Lorcaserin for Cannabis Use Disorder

Cannabis use disorder (CUD) is a major public health problem associated with significant
psychiatric and medical morbidity, poor performance, and legal consequences.4 4.2 million
people in the United States meet criteria for CUD.5 15% of all admissions for substance abuse
treatment were related to cannabis as the primary, presenting problem in 2014 and 86% of
those admissions were referred for ambulatory care.6 Despite the large number of patients
with CUD seeking outpatient treatment, the investigators have limited options available.
While evidence-based practices (EBP), and specifically psychotherapies, have been studied to
treat CUD and various approaches have been shown to have clinical utility,7-9 many patients
have difficulty achieving significant reductions in their use or sustained abstinence.10 This
is further complicated by patients' limited access to EBPs,11 frequent poor adherence by
therapists in the community to EBP interventions,12-14 and challenges in treating CUD with
EBPs when available in community settings.10 Finding effective medications for the treatment
of CUD is essential. There are no FDA approved medications for CUD. A number of
pharmacological treatment trials for CUD have been performed.1* While some agents have shown
promise,15-17 no medication strategy has emerged as clearly efficacious in producing
abstinence.1,18 As the changing legal landscape influences patients' goals for reductions in
cannabis use as compared to abstinence only, and with increasing support from the research
community, future studies need to identify medications that lead to reductions in cannabis
use.

Impulsivity has been linked to the predisposition,19 severity,20 and poor treatment
outcomes21, 22 in cannabis users and CUD, making it a prime pharmacology target. Notably,
there is an entwined relationship between cannabis and impulsivity. Impulsivity as a
neurobehavioral trait is associated with cannabis use,and acute and chronic use of cannabis
has been shown to exacerbate impulsivity, with some mixed evidence likely attributable to
diverse constructs of impulsivity used across studies. While the investigators may not be
able to fully determine which came first—the impulsivity or the cannabis use, further
research is needed to demonstrate whether reductions across constructs of impulsivity can
lead to improvements in CUD, and vice versa. Over the last two decades, 5HT2C receptor
agonists have been shown to alter neurobiological systems of addiction and relevant drug use
behavior in the preclinical literature by increasing inhibitory control on mesolimibic
dopamine processes and resultant incentive motivation based behaviors,23 both directly and
indirectly, particularly with regards to their impact on reducing impulsivity.24 In 2012,
lorcaserin, a selective 5HT2C receptor agonist, was approved by the FDA, allowing for
clinical exploration of its role in the treatment of substance use disorders, including
CUD.25 Recently, a fully powered clinical trial of lorcaserin for tobacco smoking cessation
was positive.26 The primary purpose of this study is therefore to investigate the effect of
lorcaserin on reductions in cannabis use and multiple constructs of impulsivity in outpatient
treatment-seeking individuals with CUD.

Additionally, the investigators will make use of the technological application of ecological
momentary assessments (EMA), to collect real-time data at key time intervals during the study
on participants' use of cannabis and other substances in addition to measuring impulsive
traits through self-initiated, fixed and random phone prompts. This will be a 13-week
randomized, double-blind, placebo-controlled trial, with week 1 focused on baseline
assessments of impulsivity (through EMA in vivo and at study visits), weeks 2-3 of medication
lead-in, and week 4 targeting a reduced cannabis use/quit day through week 13. This "proof of
concept" study will provide Dr. Brezing with training in randomized controlled trial
operations, multiple constructs to measure impulsivity, utilization of technology as a
measurement tool, and identification of outcomes that may prove important to reductions in
cannabis use.

Primary Aims:

(Aim 1) Examine the effect of lorcaserin compared to placebo, on reductions in cannabis use
among treatment-seeking outpatients with CUD, with the primary outcome measured by average
weekly mean episodes of any cannabis use (including edibles, vaping, and other variable
potency cannabinoid products) per day. (Aim 2) Examine the effect of lorcaserin compared to
placebo on behavioral and self-report measures of impulsivity among individuals with CUD
during the medication lead-in phase (weeks 2-3).

Secondary Aim: If the hypotheses of the Primary Aims are supported, the investigators will
examine whether reductions in impulsivity (during weeks 2-3) mediates the effect of
lorcaserin on cannabis use (during weeks 8-13).

Exploratory Aims: To explore the effect of lorcaserin compared to placebo on (1) drop-out
rates, (2) time to discontinuation from study, (3) treatment adherence, and (4) nicotine use.

Inclusion Criteria:

1. Individuals between the ages of 18-70

2. Meets DSM-V criteria for a current cannabis use disorder

3. Seeking treatment for cannabis use disorder

4. THC-positive urine drug screen

5. Capable of giving informed consent and complying with study procedures

6. Has regular access to the internet by any means

7. Not underweight (Defined as BMI ≥18.5)

Exclusion Criteria:

1. Lifetime history of DSM-V diagnosis of schizophrenia or schizoaffective disorder

2. Current DSM-V criteria for a psychiatric disorder supported by the MINI that in the
investigator's judgment is unstable, would be disrupted by the study medication, or is
likely to require new pharmacotherapy or psychotherapy during the study period.
Individuals who are currently stable on psychotropic medication for at least 3months
may be included if in the investigator's opinion the psychotropic medication is
compatible with the study medication (lorcaserin).

3. Individuals who meet DSM-V criteria for any moderate to severe substance use disorder
other an cannabis, caffeine or nicotine use disorders

4. Pregnancy, lactation, or failure to use adequate contraceptive method in female
patients who are currently engaging in sexual activity with men

5. Unstable medical conditions, such as AIDS, cancer, uncontrolled hypertension,
uncontrolled diabetes, pulmonary hypertension or heart disease; or individuals with a
history of serotonin syndrome

6. Legally mandated to participate in a substance use disorder treatment program

7. Current or recent history of significant violent or suicidal behavior, risk for
suicide or homicide

8. Currently meets DSM-V diagnosis for an eating disorder or is underweight (BMI <18.5)

9. Elevated liver function tests (AST and ALT > 3 times the upper limit of normal) or
impaired renal function

10. Known history of allergy, intolerance, or hypersensitivity to lorcaserin

11. Concurrent use of migraine medications ergotamine (Cafergot, Ergomar) or
dihydroergotamine (Migranal), 5HT2B receptor agonists like cabergoline, medications
metabolized by CYP2D6 (thioridazine, tamoxifen, metoprolol, aripiprazole, codeine,,
MAOIs, or St. John's Wort