Release Date:  November 21, 2000

RFA:  DA-01-004

National Institute on Drug Abuse

Letter of Intent Receipt Date:  January 23, 2001
Application Receipt Date:       February 23, 2001



The National Institute on Drug Abuse (NIDA) invites applications for research 
to broaden our understanding of the transition from drug use to drug 
NIDA-supported research has significantly advanced our understanding of the 
behavioral, biological, and molecular factors both underlying initial drug 
use and characterizing the state of being addicted.  As a result, we have 
accumulated a significant knowledge base about why people start using drugs; 
the risk factors for continued use and dependence; the patterns of use among 
individuals and groups; the effects of drugs on behavior, mood, cognitive 
processes, and performance; and the effects of drugs on the basic 
neurobiology of the brain.  We can now begin to describe the biological and 
behavioral differences between a voluntary drug user and an addict.   

However, we actually know very little about the predisposing factors, 
cellular and neural mechanisms, and behavioral and social processes 
associated with the transition from drug use to drug addiction.  There is a 
tremendous gap in our understanding of how individuals move from early stages 
of drug use to later stages of drug addiction and the mechanisms that 
underlie the actual transition from one state to another.  Research is needed 
to better characterize the stages of drug addiction and transitions to and 
from them.  The knowledge gained will form the basis for improving our 
understanding of addiction and developing improved prevention and treatment 

This topic has been identified by the National Advisory Council on Drug Abuse 
as a major area of research need, requiring new, innovative, intensive, and 
focused attention.  The intent of this Request for Applications (RFA) is to 
stimulate research on the processes and mechanisms underlying the transition 
from drug use to drug addiction from a wide variety of academic disciplines 
and approaches.  Research from epidemiologic, basic, and clinical 
disciplines, including research on other transitional states with relevance 
to addiction, will be supported under this RFA.


The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a PHS-
led national activity for setting priority areas.  This RFA, "The Transition 
from Drug Use to Addiction:  Unearthing the Switch," is related to one or 
more of the priority areas.  Potential applicants may obtain a copy of 
"Healthy People 2010" at


Applications may be submitted by domestic, for-profit and non-profit 
organizations, public and private, such as universities, colleges, hospitals, 
laboratories, units of State and local governments, and eligible agencies of 
the Federal government.  Racial/ethnic minority individuals, women, and 
persons with disabilities are encouraged to apply as Principal Investigators.


This RFA will use the National Institutes of Health (NIH) research project 
grants (R01) award mechanism.  Responsibility for the planning, direction, 
and execution of the proposed project will be solely that of the applicant.  
The total project period for an application submitted in response to this RFA 
may not exceed 5 years.  This RFA is a one-time solicitation.  Future 
unsolicited competing continuation applications will compete with all 
investigator-initiated applications and be reviewed according to the 
customary peer review procedures.  The anticipated award date is September 
30, 2001.

NIDA intends to commit approximately $4 million in FY 2001 to fund 10 to 15 
new and/or competitive continuation grants in response to this RFA.  An 
applicant may request a project period of up to 5 years and a budget for 
direct costs of up to $400,000 per year.  Because the nature and scope of the 
research proposed may vary, it is anticipated that the size of each award 
will also vary.  Although the financial plans of NIDA provide support for 
this program, awards pursuant to this RFA are contingent upon the 
availability of funds and the receipt of a sufficient number of meritorious 
applications.  At this time, it is not known if this RFA will be reissued.



Drug addiction is a chronic relapsing disease that may have many 
characteristics, including a persistent desire or compulsion to use a drug, 
loss of control of drug intake, reduction in other important activities 
because of drug use, continued use despite knowledge of harm, marked 
tolerance, characteristic withdrawal symptoms, and an increased negative 
emotional state or stress when the drug is unavailable.  The process of 
becoming addicted to drugs often begins with non-compulsive or less frequent 
use, which, over time, can lead to compulsive uncontrollable drug taking.  
Relapse to drug use occurs following short or long periods of abstinence and 
may result from stress and/or re-exposure to a drug or environments 
previously associated with drug use.  Individuals addicted to drugs have been 
known to report intense "craving" for an abused drug.

There is a need to learn more about both how the brain changes and how 
behavior changes from first drug use (a voluntary behavior) to compulsive use 
(behavior characterized by a loss of control).  How does taking a drug 
repeatedly over time change the brain in such a way as to lead to the 
compulsive patterns of drug use that characterize addiction?  Why do some 
drug users intensify their use and others do not?  What are the experiences 
of individuals making such transitions in drug use, and how do these 
experiences relate to changes in brain function?  What are the genetic and 
environmental factors that predispose individuals to make such transitions or 
be resistant to them?  Is addiction a defined neurobiological state of the 
brain, and is it dependent upon the environmental conditions in which drug 
use takes place?  Does addiction occur suddenly, as if a switch is flipped, 
or is it a more gradual, incremental process?  Answers to these and related 
questions will (1) provide a logical and strategic basis for the development 
of new and more effective prevention and treatment approaches, (2) allow more 
accurate identification of individuals at high risk for addiction and the 
environmental conditions related to risk, (3) further our basic understanding 
of the behavioral, cognitive, neurobiological, molecular, and biochemical 
effects of drugs, and (4) provide a more complete understanding of the basic 
mechanisms of brain function.

To begin to address some of these questions, NIDA is developing and beginning 
to implement a multi-staged, strategic effort to stimulate research to 
address these issues from a variety of disciplines and perspectives.  

The overall research objective of this initiative is to gain a better 
understanding of the processes and mechanisms underlying the transition to 
addiction, and to ultimately use that knowledge to improve prevention and 
treatment approaches.  NIDA envisions that such new knowledge will come from 
a wide variety of experimental approaches and disciplines and plans to 
support studies to:

o  Identify and characterize specific neurobiological changes in the brain 
related to drug-seeking behavior.

o  Identify the genes and gene products expressed during the process of 
addiction and their functions.

o  Develop and improve animal models of the addiction process, including the 
study of drug-induced narrowing of the behavioral repertoire and compulsive 
drug use; and determine the behavioral, neurobiological, and molecular 
mechanisms associated with these addiction processes.

o  Investigate the role of behavioral, psychological, cognitive, and 
environmental factors in the transition from initial to compulsive drug use 
and their interaction with neurobiological factors.

o  Characterize the changes in drug use patterns and the phenomenological 
experiences in  individuals as they transition from drug use to addiction.

Areas of Interest

The following are illustrative examples of the types of research that would 
be responsive to this RFA.  They are intended as a guide only and not meant 
to limit the themes or approaches that could be proposed:

o  Studies of neurobiological responses to repeated drug administration and 
identification of long-term neuroadaptations that may underlie the transition 
to compulsive drug taking.
o  Cross-disciplinary research to combine basic and clinical approaches to 
identify candidate neurobiological mechanisms underlying transitional states 
in addiction.

o  Collaboration between genetic epidemiologists, molecular geneticists, and 
behavioral scientists to more fully characterize the genes and their actions 
that may contribute to drug use initiation vs. compulsive use and drug 

o  Studies of learning and memory in the development of addiction, including 
those measuring or characterizing state change and plasticity in the central 
nervous system and relating these changes to how knowledge is organized and 
how that organization can change with experience.  Also, studies applying 
operant and associative learning models to transitional states in drug 
addiction, consolidation of memories, encoding, perseveration, and the 
transition of learned actions into habits.

o  Studies of the specificity of the transition.  Is there a discrete 
“transition point” (i.e., the set point at which one goes from nonaddicted to 
addicted – the “switch”), and is it related to a particular biological state, 
or is it dependent upon particular behavioral or environmental variables?  Is 
the “transition point” different for different drugs or drug classes, routes 
of administration, stage of drug use, age, drug use history, environmental 
conditions, etc.?

o  Studies of behavioral/neurobehavioral markers that may predict the 
transition from drug use to drug addiction and individual differences in the 
rate of the transition.
o  Research to characterize the cognitive, neurobiological, environmental, 
and genetic factors that contribute to vulnerability or confer resilience 
against the progression to addiction.

o  Studies of cellular, physiological, and/or behavioral changes related to 
transitional states – normal and pathological – outside of addiction that 
could have relevance to addiction.  These could include studies of learning 
and memory (or other cognitive processes), fixed action patterns (e.g., 
imprinting), and parental behaviors.

o  Research to determine how transcription factors and signaling molecules 
activated during learning and by drugs of abuse produce changes in cell 
physiology, cell morphology, and synaptic transmission in neural systems that 
underlie transitional states in addiction.

o  Studies to identify and compare stages of transition relevant to addiction 
in other diseases/disorders, such as bulimia, anorexia nervosa, obsessive 
compulsive disorders, etc.

o  Studies using computational approaches/mathematical models of transition 
dynamics and state dependence in neural networks.

o  Studies of variables (e.g., drug pharmacology, drug availability, 
behavioral alternatives) that differentiate or predict the characteristics of 
the transition for single drugs or classes of drugs.

o  Studies to examine the role of conditioned environmental stimuli and other 
environmental factors (e.g., stressors) in the transition process.

o  Studies of the variability in susceptibility to addiction, including 
resiliency to addiction, such as the subset of cigarette smokers who 
regularly smoke but do not become addicted (“chippers”), and rapid 
development of addiction, such as the subset of adolescent smokers who 
develop symptoms of nicotine dependence after only a few exposures to the 

o  Epidemiological and ethnographic investigations of drug use patterns 
during transitional periods, characterization of different trajectories of 
drug involvement, and the effects of genetic and environmental (community, 
social, familial) factors.

o  Prospective multidisciplinary studies of high-risk drug users to track the 
onset of addictive use and of specific symptoms of addiction, associated 
phenomenological experiences, and neurobiological profiles.

o  Studies of differential patterns of transition in individuals with 
different psychiatric comorbidities.


All applications must include plans to share data; reviewers will assess the 
adequacy of the proposed plan.

It is the policy of the NIH that women and members of minority groups and 
their sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided indicating that inclusion 
is inappropriate with respect to the health of the subjects or the purpose of  
the research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43). 

All investigators proposing research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
a complete copy of the updated Guidelines are available at  The 
revisions relate to NIH defined Phase III clinical trials and require:  a) 
all applications or proposals and/or protocols to provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) all investigators to report accrual and to conduct and report 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 


It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in 
Research Involving Human Subjects that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning these policies.


The National Advisory Council on Drug Abuse recognizes the importance of 
research involving the administration of drugs to human subjects and has 
developed guidelines relevant to such research.  Potential applicants are 
encouraged to obtain and review these recommendations of the Council before 
submitting an application that will administer compounds to human subjects.  
The guidelines are available on NIDA's Home Page at 
under Funding or may be obtained by calling (301) 443-2755.


All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, Internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.


Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research; the name, address, and telephone 
number of the Principal Investigator; the identities of other key personnel 
and participating institutions; and the number and title of the RFA in 
response to which the application may be submitted.  Although a letter of 
intent is not required, is not binding, and does not enter into the review of 
a subsequent application, the information that it contains allows NIDA staff 
to plan the review.

The letter of intent is to be sent to the following office by the letter of 
intent receipt date listed above:

Director, Office of Extramural Affairs
National Institute on Drug Abuse
6001 Executive Boulevard, Room 3158, MSC 9547
Bethesda, Maryland 20892-9547
Telephone: (301) 443-2755
FAX: (301) 443-0538


The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  These forms are available at most institutional 
offices of sponsored research and from the Division of Extramural Outreach 
and Information Resources, National Institutes of Health, 6701 Rockledge 
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email:

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only 
when there is a possibility for an award.  It is anticipated that these 
changes will reduce the administrative burden for the applicants, reviewers, 
and Institute staff.  The research grant application form PHS 398 (rev. 4/98) 
is to be used in applying for these grants, with the modifications noted 



Modular Grant applications will request direct costs in $25,000 modules, up 
to a total direct cost request of $250,000 per year.  (Applications that 
request more than $250,000 direct costs in any year must follow the 
traditional PHS 398 application instructions.)  The total direct costs must 
be requested  in accordance with the program guidelines and the modifications 
made to the standard PHS 398 application instructions described below:

PHS 398

o FACE PAGE - Items 7a and 7b should be completed, indicating Direct Costs 
(in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular 
Total Direct plus Facilities and Administrative  (F&A) costs] for the initial 
budget period.  Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

of the PHS 398.  It is not required and will not be accepted with the 

categorical budget table on Form Page 5 of the PHS 398.  It is not required 
and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page. (See for 
sample pages.)  At the top of the page, enter the total direct costs 
requested for each year.  This is not a Form page.

Under Personnel, list all project personnel, including their names, percent 
of effort, and roles on the project.  No individual salary information should 
be provided.  However, the applicant should use the NIH appropriation 
language salary cap and the NIH policy for graduate student compensation in 
developing the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the 
nearest $1,000.  List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of all personnel, 
and their role on the project.  Indicate whether the collaborating 
institution is foreign or domestic.  The total cost for a 
consortium/contractual arrangement is included in the overall requested 
modular direct cost amount.  Include the Letter of Intent to establish a 

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by  
reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team.  A biographical sketch is required for 
all all personnel, following the instructions below.  No more than three 
pages may be used for each person.  A sample biographical sketch may be 
viewed at:

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications with full citations;

o CHECKLIST - This page should be completed and submitted with the 
application.  If the F&A rate agreement has been established, indicate the 
type of agreement and the date.  All appropriate exclusions must be applied 
in the calculation of the F&A costs for the initial budget period and all 
future budget years.

The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review. 

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review committee 
in time for review.  In addition, the RFA title and number must be typed on 
line 2 of the face page of the application form and the YES box must be 

The sample RFA label is available at: has been modified to 
allow for this change.  Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, photocopies, in one package to:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must be 
sent to:

Director, Office of Extramural Affairs
National Institute on Drug Abuse
6001 Executive Boulevard, Room 3158, MSC 9547
Bethesda, Maryland 20892-9547

Applications must be received by the application receipt date listed in the 
heading of this RFA.  If an application is received after that date, it will 
be returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed.  This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must 
include an introduction addressing the previous critique.


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by NIDA.  Incomplete and/or non-responsive applications will 
be returned to the applicant without further consideration.

Applications that are complete and responsive to the RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group 
convened by NIDA in accordance with the review criteria stated below.  As 
part of the initial merit review, all applications will receive a written 
critique and undergo a process in which only those applications deemed to 
have the highest scientific merit, generally the top half of the applications 
under review, will be discussed, assigned a priority score, and receive a 
second level review by the National Advisory Council on Drug Abuse.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments reviewers will be asked to discuss the following aspects 
of the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  Each 
of these criteria will be addressed and considered in assigning the overall 
score, weighting them as appropriate for each application.  Note that the 
application does not need to be strong in all categories to be judged likely 
to have major scientific impact and thus deserve a high priority score.  For 
example, an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

(1)  Significance:  Does this study address an important problem?  If the 
aims of the application are achieved, how will scientific knowledge be 
advanced?  What will be the effect of these studies on the concepts or 
methods that drive this field?

(2)  Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

(3)  Innovation:  Does the project employ novel concepts, approaches or 
method?  Are the aims original and innovative?  Does the project challenge 
existing paradigms or develop new methodologies or technologies?

(4)  Investigator:  Is the investigator appropriately trained and well suited 
to carry out this work?  Is the work proposed appropriate to the experience 
level of the principal investigator and other researchers (if any)?

(5)  Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals, or the 
environment, to the extent they may be adversely affected by the project 
proposed in the application.

o  The adequacy of the proposed plan to share data.


Letter of Intent Receipt Date:    January 23, 2001
Application Receipt Date:         February 23, 2001
Peer Review Date:                 June/July/Aug 2001
Council Review:                   September 2001
Earliest Anticipated Start Date:  December 2001


Award criteria that will be used to make award decisions include:  scientific 
merit (as determined by peer review), availability of funds, and programmatic 


Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or answer questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Steven Gust, Ph.D.
National Institute on Drug Abuse
6001 Executive Boulevard, Room 5274, MSC 9581
Bethesda, MD  20892-9581
Telephone:  (301) 443-6480
FAX:  (301) 443-9127

Direct inquiries regarding review matters to:

Teresa Levitin, Ph.D.
Office of Extramural Affairs
National Institute on Drug Abuse
6001 Executive Boulevard, Room 3158, MSC 9547
Bethesda, Maryland 20892-9547
Telephone: (301) 443-2755
FAX: (301) 443-0538

Direct inquiries regarding fiscal matters to:

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
6001 Executive Boulevard, Room 3131, MSC 9541
Bethesda, MD  20892-9541
Telephone:  (301) 443-6710
FAX :  (301) 594-6847


This program is described in the Catalog of Federal Domestic Assistance No. 
93.279.  Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.

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