surveillance.
Begin once-daily dosing on an empty stomach 30 minutes before breakfast. Increased bowel movements may occur within 24 hours. Some patients experience loose stools or diarrhea in the first few days as the gut adjusts to increased fluid secretion. This typically self-resolves.
Improvement in stool frequency and consistency is often measurable within the first week. Complete spontaneous bowel movements (CSBMs) increase. Abdominal bloating may begin to reduce. If diarrhea is persistent or severe, dose reduction (290 mcg to 145 mcg, or 145 mcg to 72 mcg) is appropriate.
Sustained improvement in bowel habits. Abdominal pain reduction becomes more apparent as extracellular cGMP accumulates and modulates visceral afferent nerve signaling. In Phase 3 IBS-C trials, significant separation from placebo in pain scores was evident by week 2-3.
Full therapeutic benefit established. In clinical trials, approximately 34% of IBS-C patients met the FDA composite responder endpoint (improvement in both pain and stool frequency) over 12 weeks. Benefits are sustained with continued daily dosing. No tolerance or dose escalation needed.
Long-term maintenance phase. A 26-week Phase 3 trial confirmed sustained efficacy without diminishing returns. Discontinuation leads to symptom recurrence within approximately 1 week, confirming the need for ongoing therapy. Annual reassessment with prescribing physician is recommended.
Days 1 to 3: GC-C receptor activation starts within hours of the first capsule. Most Phase 3 patients saw bowel movement improvement within 24 hours. Community reports confirm a strong first-day effect for many users, with urgency kicking in 1 to 3 hours after dosing. Others notice nothing for 2 to 3 days. Diarrhea, cramping, and flatulence tend to peak in this window, particularly at 290 mcg. Week 1: Stool frequency picks up measurably. Complete spontaneous bowel movements (CSBMs) increase; stool consistency improves on the Bristol Stool Scale. Bloating may start easing. Diarrhea stabilizes for some users but remains problematic for others at the higher dose. Dose reduction requests are common at this point. Weeks 2 to 4: Pain reduction becomes more noticeable. Phase 3 IBS-C trials showed significant separation from placebo in visceral pain scores by weeks 2 to 3. The extracellular cGMP pathway modulating afferent nerve signaling needs sustained activation to build up. Community users describe feeling "back to normal" during this stretch; a subset finds 145 mcg works as well as 290 mcg with fewer side effects. Weeks 4 to 12: The responder/non-responder split becomes clear. Around 34% hit the FDA composite endpoint for IBS-C (pain reduction plus stool frequency gain). Benefits hold steady without dose escalation or tolerance. Non-responders typically recognize their status by weeks 4 to 8 and look for alternatives like plecanatide or lubiprostone. Month 3 and beyond: Long-term maintenance. The 26-week Phase 3 trial confirmed sustained efficacy without diminishing returns. No tachyphylaxis or GC-C desensitization documented. Symptoms return within about a week of stopping (confirmed in the 4-week randomized withdrawal phase). Ongoing issues for long-term users are mainly cost (for uninsured patients) and occasional loose stools.
GC-C receptor activation occurs within hours of first dose. Luminal fluid secretion begins immediately, increasing transit speed. Bowel movement improvement observed within 24 hours in most Phase 3 patients.
Strong first-day effect common: many describe urgency within 1–3 hours. Others notice nothing for 2–3 days. Diarrhea is typically worst in this window, especially at 290 mcg.
Significant increase in complete spontaneous bowel movements (CSBMs) vs. placebo measurable by week 1 in Phase 3 data. Bristol Stool Scale type improves (softer, better-formed stools).
Most users notice clear improvement in bowel frequency. Bloating may begin to reduce. Diarrhea stabilizing for some; still problematic for others at 290 mcg. Many seek dose reduction at this point.
Significant separation from placebo in visceral pain scores by weeks 2–3 in Phase 3 IBS-C trials. Extracellular cGMP modulation of submucosal afferent nerve endings requires sustained receptor activation to accumulate.
Pain and bloating relief becomes more apparent. Many users describe feeling "back to normal." Diarrhea stabilizes. Subset of users find 145 mcg achieves equivalent results to 290 mcg with fewer side effects.
~34% composite responder rate (IBS-C, 290 mcg); ~21–25% above placebo for CIC (145 mcg). Benefits sustained without dose escalation or attenuation across 12-week trial period.
Clear responder/non-responder split. Non-responders typically recognize this by week 4–8 and seek alternatives. Responders report significant quality-of-life gains: less cramping, more predictable bowel habits.
26-week Phase 3 trial confirmed sustained efficacy without attenuation. No tachyphylaxis, dose escalation, or GC-C desensitization documented. Symptoms return within ~1 week of stopping (confirmed in 4-week randomized withdrawal phase).
Long-term users report stable, consistent benefit. Main ongoing issues are cost (for uninsured patients) and occasional loose stools. Annual prescriber reassessment recommended.
Source: Systemic half-life is not measurable: linaclotide plasma concentrations are below the limit of quantification after therapeutic doses (72-290 mcg). The peptide and its active metabolite MM-419447 are degraded within ~1 hour in the intestinal lumen through disulfide bond reduction. The 0.05-hour value represents a nominal placeholder; the drug has no meaningful systemic PK (FDA label, Section 12.3)
Loading the interactive decay curve.
Linaclotide (Linzess) is FDA-approved for three indications: IBS-C in adults (290 mcg, approved 2012), chronic idiopathic constipation in adults (72 and 145 mcg, approved 2012), and pediatric IBS-C in patients aged 7 to 17 (145 mcg, approved November 5, 2025). Pediatric functional constipation (ages 6 to 17) at 72 mcg is also an approved indication. Linzess is a prescription-only medication manufactured by Ironwood Pharmaceuticals (marketed with AbbVie). It is dispensed through licensed US pharmacies. No compounding market exists for this drug. It is not a controlled substance. No generic version is available. Mylan holds ANDA 209564, but patent settlements block market entry until approximately 2029 for the 145 and 290 mcg strengths, and roughly 2031 for 72 mcg. Linaclotide is not listed on the WADA Prohibited List. It has no ergogenic properties or systemic activity relevant to athletic performance. This content is for informational purposes only and does not constitute medical advice. Consult a licensed healthcare provider before starting or changing any medication.
Peptide Schedule Research TeamReviewed Apr 20266 Citations
