Full Text DA-96-003


NIH GUIDE, Volume 24, Number 41, December 1, 1995

RFA:  DA-96-003

P.T. 34

  Drugs/Drug Abuse 
  Chemotherapeutic Agents 

National Institute on Drug Abuse

Letter of Intent Receipt Date:  January 19, 1996
Application Receipt Date:  February 21, 1996


The purpose of this Request for Applications (RFA) is to encourage
clinical testing of innovative and non-traditional pharmacotherapies
for treatment of cocaine/psychostimulant (amphetamines) dependence.
Two types of medications will be considered:  (1) traditional
pharmacotherapies addressing novel neurochemical mechanisms (beyond
classical biogenic amines or compounds previously extensively
tested); (2) non-traditional (alternative) pharmacotherapies selected
to restore brain homeostasis or to repair/compensate for existing
neurological/neurochemical deficits in chronic psychostimulant
abusers (e.g., special nutritional factors, amino acids,
neurotransmitter precursors, hormones, antihormones, supplements,
etc.).  Special emphasis will be put on testing natural compounds
with very low or no toxicity, which could be potentially also
utilized for treatment of children and pregnant women.

Investigators should study the safety and efficacy of novel
medications in either relapse prevention in detoxified
cocaine/psychostimulant dependent participants or reduction of drug
use.  The primary focus will be on relapse prevention.  Applications
will be also required to assess the impact of investigational agent
on HIV risk behaviors.  Applications that propose to evaluate
compounds already extensively studied in psychostimulant dependence
(traditional medications that act at dopamine, noradrenaline, or
serotonin systems, or carbamazepine, etc.) will not be considered


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 RFA,
Novel Pharmacotherapies for Cocaine and Other Psychostimulant
Dependence, is related to the priority areas 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, DC 20402-9325 (telephone


Applications may be submitted by domestic, for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State or 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.  Foreign institutions are not
eligible for the First Independent Research Support and Transition
(FIRST) award (R29).

International collaborative studies, which must include a U.S.
principal investigator, will also be considered.  For example, if the
investigational compound is not available on the U.S. market, but is
available in European or Asian pharmacopeias, the pilot studies may
be conducted in a foreign country.


This RFA will use the National Institutes of Health (NIH) research
project grant (R01), FIRST (29) award, exploratory/developmental
grant (R21), and small grant (R03).  Research grants are awarded to
institutions on behalf of Principal Investigators who have designed
and will direct a specific project or set of projects.

Because the small grants and FIRST awards have special eligibility
requirements, application formats, and review criteria, applicants
are strongly encouraged to consult with the program staff (listed
under INQUIRIES) and to obtain the appropriate additional
guidelines/announcements for those grant mechanisms.


It is anticipated that approximately $4 million will be available to
support projects submitted under this RFA.  Because the nature and
scope of the research proposed in response to this RFA may vary, the
size of an award will vary also.  However, it is anticipated that
between 12 and 20 new awards will be made under this RFA.  About 70
percent of funds will be directed toward projects testing novel
medications for relapse prevention, and about 30 percent toward
projects testing effects of novel medications on reduction of drug


Recent findings in clinical and preclinical neurosciences reveal
complex biological determinants underlying psychostimulant
dependence.  These include psychopathological, neuroanatomical,
pathophysiological, neuroadaptive, neurochemical, and hormonal
factors, and may involve a variety of nutritional, environmental and
toxicological substrates as underlying causes of drug addictions.
Psychostimulant dependence is associated with various degrees of
neuropathology and significant comorbidity with other neurological
and psychiatric disorders, including attention and mood disorders,
hypodopaminergia, hyposerotonergia, and hypofrontalism, manifested in
perfusion and metabolic/bioenergetic deficits, among others.  The
bioenergetic deficits induced by psychostimulants may promote brain
aging and facilitate neurodegenerative disorders in chronic
psychostimulant abusers.

Rational pharmacological interventions in these
biological/pathological substrates could be effective in treating
psychostimulant dependence.  Moreover, recent reemergence, reported
therapeutic success and safety of non-traditional pharmacotherapies,
including medically designed nutrition, supplements, vitamins, amino
acids, hormones and other natural compounds, in treating variety of
chronic disorders suggest exploration of non-traditional treatments
as potential therapies for cocaine/psychostimulant dependence.  Such
natural therapies, designed to normalize brain functions may be more
acceptable to treatment-seeking addicts, who often refuse to be
treated with conventional medications, and be more beneficial than
traditional pharmacotherapies, which often produce undesirable side
effects. It is expected that such therapies may be safe enough to be
used for treatment of addicted children, adolescents or pregnant

The main objective of this RFA is to encourage clinical evaluation
of: (1) novel traditional medications with compounds and classes of
compounds previously not studied in clinical trials to treat
psychostimulant dependence, and; (2) non-traditional
pharmacotherapies, in relapse prevention designs in detoxified
cocaine/stimulant dependent participants, or reduction of drug use in
psychostimulant addicts.

The hypothesis and rationale for testing these novel medications
should address one or more of the following research/clinical

1.  the persistent neurochemical imbalance and/or
neuroadaptive/neuropathological changes that have been described in
cocaine/psychostimulant dependent individuals or in animals treated
chronically with stimulants;

2.  the pharmacological intervention in neurochemical and
psychological factors contributing to vulnerability to stimulant
dependence (e.g., attention deficit hyperactivity disorder,
post-traumatic stress disorder);

3.  the hormonal abnormalities in cocaine/stimulant dependent

4.  the biochemical mechanism relevant for behavioral outcomes for
cocaine dependence (e.g., drug craving);

5.  neurochemical factors involved in expression of euphorigenic and
dependence-producing effects of psychostimulants;

6.  neurochemical factors responsible for persistent anhedonia,
depression, and anxiety, associated with psychostimulant withdrawal
and accompanying abstinence in chronic psychostimulant abusers;

7.  the availability of open clinical trial data or promising
preclinical results;

8.  other scientific or clinical rationales.

Investigators are encouraged to study novel medications, yet untested
for treatment of psychostimulant dependence (including those not
approved in the U.S., but approved in European and Asian
pharmacopeias) as well as a variety of nutritional factors,
supplements, and naturally occurring substances, rationally selected
to compensate for biochemical and functional deficits reported in
stimulant addicts (e.g., apparent deficiency of biogenic amines, an
imbalance in endogenous opioid peptides and other neurotransmitters)
and to restore the brain homeostasis in psychostimulant dependent
individuals.  We are soliciting applications that test the hypothesis
that correcting for persistent or permanent neuropathologies that are
associated with psychostimulant dependence with novel
pharmacotherapies may be effective in treating this disorder.

Possible examples of such treatments include: precursors of biogenic
amines and other neurotransmitters, vitamins and supplements that
modify neurotransmitter metabolism and energy metabolism, and herbs
of known therapeutic profile.  Examples of potential therapeutic
herbs may include: Ginkgo Biloba, Kudzu, Ginseng, Gotu Cola, and
Kelp, among others.  Encouraged also are pharmacological and natural
interventions in hormonal systems (e.g.,
hypothalamo-pituitary-adrenal axis, hypothalamo-pituitary-gonadal
axis, thyroid system, endogenous opioid peptides) that have been
shown to play a role in drug dependence. Medications designed to
improve deficient brain circulation, energy and phospholipid
metabolism, and cognition, will be also considered along with
rational combinations of treatments.

Because no pharmacotherapy is expected to be optimally effective
without concurrent behavioral therapy, adjunct therapies may
concentrate on psychological, behavioral processes such as motivation
building, relapse prevention skills, coping skills, skills for
utilization of alternative reinforcers, as well as meditation, or

Drug dependence encompasses both physical and psychological
symptomatology; therefore, developing and testing integrative
approaches for treatment of psychostimulant dependence is encouraged
(i.e., treatments that stress pharmacotherapy, psychological support,
behavioral and nutritional adjustments, and social adaptations).  In
addition to testing potential treatments that affect primary
psychostimulant dependence, applications are encouraged to evaluate
novel treatments for disorders comorbid with drug dependence; these
include anxiety, depression, anhedonia, attention deficit and
cognitive impairments, antisocial behavior, post-traumatic stress
disorder, and other diagnoses that may contribute to continued
psychostimulant abuse and relapse.

The proposed studies should test the safety and efficacy of novel
therapeutic approaches in rigorously designed and executed clinical
trials to prevent relapse in persons detoxified from
cocaine/psychostimulant dependence or to reduce drug use in addicts.
Identified treatment modalities may be assessed in clinical
pharmacologic-therapeutic paradigms (laboratory clinical assessments)
and/or in phase I/II clinical trials that meet accepted standards for
Good Clinical Practice (GCP) guidelines established by FDA (21 CFR).
Because most psychostimulant abusers also co-abuse other substances
(alcohol, benzodiazepines, opiates), evaluation of the impact of
proposed new therapies on the use of the above drugs, in addition to
psychostimulants, will be also required.  Applications will be also
required to assess impact of the investigational agent on HIV risk
behaviors. Proposals must seek and obtain IRB review and approval
prior to submission or review of the application.


The exploratory, developmental (R21) and Small Grant (R03)
applications are limited to two years, are non-renewable, and are
limited in direct cost amount per year (R03, $50,000; R21, $90,000).
The R03 mechanism is intended for new, inexperienced investigators
and both are intended for established investigators exploring new
areas or departing from their usual research topics.  There are
special requirements for these mechanisms.  An applicant intending to
apply for them under this RFA should contact the named program person
in the INQUIRIES section for further information.


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 new policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990.  This new policy contains some new
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research", which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts of March 18, 1994, Volume
23, Number 11.

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

This RFA requires that proposed studies conduct gender comparisons of
clinical responses (side effects, efficacy, etc.) to the new
medications and strongly encourages examination of menstrual cycle
effects on the pharmacokinetics and pharmacodynamics of proposed new


Prospective applicants are asked to submit, by January 19, 1996, a
letter of intent that includes a descriptive title of the proposed
research, the proposed mechanism of support, the telephone number of
the Principal Investigator, the identities of other key personnel and
participating institution, and the number and title of this RFA.
Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains allows NIDA staff to estimate the potential review
workload and to avoid conflict of interest review.

The letter of intent is to be sent to:

Office of Extramural Program Review
National Institute on Drug Abuse
5600 Fishers Lane, Room 10-42
Rockville, MD  20857
Telephone:  (301) 443-2755
FAX:  (301) 443-0538


The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research and may be obtained from
the Office of Grant Information, Division of Research Grants,
National Institutes of Health, 6701 Rockledge Drive, Room 3032, MSC
7762, Bethesda, MD 20892-7762, telephone (301) 710-0267; email:

FIRST applications must include at least three sealed letters of
reference attached to the Face Page of the original application.
FIRST applications submitted without the required number of reference
letters will be considered incomplete and will be returned without

The RFA label in the form PHS 398 application kit must be affixed to
the bottom of the original face page.  Failure to use the RFA label
and to follow instructions 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 in
Item 2 of the face page and YES box marked.

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

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

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

Director, Office of Extramural Program Review
National Institute on Drug Abuse
5600 Fishers Lane, Room 10-42
Rockville, MD  20857


Upon receipt, applications will be reviewed for completeness by the
Division of Research Grants (DRG) and for responsiveness by NIDA.
Incomplete applications will be returned to the applicant without
further consideration.  If the application is not responsive to the
RFA, it will be returned without review.

Applications that are complete and responsive to the RFA will be
evaluated for scientific/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, a streamlined
review will be used by the initial review group in which application
will be determined to be competitive or noncompetitive based on their
scientific merit relative to other applications received in response
to this RFA.  Applications determined to be non-competitive will be
withdrawn from further consideration and the Principal Investigator
and the official signing for the application will be notified.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or principal investigator could be included
with the application.

Review Criteria

o  merit, scientific, technical or medical significance and
originality of proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area or proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research; and

o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.

o  adequacy of plans regarding assessment of effects of proposed new
medications on HIV risk behaviors.  Plans for recruitment and
retention of subjects will also be evaluated.

The initial review group will also examine the provisions for the
protection of human subjects and the safety of the research


Applications recommended for further consideration by an appropriate
Advisory Council will be considered for funding on the basis of
overall scientific and technical merit of the proposal as determined
by peer review, appropriateness of budget estimates, program needs
and balance, policy considerations, adequacy of provisions for the
protection of human subjects, and availability of funds.


Letter of Intent Receipt Date:  January 19, 1996
Application Receipt Date:       February 21, 1996
Initial Review Date:            April 1996
Advisory Council Date:          May 1996
Earliest Start Date:            July 1996


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

Direct inquiries regarding programmatic issues to:

Maria Dorota Majewska, Ph.D.
Medications Development Division
National Institute on Drug Abuse
5600 Fishers Lane, Room 11A-55
Rockville, MD  20857
Telephone:  (301) 443-3318
FAX:  (301) 443-2599
Email:  mm158w@nih.gov

Direct inquiries regarding fiscal and grants management issues to:

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
5600 Fishers lane, Room 8A-54
Rockville, MD  20857
Telephone:  (301) 443-6710
Email:  gfleming@aoada1.ssw.dhhs.gov


This program is described in the Catalogue of Federal Domestic
Assistance No. 93.279. Awards are made under authorization of the
Public health Service Act, Section 301, and administered under PHS
grants policies and federal regulations at Title 42 CFR 52 "Grants
for Research projects", Title 45 CFR Part 74 & 92 "Administration of
Grants"  and 45 CFR Part 46, "Protection of Human Subjects". Title 42
CFR part 2, "Confidentiality of Alcohol and Drug Abuse patient
records" may also be applicable to these awards. This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health System Agency review.

Sections of the Code of Federal regulation are available in booklet
form from the U.S. Government Printing Office.  Grants must be
administered in accordance with the PHS Grants Policy Statement
(revised 4/94), which may be available from your office of sponsored

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 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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