Phase I Functional Magnetic Resonance Imaging (fMRI) Pharmacodynamic Studies of Compounds for Opioid Use Disorder and Cocaine Use Disorder

During the screening period (Study Days -3 and -2), the urine drug screen (UDS) must be
negative for cocaine and opioids, and the self-reported last use of cocaine or opioids must
be at least seven days prior to this result, in order to ensure that possible cocaine or
opioid withdrawal has ended. After these criteria have been met, all subjects will receive
placebo at 8:30 AM for one day during the Placebo Pretreatment Baseline Day (Study Day -1).
The first fMRI session (fMRI #1) will take place at 10:00 AM on the following day (Study Day
1). Following fMRI #1, the subjects will be randomized into two parallel groups (Group A:
Lorcaserin; Group B: Parallel Placebo). Based on the information that a lower dose of
lorcaserin has the potential to be clinically effective , and based on the safety and abuse
potential data from human studies, as well as the preclinical data on interaction with
cocaine , the study will begin with the lower dose of lorcaserin (10 mg per day). For Group A
(lorcaserin group), the lorcaserin dose will be 10 mg orally per day for 7 days. For Group B
(parallel placebo group), identical appearing placebo will be given orally according to the
same schedule as lorcaserin for 7 days. After the 7 days of treatment with study medications,
fMRI #2 will take place, then study medications will be discontinued. A follow-up visit will
occur one week after the last dose of study medication. See Section II.b for details and
criteria for stopping or continuing this dosage based on the results of the interim analysis,
which will take place after 15 subjects have completed at each arm. Based on the interim
analysis, if there is no significant effect and no trend towards significant effect (p >
0.10) for the lower dose lorcaserin in the primary regions of interest for the cue-reactivity
fMRI task, and no significant accumulation of adverse effects, then testing will stop for the
lower dose of lorcaserin, and testing will begin for the higher dose of lorcaserin (10 mg
twice per day) 7 days. The higher dose of lorcaserin will be tested in a two group parallel
arm design, initially with 15 subjects in the high dose lorcaserin arm and 15 subjects in the
parallel placebo arm. Another interim analysis will take place after 15 subjects have
completed at each arm in the higher dose lorcaserin study.

Inclusion Criteria:

1. Males and females treatment-seeking cocaine and/or opioid users between 18 and 55
years-of-age.

2. Understand the study procedures and provide written informed consent.

3. Must be in residential or outpatient treatment for substance use disorder.

3. Meet current DSM-5 criteria for Cocaine Use Disorder and/or Opioid Use Disorder with
moderate or severe severity, and current DSM-IV diagnosis of cocaine dependence and/or
opioid dependence.

4. Have been abstinent from cocaine and opioid use for at least 1 week 5. Have vital signs
as follows: resting pulse between 55 and 95 bpm, blood pressures between 90-139 mm Hg
systolic and 50-89 mm Hg diastolic.

6. Have hematology and chemistry laboratory tests that are within normal limits, except
that liver function tests must be less than twice the upper limit of normal and judged by
the study physician to be clinically insignificant.

7. Have a normal baseline ECG as shown by normal sinus rhythm with the exception of sinus
arrhythmia or mild sinus bradycardia (heart rate 50 to 59 beats per minute), and with
normal conduction (including normal QTcF), with the exception of early repolarization
judged to be clinically insignificant by both the study physician and study cardiologist.

8. Have no contraindications for study participation as determined by history and physical
examination.

9. Be able to demonstrate an understanding of study procedures and follow instructions
including behavioral laboratory and fMRI testing.

10. No pregnant or nursing women will be permitted in the study, and women must either be
unable to conceive (i.e., surgically sterilized, sterile, or postmenopausal) or be using a
reliable form of contraception (e.g., abstinence, birth control pills, intrauterine device
with spermicide, or condoms). Men will be advised to use condoms. All females must provide
negative pregnancy urine tests before study entry, at each visit during the study, and at
the end of study participation.

Exclusion Criteria:

1. Have concurrent DSM-5 diagnosis of any psychoactive substance use disorder other than
cocaine, nicotine, opioid, or marijuana use disorder, or meet DSM-5 criteria for
cocaine or opioid withdrawal

2. Have a DSM-5 axis I psychiatric disorder other than substance use disorder, including
but not limited to Bipolar Disorder, Major Depressive Disorder, ADHD, or
Schizophrenia, or a neurological disorder requiring ongoing treatment and/or making
study participation unsafe.

3. Subjects with evidence or history of any clinically significant medical disorder
including cardiovascular, endocrine, pulmonary, CNS, hepatic, or renal, except that
controlled hypertension, controlled hypothyroidism, and cancer in remission will not
be excluded.

4. Subjects who have Type 1 or Type 2 diabetes mellitus, since weight loss may increase
the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with
insulin and/or insulin secretagogues (eg, sulfonylureas), and lorcaserin has not been
studied in combination with insulin.

5. Subjects with an abnormal QTcF on ECG.

6. Have a history of seizures (excluding childhood febrile seizures), or loss of
consciousness for more than 20 minutes.

7. Have significant current suicidal or homicidal ideation or a suicide attempt within
the past 6 months.

8. Be HIV positive by self-report or history.

9. Be pregnant or nursing or not using a reliable form of contraception if able to
conceive. All females must provide negative pregnancy urine tests before study entry,
at each visit during the study, and at the end of study participation.

10. Have any other illness, or condition, which in the opinion of the PI would preclude
safe and/or successful completion of the study.

11. Be using any medications or drugs that can affect the central nervous system other
than cocaine, marijuana, alcohol, caffeine, and nicotine.

12. Allowed concomitant medications should be maintained on a stable dose from screening
until the end of the study. Stable regular doses of dihydropyridines, such as
amlodipine (Norvasc), to control blood pressure are permitted. (However,
cardiovascular drugs that are taken as prn that could affect the blood flow centrally
are excluded).

12. Prior to starting study medication, and prior to each MRI scanning session, have
positive breath alcohol level, or have a positive urine drug screen for any drug of abuse
other than marijuana.

13. Have metal fragments or other bodily metal (e.g., pacemaker) or significant
claustrophobia that would put the subjects at risk for MRI scanning.

14. Subjects who are allergic to lorcaserin. 15. Subjects who have taken any
investigational drug within 90 days prior to baseline