79450 Federal Register / Vol. 85, No. 238 / Thursday, December 10, 2020 / Proposed Rules 

The Proposed Amendment 

In consideration of the foregoing, the 

Federal Aviation Administration 

proposes to amend 14 CFR part 71 as 

follows: 

PART 71—DESIGNATION OF CLASS A, 

B, C, D, AND E AIRSPACE AREAS; AIR 

TRAFFIC SERVICE ROUTES; AND 

REPORTING POINTS 

■ 1. The authority citation for part 71 

continues to read as follows: 

Authority: 49 U.S.C. 106(f), 106(g); 40103, 

40113, 40120; E.O. 10854, 24 FR 9565, 3 CFR, 

1959–1963 Comp., p. 389. 

§ 71.1 [Amended] 

■ 2. The incorporation by reference in 

14 CFR 71.1 of FAA Order 7400.11E, 

Airspace Designations and Reporting 

Points, dated July 21, 2020 and effective 

September 15, 2020, is amended as 

follows: 

Paragraph 2066 United States Area 

Navigation Routes. 

* * * * * 

Q–437 VILLS, NJ to SLANG, VT [New] 

VILLS, NJ FIX (Lat. 39°18′03.87′′ N, long. 075°06′37.89′′ W) 

DITCH, NJ FIX (Lat. 39°47′37.86′′ N, long. 074°42′59.88′′ W) 

LUIGI, NJ FIX (Lat. 40°04′09.65′′ N, long. 074°26′40.32′′ W) 

HNNAH, NJ FIX (Lat. 40°28′12.73′′ N, long. 074°02′36.62′′ W) 

LLUND, NY FIX (Lat. 40°51′45.04′′ N, long. 073°46′57.30′′ W) 

BIZEX, NY WP (Lat. 41°17′02.86′′ N, long. 073°34′50.20′′ W) 

BINGS, NY WP (Lat. 42°00′33.26′′ N, long. 073°30′01.81′′ W) 

WARUV, NY FIX (Lat. 42°45′52.14′′ N, long. 073°34′41.41′′ W) 

SLANG, VT WP (Lat. 43°14′24.64′′ N, long. 073°11′09.69′′ W) 

* * * * * 

Issued in Washington, DC, on December 2, 

2020. 

George Gonzalez, 

Acting Manager, Rules and Regulations 

Group. 

[FR Doc. 2020–26947 Filed 12–9–20; 8:45 am] 

BILLING CODE 4910–13–P 

DEPARTMENT OF JUSTICE 

Drug Enforcement Administration 

21 CFR Part 1308 

[Docket No. DEA–665] 

Schedules of Controlled Substances: 

Removal of Samidorphan From Control 

AGENCY: Drug Enforcement 

Administration, Department of Justice. 

ACTION: Notice of proposed rulemaking. 

SUMMARY: The Drug Enforcement 

Administration (DEA) proposes to 

remove samidorphan (3-carboxamido-4- 

hydroxy naltrexone) and its salts from 

the schedules of the Controlled 

Substances Act (CSA). This scheduling 

action is pursuant to the CSA which 

requires that such actions be made on 

the record after opportunity for a 

hearing through formal rulemaking. 

Samidorphan is currently a schedule II 

controlled substance because it can be 

derived from opium alkaloids. This 

action would remove the regulatory 

controls and administrative, civil, and 

criminal sanctions applicable to 

controlled substances, including those 

specific to schedule II controlled 

substances, on persons who handle 

(manufacture, distribute, reverse 

distribute, dispense, conduct research, 

import, export, or conduct chemical 

analysis) or propose to handle 

samidorphan. 

DATES: Interested persons may file 

written comments on this proposal in 

accordance with 21 CFR 1308.43(g). 

Electronic comments must be 

submitted, and written comments must 

be postmarked, on or before January 11, 

2021. Commenters should be aware that 

the electronic Federal Docket 

Management System will not accept 

comments after 11:59 p.m. Eastern Time 

on the last day of the comment period. 

Interested persons may file a request 

for hearing or waiver of participation 

pursuant to 21 CFR 1308.44 and in 

accordance with 21 CFR 1316.45, 

1316.47, 1316.48, or 1316.49, as 

applicable. Requests for hearing, notices 

of appearance, and waivers of an 

opportunity for a hearing or to 

participate in a hearing must be 

received on or before January 11, 2021. 

ADDRESSES: To ensure proper handling 

of comments, please reference ‘‘Docket 

No. DEA–665’’ on all correspondence, 

including any attachments. 

• Electronic comments: DEA 

encourages that all comments be 

submitted through the Federal 

eRulemaking Portal, which provides the 

ability to type short comments directly 

into the comment field on the web page 

or to attach a file for lengthier 

comments. Please go to http:// 

www.regulations.gov and follow the 

online instructions at that site for 

submitting comments. Upon completion 

of your submission you will receive a 

Comment Tracking Number for your 

comment. Please be aware that 

submitted comments are not 

instantaneously available for public 

view on Regulations.gov. If you have 

received a comment tracking number, 

your comment has been successfully 

submitted and there is no need to 

resubmit the same comment. 

• Paper comments: Paper comments 

that duplicate an electronic submission 

are not necessary and are discouraged. 

Should you wish to mail a comment in 

lieu of an electronic format, it should be 

sent via regular or express mail to: Drug 

Enforcement Administration, Attention: 

DEA Federal Register Representative/ 

DPW, 8701 Morrissette Drive, 

Springfield, Virginia 22152. 

• Hearing requests: All requests for 

hearing and waivers of participation 

must be sent to: Drug Enforcement 

Administration, Attn: Hearing Clerk/ 

OALJ, 8701 Morrissette Drive, 

Springfield, Virginia 22152. 

FOR FURTHER INFORMATION CONTACT: 

Terrence L. Boos, Drug & Chemical 

Evaluation Section, Diversion Control 

Division, Drug Enforcement 

Administration; Mailing Address: 8701 

Morrissette Drive, Springfield, Virginia 

22152; Telephone: (571) 362–3261. 

SUPPLEMENTARY INFORMATION: 

Posting of Public Comments 

Please note that all comments 

received in response to this docket are 

considered part of the public record. 

They will, unless reasonable cause is 

given, be made available by DEA for 

public inspection online at http:// 

www.regulations.gov. Such information 

includes personal identifying 

information (such as your name, 

address, etc.) voluntarily submitted by 

the commenter. The Freedom of 

Information Act applies to all comments 

received. If you want to submit personal 

identifying information (such as your 

name, address, etc.) as part of your 

comment, but do not want it to be made 

publicly available, you must include the 

phrase ‘‘PERSONAL IDENTIFYING 

INFORMATION’’ in the first paragraph 


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1As discussed in a memorandum of 

understanding entered into by the Food and Drug 

Administration (FDA) and NIDA, FDA acts as the 

lead agency within the HHS in carrying out the 

Secretary’s scheduling responsibilities under the 

CSA, with the concurrence of NIDA. 50 FR 9518, 

March 8, 1985. The Secretary of the HHS has 

delegated to the Assistant Secretary for Health of 

the HHS the authority to make domestic drug 

scheduling recommendations. 58 FR 35460, July 1, 

1993. 

2Administrative responsibilities for evaluating a 

substance for control under the CSA are performed 

for HHS by the Food and Drug Administration 

(FDA), with the concurrence of NIDA, according to 

a Memorandum of Understanding (50 FR 9518; 

March 8, 1985). 

3 28 CFR 0.100(b). 

of your comment. You must also place 

the personal identifying information 

you do not want made publicly 

available in the first paragraph of your 

comment and identify what information 

you want redacted. 

If you want to submit confidential 

business information as part of your 

comment, but do not want it to be made 

publicly available, you must include the 

phrase ‘‘CONFIDENTIAL BUSINESS 

INFORMATION’’ in the first paragraph 

of your comment. You must also 

prominently identify confidential 

business information to be redacted 

within the comment. 

Comments containing personal 

identifying information and confidential 

business information identified as 

directed above will generally be made 

publicly available in redacted form. If a 

comment has so much confidential 

business information or personal 

identifying information that it cannot be 

effectively redacted, all or part of that 

comment may not be made publicly 

available. Comments posted to http:// 

www.regulations.gov may include any 

personal identifying information (such 

as name, address, and phone number) 

included in the text of your electronic 

submission that is not identified as 

directed above as confidential. 

An electronic copy of this document 

and supplemental information to this 

proposed rule are available at http:// 

www.regulations.gov for easy reference. 

DEA specifically solicits written 

comments regarding DEA’s economic 

analysis of the impact of these proposed 

changes. DEA requests that commenters 

provide detailed descriptions in their 

comments of any expected economic 

impacts, especially to small entities. 

Commenters should provide empirical 

data to illustrate the nature and scope of 

such impact. 

Request for Hearing, Notice of 

Appearance at or Waiver of 

Participation in Hearing 

Pursuant to 21 U.S.C. 811(a), this 

action is a formal rulemaking ‘‘on the 

record after opportunity for a hearing.’’ 

Such proceedings are conducted 

pursuant to the provisions of the 

Administrative Procedure Act (5 U.S.C. 

551–559). 21 CFR 1308.41–1308.45, and 

21 CFR part 1316 subpart D. In 

accordance with 21 CFR 1308.44 (a)–(c), 

requests for hearing, notices of 

appearance, and waivers of an 

opportunity for a hearing or to 

participate in a hearing may be 

submitted by interested persons. Such 

requests or notices must conform to the 

requirements of 21 CFR 1308.44(a) or 

(b), and 1316.47 or 1316.48, as 

applicable, and include a statement of 

the interest of the person in the 

proceeding and the objections or issues, 

if any, concerning which the person 

desires to be heard. Any waiver must 

conform to the requirements of 21 CFR 

1308.44(c) and 1316.49, including a 

written statement regarding the 

interested person’s position on the 

matters of fact and law involved in any 

hearing. 

Please note that, pursuant to 21 U.S.C. 

811(a)(2), the purpose of a hearing 

would be to determine whether 

samidorphan should be removed from 

the list of controlled substances based 

on a finding that the drug does not meet 

the requirements for inclusion in any 

schedule. All requests for hearing and 

waivers of participation must be sent to 

DEA using the address information 

above, on or before the date specified 

above. 

Legal Authority 

The CSA provides that proceedings 

for the issuance, amendment, or repeal 

of the scheduling of any drug or other 

substance may be initiated by the 

Attorney General (1) on his own motion, 

(2) at the request of the Secretary of the 

Department of Health and Human 

Services (HHS),1 or (3) on the petition 

of any interested party. 21 U.S.C. 811(a). 

This action was initiated by a petition 

to remove samidorphan from the list of 

scheduled controlled substances of the 

CSA, and is supported by, inter alia, a 

recommendation from the Assistant 

Secretary of HHS and an evaluation of 

all relevant data by DEA. If finalized, 

this action would remove the regulatory 

controls and administrative, civil, and 

criminal sanctions applicable to 

controlled substances, including those 

specific to schedule II controlled 

substances, on persons who handle or 

propose to handle samidorphan. 

Background 

Samidorphan (3-carboxamido-4- 

hydroxy naltrexone), is a chemical 

entity that is structurally similar to 

naltrexone, a mu (m)-opioid receptor 

antagonist. Samidorphan (other 

developmental code names: RDC–0313 

or ALKS 33) is a mu-opioid receptor 

antagonist with a weak partial agonist 

activity at the kappa (k)- and delta (d)- 

opioid receptors. According to HHS, 

products containing samidorphan are 

currently being developed for medical 

use. 

Samidorphan is currently controlled 

in Schedule II of the CSA, as defined in 

21 CFR 1308.12(b)(l), because it can be 

derived from opium alkaloids. On April 

14, 2014, DEA received a petition to 

initiate proceedings to amend 21 CFR 

1308.12(b)(1) so as to decontrol 

samidorphan from schedule II of the 

CSA. The petition complied with the 

requirements of 21 CFR 1308.43(b) and 

was accepted for filing. The petitioner 

contended that samidorphan has been 

characterized as an opioid receptor 

antagonist, a class of drugs with no 

abuse potential. 

Proposed Determination To Decontrol 

Samidorphan 

Pursuant to 21 U.S.C. 811(b), on April 

24, 2015, DEA, having gathered the 

necessary data on samidorphan, 

forwarded that data and the petition to 

HHS 2 with a request for scientific and 

medical evaluation and scheduling 

recommendation for samidorphan. On 

January 9, 2020, DEA received from 

HHS a scientific and medical evaluation 

(dated December 19, 2019) conducted 

by the Food and Drug Administration 

(FDA) entitled ‘‘Basis for the 

Recommendation to Remove 

Samidorphan (3-Carboxamido-4- 

Hydroxy Naltrexone) and its Salts from 

All Schedules of Control Under the 

Controlled Substances Act’’ and a 

scheduling recommendation. The 

National Institute on Drug Abuse 

(NIDA) concurred with the scientific 

and medical evaluation conducted by 

FDA. Based on the totality of the 

available scientific data, samidorphan 

does not conform with the findings for 

schedule II in 21 U.S.C. 812(b)(2) or in 

any other schedule as set forth in 21 

U.S.C. 812(b). Based on FDA’s scientific 

and medical review of the eight factors 

and findings related to the substance’s 

abuse potential, legitimate medical use, 

and dependence liability, HHS 

recommended that samidorphan and its 

salts be removed from all schedules of 

control of the CSA. 

The CSA requires DEA, as delegated 

by the Attorney General,3 to determine 

whether HHS’s scientific and medical 

evaluation, scheduling 

recommendation, and all other relevant 

data constitute substantial evidence that 

a substance should be scheduled. 21 


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4Comprehensive 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, 4603. 

5The NFLIS is a national forensic laboratory 

reporting system that systematically collects results 

from drug chemistry analyses conducted by State 

and local forensic laboratories in the United States. 

6STRIDE is a database of drug exhibits sent to 

DEA laboratories for analysis. Exhibits from the 

database are from DEA, other federal agencies, and 

some local law enforcement agencies. 

7STARLiMS is a laboratory information 

management system that systematically collects 

results from drug chemistry analyses conducted by 

DEA laboratories. On October 1, 2014, STARLiMS 

replaced STRIDE as the DEA laboratory drug 

evidence data system of record. 

U.S.C. 811(b). DEA reviewed the 

scientific and medical evaluation and 

scheduling recommendation provided 

by HHS, and all other relevant data, and 

completed its own eight-factor review 

document on samidorphan pursuant to 

21 U.S.C. 811(c). Included below is a 

brief summary of each factor as 

analyzed by HHS and DEA, and as 

considered by DEA in this proposal to 

remove samidorphan from the 

schedules of the CSA. Please note that 

both DEA and HHS analyses are 

available in their entirety under 

‘‘Supporting and Related Material’’ of 

the public docket for this rule at http:// 

www.regulations.gov under docket 

number DEA–665. 

1. The Drug’s Actual or Relative 

Potential for Abuse. 

The first factor that must be 

considered is the actual or relative 

potential for abuse of samidorphan. The 

term ‘‘abuse’’ is not defined in the CSA. 

However, the legislative history of the 

CSA suggests the following points in 

determining whether a particular drug 

or substance has a potential for abuse: 4

a. Whether there is evidence that 

individuals are taking the drug or drugs 

containing such a substance in amounts 

sufficient to create a hazard to their 

health or to the safety of other 

individuals or to the community. 

As stated by HHS, samidorphan is not 

readily available or marketed in any 

country, so there is a lack of evidence 

to date regarding samidorphan 

diversion, illicit manufacturing, or use 

outside of clinical trials. There are no 

anecdotal reports of samidorphan abuse 

in the published literature or in drug 

abuse discussion platforms (e.g., 

PubMed, erowid.org). 

b. Whether there is significant 

diversion of the drug or drugs 

containing such a substance from 

legitimate drug channels. 

According to HHS, there were no 

reports of diversion of samidorphan in 

clinical trials conducted with this 

substance. DEA further notes that there 

are no reports of law enforcement 

encounters of samidorphan in the 

National Forensic Laboratory 

Information System (NFLIS),5 the 

System to Retrieve Information from 

Drug Evidence (STRIDE) 6 and 

STARLiMS 7 (Queried October 14, 

2020). Thus, there is no evidence of 

diversion of samidorphan. 

c. Whether individuals are taking the 

drug or drugs containing such a 

substance on their own initiative rather 

than on the basis of medical advice 

from a practitioner licensed by law to 

administer such drugs in the course of 

his professional practice. 

According to HHS, there is no 

evidence of individuals taking 

samidorphan on their own initiative. 

DEA notes that a review of scientific 

literature, STRIDE, STARLiMS, and 

NFLIS databases revealed no history of 

abuse of samidorphan. Thus, there is no 

evidence that individuals are taking 

samidorphan on their own initiative 

rather than on the basis of medical 

advice from a practitioner licensed by 

law to administer the same. There are 

no anecdotal reports of samidorphan 

abuse in the published literature or in 

drug discussion platforms (e.g., 

PubMed, erowid.org, bluelight.org). 

d. Whether the drug or drugs 

containing such a substance are new 

drugs so related in their action to a 

substance already listed as having a 

potential for abuse to make it likely that 

it 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 they 

have a substantial capability of creating 

hazards to the health of the user or to 

the safety of the community. 

According to HHS, actions of 

samidorphan are not related to a 

substance already listed as having a 

potential for abuse. There is no evidence 

that individuals are taking samidorphan 

to create a hazard to their health or to 

the safety of other individuals or to the 

community. Samidorphan is not 

currently marketed and there is no 

evidence of diversion of samidorphan 

from legitimate drug channels. There is 

no evidence that individuals are taking 

samidorphan on their own initiative 

without medical advice. Samidorphan is 

not related in its action to any known 

substance with abuse liability. 

Substances such as naloxone and 

naltrexone, with pharmacological effects 

of mu-opioid receptor antagonists 

similar to that of samidorphan, have 

been decontrolled under the CSA. Thus, 

these data collectively indicate that 

samidorphan has no potential for abuse. 

2. Scientific Evidence of the Drug’s 

Pharmacological Effects, If Known. 

Preclinical studies 

In Vitro Studies 

According to HHS, opioid receptor 

binding and functional studies with 

samidorphan have been conducted in 

vitro in cloned human opioid receptors 

expressed in Chinese hamster ovary 

(CHO) cells. These studies showed that 

samidorphan binds to human mu- and 

kappa-opioid receptors with subnanomolar Ki values of 0.052 nM and 

0.23 nM, respectively. Samidorphan 

also binds to the delta-opioid receptors 

with nanomolar affinity (Ki of 2.7 nM). 

These values demonstrate that, like the 

opioid receptor antagonist naltrexone, 

samidorphan has a high affinity for the 

mu- and kappa-opioid receptors. A 

cellular functional study with 

[35S]GTPgS assay in CHO cells further 

showed that samidorphan has 

subnanomolar antagonist activity at the 

mu-opioid receptor and is comparable 

to that of naltrexone. 

Safety Pharmacology Studies 

According to the HHS’ review, several 

safety studies were conducted to 

determine the cardiovascular, 

respiratory, and neurological effects of 

the drug and can help determine if 

samidorphan has depressant, stimulant, 

or other psychoactive effects related to 

abuse potential. 

Cardiovascular and Respiratory Effects 

According to HHS, a study evaluating 

in vitro effects of samidorphan (0.5, 5, 

and 50 mM) on the QT-interval, QRS 

duration, contractility and maximum 

rate of contraction was conducted in 

isolated retrograde perfused rabbit heart 

preparation. Results showed that, at the 

lowest concentration, 0.5 mM, 

samidorphan significantly decreased 

contractility. But, samidorphan at 5 and 

50 mM concentrations did not 

significantly affect contractility. 

An animal study revealed the 

cardiovascular and pulmonary effects of 

orally administered (per os or PO) 

samidorphan (0.5, 3, and 10 mg/kg 

doses) in beagle dogs. The high doses of 

samidorphan resulted in several cases of 

emesis and excessive salivation. For 

pharmacokinetic (PK) measurements, 

animals were given either a low dose of 

0.5 mg/kg or a high dose of 20 mg/kg of 

samidorphan. Male dogs given a single 

PO dose of samidorphan had average PK 

measurements of Cmax = 4320 ng/mL, T 

max = 1.2 hr, half-life = 4.1 hr, and AUC 

last = 30,500 hr•ng/mL. In regard to 

cardiac activity, the female and male 

groups produced a slight decrease in 


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systolic blood pressure (an average 

insignificant decrease of 17 to 26 mm 

Hg) and no significant differences in 

cardiac contractility or body 

temperature. Based on the results, this 

investigation reported no observed 

adverse effects at the level of 10 mg/kg 

in beagle dogs. In the same study, 

samidorphan at any of the doses tested 

did not cause any significant effects on 

respiratory rate, tidal volume, and 

minute volume. 

According to HHS’ review, 

samidorphan reversed cardiac and 

respiratory effects produced by 

continuous intravenous infusion (IV) of 

fentanyl, a mu-opioid receptor agonist, 

in beagle dogs and Cynomolgus 

monkeys. Overall, samidorphan does 

not appear to produce mu-opioid 

receptor agonist related cardiac or 

pulmonary effects. 

Central Nervous System Effects 

According to HHS, central nervous 

system effects of samidorphan (3.5, 35, 

or 350 mg/kg, PO) on functional 

observational battery in a study 

conducted in Sprague-Dawley rats are 

most consistent with that of depressants 

such as opioids, cannabinoids, and 

GABAA channel modulators. 

Unlike mu-opioid receptor agonists 

that typically produce analgesic effects 

in assays on thermal and inflammatory 

painful stimulation, samidorphan 

produced no measurable analgesic 

effects. In the hot plate test in male 

Sprague-Dawley rats, samidorphan did 

not produce thermal analgesia when 

administered subcutaneously (SC) at 

doses of 0.003 to 0.1 mg/kg or when 

administered intraperitoneally at doses 

in the range of 0.01 to 30 mg/kg. 

However, samidorphan blocked 

morphine-induced (15 mg/kg, SC) 

analgesia in rats with ED50 values of 

0.01 mg/kg (SC administration) and 0.3 

mg/kg (PO administration), respectively. 

Its blockade of morphine’s analgesic 

effects lasted for approximately 4 hours. 

Because morphine is known to produce 

its analgesic effects as an agonist of the 

mu-opioid receptor, this study suggests 

that samidorphan blocks this 

mechanism of action similar to other 

mu-opioid receptor antagonists, such as 

naloxone and naltrexone, which also 

possess this blockade effect. 

In a tail-flick assay used to measure 

thermal-nociception, the result showed 

that administered subcutaneously 

samidorphan did not produce analgesia 

up to the highest dose tested of 10 mg/ 

kg. Furthermore, samidorphan 

antagonized morphineinduced antinociception when administered either 

SC or PO. These data indicate that 

samidorphan acts as an antagonist at the 

mu-opioid receptor because it blocked 

the analgesic effects of the mu-opioid 

receptor agonist morphine without 

producing analgesic effects of its own. 

Abuse Liability Studies 

Effects on Ethanol Self-Administration 

According to HHS, a selfadministration study in male Wistar rats 

was conducted to determine if 

samidorphan has effects similar to that 

of other opioid receptor antagonists 

such as naltrexone in reducing ethanol 

drinking behavior. Rats were trained to 

self-administer ethanol on a fixed ratio 

(FR) 2 schedule of reinforcement. Effects 

of samidorphan (0 to 3 mg/kg, SC) 

administered 30 minutes prior to the 

placement of the rats into the test cages 

on ethanol drinking behavior were 

studied. Naltrexone, the positive control 

drug (3 or 6 mg/kg, SC), was only able 

to decrease lever responding by 

approximately 75 percent. The highest 

dose of samidorphan (3 mg/kg, SC) 

decreased lever responding by 

approximately 50 percent. According to 

HHS, these data demonstrate that 

pretreatment with samidorphan can 

decrease, but not eliminate, the 

reinforcing effects of 10 percent ethanol 

and these results are consistent with 

that of other mu-opioid receptor 

antagonists such as naltrexone, which is 

indicated for the treatment of alcohol 

dependence. 

Drug Discrimination Studies 

Drug discrimination assays in animals 

can be used to predict if a test drug will 

have abuse potential in humans. 

According to HHS, a drug 

discrimination study was conducted to 

test the stimulus effects of samidorphan 

in rats trained to discriminate the 

stimulus effects of subcutaneously 

administered morphine (3 mg/kg) to its 

vehicle (0.9 percent sodium chloride for 

injection, USP) in a two-lever operant 

chamber on a FR10 schedule of 

reinforcement. Samidorphan (0.1, 0.3, 1 

or 3 mg/kg) did not generalize to the 

morphine cue. Samidorphan did not 

affect lever press response rates 

indicating that the rats were not 

incapacitated by the drug. These data 

indicate that samidorphan does not 

produce a discriminative cue similar to 

that of morphine (at 3 mg/kg). 

Self-Administration Studies 

HHS cited two self-administration 

studies assessing the reinforcing effects 

of samidorphan in rats. In the first 

study, rats were trained to lever press on 

a FR5 schedule for intravenous selfadministration of morphine (0.56 mg/ 

kg/injection). When samidorphan was 

tested at 0.0136, 0.0408, and 0.068 mg/ 

kg/injection, the animals did not 

respond at levels seen with the positive 

control, morphine. Therefore, it was 

concluded that samidorphan did not 

produce reinforcing effects similar to 

that of morphine in rats. However, the 

total number of infusions of 

samidorphan was statistically higher 

than the vehicle. According to HHS, this 

could have been the result of the 

inadequate extinction due to the 

reintroduction of the training drug 

between doses of samidorphan; this 

could have artificially inflated the 

responding of samidorphan because 

animals never fully underwent 

extinction. As a result, a second selfadministration study with heroin as the 

training drug using FR5 and a 

progressive schedule of reinforcement 

was conducted. There was no 

reintroduction of the training drug 

between doses of samidorphan with an 

additional referred arm of naltrexone. 

The result showed that the number of 

samidorphan (0.068 mg/kg/injection) 

injections, similar to naltrexone, was 

significantly higher than the number of 

saline injections, but was significantly 

lower than that of heroin. A progressive 

ratio schedule of reinforcement is used 

to determine the reinforcing efficacy of 

a drug by measuring the break point. A 

breakpoint is defined as the number of 

operant responses (lever presses) at 

which the subject ceases selfadministration of the reinforcer. Results 

of the study using the PR schedule of 

reinforcement were similar to that of the 

FR5 study: All doses of samidorphan 

tested produced breakpoints that were 

significantly lower than heroin and only 

the highest dose of samidorphan (0.068 

mg/kg/injection) was significantly 

higher than saline. Importantly, 

naltrexone, tested at the same doses as 

samidorphan, produced results similar 

to that of samidorphan. According to 

HHS, these studies suggest that 

samidorphan has a profile similar to 

that of naltrexone and does not produce 

statistically significant reinforcing 

effects. 

Intra-Cranial Self-Stimulation Study 

Intracranial self-stimulation (ICSS) is 

a behavioral study that can be used to 

evaluate brain rewarding or aversive 

effects of drugs. HHS provided an ICSS 

study report of samidorphan in rats. 

Following implantation with permanent 

indwelling electrodes in the right 

medial forebrain at the level of the 

lateral hypothalamus, the animals were 

trained to respond (i.e., lever press) to 


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8This statement and the subsequent content in 

this paragraph are based on the revised information 

provided under MOU by FDA/Controlled Substance 

Staff (CSS). 

receive brain stimulation.8 Baseline 

ICSS training generated a frequency 

response curve where increasing the 

intensity of brain stimulation increased 

the rate of lever pressing. After baseline 

ICSS levels were established, rats were 

administered several doses of 

samidorphan. The subcutaneous 

administration of samidorphan at doses 

of 0.03, 0.1, 0.3, and 1.0 mg/kg did not 

shift the frequency response curve 

relative to baseline and did not change 

the maximum rate of responding. This 

study indicates that samidorphan does 

not affect the brain reward pathway in 

rats. 

Clinical Abuse Liability Studies 

The HHS review describes two 

studies to assess the abuse potential of 

samidorphan in human subjects. The 

first one, a randomized, double-blind, 

placebo and positive control, crossover 

study was to compare samidorphan (2.5, 

10, and 20 mg, PO), oxycodone (15 and 

30 mg, PO), and the placebo in 41 nondependent recreational opioid users. 

The primary pharmacodynamic (PD) 

assessment was At the Moment Drug 

Liking measured by a visual analog 

scale (VAS), with secondary endpoints 

that measured Overall Drug Liking, Take 

Drug Again, and Alertness, all on a 

bipolar VAS. High, Good Effects and 

Bad Effects were measured on a 

unipolar VAS. Oxycodone at 30 and 15 

mg doses produced mean Drug Liking 

scores of 81 and 73.3, respectively and 

these scores were significantly higher 

than the placebo. All three doses of 

samidorphan produced At the Moment 

Drug Liking, Overall Drug Liking, and 

Take Drug Again scores that were not 

significantly different from the placebo 

(50 to 51). There was one report (2.1 

percent) of euphoria as an adverse event 

(AE) after taking samidorphan (20 mg) 

versus 11 reports (22.4 percent) 

following the positive control 

oxycodone dose (30 mg). This study 

concluded that samidorphan does not 

produce PD measurements that are 

consistent with abuse potential. 

A second abuse potential study was 

conducted by using a placebo (PO), 

samidorphan (10 and 30 mg, PO), 

oxycodone (40 mg, PO), pentazocine (30 

mg, IV), and naltrexone (100 mg, IV) in 

42 healthy non-dependent recreational 

opioid users. The primary PD 

assessment was At the Moment Drug 

Liking measured by the bipolar VAS, 

with secondary endpoints that 

measured Overall Drug Liking, Take 

Drug Again, and Alertness. The study 

also took PK measurements to 

determine a correlation between blood 

levels and time of onset of the PD 

assessment. The positive controls, 

oxycodone (40 mg) and pentazocine (30 

mg), produced the Emax of Drug Liking 

VAS scores of 76.1 and 82, respectively 

and these were significantly higher than 

the placebo. The Emax drug liking scores 

following 10 and 30 mg samidorphan 

were not significantly different from the 

placebo or naltrexone (100 mg). 

Euphoric mood was indicated as an AE 

in 30 subjects (53.6 percent) for 

oxycodone and in 30 subjects (52.6 

percent) for pentazocine. The 30 and 10 

mg doses of samidorphan produced a 

euphoric mood as an AE in 9 (15 

percent) and 7 (12.3 percent) subjects, 

respectively; however, 5 subjects (8.6 

percent) reported euphoria when 

receiving naltrexone, and 5 subjects (8.8 

percent) reported euphoria when 

receiving the placebo. There were no 

reports of abuse of the drug or diversion 

in the study. HHS concludes that 

samidorphan produces stimulus effects 

similar to the placebo and naltrexone 

and does not have abuse potential. DEA 

notes that a recent peer-reviewed 

published clinical report describes that 

samidorphan, similar to a placebo and 

naltrexone, lacks abuse potential. 

In summary, data from in vitro studies 

showed that samidorphan is a muopioid receptor antagonist with weak 

partial agonist activity at the kappa- and 

delta-opioid receptors. Data from in vivo 

studies further supported this 

conclusion; samidorphan blocked the 

analgesic effects of the mu-opioid 

receptor agonist morphine and the 

respiratory depressive effects of 

fentanyl. Samidorphan neither 

produced a discriminative cue similar to 

that of morphine nor had reinforcing 

effects in in vivo abuse liability studies 

in animals. Data from two clinical abuse 

potential studies suggested that 

samidorphan does not produce drug 

liking scores similar to oxycodone (a 

mu-opioid receptor agonist) or 

pentazocine (a kappa-opioid receptor 

agonist); instead, drug liking scores 

produced by samidorphan were similar 

to the negative controls, placebo and 

naltrexone. Overall, these data support 

the conclusion that samidorphan does 

not have abuse liability. 

3. The State of Current Scientific 

Knowledge Regarding the Drug or Other 

Substance. 

Samidorphan’s molecular formula is 

C21H26N2O4 with a molecular weight of 

370.44 g/mol. Currently, there are two 

salt forms, a hydrochloric acid salt 

(RDC–0313–01; molecular weight is 

406.90 g/mol) and a malic acid salt 

(RDC–0313–02; molecular weight is 

504.53 g/mol). Samidorphan is a 

derivative of naltrexone and it shares 

structural similarity with naltrexone. A 

multi-step process of samidorphan 

synthesis starts with naltrexone, with an 

end product of its malate salt. 

According to HHS, samidorphan is 

rapidly absorbed both orally and 

sublingually. The Tmax is approximately 

60 minutes after orally dosing, with a 

half-life of six to eight hours depending 

on the dose. The plasma levels of 

samidorphan increase linearly with 

each dose and it rapidly distributes 

throughout the body. Samidorphan is 

metabolized into two main products, 

RDC–9986 (N-dealkylated metabolite) 

and RDC–1066 (N-oxide metabolite), 

and they can be detected in human 

plasma at greater than 10 percent of the 

total drug-related exposure. Both RDC– 

9986 and RDC–1066 have nanomolar 

affinity for the mu-, kappa-, and deltaopioid receptors. RDC–9986 is an 

agonist at all three opioid receptors 

whereas RDC–1066 showed antagonist 

activity at the mu-opioid receptor as 

assessed by the [35S]GTPgS functional 

assay. DEA further notes that 

samidorphan has been reported to have 

high bioavailability following both 

sublingual and oral administration, it is 

not subject to extensive first-pass 

metabolism, and the PK parameters are 

not affected by food or age in health 

volunteers. 

In summary, samidorphan shares 

chemical structural features with muopioid antagonists such as naltrexone. It 

is synthesized from the non-controlled 

substance naltrexone. Samidorphan 

exhibits high oral bioavailability and is 

rapidly absorbed. Clinical studies 

suggest that samidorphan was generally 

well-tolerated following single and 

multiple doses. RDC–9986 and RDC– 

1066, the two main metabolites of 

samidorphan, though they bind to 

opioid receptors, do not contribute 

significantly to pharmacodynamics of 

samidorphan. 

4. Its History and Current Pattern of 

Abuse. 

According to HHS, samidorphan has 

not been marketed in any country and 

thus information about the history and 

current pattern of its abuse is not 

available. Preclinical and clinical 

studies evaluating abuse potential of 

samidorphan did not show any abuserelated signals (see Factor 1 and 2, DEA 

and HHS Eight Factor Analyses). 

Instead, samidorphan showed effects 

similar to those of mu-opioid 

antagonists, a class of drugs not known 

to have abuse potential. The opioid 

antagonists, naloxone and naltrexone, 

were both originally schedule II 


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9Office of Mgmt. & Budget, Exec. Office of The 

President, Interim Guidance Implementing Section 

2 of the Executive Order of January 30, 2017 Titled 

‘‘Reducing Regulation and Controlling Regulatory 

Costs’’ (Feb. 2, 2017). 

substances as ‘‘opiate derivatives,’’ and 

both are synthesized from thebaine. 

However, because they lacked opioid 

agonist activity, these were decontrolled 

in 1974 (naloxone), and in 1975 

(naltrexone). More recently, the opioid 

antagonist naloxegol, a FDA-approved 

drug for the treatment of opioid induced 

constipation, was decontrolled in 2015. 

In addition, as mentioned earlier (see 

Factor 1, DEA and HHS Eight Factor 

Analyses), NFLIS, STRIDE, and 

STARLiMS had no mentions of 

samidorphan. 

5. The Scope, Duration, and 

Significance of Abuse. 

As stated by HHS, information about 

the scope, duration, and significance of 

samidorphan abuse is not available 

because it has not been marketed in any 

country. As mentioned in Factor 4 (DEA 

and HHS Eight Factor Analyses), a 

comprehensive review and research on 

available databases performed by both 

HHS and DEA revealed no reports of 

abuse of samidorphan. Data from 

preclinical and clinical studies showed 

no evidence of abuse potential for 

samidorphan. As stated by HHS, 

samidorphan upon its approval and 

availability for marketing is unlikely to 

be abused. 

6. What, if any, Risk There is to the 

Public Health. 

Based on the data and scientific 

information of preclinical and clinical 

study data reviewed by both HHS and 

DEA, there are no signals that indicate 

that samidorphan has abuse potential 

(see Factor 1 and 2, DEA and HHS Eight 

Factor Analyses). Currently, there is no 

evidence of drug dependence, abuse, 

and diversion. Thus, there is likely to be 

little or no risk of abuse and public 

health risk from samidorphan if it 

becomes available on the market. 

7. Its Psychic or Physiological 

Dependence Liability. 

According to HHS, several long-term 

toxicology studies were conducted 

using samidorphan in rats and dogs 

lasting 13, 26, or 39 weeks at doses of 

250, 50, and 10 mg/kg/day. The animals 

were continually monitored after the 

study for withdrawal signs, such as 

weight changes, food consumption, 

morbidity, mortality, and locomotion 

effects. These studies did not find any 

behaviors or physical manifestations 

that were different from the control 

groups, indicating that samidorphan 

lacks potential to produce physical 

dependence. Data from these clinical 

studies showed no signals related to 

withdrawal or physical dependence. 

The lack of samidorphan’s ability to 

function as a positive reinforcer in selfadministration studies in animals 

suggests that the use of samidorphan 

will not lead to psychological 

dependence. Similar to naltrexone (see 

Factor 2, DEA and HHS Eight Factor 

Analyses), samidorphan would not be 

expected to produce psychological 

dependence, and no evidence of 

psychological dependence was observed 

in clinical studies. 

8. Whether the Substance is an 

Immediate Precursor of a Substance 

Already Controlled Under the CSA. 

Samidorphan is not considered an 

immediate precursor of any controlled 

substance listed under the CSA as 

defined by 21 U.S.C. 802(23). 

Conclusion 

Based on consideration of the 

scientific and medical evaluation and 

accompanying recommendation of HHS, 

and based on DEA’s consideration of its 

own eight-factor analysis, DEA finds 

that these facts and all relevant data 

demonstrate that samidorphan does not 

possess abuse or dependence potential. 

According to HHS, medical product 

formulations containing samidorphan 

are under development. However, the 

finding that samidorphan lacks abuse 

potential would, irrespective of other 

findings, permit decontrol of 

samidorphan prior to or in the absence 

of an FDA action under 21 U.S.C. 

355(c). Therapeutic and 

supratherapeutic doses of samidorphan 

did not produce physical or 

psychological dependence both in nonclinical (in rats and dogs) and in clinical 

studies. Accordingly, DEA finds that 

samidorphan does not meet the 

requirements for inclusion in any 

schedule, and should be removed from 

control under the CSA. 

Regulatory Analyses 

Executive Orders 12866, 13563, and 

13771, Regulatory Planning and Review, 

Improving Regulation and Regulatory 

Review, and Reducing Regulation and 

Controlling Regulatory Costs 

In accordance with 21 U.S.C. 811(a), 

this scheduling action is subject to 

formal rulemaking procedures done ‘‘on 

the record after opportunity for a 

hearing,’’ which are conducted pursuant 

to the provisions of 5 U.S.C. 556 and 

557. The CSA sets forth the criteria for 

removing a drug or other substance from 

the list of controlled substances. Such 

actions are exempt from review by 

Office of Management and Budget 

(OMB) pursuant to section 3(d)(1) of 

Executive Order (E.O.) 12866 and the 

principles reaffirmed in E.O. 13563. 

This final rule is not an E.O. 13771 

regulatory action pursuant to E.O. 12866 

and OMB guidance.9

Executive Order 12988, Civil Justice 

Reform 

This regulation meets the applicable 

standards set forth in sections 3(a) and 

3(b)(2) of E.O. 12988 Civil Justice 

Reform to eliminate drafting errors and 

ambiguity, minimize litigation, provide 

a clear legal standard for affected 

conduct, and promote simplification 

and burden reduction. 

Executive Order 13132, Federalism 

This rulemaking does not have 

federalism implications warranting the 

application of E.O. 13132. The rule does 

not have substantial direct effects on the 

States, on the relationship between the 

Federal Government and the States, or 

the distribution of power and 

responsibilities among the various 

levels of government. 

Executive Order 13175, Consultation 

and Coordination With Indian Tribal 

Governments 

This rule does not have tribal 

implications warranting the application 

of E.O. 13175. This rule does not have 

substantial direct effects on one or more 

Indian tribes, on the relationship 

between the Federal Government and 

Indian tribes, or on the distribution of 

power and responsibilities between the 

Federal Government and Indian tribes. 

Regulatory Flexibility Act 

The Acting Administrator, in 

accordance with the Regulatory 

Flexibility Act (RFA) (5 U.S.C. 601– 

612), has reviewed this proposed rule 

and by approving it certifies that it will 

not have a significant economic impact 

on a substantial number of small 

entities. The purpose of this rule is to 

remove samidorphan from the list of 

schedules of the CSA. This action will 

remove regulatory controls and 

administrative, civil, and criminal 

sanctions applicable to controlled 

substances for handlers and proposed 

handlers of samidorphan. Accordingly, 

it has the potential for some economic 

impact in the form of cost savings. 

If finalized, the proposed rule will 

affect all persons who would handle, or 

propose to handle samidorphan. 

Samidorphan is not currently available 

or marketed in any country. Due to the 

wide variety of unidentifiable and 

unquantifiable variables that potentially 


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79456 Federal Register / Vol. 85, No. 238 / Thursday, December 10, 2020 / Proposed Rules 

could influence the distribution and 

dispensing rates, if any, of samidorphan, 

DEA is unable to determine the number 

of entities and small entities which 

might handle samidorphan. In some 

instances where a controlled 

pharmaceutical drug is removed from 

the schedules of the CSA, DEA is able 

to quantify the estimated number of 

affected entities and small entities 

because the handling of the drug is 

expected to be limited to DEA 

registrants even after removal from the 

schedules. In such instances, DEA’s 

knowledge of its registrant population 

forms the basis for estimating the 

number of affected entities and small 

entities. However, DEA does not have a 

basis to estimate whether samidorphan 

is expected to be handled by persons 

who hold DEA registrations, by persons 

who are not currently registered with 

DEA to handle controlled substances, or 

both. Therefore, DEA is unable to 

estimate the number of entities and 

small entities who plan to handle 

samidorphan. 

Although DEA does not have a 

reliable basis to estimate the number of 

affected entities and quantify the 

economic impact of this final rule, a 

qualitative analysis indicates that this 

rule is likely to result in some cost 

savings. As noted above, DEA is 

specifically soliciting comments on the 

economic impact of this proposed rule. 

DEA will revise this section if warranted 

after consideration of any comments 

received. Any person planning to 

handle samidorphan will realize cost 

savings in the form of saved DEA 

registration fees, and the elimination of 

physical security, recordkeeping, and 

reporting requirements. 

Because of these factors, DEA projects 

that this rule will not result in a 

significant economic impact on a 

substantial number of small entities. 

Unfunded Mandates Reform Act of 1995 

On the basis of information contained 

in the ‘‘RFA’’ section above, DEA has 

determined and certifies pursuant to the 

Unfunded Mandates Reform Act of 1995 

(UMRA), 2 U.S.C. 1501 et seq., that this 

action would not result in any federal 

mandate that may result ‘‘in the 

expenditure by State, local, and tribal 

governments, in the aggregate, or by the 

private sector, of $100,000,000 or more 

(adjusted for inflation) in any one year 

* * *.’’ Therefore, neither a Small 

Government Agency Plan nor any other 

action is required under provisions of 

UMRA. 

Paperwork Reduction Act 

This action does not impose a new 

collection of information requirement 

under the Paperwork Reduction Act, 44 

U.S.C. 3501–3521. This action would 

not impose recordkeeping or reporting 

requirements on State or local 

governments, individuals, businesses, or 

organizations. 

List of Subjects in 21 CFR Part 1308 

Administrative practice and 

procedure, Drug traffic control, 

Reporting and recordkeeping 

requirements. 

For the reasons set out above, 21 CFR 

part 1308 is proposed to be amended to 

read as follows: 

PART 1308—SCHEDULES OF 

CONTROLLED SUBSTANCES 

■ 1. The authority citation for 21 CFR 

part 1308 continues to read as follows: 

Authority: 21 U.S.C. 811, 812, 871(b), 

956(b), unless otherwise noted. 

■ 2. In § 1308.12, revise the introductory 

text of paragraph (b)(1) to read as 

follows: 

§ 1308.12 Schedule II. 

* * * * * 

(b) * * * 

(1) Opium and opiate, and any salt, 

compound, derivative, or preparation of 

opium or opiate excluding 

apomorphine, thebaine-derived 

butorphanol, dextrorphan, nalbuphine, 

naldemedine, nalmefene, naloxegol, 

naloxone, 6b-naltrexol, naltrexone, and 

samidorphan, and their respective salts, 

but including the following: 

* * * * * 

Timothy J. Shea, 

Acting Administrator. 

[FR Doc. 2020–26812 Filed 12–9–20; 8:45 am] 

BILLING CODE 4410–09–P 

DEPARTMENT OF TRANSPORTATION 

National Highway Traffic Safety 

Administration 

49 CFR Part 571 

[Docket No. NHTSA–2020–0109] 

RIN 2127–AM04 

Federal Motor Vehicle Safety 

Standards: Test Procedures 

AGENCY: National Highway Traffic 

Safety Administration (NHTSA), 

Department of Transportation (DOT). 

ACTION: Advance notice of proposed 

rulemaking (ANPRM). 

SUMMARY: NHTSA is issuing this 

ANPRM to seek public comment on 

whether any test procedures for any 

Federal Motor Vehicle Safety Standards 

(FMVSS) may be a candidate for 

replacement, repeal, or modification, for 

reasons other than for considerations 

relevant only to automated driving 

systems (ADS). This document is a 

continuation of the Agency’s efforts to 

improve the FMVSS and minimize 

burdens. The Agency takes this action 

in response to its review of the FMVSS 

and to public comments solicited by 

DOT in a 2017 notice on its regulatory 

reform efforts. The commenters 

requested that NHTSA amend test 

procedures for air brakes and occupant 

crash protection. NHTSA has also 

identified some possible additional test 

procedure issues and discusses them in 

this Notice. In addition, this ANPRM 

also seeks comments and supporting 

information relating to any other test 

procedures which may be a candidate 

for replacement, repeal or modification, 

not just those specifically discussed in 

this Notice. 

DATES: Comments must be received no 

later than February 8, 2021. See the 

Public Participation heading of the 

SUPPLEMENTARY INFORMATION section of 

this document for more information 

about written comments. 

ADDRESSES: You may submit comments 

to the docket number identified in the 

heading of this document by any of the 

following methods: 

• Federal eRulemaking Portal: Go to 

http://www.regulations.gov. Follow the 

online instructions for submitting 

comments. 

• Mail: Docket Management Facility: 

U.S. Department of Transportation, 1200 

New Jersey Avenue SE, West Building 

Ground Floor, Room W12–140, 

Washington, DC 20590–0001 

• Hand Delivery or Courier: 1200 

New Jersey Avenue SE, West Building 

Ground Floor, Room W12–140, between 

9 a.m. and 5 p.m. ET, Monday through 

Friday, except Federal holidays. 

• Fax: 202–493–2251. 

Instructions: For detailed instructions 

on submitting comments and additional 

information on the rulemaking process, 

see the Public Participation heading of 

the SUPPLEMENTARY INFORMATION section 

of this document. Note that all 

comments received will be posted 

without change to http:// 

www.regulations.gov, including any 

personal information provided. Please 

see the ‘‘Privacy Act’’ heading below. 

Privacy Act: Anyone is able to search 

the electronic form of all comments 

received into any docket by the name of 

the individual submitting the comment 

(or signing the comment, if submitted 

on behalf of an association, business, 

labor union, etc.). You may review 


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