Oxytocin in Alcohol Use Disorder

Objective:

There is compelling evidence to support that the neuropharmacology of oxytocin (OT) warrants
further investigation as a potential therapeutic agent for addiction. To that end, the link
between OT and dopaminergic pathways, with respect to motivated behaviors such as drug and
social reward, is important to establish as a mechanism. Although preliminary clinical
findings suggest a role of OT to treat withdrawal in alcoholic individuals, there is no
direct human evidence on the effects of OT administration on dopamine release. Additionally,
there is no direct human evidence on the effects of OT on the subjective response to alcohol.
There have been no studies investigating the differential effect, if any, of OT, on the
neurobehavioral response to various rewarding stimuli including alcohol, food and social
reward. We propose, therefore, to investigate whether intranasal administration of OT is able
to significantly reduce subjective response to alcohol, alcohol cue-induced craving and
self-administration, as well as to examine the neural response to social, alcohol and food
stimuli.

Study Population:

32 (24 completers) males with Alcohol Use Disorder (AUD) as defined by DSM-5 and
non-treatment seekers for AUD.

Design:

A within-subject, double-blind placebo-controlled study investigating the effect of
intranasal OT on the response to alcohol challenge, cue reactivity and alcohol
self-administration, and the neural response to rewarding stimuli. Outcome measures: a)
effect of OT on subjective response to cumulative alcohol challenge, cue reactivity and
alcohol self-administration; b) neurobehavioral response to social, alcohol and food stimuli.

Outcome measures:

A) effect of OT on subjective response to cumulative alcohol challenge, cue reactivity and
alcohol self-administration; B) neurobehavioral response to social, alcohol and food stimuli.

- INCLUSION CRITERIA:

- 21-55 year old male subjects. Justification: women will not be included due to: 1) the
confound of the estrogen-modulating effect of OT; 2) the need to control for menstrual
cycle phase across repeated days of study procedures which would significantly limit
the feasibility of the study

- Must meet DSM-5 criteria for AUD based on the SCID

- Right handed

EXCLUSION CRITERIA:

- Non-drinkers (alcohol-naive individuals or current abstainers).

- Currently seeking treatment to reduce or stop alcohol use.

- Current diagnosis of substance use disorder other than nicotine as determined by
DSM-5.

- Current clinically significant major depression or anxiety; or lifetime diagnosis of
schizophrenia, schizoaffective disorder, bipolar disorder, or obsessive compulsive
disorder.

- Lifetime history of suicide attempts.

- Contraindications for MRI scanning, including metal in body that are contraindicated
for MRI (such as implants, pacemaker, prostheses, shrapnel, irremovable piercings),
left-handedness, claustrophobia or unable to lie comfortably supine for up to 2 hours
in the and MRI scanner as determined from history and physician examination and the
MRI safety form.

- BMI>40 or if Investigators determine that subject s body shape precludes acquisition
of an adequate MRI scan.

- Unable to provide a negative urine drug test (UDT).

- Medical contraindications: Current clinically significant disease, including CNS,
seizures, cardiovascular, hypertension, arrhythmias, glaucoma, respiratory,
gastrointestinal, hepatic, renal, endocrine, or reproductive disorders as determined
by history and clinical exam at screening. Specifically, unstable hypertension,
clinically significant EKG abnormalities, GFR rate > 60ml/min, liver cirrhosis, AST or
ALT > 3X the upper normal limit, hemoglobin < 10.5 g/dl.

- Participants who have significant alcohol withdrawal symptoms as defined by CIWA-Ar>8.

- History of alcohol related seizures

- Requirement for or use in the past two weeks of psychoactive medications (four weeks
for fluoxetine).

- Use of prescription or OTC medications known to interact with alcohol within 2 weeks
of the study. These include, but may not be limited to: isosorbide, nitroglycerine,
benzodiazepines, warfarin, anti-depressants such as amitriptyline, clomipramine and
nefazodone, anti-diabetes medications such as glyburide, metformin and tolbutamide,
H2-antagonists for heartburn such as cimetidine and ranitidine, muscle relaxants,
anti-epileptics including phenytoin and phenobarbital codeine, and narcotics including
darvocet, percocet and hydrocodone. Drugs known to inhibit or induce enzymes that
metabolize alcohol should not be used for 4 weeks prior to the study. These include
chlorzoxazone, isoniazid, metronidazole and disulfiram. Cough-and-cold preparations,
which contain anti-histamines, pain medicines and anti-inflammatories such as aspirin,
ibuprofen, acetaminophen, celecoxib and naproxen, should be withheld for at least 72
hours prior to each study session.

- History of hypersensitivity to oxytocin.

- Clinically significant electrolyte abnormalities, current rhinitis or use of
vasoconstricting medications or prostaglandins

- Head trauma with loss of consciousness for more than 30 minutes.

- Any individuals with colorblindness that would prevent them from completing the Stroop
task.

- Any other reason for which the Investigators will determine that it is not in the best
interest of the participant to take part in this research.