RESEARCH ON THE ORIGINS AND PATHWAYS TO DRUG ABUSE

Release Date:  September 30, 1999

PA NUMBER:  PAR-99-168 (see replacement PA-04-100)

National Institute on Drug Abuse

THIS PROGRAM ANNOUNCEMENT (PA) USES THE "MODULAR GRANT" CONCEPT.  IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

PURPOSE

This PA replaces PA-97-043, which was published in the NIH Guide, Vol. 26, No.
8, March 14, 1997.

This PA encourages research exploring the origins of and pathways to drug
abuse and addiction.  Of particular interest are multidisciplinary,
integrative, and developmental approaches.  A comprehensive understanding of
the factors and processes that predispose and/or protect an individual from
drug abuse, from initial use through different stages of drug involvement and
addiction, is essential to the successful prevention and treatment of drug
abuse.  Investigators from diverse scientific disciplines are encouraged to
apply.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of Healthy People 2000, a PHS-led national
activity for setting priority areas.  This PA is primarily related to the
priority area of alcohol and other drugs.  Potential applicants may obtain a
copy of Healthy People 2000 (Full Report:  Stock No. 017-001-00474-0, or
Summary Report: Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, D.C. 20402-9325 (telephone:
202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic for-profit and nonprofit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of state or local governments, and eligible agencies of
the federal government.  Foreign institutions are not eligible for program
project or centers (P-Series) awards.  Women and minority investigators are
encouraged to apply.

MECHANISM OF SUPPORT

The mechanisms available for support of this PA includes traditional research
project grants (R01), small grants (R03), exploratory/developmental grants
(R21), program projects (P01), and research centers (P30, P50, and P60). 
Application for Research Centers must be in accordance with the National
Institute on Drug Abuse (NIDA) Research Center Consolidated Program and Review
Guidelines.  More specific information about individual research mechanisms
can be obtained from the NIDA home page at
http://www.nida.nih.gov/Funding.html.

Because the nature and scope of the research proposed in response to this PA
might vary, it is anticipated that the size of an award will vary also.

Applications requesting direct costs of $500,000 or more in any one year must
obtain agreement from the assigned institute that the application will be
accepted for review and consideration of award, in accordance with NIH policy,
which is available at
http://grants.nih.gov/grants/guide/notice-files/not98-030.html.  Applicants
must identify in the cover letter sent with the application the specific NIH
office and staff member who agreed to accept assignment of the application.

Specific application instructions have been modified to reflect "MODULAR
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.
Complete and detailed instructions and information on Modular Grant
applications can be found at
http://grants.nih.gov/grants/funding/modular/modular.htm

RESEARCH OBJECTIVES

Background and Significance

Research clearly shows that individuals are differentially at risk for illicit
drug initiation and for making the transition from lower levels of drug
involvement to higher levels of drug abuse and addiction.  Insufficient
information is available on the diverse factors that account for this, their
interactions, and the multiple patterns in which these factors occur.

Earlier attempts to understand the origins of drug abuse and dependence often
utilized simple linear models in which susceptibility to drug involvement was
construed and investigated in terms of the magnitude of a single risk factor
or the sum of a limited set of identified risk factors.  In more recent
research, even when multiple contributive factors have been considered, the
emphasis has commonly been on simple additive models of predispositional
factors, and these models have typically concentrated on factors from a single
domain (i.e., the biological, the psychological/behavioral, or the
environmental).

Resilience and protective factors have been given little attention in the
field of drug abuse research. They have typically been assumed to be the
absence or opposite of given risk factors rather than important, active,
possibly independent influences. Attempts to understand the origins and nature
of drug abuse have typically been based on non-systemic and static models
focusing almost exclusively on concepts of risk and vulnerability placing
little emphasis on protection and resilience. Predispositional and protective
factors have typically been assumed to be absolute, neither changing nor
having different influences over time, across populations or cultures, at
different stages of an individual's maturation and development, or at
different points of one's drug involvement history (i.e., initiation,
escalation, maintenance, relapse). Of great concern, research has rarely
considered the interaction of predispositional and protective factors or the
interaction of factors from differing domains or fields of inquiry.

In addition, there is considerable evidence that there are major
biological/neurological components to vulnerability to abuse and addiction and
evidence that at least some of these factors are influenced, if not
determined, by genetic contributions. However, most research on resilience to
drug abuse and dependence has been in the psychological, behavioral, and
environmental research domains.  There has been very little research exploring
the ways in which biological factors may increase individuals' resistance to
drug abuse, escalation, and dependence.  In the fields of alcohol and nicotine
research, biologically based protective factors have been identified.  While
additional research is needed to further identify and characterize the
biological factors that can increase drug abuse and dependence, research is
particularly encouraged to focus on the phenomenon of lower risk of drug
dependence, in order to discover the biological factors and genetic variants
that can help protect against drug abuse and dependence.  The interaction of
biological predispositional and protective factors will be a necessary focus
of research, as will the interaction of these factors with vulnerability and
resilience factors in other domains.

Drug addiction is a chronic relapsing disorder characterized in part by
critical transitions at each stage.  These transitions, particularly the
transitions from early use to higher levels of drug involvement and from heavy
use to addiction, are not well understood.  While it is known that there is
considerable variability among individuals, little is known about the factors
that characterize these transitions or that predispose individuals to make
them or not.  A thorough understanding of the determining factors and
characteristics of these transitions is necessary in order to effectively
limit the progressive course of drug abuse and addiction.

Research has generally not considered the origins of drug abuse and addiction
from a developmental perspective nor incorporated concepts related to
developmental psychopathology or the developmental stages and transitions
experienced by individuals. Similarly, there has been little research which
investigates the ways in which drug involvement may alter or influence the
psychological and social development of drug using adolescents and the ways in
which this may influence their future vulnerability to drug abuse. Few studies
have taken a life span approach and investigated the natural waxing and waning
of drug involvement that typically occurs over the course of an individual's
drug using career or examined the developmental aspects of drug abuse and
dependence in adulthood. Also, there has been only limited research and theory
on the developmental changes and transitions associated with drug abuse,
particularly heuristic efforts that recognize the plasticity of individuals
and that incorporate a focus on the interactions of influences from multiple
domains. Lastly, models and research on the origins of drug abuse have often
assumed that drug abuse and drug abusers are basically homogeneous, giving
little attention, for example, to understanding individual differences in drug
involvement, to identifying different patterns of drug involvement, or to
differences in drug involvement associated with different drugs. Although
research to date on the origins and development of drug abuse has made much
progress and produced critical information, further progress requires a
sophisticated advance in the basic approaches being used. It is this next
generation of research on the origins of and multiple pathways to drug abuse
and the factors that determine individuals' susceptibility and/or resistance
to each potential stage of drug involvement which this PA seeks to support.

Researchers are encouraged to use biological, socio-cultural, psychological,
and developmental perspectives in both cross-sectional and longitudinal
studies to investigate the origins of and pathways to drug abuse.
Multifactorial and multidimensional research is needed to determine: the
interactions and cumulative impact of factors from the various domains
(genetic, neurobiological, psychological, social and cultural, and
environmental factors and processes); the role of intermediary factors and
processes; the interaction of predispositional and protective factors,
processes, and systems; and the various potential stages and transitions of
drug involvement (initiation, escalation, resistance to drug involvement and
escalation, continuation, discontinuation, relapse, and recovery from drug
abuse and dependence). Researchers are also encouraged to recognize and
investigate the powerful and diverse effects of gender, culture, age
throughout the life span, racial/ethnic minority group membership, sexual
orientation, and other crosscutting influences on the various aspects,
patterns, stages of and predisposition to and/or protection from drug abuse.

In addition to the research objectives described above, NIDA is interested in
applications that address the following topics:

The interactive influences and relationship of drug abuse and its development
to other frequently co-occurring problems, particularly:

Pathological, dysfunctional, deviant, delinquent, criminal, and other risky
behaviors;

Mental disorders, dysfunctions and subclinical impairments, including
psychological, cognitive, and affect and behavior regulation impairments.
Examples include psychophysiologic responses to anger, stress reactivity,
executive cognitive functioning, sensation or novelty seeking, and other
temperament and personality constructs.

Childhood psychopathologic and developmental conditions that are associated
with vulnerability to later development of drug abuse and dependence,
including disruptive behavior disorders; mood disorders; anxiety disorders;
learning, attention, and language impairments; cognitive dysfunction; as well
as their co-occurrence.  Particularly needed are studies that move beyond
diagnostic categories, to examine underlying protective factors and underlying
vulnerability mechanisms and deficits; studies of clinical subtypes,
subclinical conditions, early stage disorders, and atypical psychiatric states
are also needed.

Subpopulations whom research has shown to be often involved with drug abuse
such as school dropouts, gang members, children of drug or alcohol abusers,
homeless people, trauma survivors, individuals with various co-occurring
psychopathologies, people with physical and cognitive disabilities,
individuals with a history of childhood physical and sexual abuse, etc.

The nature of drug abuse and the development of different patterns of drug
involvement including the role of community factors; the impact of immigration
status; the influence of cultural assimilation; the effects of such factors as
poverty, racism, poor housing conditions, limited educational and employment
opportunities, historical time period, generation, familial constellations,
etc.

Methods of "early" premorbid determination of the nature and degree of
individuals' susceptibility to drug involvement and methods for the
identification of individuals who might particularly benefit from early
preventive intervention.

Models which identify potentially effective points, targets, and goals of
successful prevention and treatment intervention for different populations; of
particular interest is information which will facilitate the further
development of interventions related to transitions associated with drug use
escalation to higher levels, heavy use to addiction, discontinuation, and
relapse.

The nature and extent to which consequences of drug abuse at one stage of
involvement can facilitate or inhibit subsequent abuse, escalation, or
discontinuation, etc.

The contributions, and the factors and processes underlying the contributions,
of the use of legal psychoactive substances (tobacco, alcohol, prescribed
psychoactives, over-the-counter medications, caffeine, etc.) on subsequent
illicit drug abuse.

Processes/characteristics hypothesized to be intrinsic to the development of
drug abuse (such as craving, self-medication, loss of control, compulsive
behaviors, risk assessment, etc.); processes/characteristics hypothesized to
be inherent in drug abuse resistance and recovery (such as resilience,
adaptiveness, responsiveness to intervention, etc.); processes and
characteristics hypothesized to be intermediary influences on drug abuse (such
as sensation seeking or "difficult temperament"); and underlying
processes/characteristics that may have multiple manifestations, one of which
may be drug abuse.

Phenomena which may be related to the development of drug abuse; such as,
common patterns and sequences of drugs used by individuals during the
escalation of their drug involvement over time, common combination of drugs
used by abusers, spontaneous quitting, etc.

The convergence and/or divergence of phenomena observed in different domains;
for example an investigation of possible neuro-biological mechanisms
underlying a behavior commonly associated with drug abuse.

Organization of information about drug abuse into coherent conceptualizations,
and tests of the validity and utility of the resultant models and theories.

Particularly encouraged are studies focusing on determinants of individual
differences in drug involvement and the development of different drug abuse
patterns, as well as studies of correlates and markers of these individual
differences.  While many of the objectives of this PA require a focus on human
subjects, when appropriate, animal models of the above research areas are
encouraged.

It is recognized that many of the types of questions addressed in this PA are
typically addressed through resource and time intensive longitudinal research
designs.  Proposals which rigorously respond to the objectives while
minimizing the expenditure of resources and long delays; for example, studies
which piggyback onto already ongoing projects are particularly encouraged.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided 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 "NIH Guidelines for Inclusion of
Women and Minorities as Subjects in Clinical Research," which was published in
the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH
Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

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 website: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

NATIONAL ADVISORY COUNCIL ON DRUG ABUSE RECOMMENDED GUIDELINES FOR THE
ADMINISTRATION OF DRUGS TO HUMAN SUBJECTS

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 before submitting an
application that will administer compounds to human subjects.  The guidelines
are available on the NIDA Home Page at http://www.nida.nih.gov/ or
may be obtained by calling 301-443-2755.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines as indicated
in the application kit.  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Division of
Extramural Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-435-
0714, Email: GrantsInfo@nih.gov.  The title and number of the PA must be typed
in Section 2 on the face page of the application.

Beginning with the June 1, 1999 receipt date, "MODULAR GRANT APPLICATION AND
AWARD" procedures will apply to all competing individual research project
grants (R01), small grants (R03), and exploratory/developmental grants (R21)
applications requesting up to $250,000 direct cost per year.  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 below.

BUDGET INSTRUCTIONS

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.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398.  It is not required and will not be accepted with the
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete 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 http://grants.nih.gov/grants/funding/modular/modular.htm for sample
pages.) At the top of the page, enter the total direct costs requested for
each year.  This is not a Form page.

o  Under Personnel, List key 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 key personnel,
and the 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 consortium.

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 key personnel, following the instructions below.  No more than three pages
may be used for each person. A sample biographical sketch may be viewed at: 
http://grants.nih.gov/grants/funding/modular/modular.htm

- 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.

o  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 completed original of the application and five legible copies must be sent
or delivered to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

REVIEW CONSIDERATIONS

Applications that are complete will be evaluated for scientific and technical
merit by an appropriate peer review group convened in accordance with the
standard peer review procedures.  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 applications under review, will be discussed, assigned a
priority score, and receive a second level review by the appropriate national
advisory council or board.

Review Criteria

The goals of NIH-supported research are to advance the 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 the study 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
support?

Program project applications will also be reviewed for integration and other
factors unique to the P mechanism.  Potential applicants should discuss these
factors and their proposed applications with NIDA staff prior to submission. 
Center applications will be reviewed in accordance with the NIDA Research
Center Grant Consolidated Program and Review Guidelines.  Potential center
applicants should also discuss their proposed applications with NIDA staff
prior to submission.

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

- 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
evaluated.

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

- 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.

- The adequacy of plans to make data available to other investigators in a
timely fashion.

AWARD CRITERIA

Applications will compete for available funds with all other recommended
applications.  The following will be considered in making funding decisions:
quality of the proposed project as determined by peer review, availability of
funds, and program priority.

INQUIRIES

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

Direct inquiries regarding the programmatic issues to:

Meyer D. Glantz, Ph.D.
Division of Epidemiology, Services and Prevention Research
National Institute on Drug Abuse
6001 Executive Boulevard, Room 5153, MSC 9589
Bethesda, MD  20892-9589
Telephone:  (301) 443-6543
Email:  mg115g@nih.gov

Direct inquires regarding fiscal issues 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
Email:  gfleming@nih.gov

Direct inquiries regarding review issues to:

Teresa Levitin, Ph.D.
Director, Office of Extramural Program Review
National Institute on Drug Abuse
6001 Executive Boulevard, Room 3158, MSC 9547
Bethesda, MD  20892-9547
Telephone:  (301) 443-2755
Email:  tl25u@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.279.  Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410), as amended by Public Law 99-158, 42 USC
241 and 285), and administered under PHS grant policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency Review.

The Public Health Service strongly encourages all grant recipients to provide
a smoke-free workplace and promote the nonuse 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 of 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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