Page 1 of 10 

### U.S. Department of Justice

Drug Enforcement Administration

Schedules of Controlled Su bstances: Placement of Lorcaserin into

Schedule I V

Background, Data, and Analysis:

Eight Factors Determinative of Control

and Findings Pursuant to 21 U.S.C

. § 812 (b)

Prepared by

Office of Diversion Control, Drug and Chemical Evaluation Section

Washington, D.C. 20537Page 2 of 10



### I. Background

Lo r caserin (( R )

- 8

- chloro

- 1

- methyl

- 2,3 ,4,5

- tetrahydro

- 1 H

- 3

- benzepine hydrochloride hemihydrate) is a new chemical entity which has central nervous system hallucinogenic properties. Lo r caserin was approved by the Food and Drug
Administration (FDA) on June 27, 2012

, as an addition to a reduced

- calorie diet and exercise, for chronic weight management ; it will be marketed under the trade name BELVIQ. Lo r caserin is a serotonin receptor agonist, at the 5

- HT 2C and 5

- HT 2A receptor subtypes (HHS review, 2012).

On J une 25, 201 2 , the Departme nt of Human Health Service (HHS) provided to the Drug Enforcement Administration (DEA) a scientific and medical evaluation entitled
“Basis for the Recommendation for Control of Lo r caserin i n Schedule I V of the Controlled Substances Act” and a scheduling re commendation. Following consideration of the eight factors and findings related to the substance’s abuse potential, legitimate medical use, and dependence liability, HHS recommended that lo r caserin be controlled in
S chedule I V of the Controlled Substances Act (CSA) under 21 U.S.C. § 812 (b).

The CSA requires DEA , as delegated by the Attorney General, 1 to determine whether the HHS’ scientific and medical evaluation and scheduling recommendation and all other
relevant data constitute substantial evidence that the substance should be scheduled

. 21 U.S.C. § 811(b).



### II. Eight Factors Determinative of Control

Pursuant to 21 U.S.C. § 811(c), DEA must consider eight factors in making any finding of substantial evidence of potential for abuse, including the data and law enforcement
information relevant thereto.

Factor 1

. Lo r caserin 's Actual or Relative Potential for Abuse

In addition to the information HHS provided in its scientific and medical
evaluation docu ment for lo r caserin , DEA considers all other relevant data regarding
lo r caserin ’s actual or relative potential for abuse. Since lo r caserin is a new chemical entity and has not been marketed in any country, information on actual abuse of
lo r caserin is not available. However , the legislative history of the CSA suggests that using the following criterion in determining whether a particular drug or substance has a potential for abuse:

1 28 CFR 0.100(b)Page 3 of 10 The drug or drugs containing such a substance are new drugs so related in their

action to a drug or drugs already listed as having a potential for abuse to make it likely that the drug will have the same potential ity for abuse as such drugs , thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community. 2

According to HHS, lorcaserin is an agonist at the 5

- HT 2C and 5

- HT 2A serotonin receptor subtypes. I n the clinical studies , the incidence of euphoria following supratherapeutic doses of lorcaserin is greater than that occurred following placebo (< 0.1%). In patients treated with 40 and 60 mg doses of lorcaserin the incidence of euph oria was 16% and 19%, respectively. The therapeutic dose of lo r caserin is 20 mg/day. In these studies, lo r caserin treat ed individuals also showed higher incidence of other safety or abuse

- related adverse events (AEs), such as feeling jittery, psychomotor hyperactivity, paresthesia, abnormal dreams, and state of confusion as compared to the subjects treated with placebo (HHS review, 2012)

.

According to HHS, o verall, the incidence of AE euphoria induced by lo r caserin was relatively low (< 1%) in Phase 1, 2, and 3 studies

. H owever, in a human abuse potential study with drug abusers

, 20

- 60 mg lo r caserin produced a high rate of the AE euphoria in 6

- 19% of the subjects. The incidence of euphoria following lo r caserin administration in the human abuse potentia l study is similar to th at reported following zolpidem (Schedule IV) administration (13

- 16%) and lower than that following ketamine (Schedule III) administrat ion (50%). Also the duration of euphoria in the lo r caserin treatment groups was more than nine ho urs and it was longer than that experienced by the zolpidem (1.5 hours) and ketamine (2.5 hours) treatment groups.

HHS described a human abuse potential study in recreational drug abusers of psychedelic drugs and CNS depressants, in which lo r caserin an d the comparator drugs zolpidem (Schedule IV) and ketamine (Schedule III) produced significant increases on positive subjective measures (visual analog scales (VAS) for “high” and “good drug
effects ” ) as well as an increase on the VAS for “hallucinations”. Lo r caserin, as well as zolpidem and ketamine, significant ly increase d reports of “sedation” on the subjective scale of the Addiction Research Center Inventory (ARCI), compared to placebo.

2 Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91

- 1444, 91 st Cong., Sess. 1 (1970); 1970 U.S.C.C.A.N. 4566, 4601.Page 4 of 10 HHS summarized that the se subject ive response data suggest that lo r caserin produces subjective effects similar to those produced by zolpidem and ketamine. T he fact that the supratherapeutic doses of lorcaseri n produce hallucinations, euphoria, and positive subjective responses is suggest iv e of its potential to produce psych i c dependence (HHS review, 2012)

.

According to HHS, lorcaserin is not available or marketed in any country. Thus
there is no evidence of lorca ser in diversion, illicit manufacturing, or deliberate ingestion.

Lorca s erin is not readily synthesized from available substances, and thus its diversion
will be likely from the legitimate channels. Because lorcaserin has been shown to produce euphoria in humans, it is anticipated that there will be significant use contrary to

or without medical advice.

In summary, i t has been demonstrated that lo r caserin does have abuse potential.

L o r caserin produces subjective effects similar to those produced by zolpidem (Schedule IV) and ketamine (Schedule III). Since lo r caserin is not curr ently marketed any country,
there is no current data of lo r caserin diversion or abuse.

Facto r 2. Scientific Evidence of Lorcaserin 's Pharmacological Effects

Neurochemistry

Lorcaserin is a 5

- HT 2C and 5

- HT 2A serotonin receptor agonist (HHS review, 2012). DEA further notes that l o r caserin is a selective agonist of the 5

- HT 2C and 5

- HT 2A serotonin receptor s , the K i value s are 15 nM and 112 nM, respectively

. Lorcaserin also
binds to the 5

- HT 2 B receptor with a K i value of 174 nM ( Thomsen et al. , 2008). 5

- HT 2C receptors are distributed in the brain regions associated with appetite and food intake. It
has been shown that 5

- HT 2C knockout mice are hyperphagic (Thomsen et al., 2008 ; Smith et al., 2009 ). It has been shown that lo r caserin through activat ion of 5

- HT 2C

re ceptors causes inositol phosphate accumulation with an EC 50 of 9 nM. Lo r caserin also
activated the 5

- HT 2A and 5

- HT 2B receptors, with EC 50 s of 168 nM and 943 nM, respectively (Thomsen et al., 2008).

It has also been shown that lorcaserin does not have significant binding to the following neurotransmitter binding sites: glutamate, GABA, sigma, acetylcholine, norepinephrine, cannabinoid, histamine, dopamine, non

- 5

- HT s serotonin sites, opioid
receptor (mu and delta subtypes), an d monoamine transporters (dopa mine, serotonin, and norepinephrine). Lorcaserin does not have significant affinity for the calcium or potassium channels (HHS review, 2012).Page 5 of 10

In vivo Pharmacology
Animals

According to the HHS review, lorcaserin is well

- tolerated at doses from 30

- 500 mg/kg in rats. Mortality occurs at 1000 mg/kg. Following lorcaserin administration, the observed behaviors are salivation, penile erection, ejaculation, piloerection, and trem ors. Acutely, lorcaserin decreases locomotor activity in rats. Tolerance does develop to this effect, because after 21 days, lorcaserin does not affect the locomotor activity of the rats.

DEA further notes that Thomsen and colleagues (2008) showed that food intake in rats was reduced after a single administration of lo r caserin. The doses administered were 3, 6, 12, and 24 mg/kg . Lo r caserin decreased the cumulative food intake at 2, 4, 6,
and 22 hours. The ED 50 for food intake inhibition was 18 mg/kg.

The HHS review states that lorcaserin does cause back muscle fasciculations and wet dog shakes , 5

- HT 2A mediated behaviors, in addition to the 5

- HT 2C mediated behaviors penile grooming and inactivity, based on their review of the New Drug Application ( NDA) from the Sponsor. Schedule I hallucinogen, 2,5

- dimethoxy

- 4

- methylamphetamine (DOM, a 5

- HT 2A and 5

- HT 2C receptor agonist), and dexfenfluramine (a drug without direct actions at 5

- HT 2A and 5

- HT 2C receptors), a Schedule IV stimulant, also produced these behaviors in this study.

A drug discrimination study conducted in DOM

- trained rats showed that locaserin (0.1

– 10 mg/kg) produced full generalization ( > 80%) to the DOM cue in 7 of 9 rats.
The se data suggest that locaserin in doses 0.1 to 10 mg/kg produces discriminative stimulus responses similar to DOM, a hallucinogen (HHS review, 2012).

Humans

As described by HHS in a human abuse potential study with individuals with a history of abusing drugs, locaserin was evaluated for its abuse potential; it was compared to ketamine (Schedule III NMDA antagonist), zolpidem (Schedule IV GABA agonist), and a placebo. In clinical trials, lorcaserin produced euphoric and hallucinogenic AEs
similar to tho se produced by ketamine and zolpidem. Lorcaserin was administered at doses of 20 mg, 40 mg, and 60 mg; ketamine was administered at a dose of 100 mg; and zolpidem was administered at doses of 15 mg and 30 mg. According to the Sponsor of
the new drug appl ication for lorcaserin, administration of 60 mg lorcaserin produced a significant increase in the E max for “drug liking” compared to the placebo on a VAS scale. Lorcaserin (40 mg and 60 mg) also produced increases on other subjective measures in
this stud y, such as “good drug effects”, “high”, “hallucinations”, and “sedation”.Page 6 of 10 According to HHS review, in the clinical studies, the incidence of euphoria following supratherapeutic doses of lorcaserin is greater than that occurred following placebo (< 0.1%). In patients treated with 40 and 60 mg doses of lorcaserin the incidence of euphoria was 16% and 19%, respectively.

DEA further notes that l o r caserin has been shown to induce weight loss of 1.8 kg, 2.6 kg, and 3.6 kg in patients administered 10 mg (4X/day), 15 mg (4X/day), and 10 mg (2X/day), respectively (Smith et al., 2009)

. There were 469 p atients enrolled in the 12

- week study. In this study, generally lo r caserin was well tolerated at the administered doses. The most frequently reported AEs we re headache, nausea, and dizziness (Smith et al., 2009). The BLOSSOM Trial included 4008 obese and overweight patients . The patients were administered 10 mg lo r caserin twice or fo u r times/day. At the end of the
52

- week study, significantly more patients treated with lo r caserin lost at least 5% of the baseline body w eight compared with the placebo

- treated group. Headache, nausea, and dizziness were the most common AEs reported by the lo r caserin treatment groups (Fidler et al., 2011)

.

Factor 3

. The Stat e of Current Scientific Knowledge Regarding Lo r caserin

Chemistry

Lo r caserin (( R )

- 8

- chloro

- 1

- methyl

- 2,3,4,5

- tetrahydro

- 1 H

- 3

- benzepine hydrochloride hemihydrate) is water

- soluble. The molecular formula is C 11 H 14 ClN and its molecular weight is 241.6 g/mol , the CAS number is 616202

- 92

- 7 (HHS Review, 2012).

Pharmacokinetics

In humans, l o r caserin is rapidly absorbed from the gastrointestinal tract after oral administration, the t max (time to reach maximum plasma concentration) is < 2 hours and
its half

- life in the plasma is about 11 hours (HHS review, 2012; Bai and Wang, 2011).

DEA further notes that after a single oral administration of 10 mg/kg lorcaserin to
rats, the absorption to from the gastrointestinal tract was rapid, resu lting in a mean

maximum plasma concentration (C max ) of 0.76  g/ml at 0.25 hour. The time from oral administration to brain maximal exposure was 1 hour (Thomsen et al., 2008).

Lo r caserin is metabolized by the live r and excreted by the kidney; the major
metabolite in the urine is N

- carbamoyl glucuronide (M5). The major circulatingPage 7 of 10

metabolite of lo r caserin is lo r caserin sulfamate (M1). M1 is considered inactive and it does not bind significantly to monoamine transporters (Bai and Wang, 2011; HHS review, 2012)

.

Factor 4. Lo r caserin’ s History and Current Pattern of Abuse of Lo r caserin

H istory and current pattern of abuse of lorcaserin abuse is not available since it has not been marketed in any c ountry . As stated in HHS’ review, lo r caserin produce d positive subjective effects in a human abuse potential study that are similar to those produced by zolpidem (Schedule IV) and ketamine (Schedule III). HHS states that the positive subjective effects reported from supratherapeut ic doses of lo r caserin administration are predictive of it potential for abuse.

Factor 5

. The Scope, Duration, and Significance of Abuse of Lo r caserin

According to the HHS review, t he information o n lo r caserin 's scope, duration and significance of abuse is not available since it has not been marketed in any country. Thus, the e valuation of abuse pattern of lorcaserin derives from positive indictors in pre

market clinical trials which are believed to be predictive of drug abuse. HHS determined

t hat based on the AEs reported in the clinical efficacy studies and the data from the human abuse potential lo r caserin study, the scope and significance of the abuse potential
of lo r caserin is similar to Schedule IV substances. HHS states that marketing lo r caserin
as a Schedule IV substance will decrease its abuse, as opposed to marketing as a n uncontrolled or Schedule V substance.

Factor 6

. What, If Any, Risk to the Public Health

According to HHS, l orcaserin produces a number of AEs that are commonly seen with other Schedule IV substances that are abused (see Factors 1 and 2)

. HHS also states that the abuse potential of lo r caserin presents a risk to the public’s health. Some of these
AEs include feeling jittery, psychomotor hyperactivity, paresthesia , abnormal dreams,
and state of confusion

. Headache, nausea, and dizziness were the most commonly reported AEs in lorcaserin clinical studies. I n a human abuse potential study, 20

- 60 mg
lo r caserin produced a high incidence of the AE euphoria in 6

- 19% of the subjects.

According to HHS, because lo r caserin binds to 5

- HT 2 receptors and generalize s to
5

- HT 2 agonists in drug discrimination studies in rats, it is expected to have a hallucin ogenic profile. DEA further notes that in the human abuse potential study conducted by Shram and colleagues (2011), supratherapeutic doses of lorcaserin werePage 8 of 10

associated with significantly higher peak scores on the “ Detached ” (40 and 60 mg),

“ Hallucinations ” (40 mg), and “ Spaced Out ” (40 and 60 mg) VAS

.

Factor 7

. Lo r caserin 's Psychic or Physiological Dependence Liability

According to HHS’ review, there were two clinical studies done to determine the ability of lorcaserin to induce physical dependence. The patient s in the se stud ies were obese and lorcaserin was administered for 4 and 12 weeks prior to drug discontinuation. Upon lorcaserin discontinuation, there were no signs of changes in mood , food interest, or body weight. Discontinuation of lorcaserin administration to animals also did not produce typical withdrawal symptoms.

According to HHS

, the ability of lorcaserin to produce hallucinations, euphoria, and positive subjective responses at supratherapeutic doses is suggest ive of its potential

to produce psych i c dependence.

Factor 8

. Whether Lo r caserin Is an Immediate Precursor of a Substance Already
Controlled

Lo r caserin is not an immediate precursor of a substance already controlled under
the CSA

.



### III. Findings for Schedule Placement Pursuant to 21 U.S.C. § 812(b)

21 U.S.C. § 812(b) requires the evaluation of a substance’s abuse potential, accepted medical use, and safety for use under medical supervision for placement in the
CSA as a controlled substance. Af ter consideration of the above eight factors determinative of control of a substance (21 U.S.C. § 811(c)), and a review of the scientific and medical evaluation and scheduling recommendation provided by the HHS,
DEA finds that lo r caserin meets the followin g criteria for placement in S chedule I V of the CSA, under 21 U.S.C. § 812 (b)(4).

1) Lo r caserin has a low potential for abuse relative to th e drugs or other substances
in S chedule I II

.

The collected information suggests that lo r caserin has abuse potential

. In a human abuse potential study, 20

- 60 mg lorcaserin produced a high incidence of the AE euphoria in 6

- 19% of the subjects. The incidence of euphoria resulting from lorcaserin
administration in th is study is similar to the incidence reported following zolpidem (Schedule IV) administration (13

- 16%) and lower than that following ketamine (SchedulePage 9 of 10

III) administration (50%). T he duration of euphoria experienced by the lorcaserin treatment groups, which was more than nine hours, was longer than t hat experienced by the zolpidem (1.5 hours) and ketamine (2.5 hours) treatment groups. Lorcaserin and the

compara tor drugs zolpidem (Schedule IV) and ketamine (Schedule III) produced significant increases on positive subjective measures (VAS for “high” an d “good drug
effects ” ) as well as an increase on the VAS for “hallucinations”. Lorcaserin, as well as zolpidem and ketamine, significantly increased reports of “sedation” on the subjective scale of the ARCI, compared to placebo. Also in other human clini cal studies, there were reports by the patients of feeling jittery, psychomotor hyperactivity, paresthesia, abnormal dreams, and state of confusion . Headache, nausea, and dizziness were the most commonly reported AEs following lorcaserin administration

. T hese data collectively
indicate that lorcaserin has a low abuse potential relative to Schedule III drugs and its abuse potential is similar to Schedule IV drugs.

2) Lo r caserin currently has a n accepted medical use in the United States.

L o r caserin (BE LVIQ) was recently approved by FDA as an addition to a reduced

calorie diet and exercise for chronic weight management and has a currently accepted
medical use in the United States.

3) Abuse of l o r caserin may lead to limited physical dependence or psychological dependence relative to th e drugs or other substances in S chedule I II

.

Lo r caserin may develop lim ited physical and psychological dependence relative to drugs in S chedule I II

. HHS states that lorcaserin produce s hallucinations, euphoria, and positive subjective responses

. The responses produced by lorcaserin are less than that produced ketamine (Schedule III) and similar to those produced by zolpidem (Schedule IV). These data suggest that abu se of lorcaserin may lead to limited psychological dependence relative to substances in Schedule III.Page 10 of 10

References

1. Bai B and Wang Y. (2011). The Use of Lorcaserin in the Management of Obesity: a Critical Appraisal. Drug Design, Development and Therapy

. 5 , 1

- 7.
2. Department of Health and Human Services, FDA Review (201 2 )

. Basis for the
Recommendation for Control of Lorcaserin in Schedule I V of the Controlled
Substances Act.
3. Fidler MC, Sanchez M, Raether B, Weissman NJ, Smith SR, Shanahan WR, and Anderson CM. (2011). A One

- Year Randomized Trial of Lorcaserin for Weight Loss ion Obese and Overweight Adults: the BLOSSOM Trial. Journal of Clinical Endocrinology Metabolism

. 96 , 3067

- 3077.
4. Shram MJ, Schoedel KA, Bartlett C, Shazer RL, Anderson CM, and Sellers EM. (2011). Evaluation of the Abuse Potential of Lorcaserin , a Serotonin 2C (5

- HT 2C ) Receptor Agonist, in Recreational Polydrug Users. Clinical Pharmacology and Therapeutics

. 89 , 683

- 692.
5. Smith SR, Prosser WA, Donahue DJ, Morgan ME, Anderson CM, and Shanahan WR. (2009). Lorcaserin (APD356), a Selective 5

- HT 2C Agonist, Reduces Body Weight in Obese Men and Women. Obesity

. 17 , 494

- 503.

6. Thomse n WJ, Grottick AJ, Menzaghi F, Reyes

- Saldana H, Espitia S, Yuskin D, Whelan K, Ma rtin M, Morgan M, Chen W, Al

- Shamma H, Smith B, Chalmers D, and Behan D. (2008). Lorcaserin, a Novel Selective Human 5

- Hydroxytryptamine 2C Agonist: in Vitro and in Vivo Pharmacological
Characterization. Journal of Pharmacology and Experimental Therapeutics

. 325

, 577

- 587.