The scale of exposure is enormous. According to the World Drug Report, roughly 0.4 percent of the global population aged 15 to 64 reported cocaine use in 2019, corresponding to about 20 million people. In the United States, cocaine has been implicated in approximately one in five overdose deaths, and an estimated 5 million Americans report using the drug. The European Monitoring Centre for Drugs and Drug Addiction ranks cocaine as the second most commonly used illicit substance in the European Union after cannabis. Yet while emergency physicians routinely associate the drug with chest pain, stroke, and seizure, its abdominal presentations remain comparatively obscure, a gap the review’s authors set out to close with a narrative synthesis of PubMed/MEDLINE, Embase, and Scopus literature searched from January 1987, the year of the first published report of cocaine-associated gastroduodenal perforation, through July 2026.

Understanding how cocaine damages the gut requires understanding its pharmacology. Cocaine is a tropane alkaloid derived from the leaves of Erythroxylon coca that acts primarily by blocking the presynaptic reuptake of norepinephrine, dopamine, and serotonin through inhibition of their membrane transporters, DAT, NET, and SERT. The resulting accumulation of catecholamines at postsynaptic receptors produces a state of profound sympathetic overdrive: tachycardia, hypertension, and, critically for the bowel, intense vasoconstriction. The drug also blocks sodium channels, producing its local anesthetic effect, and interacts with NMDA, sigma, and kappa-opioid receptors, though the clinical implications of those interactions remain incompletely characterized.

The vascular story deepens at the level of the microcirculation. Cocaine activates platelets by increasing expression of platelet factor 4, thromboglobulin B, and P-selectin, and induces endothelial dysfunction through increased endothelin-1 with concurrently reduced nitric oxide. It raises fibrinogen, von Willebrand factor, and plasminogen activator inhibitor-1 while lowering protein C and antithrombin III, creating a pro-thrombotic state that heightens platelet sensitivity to agonists such as ADP and collagen. Cocaine also increases reactive oxygen species production in hepatocytes and endothelial cells, and its hepatic cytochrome P450 metabolism generates norcocaine and cocaethylene, metabolites more hepatotoxic than the parent compound. The net effect is a drug that simultaneously chokes off blood flow, promotes clotting, and poisons cells directly.

The ischemic consequences are the most dramatic. Cocaine-induced mesenteric vasospasm can critically reduce intestinal blood flow, and intestinal ischemia is generally considered to occur with a reduction of 75 percent or more in intestinal blood flow sustained for more than 12 hours. Symptoms begin anywhere from one hour to two days after use, occasionally delayed up to 72 hours. Acute mesenteric ischemia presents classically with sudden, severe abdominal pain out of proportion to examination findings, and reported cases include fatal superior mesenteric artery thrombosis in chronic users. Chronic mesenteric ischemia, or intestinal angina, produces recurrent postprandial pain as digestive demand for blood flow exceeds the supply constrained by chronic vasoconstriction and structural arterial change; one 2024 case report described chronic bowel ischemia manifesting as small-bowel obstruction from extensive intestinal-wall fibrosis in a young woman.

Ischemic colitis is among the more commonly reported complications, ranging from transient self-limited inflammation to fulminant disease. The colon’s watershed areas, the splenic flexure and rectosigmoid junction, are particularly vulnerable because of limited collateral circulation. An earlier case series identified 28 reported cases of cocaine-associated colonic ischemia with a mean patient age of just 32.6 years and symptom onset ranging from one hour to two days after use. The quantitative picture, thin as it is, is sobering: Elramah and colleagues, in a hybrid cohort/case-control study, found that cocaine-associated ischemic colitis carried a substantially higher mortality risk, with an odds ratio of 5.77 and reported mortality as high as 26 percent, compared with non-cocaine-related ischemic colitis, and more recent single-center reports describe mortality approaching 50 percent in severe, delayed-diagnosis presentations. A 2025 case report even described cocaine-associated non-occlusive ischemic colitis mimicking acute appendicitis in a previously healthy 27-year-old woman who required ileocecal resection for transmural necrosis.

Beyond ischemia, the review catalogs ulcerative and perforative disease. Crack cocaine is particularly associated with gastroduodenal perforation, first systematically described in a 1990 case series, most often affecting the first portion of the duodenum or the pylorus. Prepyloric perforation accounted for 42 percent of gastric perforations in one study of patients with a history of cocaine use, and approximately 16 percent of patients with perforated peptic ulcer disease at one large safety-net hospital had cocaine exposure. The pathophysiology is multifactorial: vasoconstrictive ischemia, direct chemical mucosal injury, and potentially increased intragastric pressure from altered motility and air-swallowing during smoking. Notably, Schuster and colleagues found that antiulcer surgical procedures were associated with no recurrence, whereas simple omental patch closure carried a 50 percent recurrence rate, suggesting the underlying ischemic mechanism demands definitive repair.

The liver and pancreas are not spared. Cocaine-associated acute pancreatitis is well recognized but rarely reported, with only seven published case reports available as of 2021, a scarcity the authors attribute to under-recognition and under-reporting rather than a true absence of cases. Hepatotoxicity ranges from mild transaminase elevation to acute liver failure, driven by reactive metabolites that undergo redox cycling, generate oxidative stress, and injure mitochondria through inhibition of respiration, ATP depletion, and caspase-3-mediated apoptosis. The review also documents splenic infarction, hematoma, and atraumatic rupture, with cocaine shown to cause up to a 20 percent transient reduction in splenic volume through vasoconstriction, plus rarer entities including gastric antral vascular ectasia, an inflammatory bowel disease-mimicking phenotype driven by cytokine-mediated barrier disruption and dysbiosis, and, in a single 2024 report, acalculous cholecystitis attributed to vasospasm of the cystic vasculature.

The authors are unusually candid about confounders. Concurrent alcohol use generates cocaethylene, which has a longer half-life and greater toxicity than cocaine itself, with an LD50 of 60 to 68.8 milligrams per kilogram versus 93.0 for cocaine; in the Miami Adult Studies on HIV cohort, concomitant cocaine-and-alcohol users with detectable cocaethylene had an odds ratio of 4.97 for liver fibrosis compared with 1.3 for cocaine-only users. Tobacco use, an independent risk factor for atherosclerosis and impaired mucosal healing, is inconsistently reported. Most striking is levamisole, a veterinary anthelmintic used to adulterate cocaine that was identified in up to 69 percent of cocaine samples analyzed in the United States as of July 2009, and that independently causes vasculopathy and agranulocytosis, compounding cocaine’s own vasospastic and thrombotic effects.

Perhaps the review’s most important contribution is its epistemic honesty. The evidence base underlying nearly every complication described remains dominated by single case reports and small case series rather than comparative studies; only three studies provide quantitative risk data, two limited to ischemic colitis and one systematic review of 53 studies and 69 patients examining route of use, which found broadly similar mortality and surgical rates across routes of cocaine use. The authors call for registry-based or multicenter comparative studies with standardized case definitions and toxicological confirmation of adulterants. In the meantime, their clinical message is unambiguous: in young patients presenting with abdominal pain or ischemic features, particularly without conventional vascular risk factors, cocaine-related gastrointestinal disease deserves a place at the top of the differential, because diagnostic delay in this population can be lethal.

Subject of Research: Cocaine's gastrointestinal complications: mechanisms, clinical spectrum, confounders, and the case-report-dominated evidence base

Article Title: Gastrointestinal complications of cocaine use: a narrative literature review

Article References: Qasim, A., Dasan, S. L. A. M., Veena, F., Kandhi, S., & Patel, H. (2026). Gastrointestinal complications of cocaine use: a narrative literature review. Frontiers in Gastroenterology, 5, Article 1907090. https://doi.org/10.3389/fgstr.2026.1907090

Image Credits: AI Generated

DOI: 10.3389/fgstr.2026.1907090

Keywords: cocaine, gastrointestinal complications, ischemic colitis, mesenteric ischemia, bowel perforation, hepatotoxicity, pancreatitis, levamisole, cocaethylene, Frontiers in Gastroenterology, Gastrointestinal, complications

The research team, led by Mukul Shyam and Sabina Evan Prince, set out to test whether the hydroalcoholic root extract of A. lappa, abbreviated ALRE, could protect both the liver and the pancreas from valproic acid toxicity. Their motivation was rooted in chemistry: valproic acid is metabolized extensively in the liver through glucuronidation, mitochondrial beta-oxidation, and cytochrome P450-mediated oxidation, generating toxic metabolites such as 4-ene-VPA and 2,4-diene-VPA. These metabolites disrupt mitochondrial fatty acid metabolism, deplete coenzyme A, inhibit carnitine palmitoyl transferase I, and ultimately damage hepatocytes. In the pancreas, the drug depletes antioxidant defenses, driving lipid peroxidation and tissue injury.

To prepare the extract, the researchers used Soxhlet hot continuous extraction, testing methanol, ethanol, acetone, water, and a 50:50 methanol-water mixture. The hydroalcoholic solvent yielded the most material — 12.80 percent by weight — and also extracted the highest levels of phenolics and flavonoids, at 21.36 milligrams of gallic acid equivalents and 19.93 milligrams of quercetin equivalents per gram of dry root, respectively. Gas chromatography–mass spectrometry tentatively identified several volatile constituents, while high-performance liquid chromatography revealed 17 peaks, with the dominant peak at 5.013 minutes accounting for nearly 70 percent of the chromatogram and provisionally identified as arctiin, the signature lignan of burdock.

Antioxidant assays confirmed the extract’s radical-scavenging capacity. In the DPPH assay, the hydroalcoholic extract showed the lowest IC50 value among the tested solvents at 370.70 micrograms per milliliter, close to the benchmark antioxidant butylated hydroxytoluene at 310.11 micrograms per milliliter. In the ABTS assay, the methanolic extract performed best at 370.43 micrograms per milliliter, with the hydroalcoholic extract close behind. These results established the hydroalcoholic preparation as the lead candidate for biological testing.

Safety screening came next. Using the MTT assay, the team measured the extract’s effect on four human cell lines: Hep3B liver cancer cells, PANC-1 pancreatic cancer cells, THLE-2 normal liver epithelial cells, and H6C7 normal pancreatic duct epithelial cells. The extract showed minimal cytotoxicity toward the normal cells, with IC50 values of 1,084.92 and 1,174.62 micrograms per milliliter for THLE-2 and H6C7 respectively — concentrations far above anything used therapeutically. Cancer cell lines were similarly resistant, with IC50 values of 1,184.46 and 1,234.11 micrograms per milliliter, suggesting the extract is not a potent cytotoxic agent but rather a gentle, cytoprotective one.

For the in vivo experiment, thirty-six male Wistar albino rats were divided into six groups. One group received normal saline as a control. A second received valproic acid at 300 milligrams per kilogram of body weight daily by oral gavage for twenty-eight days — a dose established in prior rodent studies to reliably induce hepatotoxicity and pancreatitis. Two further groups received valproic acid plus ALRE at 300 or 500 milligrams per kilogram. A fifth group received valproic acid plus L-carnitine at 300 milligrams per kilogram, a clinically used protective agent included as a positive control. The final group received ALRE alone at 500 milligrams per kilogram to assess safety at the highest dose.

The results were striking. Valproic acid drove serum alanine aminotransferase to 127.67 units per liter, aspartate aminotransferase to 153.67, alkaline phosphatase to 178.67, and gamma-glutamyl transferase to 7.67 — all dramatically above control values. Pancreatic enzymes rose in parallel, with amylase climbing to 47.33 and lipase to 49.00 units per liter. Co-administration of ALRE reversed these elevations in a dose-dependent manner, with the 500-milligram dose bringing ALT down to 48.67 and AST to 42.33 units per liter, approaching the levels seen with L-carnitine. The extract alone produced no adverse changes in any measured parameter.

Beyond serum chemistry, the researchers examined oxidative stress markers in liver and pancreatic tissue. Valproic acid depleted superoxide dismutase, catalase, and reduced glutathione while elevating malondialdehyde, the end product of lipid peroxidation. ALRE treatment restored all three antioxidant enzymes and lowered malondialdehyde in both organs, with the higher dose again showing the stronger effect. Histopathological examination under blinded scoring confirmed the biochemical findings: livers from valproic acid-treated rats showed lobular disorganization, cellular swelling, and inflammatory infiltration, while pancreases showed acinar derangement and early connective tissue proliferation. Both organs appeared markedly better preserved in the ALRE-treated groups, with the 500-milligram dose yielding near-normal architecture.

Immunohistochemistry added a molecular dimension. Staining for tumor necrosis factor-alpha and interleukin-1 beta — two pro-inflammatory cytokines central to the inflammatory cascade — was intense in the livers and pancreases of valproic acid-treated rats, localized around central veins, portal areas, and pancreatic ducts. In the ALRE-treated groups, this staining diminished markedly and dose-dependently, and the extract-alone group showed virtually no immunoreactivity, comparable to healthy controls. The researchers quantified these differences using ImageJ software with color deconvolution, providing objective measurement rather than subjective scoring.

The authors are careful to frame their findings within limits. This is the first study to demonstrate protection against valproic acid-induced hepatopancreatic toxicity with A. lappa, but the molecular pathways — including NF-kappa B, Nrf2, and GSK-3 beta signaling implicated in prior burdock research — were not directly probed here. Pharmacokinetic interactions between the extract and valproic acid metabolism remain unexamined, as do long-term effects and chronic toxicity. The cytotoxicity assessment used a single 24-hour time point, and food and water intake were not quantitatively recorded. Sample size was constrained to six animals per group by ethical considerations under the 3Rs framework, though the observed differences reached statistical significance.

Future work, the researchers write, should use western blotting and quantitative PCR to dissect the signaling pathways involved, and liquid chromatography–tandem mass spectrometry to measure whether ALRE alters the accumulation of toxic valproic acid metabolites such as 4-ene-VPA and 2,4-diene-VPA. Such studies would clarify whether the protection is purely antioxidant and anti-inflammatory or also involves modulation of drug metabolism itself. For now, the study adds burdock root to a growing list of plant-derived agents — including curcumin, resveratrol, silymarin, and ellagic acid — showing experimental protection against valproic acid organ injury, and offers a promising, low-toxicity lead for a clinical problem that has long needed better solutions.

Subject of Research: Hepatoprotective and pancreatoprotective effects of Arctium lappa root extract against valproic acid-induced toxicity in rats

Article Title: Hepatoprotective and pancreatoprotective effects of Arctium lappa root extract in valproic acid–induced toxicity: biochemical, histopathological, and immunohistochemical analysis

Article References: Shyam, M., & Evan Prince, S. (2026). Hepatoprotective and pancreatoprotective effects of Arctium lappa root extract in valproic acid–induced toxicity: biochemical, histopathological, and immunohistochemical analysis. Frontiers in Pharmacology, 17, Article 1883451. https://doi.org/10.3389/fphar.2026.1883451

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1883451

Keywords: Arctium lappa, burdock root, valproic acid, hepatotoxicity, pancreatitis, oxidative stress, antioxidant, phytochemistry, liver injury, pancreatic enzymes, L-carnitine, Wistar rats

The embryology behind the condition is elegantly precise. The pancreas forms from two outgrowths of the primitive foregut: a ventral bud and a dorsal bud. The ventral bud gives rise to the head of the pancreas and its uncinate process, whereas the dorsal bud builds the majority of the organ, including the neck, body, and tail, along with the accessory duct of Santorini. When the dorsal bud never appears, the distal pancreas simply does not exist. The clinical consequences can range from complete silence, discovered only incidentally, to abdominal pain, acute or recurrent pancreatitis, exocrine pancreatic insufficiency, and diabetes mellitus. The diabetes is thought to follow directly from the missing tissue: a substantial fraction of the insulin-producing beta cells reside in the body and tail, so their congenital absence reduces endocrine reserve from the very start of life.

In the weeks before his emergency presentation, the young man had been losing weight, roughly four kilograms over eight weeks, and had developed the classic warning signs of rising blood sugar: excessive urination and unquenchable thirst. He had also noticed intermittent discomfort after meals. On the day of admission, the picture crystallized. His blood glucose measured an alarming 412 milligrams per deciliter, his urine tested strongly positive for ketones, and his venous pH of 7.31 with a bicarbonate of 17.2 milliequivalents per liter indicated mild metabolic acidosis, treated clinically as mild diabetic ketoacidosis. At the same time, his serum lipase of 486 units per liter and amylase of 312 units per liter both exceeded their upper reference limits more than threefold, and combined with his epigastric pain and imaging evidence of peripancreatic inflammation, this satisfied the standard diagnostic criteria for acute pancreatitis.

Contrast-enhanced computed tomography delivered the decisive finding. The scan showed complete absence of the pancreatic neck, body, and tail distal to the splenic vein, together with an enlarged pancreatic head measuring 4.1 centimeters in its anteroposterior diameter, minimal peripancreatic fat stranding, and no signs of necrosis, pseudocyst, or fluid collections. A subtle but diagnostically valuable clue, the dependent stomach sign, was also present: with the distal pancreas missing, the stomach settles into the space it would normally occupy. Magnetic resonance cholangiopancreatography, performed eight weeks after discharge, added ductal confirmation by demonstrating a preserved ventral pancreatic duct, the duct of Wirsung, and a completely absent dorsal pancreatic duct, the duct of Santorini. Together, the morphological and ductal evidence established the congenital nature of the defect beyond reasonable doubt.

Reaching that conclusion required excluding a long list of impostors. Pancreatic lipomatosis, in which functioning tissue is replaced by fat, can create the illusion of a missing gland. Chronic pancreatitis can cause distal atrophy and ductal changes, but this patient had no history of chronic inflammation. Prior trauma, necrotizing pancreatitis, or surgery were ruled out by his history. A pancreatic tumor was considered unlikely given his age and the absence of any discrete mass or obstructive lesion on imaging. The etiological workup for pancreatitis also came back clean: triglycerides of 184 milligrams per deciliter and calcium of 9.1 milligrams per deciliter excluded the two major metabolic causes, liver enzymes showed no evidence of biliary obstruction, no gallstones were seen, and the patient denied alcohol, tobacco, drugs, and relevant medications.

The diabetes workup proved equally revealing. Twelve weeks after admission, his fasting C-peptide level was just 0.31 nanograms per milliliter, confirming profoundly low insulin production, while tests for the GAD65, IA-2A, and ZnT8 autoantibodies, the immunological fingerprints of classic type 1 diabetes, were all negative. This combination, severe insulin deficiency without autoimmune markers, in the presence of a major structural pancreatic defect, points toward a structural rather than autoimmune explanation. The authors were careful, however, not to over-classify. Type 3c diabetes, or pancreatogenic diabetes, formally requires evidence of exocrine pancreatic insufficiency in addition to structural disease and absent autoimmunity. In this patient, fecal elastase measured 210 micrograms per gram, within acceptable range, and there was no steatorrhea or malabsorption, so the team preferred the more cautious description of diabetes associated with dorsal pancreatic agenesis and severe insulin deficiency.

Treatment followed established pathways for both conditions simultaneously. The patient received intravenous fluid resuscitation, insulin infusion, analgesia, electrolyte monitoring, and a gradual reintroduction of oral feeding, and his abdominal symptoms resolved without any surgical intervention. Because his admission potassium of 4.3 milliequivalents per liter was normal, no supplementation was needed before starting insulin. He was discharged on a basal-bolus regimen combining once-nightly glargine insulin with pre-meal lispro. Pancreatic enzyme replacement was deliberately withheld given his preserved exocrine function. By week twelve, his fasting glucose ranged from 110 to 140 milligrams per deciliter and postprandial values from 140 to 180, his HbA1c had fallen from 9.73 percent to 7.1 percent, and he had experienced no hypoglycemic episodes, no recurrence of abdominal pain, and no further attacks of pancreatitis.

The case also carries an instructive lesson about the limits of diagnostic imaging. An initial ultrasound described the pancreatic body and tail as normal, but retrospective review showed this reflected inadequate visualization rather than genuine confirmation, a discrepancy fully explained by the well-known difficulty of imaging the distal pancreas through the stomach. The authors were similarly transparent about their own limitations: the only archived CT images were labeled as plain scans, preventing independent verification of the contrast phase, β-hydroxybutyrate levels were never measured, the paired glucose reference for the C-peptide test was not recorded, genetic testing was not performed, and follow-up lasted only twelve weeks. These caveats matter, because they remind readers that even striking case reports rest on imperfect data, and that the enlarged pancreatic head seen during active pancreatitis could reflect inflammatory edema rather than true compensatory hypertrophy.

What makes this report resonate beyond its rarity is the diagnostic challenge it poses to routine thinking. Diabetes in an 18-year-old is usually presumed to be autoimmune type 1 disease, and most of the time that presumption is correct. But this case demonstrates why severe new-onset diabetes deserves a structural look at the pancreas itself. Dorsal pancreatic agenesis has been linked to mutations in developmental genes such as GATA6, a recognized cause of human pancreatic agenesis, and recessive regulatory mutations in PTF1A have been described in isolated pancreatic agenesis, although no molecular mechanism could be attributed in this patient without genetic testing. Compared with previously published cases, including a systematic review of 53 patients and individual reports of DPA with diabetes or ketoacidosis, this patient stands out for the simultaneous occurrence of complete dorsal agenesis, acute pancreatitis, and antibody-negative severe insulin deficiency in one young man. The message for clinicians is clear: when the pancreas is missing half of itself, the diagnosis of diabetes should rest on imaging, C-peptide levels, and antibody studies together, not on age or assumption alone.

Subject of Research: Dorsal pancreatic agenesis presenting with new-onset diabetes and acute pancreatitis

Article Title: Dorsal Pancreatic Agenesis Associated With New‐Onset Diabetes Mellitus and Acute Pancreatitis in an 18‐Year‐Old Man: A Case Report

Article References: Rab, M., Javaid, M. H., Numani, R. N., Khanam, F., Khalid, M., & Segawa, F. (2026). Dorsal Pancreatic Agenesis Associated With New‐Onset Diabetes Mellitus and Acute Pancreatitis in an 18‐Year‐Old Man: A Case Report. Clinical Case Reports, 14(10), Article e73606. https://doi.org/10.1002/ccr3.73606

Image Credits: AI Generated

DOI: 10.1002/ccr3.73606

Keywords: dorsal pancreatic agenesis, pancreatitis, diabetes mellitus, diabetic ketoacidosis, C-peptide, MRCP, congenital anomaly, pancreatic imaging, type 3c diabetes, GATA6, insulin deficiency, case report