Assessment of Abuse 
Potential of Drugs 
 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2017 
Clinical Medical 
 
   
 
Assessment of Abuse  
Potential of Drugs 
 
 
Guidance for Industry 
 
 
 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information, 
Center for Drug Evaluation and Research, 
Food and Drug Administration 
10001New Hampshire Ave., Hillandale Bldg. 4th Floor 
Silver Spring, MD  20993-0002 
Phone:  855-543-3784 or 301-796-3400; Fax:  301-431-6353 
Email:  druginfo@fda.hhs.gov 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2017 
Clinical Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION.......................................................................................................................... 1 
II.  BACKGROUND ............................................................................................................................ 2 
A.  Scope of Guidance ............................................................................................................. 2 
B.  Definitions .......................................................................................................................... 4 
III.    ASSESSING THE ABUSE POTENTIAL OF A DRUG ............................................................ 5 
A.  Key Decision Points and Recommended Studies in Assessing Abuse Potential .......... 5 
B.  When Abuse-Related Studies Should Be Conducted ..................................................... 7 
C.  Preparing the NDA Submission ....................................................................................... 8 
D.  NDA Review and Product Labeling Related to Abuse Potential .................................. 9 
E.  The Drug Scheduling Process ........................................................................................ 10 
IV.  ABUSE-RELATED DATA FROM CHEMISTRY AND NONCLINICAL STUDIES ......... 11 
A.  Chemistry and Manufacturing ...................................................................................... 12 
B.   Screening with Receptor-Ligand Binding Studies ....................................................... 13 
C.  Use of Nonclinical Pharmacokinetic Data in Animal Abuse-Related Studies ........... 14 
D.  Animal Abuse-Related Behavioral Pharmacology Studies ......................................... 14 
V.   ABUSE-RELATED DATA FROM HUMAN STUDIES ......................................................... 20 
A.  Use of Clinical Pharmacokinetic Data in Human Abuse-Related Studies ................ 20 
B.  Abuse-Related Adverse Events in Clinical Safety and Efficacy Studies .................... 21 
C.   Human Abuse Potential Study in Recreational Drug Users ....................................... 23 
D.   Clinical Studies That Evaluate Cognition and Performance ...................................... 30 
E.   Clinical Evaluation of Physical Dependence ................................................................ 30 
VI.    POST-MARKETING AND ILLICIT DRUG ABUSE DATA ................................................. 32 
ABBREVIATIONS ................................................................................................................................... 34 
 
  Contains Nonbinding Recommendations 
 
Assessment of Abuse Potential of Drugs 
1
Guidance for Industry  
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA 
or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA office 
responsible for this guidance as listed on the title page. 
 
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to assist sponsors of investigational new drugs and applicants for 
approval of a new drug in evaluating whether their new drug product has abuse potential.  This 
guidance also provides recommendations to applicants who intend to submit new drug 
applications (NDAs) for prescription drug products that may have abuse potential.   
 
Drug products with abuse potential generally contain drug substances that have central nervous 
system (CNS) activity and produce euphoria (or other changes in mood), hallucinations, and 
effects consistent with CNS depressants or stimulants. Thus, if a drug substance is CNS-active, 
the new drug product containing that drug substance will likely need to undergo a thorough 
assessment of its abuse potential and may be subject to control under the Controlled Substances 
Act (CSA) (see generally 21 U.S.C. 811).  The CSA contains five schedules of control: 
Schedules I, II, III, IV and V.  Drugs or other substances with a high abuse potential, no 
currently accepted medical use, and a lack of accepted safety for use under medical supervision 
are controlled in Schedule I.  Drugs or other substances with abuse potential that do have a 
currently accepted medical use (e.g., the drug or substance is in an FDA-approved product) are 
placed into Schedule II, III, IV, or V. The specific placement of a drug or other substance within 
Schedules II-V is determined by the relative abuse potential of the drug or substance and the 
relative degree to which it induces psychological or physical dependence (21 U.S.C. 812(b)).   
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
                                                           
1 This guidance has been prepared by the Controlled Substance Staff (CSS) in the Center for Drug Evaluation and 
Research (CDER) at the Food and Drug Administration.  
  1  Contains Nonbinding Recommendations 
 
 
II.  BACKGROUND 
 
The assessment of the abuse potential of a drug product under development is generally 
conducted as a component of its safety evaluation.  In this guidance, the term abuse-related 
will be used to designate nonclinical and clinical information that is related to the assessment of 
abuse potential of a new drug. 
 
As described in Sections III through VI, the results from a broad range of studies and other 
sources of information contribute to the assessment of a new drugs abuse potential. This 
includes the results of studies investigating chemistry, pharmacology, pharmacokinetics, animal 
and human behavior, abuse-related adverse events (AEs) in human studies, and reports of abuse 
from various sources, such as law enforcement, poison control centers, hospital emergency 
departments and medical examiners.  All abuse-related study protocols and resultant data should 
be compiled and cross-linked by the applicant to constitute the abuse potential assessment within 
an NDA submission.  The assessment should include a proposal for scheduling under the CSA.  
(Under 21 CFR 314.50(d)(5)(vii), if the drug has a potential for abuse, a description and analysis 
of studies or information related to abuse of the drug, including a proposal for scheduling under 
the CSA, are required.)  Following the Agencys review, these data inform both the appropriate 
labeling of the drug product and our recommendations for drug scheduling under the CSA.  In 
this guidance, this required section of the NDA submission is referred to as the abuse potential 
assessment.  If an applicant concludes that its new drug product does not warrant scheduling 
under the CSA, the scheduling proposal in the NDA should state this position, and should 
provide justification for this position based on relevant data in the NDA.  
 
A.  Scope of Guidance 
 
Drug products that are addressed in this guidance include those that contain CNS-active new 
molecular entities (NMEs) as well as those products that contain CNS-active substances that are 
already controlled under the CSA.2  Generic drug products seeking approval under section 505(j) 
of the Federal Food, Drug & Cosmetic Act are not typically reassessed for abuse potential, and 
are usually placed in the same schedule of the CSA as the innovator drug product. Drug products 
that are determined to have abuse potential may contain substances that are chemically or 
pharmacologically similar to other controlled substances, or they may have novel chemical 
structures and/or mechanisms of action in the brain.    
 
This guidance provides the following: 
 
  Definitions of drug abuse, abuse potential, and other related terminology 
 
                                                           
2 The complete list of all scheduled substances can be found in 21 CFR 1308, which is updated following 
publication in the Federal Register (FR) of a drug scheduling action by the Drug Enforcement Administration. 
  2  Contains Nonbinding Recommendations 
 
  A discussion as to which studies we recommend be included in an  abuse potential 
assessment for a CNS-active drug in order to satisfy the requirements of 21 CFR 
314.50(d)(5)(vii), with recommendations for the battery of relevant studies that may be 
conducted in a logical sequence that builds on new data acquired during drug 
development 
 
  A discussion as to when to conduct the recommended abuse-related studies, and how to 
appropriately design them 
  
  General administrative recommendations for obtaining FDA advice, consistent with 
CDERs 21st Century review policies3 and draft guidance for industry, Formal Meetings 
Between the FDA and Sponsors or Applicants of PDUFA Products4 
 
  A discussion regarding the abuse-related components of a NDA, including a proposal 
(with justification) addressing whether the drug product should be scheduled under the 
CSA, and if so, a proposed schedule (see 21 CFR 314.50(d)(5)(vii)).  A scheduling 
proposal may request any of the following:  to control a substance in a particular 
schedule, to decontrol a substance, to transfer a substance to a new schedule, or to not 
control the substance.   
 
It is beyond the scope of this guidance to discuss the abuse assessment of anabolic steroids (all of 
which are in Schedule III of the CSA unless subject to an exemption, see 21 U.S.C. 
 811(g)(3)(C), 812).  This guidance also does not discuss the studies that should be conducted 
to demonstrate that a given opioid formulation has abuse-deterrent properties because that is 
addressed in a separate FDA guidance for industry, Abuse-Deterrent Opioids  Evaluation and 
Labeling (2015). 5  Biological products that are evaluated by the Center for Drug Evaluation and 
Research (CDER) are not discussed in this guidance, but are still evaluated for abuse potential 
based on the principles in Section III.A.6 
                                                           
3 Available at 
http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/UCM218757.pdf. 
 
4 Available for notice and comment purposes at 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm437431.pdf.  We 
update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA Drugs 
guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
   
5 Available at 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm334743.pdf.  We 
update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA Drugs 
guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  
6 Assessments of abuse for biological products evaluated by the Center for Biologics Evaluation and Research 
(CBER) are not discussed in this guidance.  
  3  Contains Nonbinding Recommendations 
 
 
B.  Definitions 
 
The CSA refers to the assessment of potential for abuse, addiction-forming or addiction-
sustaining liability, and dependence in 21 U.S.C. 802, but does not define these terms.  In this 
guidance, the following definitions are applicable: 
 
Drug abuse is defined as the intentional, non-therapeutic use of a drug product or substance, 
even once, to achieve a desired psychological or physiological effect.  Therefore, abuse potential 
refers to the likelihood that abuse will occur with a particular drug product or substance with 
CNS activity.  Desired psychological effects can include euphoria, hallucinations and other 
perceptual distortions, alterations in cognition, and changes in mood.  Throughout this guidance, 
the term abuse potential will be used, although abuse liability represents a similar concept.7,8  
 
Dependence refers to physical or psychological dependence.  Physical dependence is a state that 
develops as a result of physiological adaptation in response to repeated drug use, manifested by 
withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a 
drug. Psychological (or psychic) dependence refers to a state in which individuals have impaired 
control over drug use based on the rewarding properties of the drug (ability to produce positive 
sensations that increase the likelihood of drug use) or the psychological distress produced in the 
absence of the drug.9   
 
Tolerance is a state that develops as a result of physiological adaptation characterized by a 
reduced response to a specific dose of drug after repeated administration of the drug (i.e., a 
higher dose of a drug is required to produce the same effect that was once obtained at a lower 
dose).    
 
The presence of physical dependence or tolerance does not determine whether a drug has abuse 
potential.  Many medications that are not associated with abuse, such as antidepressants, beta-
blockers, and centrally acting antihypertensive drugs, can produce physical dependence and/or 
tolerance after chronic use.  However, if a drug has rewarding properties, the ability of that drug 
to induce physical dependence or tolerance may influence its overall abuse potential. 
 
 
                                                           
7 See the DEA Web site for the schedules of drugs, contact information, pertinent information regarding the 
Controlled Substances Act, and related topics (http://www.deadiversion.usdoj.gov). 
 
8 Conference on Abuse Liability Assessment of CNS Drugs, Drug Alcohol and Dependence, 70:3 Suppl. 2003. 
 
9 The term psychological dependence conveys a similar state to that of addiction (American Society for 
Addiction Medicine (ASAM), 2011) and substance dependence (American Society for Addiction Medicine 
(DSM)-IV-TR, 2000). 
  4  Contains Nonbinding Recommendations 
 
III.  ASSESSING THE ABUSE POTENTIAL OF A DRUG 
 
This section describes the key decision points in an abuse potential assessment, the types of 
abuse-related studies that may be important, the recommended time frame within the drug 
development program for conducting such studies, and the organization of abuse-related 
information in an NDA submission.    
 
A.  Key Decision Points and Recommended Studies in Assessing Abuse Potential 
 
The Controlled Substance Staff (CSS), located in CDERs Office of the Center Director, has the 
central role in CDER in advising sponsors regarding the abuse potential assessment of a drug 
product.  FDA does not recommend that every drug under development undergo an evaluation of 
abuse potential. An evaluation of abuse potential is most relevant for NMEs with CNS activity 
that have not previously been assessed by FDA for abuse potential.  However, if a drug 
substance with CNS activity is already controlled under the CSA and a different dosage strength, 
dosage form, route of administration, patient population, or therapeutic indication is proposed 
under an NDA or NDA supplement, a modified abuse potential assessment may be necessary 
and should be discussed with CSS (see Section III. B).   
 
For NMEs, the decisions regarding whether an abuse potential assessment will be required under 
21 CFR 314.50(d)(5)(vii), and what studies should be conducted, as well as the conclusions 
regarding a drugs abuse potential, generally depend on the answers to the following questions 
which arise during drug development: 
 
Question 1: Is the new drug (or any major metabolite) active within the CNS? 
 
Drugs with abuse potential almost always have activity within the CNS, so if a new drug or its 
major metabolite(s)10 have CNS activity, additional studies will be recommended.  Examples of 
data relevant to the assessment of whether the drug has activity within the CNS include: 
 
  Chemistry studies (drug structure and ability to pass blood brain barrier) 
  Receptor binding studies with the drug and major metabolites at CNS sites 
  Second messenger system studies (if available) to identify functionality at binding sites  
  Pharmacokinetic studies showing the drugs relative distribution to and penetration of the 
brain 
                                                           
10Our use of the term major metabolite is responsive to the following: Nonclinical characterization of a human 
metabolite(s) is only warranted when that metabolite(s) is observed at exposures greater than 10% of total drug-
related exposure and at significantly greater levels in humans than the maximum exposure seen in the toxicity 
studies, as described in ICH M3(R2) Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical 
Trials and Marketing Authorization for Pharmaceuticals  (2009), available at: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M3_R2/Step4/M3_R2_
_Guideline.pdf.  
 
  5  Contains Nonbinding Recommendations 
 
  Pharmacodynamic studies showing ability of the drug to induce general behavioral 
changes in animals and humans indicative of CNS activity  
 
If assessment of data from these studies or subsequent studies leads to the conclusion that the 
new drug has CNS activity, an abuse potential assessment will likely be required under 
314.50(d)(5)(vii).  
 
Question 2:  For CNS-active new drugs, what is the next step for assessing abuse potential? 
 
For new drugs determined to be CNS-active, the next step for sponsors should be to design and 
conduct abuse-related animal behavioral studies, such as drug discrimination and self-
administration studies.  Detailed descriptions and considerations in designing these abuse-related 
animal behavioral studies are discussed in Section IV.D.  
 
The results from these abuse-related animal behavioral studies are important factors for the third 
key question: 
 
Question 3:  Should a human abuse potential (HAP) study be conducted? 
 
A HAP study (also known as a human abuse liability (HAL) study) assesses abuse potential in 
individuals with a history of recreational use of drugs of abuse.  In determining whether a HAP 
study should be conducted, it is important to assess whether there is evidence that the new drug 
produces any of the following: 
 
  Responses in animals in general behavioral studies that are similar to responses to known 
drugs of abuse   
  Generalization (similar effects) to a known drug of abuse in animal drug discrimination 
studies 
  Rewarding properties that support animal self-administration or conditioned place 
preference 
  A profile of abuse-related AEs (including euphoria-related AEs) in clinical studies in 
healthy individuals (phase 1) and in individuals with the disease of study (phase 2/3) 
 
These studies are discussed in detail in Sections IV and V.  If evaluation of the data from these 
animal and human studies identifies abuse-related signals, it is likely a HAP study will be 
necessary to conduct.  Detailed descriptions and considerations in designing a HAP study are 
discussed in Section V.C.  
  
If an evaluation of data from animal and human studies does not show evidence of abuse-related 
signals, a HAP study is not likely to be recommended.  However, the sponsor should discuss 
available data with the Agency to confirm whether or not a HAP study should be conducted. 
 
Once the data from all appropriate abuse-related studies in animals and humans are evaluated, 
final decisions can be made regarding the fourth key question: 
 
  6  Contains Nonbinding Recommendations 
 
Question 4:  Do the animal and human abuse-related data show that the drug has abuse 
potential, and will it therefore be subject to control under the CSA? 
 
The abuse potential assessment submitted by the applicant in the NDA should include full 
protocols and primary data, as well as a statistical analysis of the data.  The assessment should 
also include a discussion regarding whether the data show that the drug has abuse potential, 
proposed labeling for the DRUG ABUSE AND DEPENDENCE section and other relevant 
sections, and a proposal for scheduling under the CSA, if appropriate (see Section III.E).  
Following the CSS review of the information submitted in the NDA, CSS determines whether 
the drug has abuse potential, suggests appropriate labeling, and drafts a CSA scheduling 
recommendation.   
 
B.  When Abuse-Related Studies Should Be Conducted  
 
Sponsors are encouraged to consult with FDA throughout the drug development program 
regarding the appropriate assessment of abuse potential.  In determining whether any specific 
abuse-related study should be conducted, a sponsor may submit abuse-related questions or issues 
to CDERs Office of New Drugs (OND) review division, which will request a consultation from 
CSS. Interaction with CSS through the review divisions can occur from the pre-IND stage 
through the NDA review cycle. 
 
In general, it is recommended that the specific abuse-related studies be conducted only after the 
therapeutic dose range is determined.  This is not usually known until phase 2 clinical studies are 
completed, at the earliest.  Knowledge of the therapeutic dose range should be used in 
determining the appropriate doses in the specific abuse-related study.  The order of the abuse-
related investigations generally starts with in vitro studies, followed by animal studies, and then 
finally by a human abuse potential study, if appropriate.  Physical dependence assessments 
should be conducted first in animals, to provide information about behavioral effects that may 
inform the design of a human physical dependence study. Assessment of human physical 
dependence should not commence until information is available regarding the ability to safely 
discontinue the test drug in study subjects, as discussed in Section V.E.  Refer to Sections IV and 
V for typical study design elements.   
 
Sponsors are advised to discuss their planned abuse-related studies with CSS, or confirm that 
such studies are not warranted, at the end of phase 2 to ensure the drug is adequately assessed for 
abuse potential.  Sponsors are also advised to summarize all abuse-related data for discussion 
during a pre-NDA meeting with the OND review division, and to request CSS participation for 
the meeting.  The pre-NDA meeting is generally the appropriate time to confirm the planned 
content for the abuse potential assessment and to describe the intended organization and data file 
formats for the NDA submission.  FDA will assess the abuse potential of a drug product and 
determine the Agencys recommendation for its scheduling under the CSA after all study 
protocols and primary data submitted in the NDA have been reviewed.   
  7  Contains Nonbinding Recommendations 
 
C.  Preparing the NDA Submission 
 
The content of an abuse potential section of an NDA typically includes (or cross-references) 
complete study protocols and all primary abuse-related data from the following: 
 
1.  Chemistry studies 
 
2.  Receptor-ligand binding studies and functional (second messenger) studies 
 
3.  Pharmacokinetic studies in animals and humans 
 
4.  Abuserelated studies in animals: 
 
a)  General behavioral observations from safety pharmacology studies 
b)  Drug discrimination study 
c)  Self-administration study 
d)  Physical dependence study  
 
5.  Abuse-related studies in humans: 
  
a)  Human abuse potential (HAP) study  
b)  Physical dependence study 
  
6.  Abuse-related AEs from clinical studies 
 
7.  Information related to overdose, both intentional and accidental, during clinical 
studies 
 
8.  Assessment of the incidence of abuse during clinical studies 
 
The abuse potential section of the NDA should also include (or cross-reference) the Integrated 
Summary of Safety (ISS), as well as data reflecting abuse of the drug substance contained in the 
new drug (or similar drugs) in the form of an approved drug product or as an illicit substance.  
Abuse-related studies and data should be submitted in the electronic common technical 
document (eCTD) as follows: 
 
  The proposal and rationale related to drug scheduling should be placed in Module 1, tab 
1.14.1.  
 
  A summary of all abuse-related animal and human data, discussion of these data, and 
conclusions about the drugs abuse potential should be placed in Module 2.  This should 
occur as a subsection under tab 2.7.4 Summary of Clinical Safety, and should have 
cross-linking to the proposal for scheduling and product labeling in Module 1, as well as 
to all abuse-related studies and data in Modules 3, 4, and 5. 
   
  8  Contains Nonbinding Recommendations 
 
  The complete study protocols and primary data from items 1-8 above  should be placed in 
the appropriate sections of the eCTD as follows: 
   
  Module 3, chemistry 
o
  Module 4, in vitro and animal pharmacology, including behavioral safety studies, 
o
pharmacokinetics and pharmacodynamics studies 
  Modules 5, clinical studies, including human abuse potential studies, human 
o
pharmacokinetics studies, and integrated summary of safety (ISS) 
  
  Reports of abuse, addiction, and deaths from the U.S. and other sources, including those 
from outside the U.S., should be placed into Module 5, postmarketing experience.   
 
D.  NDA Review and Product Labeling Related to Abuse Potential  
 
NDAs are submitted to the appropriate prescription drug review division in OND, based on the 
proposed indications and usages of the drug product.  CSS is consulted by OND prescription 
drug review divisions to evaluate abuse-related data submitted in the NDA and to determine 
whether the drug product has abuse potential.  CSS also provides recommendations for the 
DRUG ABUSE AND DEPENDENCE section of the drug labeling, as well as other sections of 
labeling with abuse-related information. 
 
Abuse-related information in the labeling is primarily described in the DRUG ABUSE AND 
DEPENDENCE section which is comprised of three subsections, as described in 21 CFR 
201.57(c)(10):  
 
 (i) 9.1 Controlled substance. If the drug is controlled by the Drug Enforcement Administration, 
the schedule in which it is controlled must be stated.  
 
(ii) 9.2 Abuse. This subsection must state the types of abuse that can occur with the drug and 
the adverse reactions pertinent to them, and must identify particularly susceptible patient 
populations. This subsection must be based primarily on human data and human experience, but 
pertinent animal data may also be used.  
 
(iii) 9.3 Dependence. This subsection must describe characteristic effects resulting from both 
psychological and physical dependence that occur with the drug and must identify the quantity of 
the drug over a period of time that may lead to tolerance or dependence, or both. Details must be 
provided on the adverse effects of chronic abuse and the effects of abrupt withdrawal. 
Procedures necessary to diagnose the dependent state and the principles of treating the effects of 
abrupt withdrawal must be described. 
 
Sponsors and applicants should engage with CSS via the OND drug review division throughout 
drug development, pre-IND to pre-NDA, to ensure that all abuse-related studies that may be 
necessary to inform the required labeling of the drug product are appropriately planned and 
conducted.   
 
  9  Contains Nonbinding Recommendations 
 
E.  The Drug Scheduling Process 
 
Following review of abuse-related data in the NDA submission, FDA makes a determination  
regarding its recommendation for the appropriate scheduling of the drug under the CSA and 
makes findings as described  in 21 U.S.C. 812(b).   If the NDA is approved, scheduling in one of 
four schedules is based on the drugs relative potential for abuse, accepted medical use in 
treatment in the United States, and relative potential for psychological or physiological drug 
dependency.  
 
Drug scheduling is a multi-step process that involves several federal agencies. Under the CSA, a 
medical and scientific analysis of the abuse potential of the drug is conducted by the Department 
of Health and Human Services (HHS) (see 21 U.S.C. 811(b)). At the conclusion of this analysis, 
the Secretary of HHS will make a recommendation for scheduling to the Drug Enforcement 
Administration (DEA),11 as described in 21 U.S.C. 811 and 812.  The role of the Secretary is 
typically delegated to the Office of the Assistant Secretary for Health (ASH) within HHS. The 
final decision on whether to control a substance in one of the schedules of the CSA is made by 
the DEA on behalf of the Attorney General. 
 
HHS designates the role of conducting the medical and scientific analysis to the FDA.   The FDA 
provides the National Institute on Drug Abuse (NIDA) with an opportunity to present its views 
on drug scheduling during this process.12  Within the FDA, this medical and scientific analysis is 
conducted by CSS, and occurs in parallel with the NDA review process.   
 
Under 21 U.S.C. 811(b) of the CSA, the medical and scientific analysis considers the following 
eight factors determinative of control of the drug under the CSA (21 U.S.C. 811(c)):  
 
1.  Its actual or relative potential for abuse.  
 
2.  Scientific evidence of its pharmacological effect, if known. 
 
3.  The state of current scientific knowledge regarding the drug or other substance.  
 
4.  Its history and current pattern of abuse.  
 
5.  The scope, duration, and significance of abuse.  
 
6.  What, if any, risk there is to the public health.  
 
                                                           
11 The Administrator of the DEA receives the scheduling recommendations and acts on behalf of the Attorney 
General of the Department of Justice with regard to these scheduling actions. 
 
12 Memorandum of Understanding with the National Institute on Drug Abuse (Notice; 50 FR 9518-20; March 8, 
1985). 
  10  Contains Nonbinding Recommendations 
 
7.  Its psychic or physiological dependence liability. 
 
8.  Whether the substance is an immediate precursor of a substance already controlled. 
 
Following the medical and scientific analysis of abuse-related data submitted in the NDA, an 
Eight Factor Analysis (8FA) document is drafted by CSS on behalf of the Secretary of HHS that 
addresses the eight factors listed above.  This 8FA takes into consideration the description and 
analysis of studies or information related to abuse of the drug, including a proposal for 
scheduling under the Controlled Substances Act submitted in the NDA in accordance with 21 
CFR 314.50(d)(5)(vii), along with all relevant and available data.  CSS and NIDA staff work 
together with the goal of gaining concurrence on the 8FA and scheduling recommendations.  
 
The 8FA is then provided to CDERs Office of the Center Director at FDA, and finally to the 
FDA Commissioner for review and comment.  The finalized 8FA is transmitted from the Office 
of the Commissioner at FDA to the ASH at HHS.  NIDA may provide to the ASH/HHS the basis 
for a separate recommendation.  After the ASH/HHS considers the 8FA and recommendations, 
the ASH/HHS transmits the final 8FA and scheduling recommendation to DEA.   
 
After DEA receives the 8FA and recommendations, DEA may respond by issuing a notice of 
proposed rulemaking, an interim final rule, or final rule on the HHS scheduling recommendation 
in the Federal Register.  After allowing time for public comment, DEA generally responds with a 
scheduling order or respond to issues raised by the public.  The final rule may respond to any 
comments received from the public, and confirms a scheduling placement for the drug and the 
effective date (see generally 21 U.S.C. 811, 21 CFR 1308.43). 
 
With the enactment of the Improving Regulatory Transparency for New Medical Therapies Act 
in 2015, FDA approval of a new drug may not take effect until DEA issuance of an interim final 
rule under 21 U.S.C. 811(j) establishing schedule placement for the drug, in accordance with 21 
U.S.C. 355(x). See Pub. L. No. 114-89, 129 Stat. 698 (Nov. 25, 2015).   
 
Once DEA has issued a final scheduling decision and assigned a controlled substance schedule, 
the controlled substance symbol, e.g., C-II, C-III, C-IV or C-V, must be included in the product 
labeling as required under 21 CFR 201.57(c)(10)(i) and 1302.03.  In order to update the labeling 
following the scheduling action, a supplement to the NDA must be submitted by the applicant to 
update product labeling to reflect the DEA scheduling action described in the final rule or 
interim final rule. See 21 CFR 314.70.  The appropriately labeled FDA-approved drug product 
may then be marketed. 
 
 
IV.  ABUSE-RELATED DATA FROM CHEMISTRY AND NONCLINICAL STUDIES 
 
Abuse-related data can be obtained from a variety of chemistry studies and nonclinical 
studies, including those that investigate pharmacology, pharmacokinetics, general animal 
behavioral effects, self-administration, drug discrimination, and physical dependence in 
animals. 
 
  11  Contains Nonbinding Recommendations 
 
 A. Chemistry and Manufacturing 
 
Data from the chemistry, manufacturing, and controls (CMC) section of the NDA that are 
relevant to the abuse potential of the drug substance and drug product under investigation should 
be submitted as part of, or be cross-referenced to, the abuse potential assessment section.    
 
The chemistry part of the abuse potential assessment section for an NME should include the 
following information about the drug substance: 
 
  Chemical structure 
 
  Molecular formula and molecular weight (salt and base, as applicable) 
 
  Chemical Abstracts Service (CAS) Registry Number(s) 
 
  Chemical name (such as the name generated using the nomenclature conventions of the 
International Union of Pure and Applied Chemistry (IUPAC), the name listed in the 
United States Adopted Names (USAN) Counsel dictionary, drug development program 
codes, and established or generic names) 
  
  Description of isomers, e.g., optical, existence of diastereomers, geometric, and 
positional isomers 
 
  Physicochemical  properties of the drug substance, for both salt and free acid/base forms, 
e.g., melting point, boiling point, dissociation equilibrium constants, and solubility in 
various solvents, such as aqueous media, buffered solutions, alcohol, and organic 
solvents 
 
  Description of the manufacturing process for the drug substance, specifically addressing 
whether it involves a precursor that is a controlled substance or a List I or List II 
chemical (21 CFR 1310.02)13    
 
The composition and physicochemical properties of the drug product should be discussed in the 
abuse potential assessment section in the context of their possible impact on the abuse potential 
of the drug substance, and relative to the drug schedule of already-marketed formulations 
containing the same drug substance if it is a controlled substance.   
 
                                                           
13 Note that if the new drug involves an immediate precursor to a drug already controlled under the CSA it may be 
subject to scheduling by a different process than that described above at III.E.  See 21 U.S.C. 811(e), 21 CFR 
1308.47. 
  12  Contains Nonbinding Recommendations 
 
B.  Screening with Receptor-Ligand Binding Studies 
 
Comprehensive screening using in vitro receptor-ligand binding studies should be conducted to 
determine the pharmacological site(s) of action of the test drug, as well as its major human 
metabolites, in the brain.  Possible CNS sites of action include receptors, transporters, and ion- 
gated channel systems. Notably, novel pharmacological mechanisms of action may be associated 
with previously unrecognized abuse potential in humans.  The outcome of receptor-ligand 
binding studies can help determine which in vitro functional assays should be conducted. 
 
Although a CNS-active drug may have a single high-affinity site, it is often the case that drugs 
have multiple mechanisms of action with varying degrees of affinity.  Some examples of 
neuronal systems related to abuse potential that should be assayed include the following:  
 
  Dopamine 
  Serotonin 
  Gamma-aminobutyric acid (GABA) 
  Opioid 
  Cannabinoid  
  N-methyl-D-aspartate (NMDA) 
  Ion-channel complexes (e.g., calcium, potassium, chloride) 
  Transporters (e.g., dopamine, serotonin, GABA)     
 
A comprehensive binding assay typically assesses many dozens of sites in the CNS, only some 
of which are currently known to be associated with abuse potential.  However, mechanisms of 
action not previously associated with abuse potential may produce abuse-related signals with a 
novel drug.  Even though most of the assayed sites will not be predictive of drug abuse, they can 
be predictive of certain animal behaviors and AEs in humans that may be observed during abuse-
related studies. 
 
General scientific principles, including the use of appropriate positive controls and internal 
standards, should be applied.  Highly selective radioligands should be used whenever available.  
The concentration of the ligand should be at least 10 M (or should be equivalent to many-fold 
greater than the anticipated therapeutic exposure).   
 
In vivo receptor-ligand binding techniques, such as positron emission tomography (PET) or 
single photon emission computed tomography (SPECT), can also provide information about the 
localized action of drugs.  These studies are typically conducted in humans (where they have 
been validated), although animal applications are possible.  Studies using these techniques may 
be useful in contributing important information about the whole-body pharmacokinetic and 
pharmacodynamic properties of the drug. 
 
Data from receptor-ligand binding assays should be evaluated on the basis of both specificity 
(whether the ligand binds at one or many sites) and selectivity (the relative affinity of a ligand 
for different binding sites).   
 
  13  Contains Nonbinding Recommendations 
 
Knowledge of the binding profile may suggest whether functional in vitro assays should be 
conducted to determine whether the drug is an agonist, antagonist, partial agonist, or mixed 
agonist-antagonist at specific binding sites.  Once the mechanisms of action of the test drug are 
known, it can be determined which animal behavioral tests may be relevant.   
 
C.  Use of Nonclinical Pharmacokinetic Data in Animal Abuse-Related Studies 
 
PK data that are generated during nonclinical evaluations of a test drug are important in 
appropriately designing and interpreting animal abuse-related studies.  The main PK parameters 
for this purpose are peak plasma concentration (C ), time to maximum concentration (T ), 
max max
time to onset of drug effects, and terminal half-life (T ) for the parent drug and any  major CNS-
12
active metabolites (>10% of parent concentration).  Other elements, such as area under the curve 
(AUC ), bioavailability, and CNS concentration and drug clearance, may be important, 
0-
depending on the drug product.  Animal PK data may also be useful in determining relative 
distribution of the test drug to the brain.   
 
The use of nonclinical PK data in designing animal abuse-related studies is described in detail 
below.  Protocols for animal abuse-related studies should include a justification of design 
elements based on nonclinical PK data, when appropriate.  All PK parameters utilized should be 
based on actual measurements, not estimations.  When the NDA is submitted, all nonclinical PK 
studies and resultant data that informed the design and interpretation of animal abuse-related 
studies should be cross-linked. 
 
D.  Animal Abuse-Related Behavioral Pharmacology Studies 
 
Abuse-related animal behavioral studies should be conducted when it has been determined that a 
test drug or any of its major metabolites are CNS-active.  These studies evaluate whether a test 
drug produces behavioral changes in animals that suggest the drug may have abuse potential in 
humans.  Safety studies that measure whether the drug influences or interferes with general 
behavior (e.g., Irwin test, motor performance test) show whether a drug produces abuse-related 
signals (e.g., hyperactivity indicative of stimulation).  Specific abuse-related studies evaluate 
whether a drug has rewarding or reinforcing properties (self-administration study and 
conditioned place preference study), and whether a drug has effects that are similar to known 
drugs of abuse (drug discrimination study).  The results of these animal studies are used (in 
conjunction with an evaluation of abuse-related AEs from clinical studies) to determine whether 
a human abuse potential study will likely be necessary and how the study protocol should be 
designed. Additionally, the ability of a drug to produce physical dependence after chronic 
administration should be evaluated.  This ability can be demonstrated by the appearance of 
withdrawal signs upon abrupt drug discontinuation. 
 
Abuse-related animal studies are not typically conducted until the end of phase 2, when the final 
therapeutic doses are usually selected.  This is because doses selected for testing in animal abuse-
related studies should be based on the plasma levels produced in humans by the highest proposed 
therapeutic dose (see discussion below).  If these animal studies are conducted with doses that do 
not reflect final therapeutic and supratherapeutic exposure, they will not be valid for assessing 
abuse potential and may need to be repeated using appropriate doses. 
  14  Contains Nonbinding Recommendations 
 
 
Animal abuse-related studies generally utilize classic designs that are adapted as appropriate for 
regulatory purposes.  A sponsor is responsible for proposing and justifying all design parameters 
of an abuse-related animal study.  If a study is not appropriately designed, the resulting data may 
not be relevant to the assessment regarding the abuse potential of the test drug. 
 
Sponsors may propose additional methods of assessing abuse potential, which should include 
justifications that demonstrate the scientific validity and reliability of these methods, especially 
with regard to assessing drugs with unknown abuse potential.     
 
As described below, each study should incorporate design parameters that facilitate the 
collection of data that are consistent with the regulatory goals of the specific study.   
 
1.  General Considerations 
 
Selection of Animals.  Typically, abuse-related animal studies are conducted in rats, because this 
species has been validated for use in these studies.  Although nonhuman primates have often 
been used for abuse assessments, the ICH guidance for industry, M3(R2) Nonclinical Safety 
Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals (2010)14 (M3(R2) guidance), states that, When the metabolite profile and the 
target for drug activity in rodents are consistent with that of humans, the nonclinical abuse 
liability evaluations should be conducted in rodents.  Nonhuman primates should be reserved 
only for those limited cases where there is clear evidence that they would be predictive of human 
abuse liability and the rodent model is inadequate.  The study protocol should justify the 
species selected, especially if a non-rodent species is proposed.  Typically, a single animal 
species is used for animal abuse-related studies.  It is appropriate to use animals of both sexes in 
these studies.  The experimental drug history of the animals (classes of drugs, as well as extent 
and recency of exposure) should be provided, if it is known and available, since prior exposure to 
drugs may influence responsivity to the current test drug.  The number of animals used in the 
study should be based on a statistical power analysis in order to ensure that the sample size is 
appropriate to detect changes in behavior that can be attributed to the test drug. 
 
Selection of Drug Doses.  The doses used in animal abuse-related studies should be selected on 
the basis of the specific test being conducted (see below).  For regulatory purposes, the doses of 
a test drug that will be evaluated in animal abuse-related studies should be derived from the C  
max
produced by the highest proposed therapeutic dose, rather than on the basis of characterizing an 
entire dose-response curve (e.g., no effect level to incapacitating level).  This is because most 
animal abuse-related studies are specialized safety studies, not studies that investigate the 
                                                           
14 Available at 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073246.pdf.  We 
update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA Drugs 
guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  Available at 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073246.pdf.   
  15  Contains Nonbinding Recommendations 
 
toxicological properties of the test drug.  Recreational drug users tend to use drugs at doses that 
are multiples of the medically-recommended dose, so abuse-related studies in animals typically 
test doses that produce C  levels that are equivalent to, as well as at least 2-3 times greater 
max
than, the C  produced by the highest proposed therapeutic dose. (This principle does not apply 
max
for a self-administration study, see below).  If a test drug has partial agonist activity at a site 
associated with abuse potential (where higher doses tend to produce antagonist activity, while 
lower doses produce agonist activity), evaluating decrements in dose may be more appropriate 
when assessing the abuse-related properties of the drug, if the therapeutic indication relies on 
receptor antagonism. 
 
Control Groups.  Abuse-related studies should include a positive control drug group and vehicle 
group for comparison with the test drug group.  In order for a study to be considered valid, the 
positive control group should produce results that are statistically significantly different from the 
vehicle group to establish that the study has assay sensitivity (i.e., the ability to demonstrate 
that an abuse signal can be produced under study conditions, to ensure that the abuse potential of 
the test drug can be determined).  Although unscheduled psychoactive drugs are sometimes 
proposed as a negative control, they are unlikely to fulfill this condition because they have not 
typically undergone a thorough abuse potential assessment.  Thus, for animal studies, we expect 
that the only appropriate negative control will be vehicle.  The drug selected as the positive 
control should be in the same pharmacological class as the test drug, whenever possible, and 
should be scheduled under the CSA.  The dose of the positive control is typically based on a dose 
utilized in published abuse-related studies, to ensure adequate abuse-related behavioral responses 
in the specific animal test.  For a test drug with a mechanism of action that is novel or does not 
correspond to a drug currently controlled under the CSA, the Agency will consider sponsor 
proposals for an alternative positive control.  This may be a drug that has a therapeutic indication 
or behavioral profile that is similar to the test drug, even if the mechanism of action is different.  
The statistical evaluation should compare the test drug to both the positive control and vehicle.   
 
Timing of Data Collection.  Data collection in animal behavioral studies should occur at T , 
max
with additional measurements made before and afterward to ensure full characterization of the 
test drug.  Since T  is determined by route of administration, data from animal PK studies 
max
should inform the time points at which observations are made.  The time to onset will be 
dependent on the specific animal behavior being evaluated, since various responses may occur at 
different times while the drug is active.   
   
Of special interest is the role of tolerance in determining study time points.    The direct 
evaluation of tolerance is not typically required for an abuse potential assessment in animals.  
However, sponsors should be aware of whether the pharmacological mechanism of a test drug is 
associated with the development of tolerance.  If so, this should influence the timing of the 
behavioral training and testing, so that drug exposure is not frequent enough to induce tolerance.  
When the possibility of tolerance is not controlled, a negative result in the test often cannot 
confidently be interpreted as failing to show a signal of abuse.  For test drugs with novel 
mechanisms of action, the likelihood of preventing the development of tolerance is increased if 
drug testing is conducted no more frequently than every other day.   
 
  16  Contains Nonbinding Recommendations 
 
Schedules of Reinforcement for Operant Studies.  When animals are first being trained in the 
test procedures for self-administration and drug discrimination studies, they typically receive a 
reward each time they respond appropriately, corresponding to a fixed ratio 1 (FR1) schedule of 
reinforcement.  The requirement for the number of correct responses (e.g., lever presses) to 
receive a reward is then increased with continued training.  However, final testing should be 
conducted using a standard FR10, rather than schedules of reinforcement with greater response 
requirements (e.g., use of fixed ratio values greater than 10, or use of progressive ratio).   
 
Application of Good Laboratory Practice (GLP).  Abuse-related nonclinical studies must be 
conducted using GLP, as these are nonclinical laboratory studies conducted to support approval 
of a drug for use in humans.  See 21 CFR 58.1.  Sponsors should refer to the following 
guidances, as well as to 21 CFR Part 58 (Good Laboratory Practice for Nonclinical Laboratory 
Studies),15 to ensure compliance with GLP requirements when conducting abuse-related 
nonclinical studies: 
 
  M3(R2) guidance 
  
  ICH guidance for industry, S7A Safety Pharmacology Studies for Human 
Pharmaceuticals (2001).16   
 
2.  General Behavioral Tests 
 
Irwin Test.  This is a study of general behavior in which animals are observed in an open cage 
after acute administration of a test drug over a period of time that covers C .  Observations 
max
may include body posture (flat, rearing), grooming, vocalization, mobility, chewing, appearance 
and ease of handling.  Data from this study can provide initial indications of whether a drug 
produces abuse-related effects such as stimulant or sedative properties.  This test should be 
conducted as part of the toxicology safety battery, so the doses used reflect a broad range of 
doses that produce plasma levels that are similar to, as well as greater than or less than, those 
produced by the proposed human therapeutic dose.  The route of administration often parallels 
                                                           
15 Note that 21 CFR 58.10 states, When a sponsor conducting a nonclinical laboratory study intended to be 
submitted to or reviewed by the Food and Drug Administration utilizes the services of a consulting laboratory, 
contractor, or grantee to perform an analysis or other service [such as abuse-related studies], it shall notify the 
consulting laboratory, contractor, or grantee that the service is part of a nonclinical laboratory study that must be 
conducted in compliance with the provisions of [the regulations in Good Laboratory Practice for Nonclinical 
Studies].  See also FDAs Proposed Rule in the Federal Register (8/24/16), Good Laboratory Practice for 
Nonclinical Laboratory Studies, available at https://www.federalregister.gov/documents/2016/08/24/2016-
19875/good-laboratory-practice-for-nonclinical-laboratory-studies. 
 
16 Available at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm074959.pdf.  We 
update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA Drugs 
guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
  17  Contains Nonbinding Recommendations 
 
that of the proposed therapeutic route.  Given that the Irwin test is a safety pharmacology study, 
it will usually include a comparison with vehicle but will not usually include a positive control. 
 
Motor Performance Tests.  These tests evaluate the ability of a test drug to interfere with normal 
motor functioning after acute administration.  Some of these tests may overlap with measures 
evaluated in the Irwin study.  Examples of these tests include observations of locomotor behavior 
in a test cage (including stereotypy), ability of an animal to maintain itself on a rotating rod 
(rotarod performance), ability to turn over when an animal is placed on its back (righting reflex), 
observations of muscle tone (tail suspension test), and ability for an animal to maintain itself on 
an elevation (inclined plane test).  These tests may be conducted as part of the safety 
pharmacology evaluation of a drug and may provide relevant information about behavioral 
similarities of a test drug relative to known drugs of abuse. 
 
3.  Evaluation of Rewarding Drug Effects 
 
Self-Administration Study.  This study evaluates whether a test drug has rewarding properties 
that are sufficient to produce reinforcement (i.e., the likelihood that an animal will repeatedly 
self-administer the test drug after initial exposure).  Animals are first trained to press a bar in the 
test cage in order to receive a food reward, using a schedule of reinforcement that typically 
increases over the training period from FR1 to FR10.  After animals consistently bar-press in 
response for food, they begin to receive an intravenous dose of a known drug of abuse (training 
drug) as the reward, instead of food.  They are also tested with vehicle to ensure that bar-pressing 
is not maintained for a substance without rewarding properties.  Once animals stably bar-press 
(self-administer) the training drug, they are then allowed to self-administer intravenous doses of 
the test drug. 
 
If the test drug produces a high level of self-administration compared to vehicle, there is a good 
probability that the drug will produce rewarding properties in humans that are supportive of drug 
abuse.  The intravenous route of administration should be used in order to optimize the temporal 
association between active lever-pressing and immediate drug effects.  The doses of the test drug 
should be fractions of the doses that produce plasma levels similar to those produced by the 
human therapeutic dose.  This is done to allow for the repeated administration of the test drug 
without the risk of immediate overdose, and to prevent immediate satiation from a single dose, 
which would obscure the ability to assess reinforcement.   
 
Any drug of abuse that is scheduled under the CSA may serve as the animal training drug for the 
self-administration study.  However, in order to validate the study, a positive control drug should 
produce self-administration levels in challenge sessions that are statistically significantly 
different from vehicle.  The ideal positive control drug is in the same pharmacological class as 
the test drug and is scheduled under the CSA.  The dose of the positive control should be 
consistent with that used in published self-administration studies.  When the test drug has a novel 
mechanism of action, the positive control drug may be one in the same therapeutic class or one 
that produces similar behavioral effects. The appropriate negative control is vehicle.   
 
Certain classes of drugs with hallucinogenic properties do not typically produce animal self-
administration (e.g., 5HT2A agonists), or are only self-administered by animals under limited 
  18  Contains Nonbinding Recommendations 
 
conditions (e.g., cannabinoids), even when they are known to be taken by humans for their 
rewarding effects.  Sponsors may propose that a self-administration study is not appropriate, 
based on similarity in mechanism of action or behavioral effects to these classes of drugs. 
 
Conditioned Place Preference (CPP).  This study evaluates whether a test drug produces 
rewarding effects that are demonstrated by an animals preference to be on the side of a cage 
where it received the test drug, as opposed to the side where it received vehicle.  Notably, CPP 
differs from self-administration in that it does not measure whether the rewarding effects of a 
drug produce reinforcement.  It is also not considered to be as sensitive or reliable as self-
administration.  The dose of the test drug should produce plasma levels that are equivalent to  
and greater than those produced by the proposed therapeutic doses.  The positive control is 
ideally a scheduled drug in the same pharmacological class as the test drug, with the dose 
consistent with that used in published CPP studies.  Route of administration is not critical as long 
as testing is conducted at T .   
max
 
4.  Evaluation of Similarity of Effects to Known Drugs of Abuse 
 
Drug Discrimination.  This study evaluates whether a test drug produces interoceptive cues 
(bodily sensations) that are similar to those produced by a known drug of abuse that is scheduled 
under the CSA (the training drug).  Animals are trained in separate sessions to press one bar in 
the test cage after receiving a training drug and the other bar after they receive vehicle, followed 
by receipt of a food reward.  Animals are typically trained up to a fixed ratio-10 (FR10) schedule 
of reinforcement.  Once animals reliably associate the interoceptive cues from training drug and 
vehicle with correct lever pressing (>80% accuracy), they are given challenge sessions with a 
range of doses of the test drug, the positive control, and vehicle.  During challenge sessions, if 
animals have been trained using FR10, they are allowed to lever press a total of 10 times on 
either lever before removal from the test cage.  Animals are not typically rewarded during 
challenge sessions in order to maintain appropriate associative training.   
 
Animals press the two different levers in the test cage based on the similarity of the interoceptive 
cue produced by the test drug to the two separate training conditions.  Full generalization to 
the training drug occurs when the animal lever presses >80% (8 of 10 times) on the lever 
associated with training drug.  No generalization occurs when the animal lever presses <20% 
on the training drug lever (e.g., >80% on the vehicle lever).  Partial generalization occurs in 
between these poles.  For regulatory purposes, partial generalization between 60-80% suggests 
that the test drug produces an interoceptive cue that has some similarity to the training drug.  In 
order to validate the study, the positive control drug should produce full generalization to the 
training drug and the vehicle should produce no generalization to the training drug.  If the test 
drug produces full or partial generalization to the training drug (a known drug of abuse), it may 
have abuse potential. 
 
Drug discrimination is dependent on mechanism of action, so only those test drugs that have 
pharmacological activity similar to that of the training drug will likely produce a significant 
degree of generalization to the training drug.  Thus, if the test drug has a novel mechanism of 
action, sponsors may prefer to propose an alternative approach for identifying an appropriate 
training drug. 
  19  Contains Nonbinding Recommendations 
 
 
5.  Evaluation of Physical Dependence and Withdrawal Behaviors 
 
Physical Dependence Study. This study evaluates whether chronic administration of a drug at 
therapeutic plasma levels produces a withdrawal syndrome upon drug discontinuation.  This 
assessment may be conducted in animals at the conclusion of a toxicology study or in a dedicated 
study.  Drug administration should typically occur for at least four weeks at stable doses that 
produce plasma levels similar to those produced by therapeutic (and possibly supratherapeutic) 
doses.  Withdrawal is preferentially initiated in animals through abrupt drug discontinuation, 
although tapered drug discontinuation and antagonist precipitation may provide additional safety 
information.  Behavioral observations should begin several days before drug discontinuation and 
continue daily for at least 7 days or for a duration equivalent until the test drug is eliminated.  A 
standardized checklist of expected withdrawal behaviors for pharmacological drug classes should 
be used.  Different pharmacological classes of drugs tend to produce different withdrawal 
syndromes (although there can be overlapping responses).  These withdrawal signs often are 
opposite to the signs observed during drug administration (e.g., benzodiazepine withdrawal may 
produce hyperactivity and seizures, while stimulant withdrawal may produce hypoactivity and 
sleep).  In order to validate the study, a positive control (a scheduled drug with known abuse 
potential, preferably in the same pharmacological class as the test drug) should produce 
withdrawal behaviors that are greater than those produced by vehicle.   
 
Although physical dependence should be assessed during the safety evaluation of a drug, it is 
also considered to be part of the abuse potential assessment because of the role aversive 
withdrawal can play in maintaining abuse of certain classes of drugs.  Also, dependence liability 
is a factor FDA must consider when recommending whether a drug should be controlled under 
the CSA.(see 21 U.S.C. 811(c)(7)).  Additionally, the scheduling placement of a drug with abuse 
potential under the CSA includes consideration of its ability to induce physical or psychological 
dependence, relative to other scheduled drugs (see 21 U.S.C. 812(b)). 
 
 
 V.  ABUSE-RELATED DATA FROM HUMAN STUDIES 
 
Abuse-related data can be obtained from numerous human studies, including a human abuse 
potential study, human studies that evaluate cognition and performance, abuse-related AEs from 
clinical studies, and human physical dependence studies. 
 
A.  Use of Clinical Pharmacokinetic Data in Human Abuse-Related Studies 
 
Pharmacokinetic data that are generated during phase 1 and 2 clinical studies with the test drug 
are important in appropriately designing and interpreting data from human abuse-related studies.  
The main PK parameters for this purpose are C , T , time to onset of drug effects, and T  for 
max max 12
the parent drug and any major CNS-active metabolites (>10% of parent concentration).  Other 
elements, such as AUC , bioavailability, and CNS concentration and drug clearance, may be 
0-
important, depending on the drug product.  Human pharmacokinetic data may be useful in 
determining relative passage of the test drug into the brain.   
 
  20  Contains Nonbinding Recommendations 
 
The recommended use of the clinical PK data in designing human abuse-related studies is 
described in detail below.  The protocols for human abuse-related studies should include a 
justification of design elements based on phase 1 and 2 clinical PK data.  All PK parameters 
utilized should be based on actual measurements, not estimations.  When the NDA is submitted, 
all clinical PK studies and resultant data that informed the design and interpretation of human 
abuse-related studies should be cross-linked. 
 
B.  Abuse-Related Adverse Events in Clinical Safety and Efficacy Studies 
 
All clinical safety and efficacy studies should be evaluated for CNS-related AEs that may 
suggest the test drug produces effects that will be sought out for abuse purposes.  A positive 
signal from abuse-related AEs does not inherently mean that a test drug has abuse potential.  
However, evaluation of clinical AE data, in conjunction with nonclinical abuse-related data 
(chemistry, receptor binding, animal studies), will determine whether a human abuse potential 
study should be conducted.   
 
The presence of a euphoria-like response is a key observation in the clinical assessment of 
whether a test drug has abuse potential.  If euphoria-related AE(s) are reported, it will be 
important to further characterize the profile of the abuse-related signals to determine if the drug 
is similar to other known drugs of abuse (a stimulant, sedative, hallucinogen, etc.).  In the 
absence of euphoria-related signals, AEs such as hallucination and dissociative state may also be 
indicative of abuse potential.  If any of these abuse-related AEs are present, the test drug will 
likely need to be evaluated in a human abuse potential study before the FDA can approve it.   
 
Abuse-related AEs should be interpreted in the context of the proposed therapeutic indication of 
a drug.  Thus, not all CNS-related AEs are equally relevant for purposes of abuse assessment.  
For example, an antidepressant that produces elevated mood or a sleep aid that produces 
somnolence in the absence of a clear euphoric signal is not likely to be interpreted from these 
AE data alone as having abuse potential.  Additionally, even though dizziness is listed under 
euphoria-related terms, this AE is not by itself indicative of abuse potential. At the time of 
publication of this guidance document, a ranking of relevant AEs as signals of abuse risk is not 
available, and all AEs are of interest for the Agency to consider in the overall assessment of risk 
to the public health. The Agencys interest extends to information about the timing of the AEs 
and the narratives from case report forms (CRFs), which are important in interpretation of the 
drug effects.  
  
The list below is a compilation of abuse-related AE terms, related to the drugs pharmacology, as 
provided in the MedDRA (Medical Dictionary for Regulatory Activities) System Organ 
Classifications (SOC).  We recommend sponsors and applicants use these terms when describing 
abuse-related AEs.  Each of the lower level terms that are shown are coded on the basis of a 
longer list of verbatim terms, words or phrases from a patient or observer.  Most preferred abuse-
related terms relate to the drugs pharmacology and fall under SOC General disorders and 
administration site conditions, SOC Nervous system disorders, and SOC Psychiatric disorders.      
 
Below are examples of MedDRA Preferred Terms (PTs), which may provide abuse-related 
information about a drug. This list is not exhaustive, however.  A MedDRA search should 
  21  Contains Nonbinding Recommendations 
 
include additional PT terms that reflect any specific effect of a drug being abused and events that 
could be observed during drug abuse  (for example, overdose, seizure), etc., coded in current 
MedDRA PTs. 
 
Euphoria-related terms 
 
Euphoric mood; Elevated mood; Feeling abnormal; Feeling drunk; Feeling of relaxation; 
Dizziness; Thinking abnormal; Hallucination; Inappropriate affect 
 
Terms indicative of impaired attention, cognition, and mood 
 
Somnolence; Mood disorders and disturbances 
 
Dissociative/psychotic terms 
 
Psychosis; Aggression; Confusion and disorientation 
 
Related terms not captured elsewhere 
 
Drug tolerance; Habituation; Drug withdrawal syndrome; Substance-related disorders  
 
Abuse-related AE data from clinical safety and efficacy studies should be systematically 
categorized, tabulated, and analyzed to determine if AE patterns exist within different human 
populations following administration of the test drug.  These AEs should be presented as both 
pooled studies and individual studies, separated by dose.  When appropriate, full CRFs should be 
evaluated in order to understand the incident that led to the AEs, establish the time at which AEs 
appear following drug administration, the duration of the AEs, and which AEs overlap 
temporally.  CRFs are also important to determine if other drugs were present at the time of the 
incident or whether the individual had other extenuating circumstances during the incident.  All 
incidents that lead to hospitalization for serious neurological or psychiatric abuse-related AEs 
may provide relevant information about abuse potential.  The history of a subject may be 
important in interpreting any abuse-related event.  Clinical studies can also provide information 
about the incidence of signals suggestive of abuse, such as substance use disorders, overdose, 
drug diversion or drug loss.   
 
Differences in AE profiles can occur between different phases of clinical drug development.  For 
example, it is not unusual for there to be a greater incidence of abuse-related AEs from a test 
drug in healthy volunteers who participate in phase 1 studies, compared to the subject 
populations who participate in phase 2 and 3 studies.  Several possibilities may account for this.  
One possibility is that phase 1 studies test a much broader range of doses than those tested in 
phase 2 and 3, including the larger doses that tend to produce a greater degree of abuse-related 
AEs.  Another possibility is that phase 2 and 3 studies test individuals who may have an altered 
responsivity to a test drug because of their underlying disease state.  For this reason, the 
tabulation of abuse-related AEs should occur not only by dose, but also by population tested.  If 
a human abuse potential study is conducted later, the resultant data should be tabulated with 
other phase 1 data in the NDA. 
  22  Contains Nonbinding Recommendations 
 
 
C.   Human Abuse Potential Study in Recreational Drug Users 
 
The primary objective of a HAP study is to provide information on the relative abuse potential of 
a test drug (generally an NME) in humans.  Data from HAP studies are important in developing 
abuse-related drug product labeling and in determining whether the drug product will be 
scheduled under the CSA.  As noted above in Section III.A, a HAP study will likely be necessary 
when abuse-related signals occur in nonclinical studies or if abuse-related AEs are observed in 
clinical studies.  HAP studies that are designed to specifically test the effectiveness of a new 
opioid formulation in providing meaningful abuse deterrence, are described in the guidance for 
industry, Abuse-Deterrent Opioids  Evaluation and Labeling (2015). 
 
During drug development, it is generally advised that HAP studies not be conducted prior to the 
end of phase 2 clinical studies.  This should ensure that the doses used in the HAP study are 
based on the final proposed therapeutic doses and have established safety following phase 1 
studies in healthy individuals and phase 2 studies in individuals with the disease of interest. 
Typically, HAP studies evaluate the highest proposed therapeutic dose of the test drug as well as 
doses that are multiples of the highest proposed therapeutic dose (usually 2-3 times greater, if 
this can be done safely) in comparison to a positive control(s) and placebo.   
 
1.    Study Site 
 
HAP studies are typically conducted in an inpatient or outpatient human pharmacology 
laboratory setting.  In the outpatient setting, subjects should be screened for drugs of abuse when 
returning to the laboratory unit prior to the administration of a study treatment.  Given that 
supratherapeutic doses are tested in these studies, medical personnel and equipment should be 
available to adequately respond to AEs that could compromise the safety of the subjects enrolled 
in the study.  Safety measures should be in place to ensure that subjects are not released from the 
laboratory unit until they are no longer impaired by drugs administered during the study. 
 
2.   Subjects and Sample Size 
 
HAP studies should be conducted in experienced recreational drug users who have a recent 
history of using drugs in the same general pharmacological class as the test drug (e.g., sedative, 
stimulant, opioid, or hallucinogen). Typically, subjects who qualify for the study have had 
numerous recent recreational experiences with the drug class.  This drug history ensures that 
subjects are so familiar with the psychoactive effects of the drug class that they can both identify 
and tolerate the drug class.  Ideally, subjects should prefer this drug class for recreational use.  It 
is not recommended that drug-naive subjects be used in HAP studies because this population has 
not been validated scientifically as being able to provide accurate information on the abuse 
potential of a drug. 
 
During screening, a thorough recreational drug history should be taken from each potential 
subject that details the drugs used, the frequency of use (overall number of times used and 
typical amount used), and the time since last use.  Individuals should be excluded from 
participation in the study if they are currently dependent on a drug (other than caffeine or 
  23  Contains Nonbinding Recommendations 
 
nicotine) or if they are in drug treatment or recovery.  Additional exclusionary criteria specific to 
a HAP study should include positive drug urine screen, positive breath alcohol test, signs of drug 
withdrawal, serious psychiatric or neurological conditions, and any medical condition that could 
be exacerbated by drug exposure or interfere with study procedures.   
 
Sponsors should include a fair representation of races and sexes as participants in clinical trials 
so that clinically significant differences in response can be detected.  The FDA Guideline for the 
Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs (1993)17 should 
be followed.  The age of HAP study subjects typically ranges from 18 to 55 years old. 
 
Study power is of special concern with HAP studies, given that the sample size is typically small.  
In order to determine the correct sample size, a power analysis should be conducted, with a 
justification of the power level that is used in the sample size calculation. The statistical analysis 
should be based on the data from those subjects who complete the study.  The number of 
completers can be influenced by AEs related to drug administration such as sedation, 
somnolence, mental status changes, or nausea/vomiting, all of which may interfere with the 
collection of data.  Thus, the definition of the completer population should include the criterion 
that randomized subjects must have at least one response on the visual analog scale (VAS) for 
Drug Liking within 2 hours of T  for each treatment in the study.  To ensure adequate power, 
max
the sponsor should take into account that there will be subjects who drop out of the study early 
and plan the sample size calculation accordingly. Proper planning should avoid any need to 
replace subjects who discontinue without completing the study. The data from all subjects who 
begin the study should be evaluated for safety signals, including ones indicative of abuse 
potential.   
 
3.   Study Design 
 
The design of a HAP study typically includes a Screening Phase, a Qualification Phase, a 
Treatment Phase, and Follow-up.  The drug administration phases are detailed below: 
 
Qualification Phase 
 
The purpose of the Qualification Phase is to select subjects who report drug liking in response to 
the positive control and demonstrate a meaningfully different response from that produced by 
placebo.  Each subject should be primarily evaluated using a bipolar Drug Liking VAS of 0-100, 
such that placebo should produce a score between 40-60 points, the positive control should 
produce a score outside of the placebo range, and there should be a difference of at least 15 
points between placebo and positive control response.  Only those subjects who produce these 
results should participate in the Treatment Phase. 
                                                           
17 Available at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126835.pdf.  We update 
guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA Drugs 
guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  24  Contains Nonbinding Recommendations 
 
 
The Qualification Phase is generally conducted with only two study treatments:  the positive 
control to be used in the Treatment Phase (at a single dose known to produce drug liking, 
preferably from previously conducted HAP studies) and placebo.  If two positive control drugs 
are used in the Treatment Phase, each of them should be included in the Qualification Phase.  
The Qualification Phase is typically conducted in a double-blind fashion.  However, if the 
positive control has a very long half-life that could necessitate an extended washout period 
between drug sessions, the placebo session may be scheduled before the positive control session 
to reduce intersession timing.  In such a case, subjects should remain blind to the study treatment 
order. 
 
For studies in which an opioid will be administered, it is recommended that subjects undergo a 
naloxone challenge prior to initiation of the Qualification Phase (and prior to the Treatment 
Phase, if they have left the laboratory unit) in order to demonstrate that they are not physically 
dependent on opioids.  In a naloxone challenge test, subjects are administered naloxone and 
evaluated for 2 hours using the Clinical Opiate Withdrawal Scale (COWS) and vital sign 
monitoring.  Those subjects who display no signs of opioid withdrawal and have a COWS score 
of <5 after each naloxone administration should be considered to be non-dependent on opioids. 
 
Treatment Phase 
 
The Treatment Phase is usually designed as a randomized, double-blind, double-dummy, 
placebo- and active-controlled, crossover study.   
 
The study treatments should include placebo, one or two doses of the positive control and at least 
three doses of the test drug.  If the test drug has multiple mechanisms of action that may produce 
a constellation of abuse-related psychoactive effects, or has a CNS-active major metabolite with 
a different mechanism of action, it may be appropriate to consider including a second positive 
control.   
 
In the interests of safety and assurance of successful results, the positive control should be an 
FDA-approved drug that is pharmacologically similar to the test drug and scheduled under the 
CSA.  When the test drug has a novel mechanism of action that presents a difficult selection for 
positive control, sponsors should explore and justify use of alternative positive control 
candidates that have been shown to be safe and elicit similar psychoactive properties as the test 
drug.       
 
The dose(s) of the positive control are ideally selected on the basis of previously-conducted HAP 
studies, in which those doses produced positive psychoactive effects indicative of abuse 
potential.  When the positive control is a drug that has not been evaluated in a HAP study before, 
it may be useful to first conduct a separate dose-finding study, to ensure that the dose selected for 
the HAP study produces positive subjective responses that differentiate statistically from 
placebo.   
 
For regulatory purposes, the doses of a test drug that will be evaluated in human abuse-related 
studies should be based on the highest proposed therapeutic dose in humans, as well as a dose 2-
  25  Contains Nonbinding Recommendations 
 
3 times that dose, if this can be done safely.  Lower doses may be appropriate when the drug has 
a narrow therapeutic index or produces differences in the pharmacokinetic profile between 
subject subgroups (e.g., sex, race, or age).  If a test drug has partial agonist activity at a site 
associated with abuse potential, evaluating decrements in dose may be more appropriate when 
assessing the abuse-related properties of the drug, if the therapeutic indication relies on receptor 
antagonism. 
 
The protocol design should address any potential impact of food on test drug absorption or the 
collection of subjective measures.  For example, consideration should be given as to whether 
orally-administered drugs should be ingested while fasting or on high fat diets.  The imposition 
of restrictions on subjects who smoke cigarettes during the study session may need to be 
considered.  
 
Most HAP studies will be conducted using an oral route of administration for all treatments.  
However, if the test drug is to be medically administered through a non-oral route, or if it is 
liable to be used for recreational purposes via a non-oral route, it may be appropriate to conduct 
the HAP study using both an oral and non-oral route of drug administration.  In this case, the 
protocol should clearly describe study procedures for the non-oral drug administration, including 
preparation of the treatments for use and training of the subjects in the procedures so that the 
entire drug dose is delivered.  The safety of alternative routes of administration should be 
demonstrated prior to the initiation of the study. 
 
Each study treatment should be administered once to each subject, using a repeated Williams 
square design.  A standard washout period between sessions should be calculated on the basis of 
the drug with the longest half-life, so that adequate drug elimination between study sessions will 
be achieved (typically within 5 half-lives).  If the test drug has a CNS-active major metabolite 
with a half-life that is longer than the parent drug, that metabolites half-life should be part of the 
calculation of the length of the washout period.  The length of the washout period may also be 
extended if information from animal or human studies shows that tolerance develops with 
repeated exposure to a test drug within a brief time period. 
 
4.    Outcome Measurements 
 
Outcome measures for a HAP study should include subjective measures, safety and 
physiological measures, pharmacokinetic data, and abuse-related AEs. 
 
Subjective Measures 
 
In HAP studies, standardized questionnaires should be used for evaluating the subjective effects 
of drugs.  Typically, study participants are asked to provide information about their responses to 
a test drug through the use of specific VAS at specific time points following drug administration.  
The VAS for Drug Liking should be selected as the primary measure.  One or two additional 
primary measures may be selected, such as VAS for High.  Secondary measures may include 
VAS that are specific for the pharmacological effects of the test drug, such as Stoned for 
cannabinoids, Hallucinations for hallucinogens, Sedation for CNS depressants, and 
Stimulated for CNS stimulants.  VAS for Overall Drug Liking, Take Drug Again and 
  26  Contains Nonbinding Recommendations 
 
Drug Similarity are secondary measures that evaluate subjective responses after peak drug 
effects have occurred, as well as next day responses.  The data from the secondary measures 
should be considered with the primary measures in determining whether the HAP study shows 
signals of abuse.  On a unipolar VAS, the scale ranges from 0 (No Response) to 100 (Highest 
Response).  On a bipolar VAS, a score of 50 represents No Response, with 0 and 100 
representing the poles of the two choices (e.g., Drug Liking/Disliking or Sleepy/Awake). 
 
The timing of the subjective measures should be established based on the pharmacokinetics of 
the test drug (as well as any CNS-active major metabolites).  Since T  is determined by route 
max
of administration, data from previously-conducted human PK studies should inform the time 
points at which observations are made.  Following oral administration of a drug, measures are 
typically taken every 30 minutes for the first several hours, and thereafter at more extended 
intervals through 24 hours after drug administration.  The timing of subjective measure 
collection should occur most frequently around the time of peak plasma level (T ).   
max
 
For drugs that have rapid onset, it may be appropriate to collect measurements earlier and more 
frequently than 30 minute intervals.  In contrast, for drugs with a very long half-life with 
persistent effects, continuing to evaluate subjective responses well after peak drug effects occur 
may be appropriate.  The time to onset is dependent on the specific human behavior being 
evaluated, since various effects may occur at different times while the drug is active.  For 
example, in a human study, signs of euphoria (assessed through a subjective measure or reported 
as an AE) may start or end at a time different from signs indicative of stimulation or 
hallucination.  Evaluating the time course of the different subjective measures in relation to each 
other (and to abuse-related AEs) can provide important information regarding why subjects may 
report positive or negative assessments of the drug before, during and after the peak of drug 
effects (T ). 
max
 
Safety and Physiological Measures 
 
Safety measures should be collected throughout the study session.  These may include clinical 
laboratory parameters, vital sign measurement, electrocardiogram, and oxygen saturation.  Other 
measures can be proposed, based on the physiological effects of the test drug.  Depending on the 
safety risks posed by the study drugs, qualified emergency response personnel and appropriate 
safety equipment should be available. 
 
Changes in physiological measures such as heart rate, blood pressure and pupil size are often 
indicative of responses to a specific drug class (e.g., miosis following opioid administration or 
tachycardia following stimulant administration).  These physiological effects can be monitored 
over the course of the study session and correlated to both the drug dose administered and the PK 
of the drug. 
 
Abuse-Related Adverse Events  
  
AEs, as observations pertinent to the investigation on each individual administered the 
investigational drug or employed as a control, must be collected in all clinical studies of 
investigational new drugs (see 21 CFR 312.62(b), (c), see also 312.60, 312.64(b)), and can 
  27  Contains Nonbinding Recommendations 
 
provide critical information regarding the abuse potential of a test drug.  However, in HAP 
studies, it is possible to directly correlate the appearance and duration of abuse-related AEs in 
relation to responses on VAS subjective measures such as Drug Liking and High.  If specific 
abuse-related AEs are reported in earlier clinical studies, HAP study staff should be informed of 
the need to increase appropriate monitoring of these AEs, as well as medical or psychiatric 
responses, during or after a study session.   
 
A test drug may induce AEs that can modulate subjective measure outcomes or interfere with the 
collection of the measures.  Examples of such AEs include sedation that prevents data collection 
or mobility related to frequent urination that may heighten the subjects awareness of the effects 
of the drug.  Considerations should be given in advance regarding how to reduce interruptions to 
study procedures because of AEs. 
 
Detailed case narratives for abuse-related AEs should be included with the study report.  
Narratives for each AE should include time of onset and duration of the event, dose of drug 
taken, severity and outcome.  If available, pharmacokinetic values for each individual subject 
who experienced these AEs should be provided to determine whether there is a temporal 
correlation between drug plasma levels and AEs. 
  
Pharmacokinetic Data 
 
Many HAP studies include an analysis of blood samples collected throughout a study session in 
order to monitor drug PK.  This is done primarily to confirm that plasma levels of the drug are 
equivalent between subjects and to evaluate whether subjective measures and AEs can be 
correlated with drug levels over time.  Typically, blood is drawn immediately after the collection 
of subjective measures is completed at each time point.  If an analysis shows that a subject had 
low plasma levels of a drug, it may account for a lack of subjective responses in a drug session. 
 
5.    Analysis of Data 
 
The statistical analysis of a HAP study should address whether:  
 
  The known drug of abuse (positive control) produces reliable abuse-related responses 
compared to placebo.  
  
  The test drug produces abuse-related responses that are smaller than the positive control. 
 
  The test drug produces abuse-related responses that are similar to placebo. 
 
To address these issues, the following hypotheses should be tested: 
 
1.  Validation test of the sensitivity and integrity of the study:  Does the positive control (C) 
produce mean responses that show greater abuse potential compared to placebo (P)? 
Thus, the hypothesis should be tested as following: 
 
      H :   versus H :  >where  >0. 
0 C P 1 a C P 1 1
  28  Contains Nonbinding Recommendations 
 
 
2.  Does the test drug (T) produce mean responses that show less abuse potential compared to 
positive control?  
 
H :   versus H :  > where  0. 
0 C T 2 a C T 2 2
 
3.  Does the test drug produce mean responses that show similar abuse potential compared to 
placebo?   
      
      H :   versus H :  < where  > 0.  
0 T P 3 a T P 3 3
 
The actual values of  ,  , and   vary according to such factors as subjective measures, drug 
1 2 3
class, and route of drug administration.  All the margins should be pre-specified and justified in 
the protocol.  The statistical tests yield multiple comparisons (all doses of positive control drug 
versus placebo; all doses of the test drug versus each dose of the positive control drug; and all 
doses of the test drug versus placebo) for each of the subjective measures collected.  For each 
hypothesis, the statistical significance of the test should be achieved on all doses. Thus, no 
multiplicity adjustment is recommended. 
 
Statistically, HAP studies should be evaluated as safety studies.  Thus, the null hypotheses for 
the test drug should be constructed based on the presumption that the test drug produces abuse 
potential similar to the positive control and therefore differentiates from placebo.  In order to 
demonstrate that the drug has no abuse potential, the null hypotheses should be rejected 
statistically.  This is in contrast to the statistical evaluation used in efficacy studies, in which the 
null hypothesis is constructed on the presumption that the test drug is not efficacious and does 
not differentiate from placebo. 
 
The statistical analysis of the data from a HAP study should begin with descriptive statistics of 
the mean, standard error, and other summary statistics such as minimum, first quartile (Q1), 
median, third quartile (Q3) and maximum for each subjective measure, each treatment and each 
paired difference among treatments.  These data should then be used to create tables and graphs.   
 
Primary Analyses  
 
The statistical model that should be used in HAP studies is a linear mixed-effects model, which 
includes period, sequence, and treatment as fixed effects, and subject as a random effect. The 
primary analyses of abuse potential should be based on testing the differences between the means 
from the primary measure(s) at the peak of drug response effects (E ) produced by the test 
max
drug, the positive control, and placebo, using proper tests and appropriate statistical methods at a 
significance level of 0.05 (1-sided).  
 
  29  Contains Nonbinding Recommendations 
 
Secondary Analyses 
 
Secondary analyses should include the secondary subjective measures and objective measures 
(such as pupil size) and time to peak effect. The analyses should follow the same procedure as 
the primary analyses.    
 
It is important to note that although the abuse-related AEs observed during HAP studies do not 
undergo a statistical evaluation, they are still an important component in assessing the abuse 
signals produced during the HAP study.   
 
All statistical analyses including primary, secondary, any alternative and supportive analyses 
should be pre-specified.   
 
D.   Clinical Studies That Evaluate Cognition and Performance 
 
Clinical studies that evaluate cognition and performance can provide additional safety 
information regarding the psychoactive effects of drugs that may have abuse potential.  If a 
sponsor wishes to evaluate these parameters, the testing may occur during a HAP study with 
recreational drug users.  Alternatively, the testing may occur during separate studies in healthy 
individuals who do not have experience with recreational drugs.  Cognitive tests include those 
that assess the effects of a test drug on memory, perception, attention, language ability, or 
consciousness.  Performance tests generally evaluate psychomotor abilities such as response time 
or amount of sway while standing.   
 
If a test drug interferes with cognition or performance, this does not inherently mean that the 
drug has abuse potential, but it does provide important information related to the drugs CNS 
pharmacology.  These responses may also suggest ways in which a test drug could endanger the 
health or safety of individuals who take the drug (or those around them).  Data from these studies 
may be useful in predicting public health risks, which is a critical area discussed in the 8FA(see 
21 U.S.C. 811(c)(6)).   
 
The ability of a drug to induce changes in cognition or performance may alter the attractiveness 
of a drug for abuse purposes.  Research regarding methods of assessing whether a particular drug 
product has more or less attractiveness to recreational drug users is ongoing. However, for 
regulatory purposes, any evaluation of the attractiveness of a drug product should be based on a 
method that is scientifically validated and reliable in terms of its ability to predict abuse 
potential. 
   
E.   Clinical Evaluation of Physical Dependence 
 
An abuse potential assessment should include an evaluation of whether a drug produces physical 
dependence, in order to: 1) provide accurate information in labeling regarding the risks 
associated with abrupt drug discontinuation (and the possible need for tapered discontinuation), 
and 2) provide information that FDA will use in determining whether a drug will be 
recommended for scheduling under the CSA, and if so, which schedule should be recommended 
(see 21 U.S.C. 811(c)(7)). 
  30  Contains Nonbinding Recommendations 
 
 
In humans, discontinuation of many CNS-active drugs produce drug withdrawal symptoms 
indicative of physical dependence, including headache, anxiety, nausea/vomiting, tremor, chills, 
decreased concentration, agitation/irritability, sleep disturbances, and mood changes.  However, 
different pharmacological classes of drugs may produce unique withdrawal symptoms that are 
often opposite to the responses produced during drug administration.  For example, opioids may 
produce constipation during drug administration but diarrhea during drug discontinuation, while 
amphetamines may produce mental acuity during administration but cognitive impairment during 
drug discontinuation.   
 
The Agency recognizes that physical dependence does not inherently indicate that a drug has 
abuse potential.  Indeed, some drug classes (such as beta-blockers and monoamine reuptake 
inhibitors) that are known to produce physical dependence are not abused and are not scheduled 
under the CSA. 
 
The assessment of physical dependence in humans does not typically involve a dedicated study.  
Instead, physical dependence is usually assessed at the conclusion of a phase 2/3 clinical efficacy 
study through a monitored discontinuation period.  Use of abrupt drug discontinuation rather 
than tapered discontinuation, or precipitated withdrawal through antagonist administration, is 
generally preferable in order to produce naturalistic conditions under which patients stop taking 
medication.  The duration of observation during drug discontinuation should persist for a period 
equivalent to at least 5 half-lives of the test drug when the drug has been fully eliminated. 
 
A human physical dependence evaluation may include: 
 
  Use of drug class-specific withdrawal scales  
  Use of disease-specific scales for evaluation of potential symptom rebound 
  Assessment of AEs before and after drug discontinuation 
  Use of VAS assessing withdrawal symptoms and mood states 
  Use of daily diary by study subject  
  Collection of physiological measures and vital signs 
  Blood sampling for association of pharmacokinetics and withdrawal signs/symptoms 
 
When clinical efficacy studies with the test drug are conducted in a vulnerable population, or 
when abrupt discontinuation of a test drug may pose a safety concern due to return of disease 
symptoms (e.g., seizures in study subjects with epilepsy or psychotic responses in subjects with 
schizophrenia), a dedicated physical dependence study conducted in healthy controls may be 
recommended.  In the design of such a study, the highest proposed therapeutic dose can be tested 
in comparison to placebo (with evaluation of withdrawal AEs and relevant scales).  If the abrupt 
withdrawal of the drug is likely to cause serious AEs in healthy subjects, an animal physical 
dependence study may be sufficient.  For a drug with a novel mechanism of action, an animal 
physical dependence study should be conducted prior to a human study, to obtain information 
about which signs and symptoms should be monitored during drug discontinuation in a human 
study.   
 
A sponsor should propose and justify all design elements of a physical dependence study.      
  31  Contains Nonbinding Recommendations 
 
 
 
VI.    POST-MARKETING AND ILLICIT DRUG ABUSE DATA 
 
When a drug substance in the new drug product has been included in drug products 
legally marketed in the U.S. or elsewhere, post-marketing data may provide information 
regarding whether the drug substance produces abuse-related signals and potential risks.  
Similarly, if a drug substance in the new drug product has been used for abuse purposes, 
information may be available regarding the rewarding effects and safety issues associated 
with the drug substance.  These data may contribute to a broader understanding of the 
abuse potential of a drug, in conjunction with animal and human laboratory data collected 
during drug development.   
 
Post-marketing data may include, but is not limited to, abuse-related information 
obtained from: 
 
  Summaries of AEs reported during clinical studies, as detailed in drug labeling for 
a legally marketed drug (including English translations for labeling used in other 
countries) 
 
  Drug abuse reports in the FDAs Adverse Events Reporting System (FAERS), 
company drug safety databases and World Health Organization (WHO) VigiBase 
 
  Publicly available federally-funded HHS databases such as the National Survey 
on Drug Use and Health (NSDUH), the Treatment Episode Data Set (TEDS), and 
Monitoring the Future (MTF) 
 
  Proprietary databases containing data on prescription drug abuse and diversion, or 
on entry into substance abuse treatment centers 
   
  Databases reporting on drug abuse in state or local communities such as poison 
control centers, treatment programs,  state boards of pharmacy, medical 
examiners, prison systems, syringe service programs, local departments of public 
health  
 
  Databases containing information on drug diversion and drug seizures, such as the 
DEAs National Forensic Laboratory Information System (NFLIS) 
 
  State or local law enforcement reports 
 
  Scientific and medical literature 
  
  Internet forums and social media sites through which drug experiences are 
reported and discussed 
 
  32  Contains Nonbinding Recommendations 
 
Each of these potential sources of abuse-related information has limitations,18 which should be 
delineated in an NDA submission if data from these sources are used.  Not all of these data 
sources are expected to be useful for all products.  Post-marketing abuse data should be 
presented within the context of prescription volume for the product(s) of interest.  Where feasible 
and appropriate, data on relevant comparator products should be included.  Applicants should 
also refer to CDERs Guidance for Industry: Good Pharmacovigilance Practices and 
Pharmacoepidemiologic Assessment (2005)19 for recommended methods of assessing and 
reporting safety through observational studies. 
 
Although post-marketing data from US or foreign sources can provide important abuse-
related information, they are not a substitute for a thorough abuse potential assessment 
conducted prior to submission of an NDA.  
                                                           
18 Secora, A.M. et al, Measures to quantify the abuse of prescription opioids: a review of data sources and metrics 
Pharmacoepidemiology and Drug Safety 2014; 23: 1227- 1237. 
 
19 Available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126834.pdf.  We update 
guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA Drugs 
guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  33  Contains Nonbinding Recommendations 
 
ABBREVIATIONS 
 
ASH    Assistant Secretary for Health  
CDER   Center for Drug Evaluation and Research 
CFR    Code of Federal Regulations  
CNS    Central nervous system 
CSA    Controlled Substances Act  
CSS    Controlled Substance Staff 
DEA    Drug Enforcement Administration  
DOJ    Department of Justice  
FAERS  FDAs Adverse Events Reporting System 
FDA    Food and Drug Administration  
HHS    Department of Health and Human Services  
IND    Investigational New Drug Application  
NDA    New Drug Application  
NIDA   National Institute on Drug Abuse  
NSDUH   National Survey on Drug Use and Health 
SAMHSA  Substance Abuse and Mental Health Services Administration 
U.S.C.   United States Code 
 
  34