Inclusion Criteria

• Males and non-pregnant, non-breastfeeding females with established diagnosis of IBS-D by modified Rome III criteria (Abdominal Pain Intensity: weekly average of worst daily score of >3.0 on a 0 to 10 point scale and Stool Consistency: at least one stool with a consistency of Type 5, 6 or 7 Bristol stool score on at least 2 days per week)
• 18-70 years old
• U.S. resident
• English-speaking (to provide consent and complete questionnaires)

Exclusion Criteria

• Structural or metabolic diseases/conditions that affect the gastrointestinal system
• Unable to withdraw the following medications 48 hours prior to the study:
  • Drugs that alter GI transit including Lomotil, and bile acid binders such as cholestyramine, prokinetics (e.g. metoclopramide, cisapride and erythromycin), narcotics (e.g. oxycodone, morphine) and anticholinergics (dicyclomine, hyoscyamine).
  • Analgesic drugs including narcotics, NSAID, cyclooxygenase-2 ( COX2) inhibitors (celecoxib, rofecoxib, and valdecoxib)
  • GABAergic agents (baclofen)
  • Benzodiazepines (e.g. lorazepam, alprazolam, and diazepam). Low stable doses of thyroid replacement, estrogen replacement, and low dose aspirin for cardioprotection and birth control pills or depot injections are permissible.
• Unable to withdraw the following medications, which are contraindications of ranolazine:
  • Strong Cytochrome P450, Family 3, Subfamily A (CYP3A) inhibitors (e.g. ketoconazole, clarithromycin, and nelfinavir)
  • CYP3A inducers (e.g. rifampin, phenobarbital, St. John's wort)
• Female subjects who are pregnant or breastfeeding.
• Current symptoms of severe depression, as measured by Hospital Anxiety And Depression Scale ( HADS) score greater than 15.
• Clinical evidence (including physical exam, ECG, laboratory studies and review of the medical history) of significant cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematological, neurological, psychiatric, or other disease that interfere with the objectives of the study.
• The Corrected QT Interval (QTc) > 490 msec.
• Active alcoholics not in remission or known substance abusers.
• Liver cirrhosis
• Patients with clinically significant hepatic disease.
• Major cardiovascular events in the last 6 months.
• Participation in another clinical trial (within 30 days).
• Incarcerated.