Crossover Study to Evaluate the Abuse Potential of Intranasal Esketamine Compared to Racemic Intravenous Ketamine in Nondependent, Recreational Drug Users

This is a single-center, single-dose, double-blind, double-dummy, placebo-controlled
(participants are randomly assigned to a test treatment or to an identical-appearing
treatment that does not contain the test drug), randomized (study medication assigned to
participants by chance), crossover study in up to 120 men and women self-identifying as
current, recreational, nondependent polydrug users. The study has a Screening Phase
(consisting of a Screening Visit and a Qualification Session) and a Treatment Phase. In the
Qualification Session participants will be randomized to receive Sequence 1: intravenous
placebo and intranasal placebo concurrently (Treatment A) on Day 1 and an intravenous dose
(0.5 mg/kg) of racemic ketamine and intranasal placebo concurrently (Treatment B) on Day 2,
or the participants will receive Sequence 2: Treatment B on Day 1 and Treatment A on Day 2.
In the Treatment Phase eligible participants will be administered 4 treatments: A, B, C
(intravenous placebo and intranasal 84 mg esketamine as 3 devices, each with 28 mg
esketamine followed by 1 device with placebo) and D (intravenous placebo and intranasal 112
mg of esketamine as 4 devices, each with 28 mg esketamine) in a cross-over manner (1
treatment per period) in Sequence 3, 4, 5, or 6. Periods 1, 2, 3, and 4 will be separated by
7 to 14 days. Primarily the drug abuse potential will be evaluated. Safety of the
participants will be monitored throughout the study.

Inclusion Criteria:

- Participants with body mass index (BMI) between 18 and 30 kilogram per square meter
(kg/m^2) (inclusive), and body weight not less than 50 kg

- Signed an informed consent document indicating they understand the purpose of and
procedures required for the study and are willing to participate in the study,
including the pharmacogenomic research component of the study

- Be a current, recreational, nondependent, polydrug user defined as nonmedical use
with at least 2 types of perception-altering drugs of abuse (example, lysergic acid
diethylamide, cannabinoids, ketamine, ecstasy/3,4-methylenedioxy-methamphetamine,
phencyclidine, psilocybin, and ring-substituted amphetamines with perception altering
effects) and at least 10 total lifetime occasions of use with perception-altering
drugs of abuse and who like their effects

- Report having used ketamine at least once in a lifetime without moderate or severe
adverse effects

- Report having used a perception-altering drug (example, lysergic acid diethylamide,
cannabinoids, ketamine, ecstasy/3,4-methylenedioxy-methamphetamine, phencyclidine,
psilocybin, and ring substituted amphetamines with perception altering effects) at
least once within 3 months prior to the screening phase without moderate or severe
adverse effects

Exclusion Criteria:

- Participant with a history of or current clinically significant medical illness
including (but not limited to) cardiac arrhythmias or other cardiac disease,
hematologic disease, lipid abnormalities, significant pulmonary disease, including
bronchospastic respiratory disease, diabetes mellitus, hepatic or renal
insufficiency, thyroid disease, neurologic disease, infection, hypertension or
vascular disorder, kidney or urinary tract disturbances, sleep apnea, myasthenia
gravis, or any other illness that the investigator considers should exclude the
participant or that could interfere with the interpretation of the study results

- Participant has a current or prior diagnosis of psychotic or bipolar disorder

- Participant with clinically significant abnormal values for hematology, clinical
chemistry, or urinalysis at screening or at admission to the study center (Day -1 of
the Qualification Session and each period of the Treatment Phase) as determined by
the investigator

- Participant with a history or presence of drug (excluding nicotine or caffeine) or
alcohol dependence according to the 4th edition of the Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV) criteria

- Participation in treatment for substance-related disorders within 3 years prior to
Screening