RELEASE DATE:  November 18, 2002

PA NUMBER:  PAS-03-029

EXPIRATION DATE:  This program announcement will expire on November 5, 
2005, unless re-issued.

National Institute on Alcohol Abuse and Alcoholism (NIAAA) 
National Institute on Drug Abuse (NIDA)

o Purpose of the PA 
o Research Objectives 
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions 
o Individuals Eligible to Become Principal Investigators 
o Where to Send Inquiries 
o Submitting an Application 
o Peer Review Process 
o Review Criteria 
o Award Criteria 
o Required Federal Citations 
o References 

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the 
National Institute on Drug Abuse (NIDA) are seeking research grant 
applications on pharmacological treatment for patients with alcohol use 
disorder (AUD) and a comorbid substance use disorder (SUD).  Substance 
use disorder may include the abuse/dependence of heroin, prescription 
narcotics, cocaine, methamphetamine and other stimulants, 
hallucinogens, sedative hypnotics, marijuana, and other substances of 
abuse.  Alcoholic abuse/dependent patients may have a co-occuring 
nicotine dependent, but must also meet the criteria for other types of 
SUD.  Research on the specific treatment needs of this population is in 
early stages, and thus well-designed studies are needed.  In 
particular, it is important to understand how the effects of treating 
one disorder affects the outcome for the other disorder.  The 
intervention strategy to treat one or both comorbid conditions might 
depend on the type of comorbidity as well as the subtype of comorbid 
AUD/SUD patient.  In addition, applications can include the utilization 
of human laboratory paradigms to screen potential medications for 
subsequent phase 2 and 3 trials as well as to determine the actions of 
the medications.  All applications submitted in response to this 
program announcement should be conducted in humans.  This program 
announcement has set aside funds for FY 2003.



Alcohol abuse and dependence commonly occurs in subjects who suffer 
from SUD.  For example, as many as 90 percent of cocaine addicts have a 
problem with alcohol in both treatment and community settings 
(Gorelick, 1992).  Patients suffering from both disorders often have 
poorer treatment outcome and are more likely to drop out of treatment. 
Unfortunately, effective treatments have yet to be established for the 
various conditions of comorbid alcohol and drug addiction. In addition 
to developing effective treatment strategies for each substance of 
abuse, one may need to take into account the physiological and 
psychological alternations that can occur from a drug-alcohol 
interaction.  For example, ingestion of alcohol and cocaine can produce 
a new metabolite, cocaethylene, which can increase craving as well as 
increased heart rate (McCance et al., 1995).

Some progress has been made in treating patients with a concurrent 
alcohol and cocaine dependence.  Carroll et al. (1998) reported that 
disulfiram combined with outpatient psychotherapy enhanced treatment 
retention and increased the duration of abstinence from both alcohol 
and cocaine use.  In a preliminary report, Higgins et al. (1993) also 
found that supervised disulfiram reduced both alcohol and cocaine 
intake in patients dually diagnosed with cocaine dependence and alcohol 
abuse/dependence. Interestingly, naltrexone at doses of 50 mg/day has 
been reported ineffective in treating comorbid alcohol and cocaine use 
disorders (Hersh et al., 1998). Nevertheless, in a preliminary report 
by Oslin et al. (1999), alcohol and cocaine dependent patients treated 
with higher doses of naltrexone (150 mg/day) reduced both their 
frequency and amount of alcohol and cocaine intake.  Studies are 
underway to test the efficacy of 150 mg of naltrexone daily and also to 
evaluate the effectiveness of the combination of naltrexone and 
disulfiram in this population.

Little research has been conducted on alcoholics with a comorbid opioid 
addiction.  In an early study, Liebson et al. (1973) reported that 
disulfiram given to alcoholic methadone patients reduced their alcohol 
intake.  However, new studies are needed to test newer medications such 
as buprenorphine for opioid dependence and naltrexone and acamprosate 
for alcoholism.   
In summary, research to evaluate effective combined pharmacological and 
behavioral treatments for patients diagnosed with AUD and SUD is in 
very early stages. The purpose of this program announcement is to 
stimulate state-of-the-art research to evaluate promising 
pharmacological treatments across a wide population of comorbid AUD and 
SUD subjects.  

Specific Areas of Interest

A wide variety of research opportunities exist for advancing the 
treatment of this understudied population.  Research topics include, 
but are not limited to:   

o Evaluate the efficacy of established and novel pharmacological agents 
for AUD patients with a comorbid SUD.  These patients may also have a 
collateral psychiatric disorder.  Appropriate combination and 
sequencing of pharmacological and behavioral therapies need to be 
explored for patients suffering from two or more concurrent disorders.  
In addition, optimal dosage and duration of treatment needs to be 
established for each medication.

o  Determine the optimal integration of pharmacological agents with 
behavioral therapies. 

o  Determine if outcome of pharmacological treatment of AUD patients 
suffering from comorbidity is different than that of non-comorbid 
patients.  Is there a gender difference? 

o Establish if the treatment of AUD or SUD improves or affects the 
outcome for the other disorder. 

o Determine if treatment for AUD and SUD should be conducted 
simultaneously or sequentially. 

o Determine if the chronology of onset of the comorbid condition (e.g., 
primary versus secondary AUD) can influence treatment outcome and alter 
treatment strategy.

o Evaluate pharmacological treatments for comorbidity in special 
populations including minorities, the elderly, adolescents, and those 
in the criminal justice system. 

o Develop techniques to enhance treatment compliance.  Compliance 
strategies may vary with the comorbid condition.

o Identify factors influencing clinical efficacy of medications using 
human laboratory behavioral pharmacology paradigms. Prior to beginning 
phase 2 clinical trials potential medications can be screened in the 
laboratory to determine the following: 1) the medication's impact to 
reduce craving and/or to diminish the negative symptoms of addiction; 
2) likelihood of adverse events, especially in the presence of alcohol; 
3) pharmacokinetics for medication combinations; and 4) optimal dosing 
regimens. Studies are sought which develop and expand use of these 
human laboratory paradigms. 

o Identify possible interactions of medications to treat AUD and SUD as 
well as interactions with alcohol .  Pharmacokinetic studies might also 
be appropriate.  For example, Ciraulo et al. (1982) demonstrated that 
at a given dose of imipramine, patients who were both alcoholic and 
depressed attained lower blood levels of the medication than 
nonalcoholic depressed subjects.


This PA will use the NIH research project grant (R01) small grant (R03) 
and Exploratory/developmental grant (R21) award mechanism.  As an 
applicant, you will be solely responsible for planning, directing, and 
executing the proposed project. The total project period for a research 
project grant (R01) application submitted in response to this Program 
Announcement may not exceed 5 years.

Under the Small Grant mechanism (R03) applicants may request either 
$25,000 or $50,000 in direct costs per year for up to two years. These 
awards are not renewable; however, a no-cost extension of up to one 
year may be granted to the grantee institution prior to expiration of 
the project period.  The R03 mechanism is intended for newer, less 
experienced investigators, for investigators at institutions without 
well-developed research traditions and resources, or for experienced 
investigators wishing to change research directions or test new methods 
or techniques.  Before completion of the R03, investigators are 
encouraged to seek continuing support for research through a research 
project grant (R01).  The NIAAA Small Grant Program is described in 
detail in PA-99-098
and the NIDA Small Grant Program is described in detail in PA-02-170, at 

Under the Exploratory/developmental Grant mechanism (R21) applicants 
may request up to $100,000/year in direct costs for up to 3 years.  The 
Exploratory/development Grant program is intended to encourage 
exploratory research projects with sound methodology and strong 
rationales in underdeveloped research areas.  The NIAAA 
Exploratory/developmental Grant Program is described in detail in PA- 
99-131 (, 
and the NIDA Exploratory/developmental Grant Program is described in 
detail in PA-02-171

This PA uses just-in-time concepts.  It also uses the modular as well 
as the non-modular budgeting formats
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  Otherwise 
follow the instructions for non-modular research grant applications.


The NIAAA intends to commit approximately $2,000,000 in FY 2003 to fund 
6 to 10 new and/or competitive continuation grants in response to this 
PA. 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 NIAAA provide support for this program, awards 
pursuant to this PA are contingent upon the availability of funds and 
the receipt of a sufficient number of meritorious applications. 


You may submit (an) application(s) if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign
o Faith-based or community-based organizations


Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.


We encourage your inquiries concerning this PA and welcome the 
opportunity answer questions from potential applicants.  Inquiries may 
fall into two areas:  scientific/research and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

Charlene E. LeFauve, Ph.D.
Division of Clinical and Prevention Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulvard, Suite 505 MSC 7003
Bethesda, MD 20892-7003
For express mail use:
Rockville, MD 20852)
Telephone: (301) 402-9401
Fax: (301) 443-8774

Ivan D. Montoya, M.D., M.P.H. 
Medications Research Grants Branch 
Division of Treatment Research and Development
National Institute on Drug Abuse 
6001 Executive Blvd. 
Bethesda, MD 20892-9551 
Phone: (301) 443-8639 
Fax: (301) 443-2599 

o Direct your questions about financial or grants management matters 

Judy Fox
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulvard, Suite 505 MSC 7003
Bethesda, MD 20892-7003
(For express mail use:
Rockville,MD 20852)
Telephone: (301) 443-2434

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


Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email:

APPLICATION RECEIPT DATES: Applications submitted in response to this 
program announcement will be accepted at the standard application 
deadlines, which are available at  Application deadlines are also 
indicated in the PHS 398 application kit.

requesting up to $250,000 per year in direct costs must be submitted in 
a modular grant format.  The modular grant format simplifies the 
preparation of the budget in these applications by limiting the level 
of budgetary detail.  Applicants request direct costs in $25,000 
modules.  Section C of the research grant application instructions for 
the PHS 398 (rev. 5/2001) at includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at

YEAR: Applications requesting $500,000 or more in direct costs for any 
year must include a cover letter identifying the NIAAA staff member who 
has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following 

1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
3) Identify, in a cover letter sent with the application, the staff 
member and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended 
or revised version of these grant application types. Additional 
information on this policy is available in the NIH Guide for Grants and 
Contracts, October 19, 2001 at 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the checklist, and five signed 
photocopies in one package 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)

APPLICATION PROCESSING: Applications must be received by or mailed 
before the receipt dates described at The CSR 
will not accept any application in response to this PA 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 a substantial revision of an 
application already reviewed, but such application must include an 
Introduction addressing the previous critique.


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review 
group convened in accordance with the standard NIH peer review 
procedures ( will evaluate 
applications for scientific and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed 
to have the highest scientific merit, generally the top half of 
applications under review, will be discussed and assigned a priority 
o Receive a second level review by the appropriate national advisory 
council or board


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 your application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these 
criteria in assigning your application's overall score, weighting them 
as appropriate for each application.  Your 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, 
you 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 your study address an important problem? If the 
aims of your application are achieved, how do they advance scientific 
knowledge?  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?  Do you acknowledge potential problem areas and 
consider alternative tactics?

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

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

(5) ENVIRONMENT:  Does the scientific environment in which your 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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  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.

INCLUSION:  The adequacy of plans to include subjects from both 
genders, all racial and ethnic groups (and subgroups), and children as 
appropriate for the scientific goals of the research.  Plans for the 
recruitment and retention of subjects will also be evaluated. (See 
Inclusion Criteria included in the section on Federal Citations, below)

BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.


Applications submitted in response to a PA will compete for available 
funds with all other recommended applications.  The following will be 
considered in making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities


components involving Phase I and II clinical trials must include 
provisions for assessment of patient eligibility and status, rigorous 
data management, quality assurance, and auditing procedures.  In 
addition, it is NIH policy that all clinical trials require data and 
safety monitoring, with the method and degree of monitoring being 
commensurate with the risks (NIH Policy for Data Safety and Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998:  

of the NIH that women and members of minority groups and their sub-
populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is 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 clinical research should read the AMENDMENT 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(; a 
complete copy of the updated Guidelines are available at
The amended policy incorporates: the use of an NIH 
definition of clinical research; updated racial and ethnic categories 
in compliance with the new OMB standards; clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new 
PHS Form 398; and updated roles and responsibilities of NIH staff and 
the extramural community.  The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or 
proposals and/or protocols must 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) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 

SUBJECTS:  The NIH maintains a policy 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, 

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 is available at 

NIH policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  You will find this policy 
announcement in the NIH Guide for Grants and Contracts Announcement, 
dated June 5, 2000, at

The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

proposals for NIH funding must be self-contained within specified page 
limitations. Unless otherwise specified in a 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.   Furthermore, we caution reviewers that their 
anonymity may be compromised when they directly access an Internet 

HEALTHY PEOPLE 2010: 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 PA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.273 (NIAAA) and 93.279 (NIDA), and 
is not subject to the intergovernmental review requirements of 
Executive Order 12372 or Health Systems Agency review.  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 described at  and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the 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. 


Carroll, K.M., Nich, C., Ball, S.A., McCance, E., and Rounsavile, B.J. 
(1998).  Treatment of cocaine and alcohol dependence with psychotherapy 
and disulfiram.  Addiction 93(5):713-728.

Ciraulo, D.A., Alderson, L.M., Chapron, D.J., Jaffe, J.H., Subbarao, 
B., and Kramer, P.A. (1982).  Imipramine disposition of alcoholics.  
Journal of Clinical Psychopharmacology 2:2-7.

Gorelick, D.A. (1992).  Alcohol and cocaine: Clinical and 
pharmacological interactions.  Recent Developments in Alcoholism 11:37-

Hersh, D., Van Kirk, J.R., and Kranzler, H.R. (1998). Naltrexone 
treatment of comorbid alcohol and cocaine use disorders.  
Psychopharmacology 139: 44-52.

Higgins, S.T., Budney, A.J., Bickel, W.K., Hughes, J.R., and Foerg, F. 
(1993).  Disulfiram therapy in patients abusing cocaine and alcohol.  
American Journal of Psychiatry 150(4):675-676.

Liebson, I., Bigelow, G., and Flamer, R. (1973).  Alcoholism among 
methadone patients: A specific treatment method.  American Journal of 
Psychiatry 130(4):483-485.

McCance, E.F., Price, L.H., Kosten, T.R., and Jatlow, P.I. (1995).  
Cocaethylene: Pharmacology, physiology and behavioral effects in 
humans.  The Journal of Pharmacology and Experimental Therapeutics 

Oslin, D.W., Pettinati, H.M., Volpicelli, J.R., Wolf, A.L., Kampman, 
K.M., and O'Brien, C.P. (1999).  The effects of naltrexone on alcohol 
and cocaine use in dually addicted patients.  Journal of Substance 
Abuse Treatment 16(2):163-167.

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