Secretin (Synthetic Human)

A synthetic copy of the 27-amino-acid duodenal hormone secretin, FDA approved since 2004 as ChiRhoStim for pancreatic function testing and gastrinoma diagnosis, and widely known for the autism trials of 1999-2012 that found no benefit.

Also referenced as: ChiRhoStim, RG1068, RG-1068, Human secretin

Also appears in: Hormone

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What is Secretin (Synthetic Human)?

Secretin is a 27-amino-acid, C-terminally amidated peptide hormone released by S cells of the duodenal mucosa when acidic chyme arrives from the stomach; it was the first substance ever named a hormone, by Bayliss and Starling in 1902 (Chey and Chang, Journal of Gastroenterology, 2003;38(11):1025-1035). The synthetic human form, with the sequence His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-Glu-Gly-Ala-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH2, molecular weight 3,039.44 and empirical formula C130H220N44O39, is an FDA-approved diagnostic drug sold as ChiRhoStim; it differs at two residues from the porcine hormone, whose sequence Mutt and colleagues solved first (Mutt et al., European Journal of Biochemistry, 1970;15(3):513-519). The peptide appears in research catalogs as a reagent-grade lyophilized powder for receptor, pancreatic and brown-fat studies, and it is widely known outside gastroenterology because of a decade of failed autism trials.

How it works

• Agonist at the secretin receptor, a class B G protein-coupled receptor. The rat receptor was cloned in 1991 by expression cloning from an NG108-15 neuroblastoma-glioma cell library; its sequence showed no meaningful similarity to any GPCR then known, and it became the founding member of what is now called the class B or secretin receptor family (Ishihara et al., The EMBO Journal, 1991;10(7):1635-1641). A cryo-EM structure of the active, Gs-coupled human secretin receptor shows the peptide’s C-terminal helix held by the extracellular domain while its N-terminus reaches into the transmembrane core to trigger coupling (Dong et al., Nature Communications, 2020;11(1):4137).
• Drives bicarbonate-rich fluid secretion from pancreatic duct cells. Receptor activation raises cAMP in ductal epithelium, opening CFTR chloride channels and driving bicarbonate and water into the duct. Vagal input adds to this: vagal stimulation increases bicarbonate output, atropine blunts secretin-stimulated secretion, and the FDA label notes a contribution from vagal-vagal neural pathways (Chey and Chang, Journal of Physiology and Pharmacology, 2003;54 Suppl 4:105-112). This is the basis of the pancreatic function test, in which duodenal fluid collected after secretin is assayed for bicarbonate concentration and volume.
• Paradoxically raises gastrin release from gastrinomas. Normal antral G cells are inhibited by secretin, but gastrinoma cells express secretin receptors and respond with a rapid gastrin surge, so a rise in serum gastrin after an intravenous bolus distinguishes Zollinger-Ellison syndrome from other causes of hypergastrinemia (Long et al., The Journal of Clinical Endocrinology and Metabolism, 2007;92(11):4394-4402).
• Activates brown adipose tissue after meals. In mice, meal-induced secretin acts on secretin receptors in brown fat to trigger thermogenesis, and this heat signal feeds back to the brain to promote satiation (Li et al., Cell, 2018;175(6):1561-1574.e12); a placebo-controlled crossover study in 15 healthy men using secretin infusion and PET imaging reproduced brown-fat glucose uptake, dampened reward-circuit responses to food cues and delayed the motivation to eat again (Laurila et al., Nature Metabolism, 2021;3(6):798-809; NCT03290846).

Research status

Approved diagnostic uses. ChiRhoStim (ChiRhoClin, NDA 021256) was approved on April 9, 2004 as a new molecular entity under priority review, for three indications: stimulating pancreatic secretions, including bicarbonate, to aid in diagnosing exocrine pancreatic dysfunction; stimulating gastrin secretion to aid in diagnosing gastrinoma; and stimulating pancreatic secretions to help identify the ampulla of Vater and accessory papilla during ERCP. The label’s safety data come from a 531-patient open-label trial in which nausea (9 patients), vomiting (3), flushing (2) and upset stomach (2) were the only adverse reactions reported in more than one patient. The predecessor product, synthetic porcine secretin (SecreFlo, NDA 021136, also held by ChiRhoClin under a Repligen trademark), was approved on April 4, 2002 with orphan designation; ChiRhoClin stopped manufacturing it in 2008, with remaining stock expected to run out by the end of September 2008, stated that the decision was not based on safety or efficacy, and pointed users to the human product. Drugs@FDA lists SecreFlo as discontinued.

Gastrinoma provocative testing. The largest prospective evaluation, 293 Zollinger-Ellison patients studied at the National Institutes of Health alongside 537 literature cases, proposed a revised positive criterion of a serum gastrin increase of at least 120 pg/mL after secretin, which gave 94% sensitivity and 100% specificity and outperformed the calcium infusion test (Berna et al., Medicine (Baltimore), 2006;85(6):331-364).

ERCP cannulation. A single-center series of 25 patients given synthetic porcine secretin when pancreatic duct cannulation proved difficult reported success in 24 (Devereaux et al., The American Journal of Gastroenterology, 2002;97(9):2279-2281), and a four-center randomized, double-blind, placebo-controlled trial in 29 patients with pancreas divisum then showed minor papilla cannulation in 89% of secretin-treated attempts versus 6% after placebo (Devereaux et al., Gastrointestinal Endoscopy, 2003;57(6):643-647).

Secretin-enhanced MRCP: an unsuccessful second NDA. Repligen developed the same molecule as RG1068 to improve magnetic resonance cholangiopancreatography. Its phase 3, multicenter, baseline-controlled trial (NCT00660335; 258 patients with acute or recurrent acute pancreatitis enrolled between March 26, 2008 and October 28, 2009, with ERCP as the reference standard) reported that secretin increased sensitivity for pancreatic duct abnormalities with minimal loss of specificity (Sherman et al., Gastroenterology, 2014;147(3):646-654.e2). Repligen filed an NDA on December 21, 2011, which received priority review, and announced on June 22, 2012 that it had received a Complete Response Letter asking for additional clinical efficacy and safety data; by its November 8, 2012 quarterly filing the company had discontinued active prosecution of both the NDA and its European application, which had been formally withdrawn on August 15, 2012. Secretin-enhanced MRCP nevertheless remains common in pancreatic imaging, performed off-label with the approved ChiRhoStim product, since MRCP is not among its labeled indications.

Autism: the trials that made the hormone famous. An uncontrolled 1998 report described improved eye contact, alertness and expressive language in three children with autistic spectrum disorders after secretin given during endoscopy (Horvath et al., Journal of the Association for Academic Minority Physicians, 1998;9(1):9-15), and national television coverage produced intense demand. The first randomized, double-blind, placebo-controlled trial randomized 60 children aged 3 to 14 with autism or pervasive developmental disorder, 56 of whom completed it, and found no advantage of a single intravenous dose of synthetic human secretin over saline on the Autism Behavior Checklist or any secondary measure at four weeks (Sandler et al., The New England Journal of Medicine, 1999;341(24):1801-1806). The Cochrane review that followed identified 16 placebo-controlled randomized trials enrolling more than 900 children, two of them available only as Repligen press releases, and concluded that neither single nor multiple doses improved the core features of autism spectrum disorders, and that further trials could only be justified by new, replicated mechanistic evidence (Williams et al., Cochrane Database of Systematic Reviews, 2012;(4):CD003495).

Other explored uses. A small double-blind study in 25 patients with schizophrenia compared a single subcutaneous dose of RG1068 with placebo and reported improved cerebellar-dependent eye-blink conditioning at 2 and 24 hours, a signal that has not been pursued (Bolbecker et al., The American Journal of Psychiatry, 2009;166(4):460-466). The brown-fat findings above have prompted continued physiological studies but, as of November 2026, no registered trial of secretin as a metabolic or weight-loss therapy. Registered studies that remained active in late 2026 are diagnostic or mechanistic, including a Mayo Clinic phase 4 study of ChiRhoStim-stimulated pancreatic fluid composition in healthy volunteers (NCT07285863, started March 11, 2026) and a Cincinnati Children’s imaging-biomarker study of pancreatic function (NCT05659147). No new secretin product was approved in the United States in 2025 or 2026; ChiRhoClin announced a manufacturing partnership with PCI Pharma Services on November 19, 2024 to head off a ChiRhoStim shortage, and an exclusive distribution agreement effective July 14, 2025.

Common dosage forms

In the United States, synthetic human secretin is supplied as ChiRhoStim and ChiRhoStim 40 (ChiRhoClin, NDA 021256): sterile lyophilized powder in single-dose vials of 16 mcg or 40 mcg, labeled for intravenous use and stored frozen at -20 °C. It is a hospital and endoscopy-suite diagnostic. The discontinued porcine product, SecreFlo, came as a 16 mcg single-dose vial. Research suppliers list human and porcine secretin as lyophilized reagent-grade powder, usually in sub-milligram to low-milligram amounts intended for laboratory use.

Key considerations

• Regulatory status. The FDA Approved status reflects ChiRhoStim, NDA 021256, originally approved on April 9, 2004 and still marketed as of November 2026, with a package insert last revised in July 2017 and a DailyMed listing updated in October 2025. The approved indications are purely diagnostic; there is no FDA-approved therapeutic use of secretin for any condition, and the RG1068 imaging application was refused in 2012 and abandoned.
• The autism evidence is unusually conclusive for a negative. Few compounds have been tested in 16 placebo-controlled randomized trials with a consistently null result. Any claim that secretin improves social or language function rests on the uncontrolled 1998 case series and anecdote, not on the controlled literature that followed.
• Metabolic claims are early-stage physiology. The brown-fat and satiation findings come from mouse genetics and a short human mechanistic study with 15 participants; there is no outcome trial, no chronic-dosing safety data and no registered development program for secretin as a weight or metabolic intervention.
• Safety and interpretation signals from the label. Patients with alcoholic or other liver disease may show an exaggerated pancreatic secretory response that can mask coexisting pancreatic disease; anticholinergic drugs can blunt the response; and proton pump inhibitors or H2 blockers can produce falsely elevated gastrin responses in the gastrinoma test. Nausea, vomiting and flushing are the only common adverse reactions reported; the label lists no contraindications.
• Naming. Human secretin (ChiRhoStim, RG1068) and porcine secretin (SecreFlo) are different peptides that differ at two residues and were approved as separate drug products; the porcine product has been discontinued in the United States since 2008. Catalog listings labeled simply “secretin” may be either species, and the hormone is distinct from the structurally related family members VIP, GLP-1 and glucagon despite the shared receptor family name.