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U.S. Department of Justice

Drug Enforcement Administration

Schedules of Controlled Substances: Placement of Lorcaserin into 

Schedule IV

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. 20537
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I. Background

Lorcaserin ((R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzepine 

hydrochloride hemihydrate) is a new chemical entity which has central nervous system 

hallucinogenic properties. Lorcaserin 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. Lorcaserin is a serotonin receptor agonist, at the 5-HT2C and 5-HT2A receptor 

subtypes (HHS review, 2012). 

On June 25, 2012, the Department 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 Lorcaserin in Schedule IV of the 

Controlled Substances Act” and a scheduling recommendation. Following consideration 

of the eight factors and findings related to the substance’s abuse potential, legitimate 

medical use, and dependence liability, HHS recommended that lorcaserin be controlled in 

Schedule IV of the Controlled Substances Act (CSA) under 21 U.S.C. § 812 (b). 

The CSA requires DEA, as delegated by the Attorney General,1to 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. Lorcaserin's Actual or Relative Potential for Abuse

In addition to the information HHS provided in its scientific and medical 

evaluation document for lorcaserin, DEA considers all other relevant data regarding 

lorcaserin’s actual or relative potential for abuse. Since lorcaserin is a new chemical 

entity and has not been marketed in any country, information on actual abuse of 

lorcaserin 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)
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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 potentiality 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-HT2C and 5-HT2A serotonin 

receptor subtypes. 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. The therapeutic dose of lorcaserin is 20 

mg/day. In these studies, lorcaserin treated 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, overall, the incidence of AE euphoria induced by lorcaserin 

was relatively low (< 1%) in Phase 1, 2, and 3 studies. However, in a human abuse 

potential study with drug abusers, 20-60 mg lorcaserin produced a high rate of the AE 

euphoria in 6-19% of the subjects. The incidence of euphoria following lorcaserin 

administration in the human abuse potential study is similar to that reported following 

zolpidem (Schedule IV) administration (13-16%) and lower than that following ketamine 

(Schedule III) administration (50%). Also the duration of euphoria in the lorcaserin 

treatment groups was more than nine hours 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 lorcaserin and 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”. Lorcaserin, as well as 

zolpidem and ketamine, significantly increased 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, 91st Cong., 

Sess. 1 (1970); 1970 U.S.C.C.A.N. 4566, 4601.
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HHS summarized that these subjective response data suggest that lorcaserin 

produces subjective effects similar to those produced by zolpidem and ketamine. The 

fact that the supratherapeutic doses of lorcaserin produce hallucinations, euphoria, and 

positive subjective responses is suggestive of its potential to produce psychic dependence

(HHS review, 2012).

According to HHS, lorcaserin is not available or marketed in any country. Thus 

there is no evidence of lorcaserin diversion, illicit manufacturing, or deliberate ingestion. 

Lorcaserin 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, it has been demonstrated that lorcaserin does have abuse potential. 

Lorcaserin produces subjective effects similar to those produced by zolpidem (Schedule 

IV) and ketamine (Schedule III). Since lorcaserin is not currently marketed any country, 

there is no current data of lorcaserin diversion or abuse. 

Factor 2. Scientific Evidence of Lorcaserin's Pharmacological Effects

Neurochemistry

Lorcaserin is a 5-HT2C and 5-HT2A serotonin receptor agonist (HHS review, 

2012). DEA further notes that lorcaserin is a selective agonist of the 5-HT2C and 5-HT2A

serotonin receptors, the Ki values are 15 nM and 112 nM, respectively. Lorcaserin also 

binds to the 5-HT2B receptor with a Ki value of 174 nM (Thomsen et al., 2008). 5-HT2C

receptors are distributed in the brain regions associated with appetite and food intake. It 

has been shown that 5-HT2C knockout mice are hyperphagic (Thomsen et al., 2008; 

Smith et al., 2009). It has been shown that lorcaserin through activation of 5-HT2C 

receptors causes inositol phosphate accumulation with an EC50 of 9 nM. Lorcaserin also 

activated the 5-HT2A and 5-HT2B receptors, with EC50s 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-HTs serotonin sites, opioid 

receptor (mu and delta subtypes), and monoamine transporters (dopamine, serotonin, and 

norepinephrine). Lorcaserin does not have significant affinity for the calcium or 

potassium channels (HHS review, 2012). 
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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 tremors. 

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 lorcaserin. The doses administered 

were 3, 6, 12, and 24 mg/kg. Lorcaserin decreased the cumulative food intake at 2, 4, 6, 

and 22 hours. The ED50 for food intake inhibition was 18 mg/kg. 

The HHS review states that lorcaserin does cause back muscle fasciculations and 

wet dog shakes, 5-HT2A mediated behaviors, in addition to the 5-HT2C 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-HT2A and 5-HT2C receptor agonist), and dexfenfluramine 

(a drug without direct actions at 5-HT2A and 5-HT2C 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. 

These 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 those 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 application for lorcaserin, administration of 60 mg lorcaserin produced a 

significant increase in the Emax 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 study, such as “good drug effects”, “high”, “hallucinations”, and “sedation”.
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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 lorcaserin 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 patients enrolled in the 12-

week study. In this study, generally lorcaserin was well tolerated at the administered 

doses. The most frequently reported AEs were headache, nausea, and dizziness (Smith et 

al., 2009). The BLOSSOM Trial included 4008 obese and overweight patients. The 

patients were administered 10 mg lorcaserin twice or four times/day. At the end of the 

52-week study, significantly more patients treated with lorcaserin lost at least 5% of the 

baseline body weight compared with the placebo-treated group. Headache, nausea, and 

dizziness were the most common AEs reported by the lorcaserin treatment groups (Fidler 

et al., 2011).

Factor 3. The State of Current Scientific Knowledge Regarding Lorcaserin

Chemistry

Lorcaserin ((R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzepine 

hydrochloride hemihydrate) is water-soluble. The molecular formula is C11H14ClN and 

its molecular weight is 241.6 g/mol, the CAS number is 616202-92-7 (HHS Review, 

2012). 

Pharmacokinetics

In humans, lorcaserin is rapidly absorbed from the gastrointestinal tract after oral 

administration, the tmax (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, resulting in a mean 

maximum plasma concentration (Cmax) 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). 

Lorcaserin is metabolized by the liver and excreted by the kidney; the major

metabolite in the urine is N-carbamoyl glucuronide (M5). The major circulating 
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metabolite of lorcaserin is lorcaserin sulfamate (M1). M1 is considered inactive and it 

does not bind significantly to monoamine transporters (Bai and Wang, 2011; HHS 

review, 2012). 

Factor 4. Lorcaserin’s History and Current Pattern of Abuse of Lorcaserin

History and current pattern of abuse of lorcaserin abuse is not available since it 

has not been marketed in any country. As stated in HHS’ review, lorcaserin produced

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 supratherapeutic doses of lorcaserin 

administration are predictive of it potential for abuse. 

Factor 5. The Scope, Duration, and Significance of Abuse of Lorcaserin

According to the HHS review, the information on lorcaserin's scope, duration and 

significance of abuse is not available since it has not been marketed in any country. 

Thus, the evaluation of abuse pattern of lorcaserin derives from positive indictors in premarket clinical trials which are believed to be predictive of drug abuse. HHS determined 

that based on the AEs reported in the clinical efficacy studies and the data from the 

human abuse potential lorcaserin study, the scope and significance of the abuse potential 

of lorcaserin is similar to Schedule IV substances. HHS states that marketing lorcaserin 

as a Schedule IV substance will decrease its abuse, as opposed to marketing as an

uncontrolled or Schedule V substance.

Factor 6. What, If Any, Risk to the Public Health

According to HHS, lorcaserin 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 lorcaserin 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. In a human abuse potential study, 20-60 mg 

lorcaserin produced a high incidence of the AE euphoria in 6-19% of the subjects. 

According to HHS, because lorcaserin binds to 5-HT2 receptors and generalizes to 

5-HT2 agonists in drug discrimination studies in rats, it is expected to have a 

hallucinogenic profile. DEA further notes that in the human abuse potential study 

conducted by Shram and colleagues (2011), supratherapeutic doses of lorcaserin were 
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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. Lorcaserin'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 patients in these studies 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 suggestive of its potential 

to produce psychic dependence.

Factor 8. Whether Lorcaserin Is an Immediate Precursor of a Substance Already 

Controlled

Lorcaserin 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. After 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 lorcaserin meets the following criteria for placement in Schedule IV of 

the CSA, under 21 U.S.C. § 812 (b)(4). 

1) Lorcaserin has a low potential for abuse relative to the drugs or other substances 

in Schedule III.

The collected information suggests that lorcaserin 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 this study is similar to the incidence reported following zolpidem 

(Schedule IV) administration (13-16%) and lower than that following ketamine (Schedule 
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III) administration (50%). The duration of euphoria experienced by the lorcaserin 

treatment groups, which was more than nine hours, was longer than that experienced by 

the zolpidem (1.5 hours) and ketamine (2.5 hours) treatment groups. Lorcaserin and the 

comparator drugs zolpidem (Schedule IV) and ketamine (Schedule III) produced 

significant increases on positive subjective measures (VAS for “high” and “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 clinical 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. These 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) Lorcaserin currently has an accepted medical use in the United States.

Lorcaserin (BELVIQ) was recently approved by FDA as an addition to a reducedcalorie diet and exercise for chronic weight management and has a currently accepted 

medical use in the United States. 

3) Abuse of lorcaserin may lead to limited physical dependence or psychological 

dependence relative to the drugs or other substances in Schedule III. 

Lorcaserin may develop limited physical and psychological dependence relative 

to drugs in Schedule III. HHS states that lorcaserin produces 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 abuse of lorcaserin may lead to limited 

psychological dependence relative to substances in Schedule III. 
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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 (2012). Basis for the

Recommendation for Control of Lorcaserin in Schedule IV 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-HT2C) 

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-HT2C Agonist, Reduces Body 

Weight in Obese Men and Women. Obesity. 17, 494-503.

6. Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D, 

Whelan K, Martin M, Morgan M, Chen W, Al-Shamma H, Smith B, Chalmers D, 

and Behan D. (2008). Lorcaserin, a Novel Selective Human 5-

Hydroxytryptamine2C Agonist: in Vitro and in Vivo Pharmacological 

Characterization. Journal of Pharmacology and Experimental Therapeutics. 325, 

577-587.