Study Design: This will be a double-blind, placebo controlled comparison of the efficacy of twice daily intranasal administration of oxytocin and placebo (saline) in reducing alcohol withdrawal symptoms, the number of bouts of withdrawal during which symptoms are of sufficient magnitude requiring prn lorazepam treatment (see definitions below) and the amount of lorazepam required to resolve withdrawal bouts. Treatment group assignment will be random within each sex. Subjects will be patients admitted to (University of North Carolina (UNC) Hospitals or the Dix Clinical Research Unit (CRU) for medical detoxification. Each treatment group will be composed of up to 40 subjects. Dr. Hamer, the study statistician, will construct a randomization plan to randomize 80 subjects to 2 groups of 40 subjects each with a blocksize of 4. This will be a permuted blocksize as this is a blind study.

Procedures: Most patients who are admitted to the UNC Neuroscience Hospital Crisis Stabilization Unit, UNC Hospitals Family Practice or Hospitalist Services, or the Dix CRU for medical detoxification from alcohol will come in through the UNC Hospitals Emergency Department or Dorothea Dix Screening and Admissions during the late evening or early morning. Physical examination, medical and psychiatric history and lab tests (including complete blood count \[CBC\], magnesium, sodium, potassium, \[blood urea nitrogen\] BUN, creatinine, glucose, albumin, liver functions tests \[ALT, AST, LDH, GGT\], throid-stimulating hormone (TSH), B12, folate, urinalysis, urine toxicology screen and pregnancy test) are routinely obtained by the emergency department (ED)/ Dorothea Dix Screening and Admissions and/or inpatient unit during the admission process. Possibly in the UNC Hospitals ED/ Dorothea Dix Screening and Admissions and definitely after admission to these units, patients will have their vital signs (VSs) measured and their withdrawal symptoms quantified using the revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar scale, Sullivan et al 1989) on the schedule in the standard alcohol detoxification order set in the UNC Hospital electronic medical records system (CPOE) system. The CRU at Dorothea Dix will use a hard copy version of the CIWA used in the CPOE at UNC Hospitals.

After consent is obtained, subjects will be randomly assigned to a treatment group (oxytocin or placebo). Prior to receiving their first intranasal treatment, an ECG will be obtained and blood drawn to obtain serum for assay of cytokine and allopregnanolone concentrations. Subjects also will rate their symptoms using the Alcohol Withdrawal Symptom Checklist (AWSC, Pittman et al 2007) prior to receiving their first test dose. These procedures will be done/overseen by research nurses or physicians. Subjects will usually receive their first intranasal test dose between 1000 and 1200 hours and will consist of 6 insufflations of Syntocinon Spray (approximately 24 IU) or placebo, with each insufflation given 30 seconds apart and alternating between nostrils. Test doses will be taken again at 1700 hr later that day (Admission Day 1) and at 0900 and 1700 hr on Admission Days 2 and 3. Oxytocin test treatments will be administered from 5 ml intranasal spray vials designed to deliver 0.1 ml metered volume per insufflation. The placebo treatments will be administered from 60 ml intranasal spray vials (each containing 30ml of solution) also designed to deliver 0.1ml metered volume per insufflation. Vials containing oxytocin and placebo spray will be blind labeled by the UNC Investigational Drug Service or the Dorothea Dix Hospital pharmacy. Research nurses or physicians will oversee subject self-administration of all intranasal test doses. After enrollment on admission day 1 and in the morning on admission days 2 and 3, subjects will be given multiple copies of the AWSC questionnaire and requested to complete one each time the unit nurses do CIWA ratings. These questionnaires will be retrieved by research staff the following morning. Shortly after the morning test dose on admission days 2 and 3, subjects will complete the Alcohol Craving Visual Analog Scales (ACVAS), the Penn Alcohol Craving Scale, and the Profile of Mood States (McNair et al, 1971). On these same admission days, research nurses will also draw (and subsequently process) blood serum samples to assay cytokine and allopregnanolone concentrations shortly after the morning test dose. Additional blood will be drawn after the morning test dose on admission day 2 to obtain serum for tests to be run in McLendon Laboratories (magnesium, chloride, calcium, sodium, potassium, BUN, creatinine, and liver function tests). Another electrocardiogram (ECG) will also be obtained shortly after the morning test treatment on admission day 2. Research staff will retrieve on a daily basis CIWA ratings and vital sign measurements obtained on each subject from their electronic medical record.

In all subjects, PRN lorazepam doses will be administered by mouth (PO) or intravenously (IV) (if subjects cannot take medication PO) whenever CIWA ratings are \> 14 per the protocol in the standard alcohol detoxification order set in the UNC Hospital CPOE system. Lorazepam doses (1 - 4 mg) and frequency (q 2 -6 h) will be adjusted based on the severity of withdrawal symptoms. This same order set will be employed at the Dorothea Dix CRU.