Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (

Components of Participating Organizations
National Institute on Drug Abuse (NIDA), (
National Institute on Alcoholism and Alcohol Abuse (NIAAA), (

Title: Complementary and Alternative Medicine for Substance and Alcohol Related Disorders (R21)

Announcement Type
This is a reissue of PA-05-097 which was previously released April 26, 2005.

Update: The following update relating to this announcement has been issued:

NOTICE: Applications submitted in response to this FOA for Federal assistance must be submitted electronically through ( using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide.


This FOA must be read in conjunction with the application guidelines included with this announcement in for Grants (hereafter called

A registration process is necessary before submission and applicants are highly encouraged to start the process at least 4 weeks prior to the grant submission date. See Section IV.

Program Announcement (PA) Number: PA-06-425

Catalog of Federal Domestic Assistance Number(s)
93.279, 93.273

Key Dates
Release/Posted Date: May 19, 2006
Opening Date: May 19, 2006 (Earliest date an application may be submitted to
Letters of Intent Receipt Date(s): Not applicable.
NOTE: On time submission requires that applications be successfully submitted to no later than 5:00 p.m. local time (of the applicant institution/organization).
Application Submission Date(s): Standard receipt dates apply. Please see: for details.
AIDS Application Receipt Date(s): Standard AIDS application receipt dates apply. Please see: for details.
Peer Review Date(s): Standard review dates apply. Please see: for details.
Council Review Date(s): Standard Council review dates apply. Please see: for details.
Earliest Anticipated Start Date(s): Standard dates apply. Please see: for details.
Additional Information To Be Available Date (Url Activation Date): Add Information Here
Expiration Date: May 2, 2008 (now May 8, 2008 per NOT-OD-07-093)

Due Dates for E.O. 12372
Not applicable.

Additional Overview Content

Executive Summary

NIDA and NIAAA invite clinical research grant applications to the PA entitled Complementary and Alternative Medicine for Substance- and Alcohol-Related Disorders . An important goal of this program is to identify, evaluate and develop safe and effective Complementary and Alternative Medicine therapies for the treatment of substance use disorders (SUD) and alcohol use disorders (AUD), including abuse or dependence on licit (alcohol and tobacco) and illicit drugs, and for the treatment of neurological, psychiatric and medical consequences of drug and alcohol addiction.

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Submission, Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

Clinical studies are needed to critically evaluate the therapeutic effects of different CAM therapies in treating various aspects of SUD and AUD, alone or in combination with conventional treatments. In cases where issues of safety arise, the clinical study protocol may be accompanied by an adjunct preclinical study protocol examining safety of the proposed therapy in an animal model. Studies involving subjects from various ethnic populations, ages, and genders are encouraged, although not necessarily in a single study, depending upon the research questions. Identification, evaluation and development of safe and effective CAM therapies for the treatment of children, adolescents and pregnant women with SUD and AUD are especially encouraged. For these vulnerable populations safety is a major concern, hence the treatments proposed should have proven safety for developing organisms.


The National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) are seeking high quality clinical research grant applications focusing on the identification, evaluation and development of safe and effective Complementary and Alternative Medical (CAM) therapies for the treatment of substance use disorder (SUD) and alcohol use disorder (AUD), as defined by DSM-IV, including abuse or dependence on all licit (alcohol and tobacco) and illicit drugs/medications. Studies may also focus on treatments of neurological, psychiatric or medical consequences of drug abuse, e.g., acute and chronic drug and alcohol toxicities, psychoses, mood disorders, neurological and cognitive impairments, and brain atrophy.

There is a growing popularity in the United States of CAM for the treatment of various disorders and diseases. The recent report prepared by the U.S. Department of Health and Human Services, Centers for Disease Control and Prevention (CDC) National Center for Health Statistics (NCHS), based on data from 2002 National Health Interview Survey (NHIS) obtained from interviews of 31,044 adult U.S. residents, shows that 62% of them used some kind of CAM during the past 12 months, while 75% have ever used CAM, ( CAM interventions appear also popular among drug addicts. A recently published survey of 548 persons with a history of intravenous drug use recruited from a methadone maintenance clinic revealed that 45% of them reported use of at least one type of CAM therapy, usually supplemental to conventional treatments, ( However, the effects of many CAM therapies in treating SUD and AUD have not been systematically examined, and the effectiveness of most CAM treatments in aiding recovery from drug and alcohol addictions is unknown. Such therapies need to be studied. For the purpose of this PA, CAM therapies are defined as those therapies that are outside of the realm of conventional medicine and consist of a broad spectrum of therapeutic modalities (their classification and examples are given further in the text). According to the National Center for Complementary and Alternative Medicine (NCCAM) of NIH, conventional medicine is medicine as practiced by holders of M.D. (medical doctor) or D.O. (doctor of osteopathy) degrees and by their allied health professionals, such as physical therapists, psychologists, and registered nurses. Other terms for conventional medicine include allopathy, Western, mainstream, orthodox, and regular medicine, and biomedicine. Other terms for CAM include but are not limited to: unconventional, non-conventional, folkloric, nutritional, herbal, naturopathic, homeopathic, and non-Western medicine or health care. Some conventional medical practitioners are also practitioners of CAM.

Background and Rationale

Substance abuse continues to be a grave threat to public health in the United States. According to the National Survey on Drug Use and Health (NSDUH) conducted by SAMHSA, based on interviews of approximately 67,500 persons, in 2002 an estimated 19.5 million Americans, or 8.3% of the population age 12 and older were current users of illicit drugs. Among 12- to 17-year-olds, current use of illicit drugs was 11.6%, and among pregnant women it was 3.3%. In addition, 6.2 million persons, or 2.6% of the population aged 12 or older, were current users of psychotropic medications taken nonmedically. A publication of the Executive Office of the President, Office of National Drug Control Policy (2001), reports that in 1998 the estimated total cost to the society due to illicit drug use was $143.4 billion. This cost has been increasing 5.9% annually between 1992 and 1998, giving an extrapolated value for 2004 (if similar trends continues) about $200 billion. (

These numbers stress the urgency and importance of identifying, evaluating and developing effective therapies for treating substance dependence and abuse.

Acute or chronic abuse of drugs and alcohol can cause serious health and social problems. It may lead to life threatening health consequences, various neuropathologies, psychiatric disorders and addictions or dependencies that might require immediate medical interventions, specialized treatments employing pharmacotherapies, behavioral therapies, or combinations thereof. Clinical and preclinical research has documented drug-and alcohol-induced alterations of brain chemistry and function in chronic drug and alcohol abusers, which are believed to contribute to persistent drug and alcohol dependencies. Drug and alcohol abuse by children and adolescents may lead to serious developmental consequences and is associated with various medical problems, poor school performance and antisocial behaviors. Acute and chronic use of inhalants and stimulants seems to have particularly devastating effects on the brain. Substance and alcohol abuse or dependence is often comorbid with other psychiatric disorders, which may precede drug and alcohol abuse or follow as a consequence of it, and may contribute to poor treatment outcomes. Whereas many SUD and AUD can be effectively treated with pharmacotherapies, behavioral treatments, or combinations thereof, there is an ongoing need for treatments with long-term efficacy in maintaining abstinence and preventing relapse to drug and alcohol abuse.

The National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health, classifies CAM therapies into 5 major categories: 1) Alternative Medical Systems e.g. homeopathic and naturopathic medicine, non-western medicine systems such as Ayurveda or traditional Chinese medicine (acupuncture, acupressure); 2) Mind-Body interventions such as meditation, yoga, spiritual and mental healing, art, music, dance therapy; 3) Biologically Based Therapies such as use of herbs, special macronutrient diets, megadoses of vitamins, minerals and other dietary supplements; 4) Manipulative and Body-Based Therapies such as chiropractic or osteopathic manipulations, therapeutic massage, balneotherapy, hyperbaric pressure therapy; and 5) Energy Therapies which utilize energy fields including unconventional use of electromagnetic fields, e.g. pulsed electromagnetic fields, alternating current or direct current fields [transcranial magnetic stimulation (TMS), transcranial direct current stimulation (TDCS)], or use biofield manipulations, such as qi gong, Reiki, and therapeutic touch, ( Research in all 5 NCAAM categories of therapies is encouraged, as it relates to the potential treatment of SUD and AUD.

Some CAM therapies have been evaluated in clinical studies for their potential in the treatment of SUD and AUD. Regarding alternative medical systems, acupuncture has received the greatest empirical attention as a potential treatment for substance and alcohol abuse and dependence, yielding equivocal results. In several clinical trials, acupuncture has been found to produce better cocaine abstinence rates (Avants et al, 2000), to reduce craving for cocaine (Avants et al, 1995), to improve mood, sleep, and appetite among substance abusers (Gurevich et al, 1996). However, other clinical trials have found no significant differences between active acupuncture conditions and comparison conditions in reducing cocaine use (Margolin et al, 2002), reducing use of or craving for crack-cocaine (Lipton et al, 1994), or reducing drug use in a prison population (Berman et al, 2004) and a population with chronic arrest histories (Russell et al, 2000). Studies that help to refine the treatment approach (e.g., duration and frequency of needle insertion, type of needle insertion, evaluation of different systems of acupuncture, etc.), the comparison condition (e.g., invasive versus non-invasive, more tightly-controlled delivery and assessment of concurrently offered psychotherapy, etc.) may help to clarify these mixed results. Applications seeking to develop, adapt, or test acupuncture or other non-biologically-based therapies for SUD or AUD based on alternative medical systems, please refer to the Behavioral Therapies Development Program Announcement (PA-03-126, for a detailed description of NIDA's conceptualization of therapy development research.

Another category of NCCAM's complementary and alternative approaches is mind-body interventions, that is those interventions designed to enhance the mind's capacity to affect bodily function and symptoms (NCCAM website, Most often, the mind-body interventions are used to complement other treatments for substance abuse, rather than to serve as an alternative to treatment. While meditation, relaxation, and mindfulness-based approaches are included in NCCAM's framework as mind-body approaches, these approaches have been well integrated into current behavioral treatment research for substance abuse. Applicants wishing to develop, adapt, or test behavioral treatments emphasizing meditation or mindfulness are encouraged to respond to the Behavioral Therapies Development Program Announcement (PA-03-126).

Other types of behavioral therapies, while not typically integrated into current behavioral treatment research, are utilized fairly widely in community settings. These include faith-based interventions such as prison ministries and community outreach, exercise therapies, and therapies incorporating dance, art, and music. Research activities in which existing interventions are described in reproducible manuals, and these manualized interventions are pilot-tested for efficacy, (i.e., reverse-engineering ) may be most appropriate for these approaches. Studies testing these therapies, and other types of therapies which could be viewed as mind-body interventions, are also encouraged under PA-03-126.

Studies proposing to develop, adapt, or test mind-body interventions for SUD and AUD populations are encouraged to follow a three-stage model of therapy development. In Stage I therapy development research, activities include creating a well-specified treatment manual, designing psychometrically-sound measures of treatment fidelity and competence, and conducting a small pilot test of the treatment. In Stage 2 research, activities include larger-scale tests of the treatment through randomized designs, or other scientifically-appropriate research designs. In Stage 3 research, activities include preparing the treatment for dissemination to community settings, including developing and testing methods of training therapists and approaches to clinical supervision in the treatment. At all stages of therapy research, activities related to clarifying the mechanisms of action (i.e., how and why a therapy works) are relevant, and research is especially encouraged that clarifies the treatment of special populations such as racial and ethnic minorities, the elderly, pregnant women, adolescents, drug-abusers with co-morbid psychiatric conditions, etc. (For a more detailed description of a guiding framework to approaching behavioral therapy research, please refer to the Behavioral Therapies Development Program Announcement, PA-03-126,

Regarding biologically based therapies: a preliminary small placebo-controlled trial demonstrated that supplemental magnesium may reduce illicit opiate use in methadone-maintained cocaine abusing patients and decrease cocaine craving (Margolin et al., J. Addict. Dis. 22:49-61, 2003). Because magnesium ion is an endogenous blocker of the NMDA receptor complex, which is implicated in stimulant and opiate dependence, further testing of this supplement is needed in controlled studies for treating opiate and stimulant dependence. In small controlled clinical studies melatonin was shown to attenuate symptoms of nicotine and benzodiazepine withdrawal, and animal studies suggest that it reverses opiate tolerance. Controlled studies evaluating effectiveness of melatonin in the treatment of nicotine, opiate and sedative dependence are needed. Preclinical studies also suggest that melatonin and L-carnitine may be protective against methamphetamine-induced neuronal toxicities. Clinical studies, using psychological and brain imaging evaluation are needed to confirm, or not, such effects in methamphetamine addicts. Some clinical studies documented that extracts of Valeriana have anxiolytic and sedative effects with fewer motor-impairing effects than benzodiazepines. Studies are needed to evaluate Valeriana's utility in the treatment of benzodiazepine/sedative abuse/dependence. Because extracts of Valeriana have GABA-ergic properties and medications from this class have shown efficacy in the treatment of cocaine dependence, it is possible that Valeriana might be effective as well. Likewise, a GABA-ergic aminoacid, taurine, might be effective in the treatment of benzodiazepine and stimulant dependence. Clinical and preclinical studies suggest that fat-enriched diets may reverse hepatotoxic and neurotoxic effects of inhalant solvents. Such diets or specific fatty supplements (e.g. fatty acids, phoshatidylcholine) may have utility in reversing toxic effects of solvents and in the treatment of solvent addicted children and adolescents.

Kudzu ( Pueraria lobata) is a medicinal plant used in traditional Chinese medicine to treat alcoholism. Kudzu extracts have been shown to decrease alcohol intake in several animal models (Keung and Vallee, Proc Natl Acad Sci 90:1008-10012, 1993; Overstreet et al., Alcohol Clin Exp Res 20:221-227, 996). Several active components of kudzu, including puerarin, daidzin and daidzein, have also reduced drinking in animals. Silymarin, the active constituent of Milk Thistle, is an herbal remedy that has shown efficacy in treating alcoholic liver disease (Saller, Drugs 61:2035-2063, 2001). This Program Announcement invites studies of these and other biologically-based therapies for their potential use in treating AUD.

Regarding energy therapies: a small double-blind crossover trial showed that high frequency repeated TMS of left dorsolateral prefrontal cortex significantly reduced cigarette smoking (Eichhammer et al., J. Clin Psychiatry, 64:8, 2003). TMS is a non-invasive neurotechnique, which offers a unique tool to selectively and regionally alter brain cortical activity. It has been reported to reduce symptoms of depression, post traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), epilepsy, migraine, Parkinson's disease, hallucination in schizophrenic patients, and to alter cognition. Repetitive TMS may alleviate drug craving by transient deactivation of certain brain regions or may stimulate hypoactive brain regions in addicts, thus promoting better control of drug-use compulsions and other behaviors. It may improve mood and enhance cognition, thus facilitating abstinence from drugs of abuse and increasing effectiveness of cognitive therapies. Preclinical studies showed that TMS induced neuronal sprouting and produced lasting plastic changes in the brain, which may aid recovery from drug dependence by promoting neuroregenerative processes and by restoring brain homeostasis. Studies are needed to evaluate effects of TMS on different psychological, physiological, neurobiological and behavioral aspects of drug abuse.

Another neurotechnique that may be utilized to bidirectionally, regionally change brain activity is TDCS, which involves transcranial application of a weak current. It has been used in neurology and psychiatry to control pain and seizures, and to alter perception or cognition. Like TMS, it may have utility in the treatment of drug use disorders by reducing drug craving, improving cognitive therapy and promoting brain plasticity, necessary for restoration of CNS homeostasis in recovering drug addicts.

Also unilateral visual field stimulation using goggles that allow vision only through one eye was shown to alter mood and anxiety in psychiatric patients, which suggests its potential utility in treating drug abuse/dependence. Kundalini yoga is another technique, which allows for lateral hemispheric control of brain activity through one nostral breathing. Applicants interested in manipulative and body-based therapies, energy therapies, and the development of treatments based upon neuroscience are also referred to PA-03-126.

The therapeutic effects of many other CAM therapies in the treatment of SUD have not been scientifically examined. Such research is needed and timely in view of the apparent popularity of CAM therapies among some drug abusing populations.

Given the high prevalence of psychiatric comorbidities such as depression, attention deficit hyperactivity disorder (ADHD), PTSD, OCD and conduct disorders with SUD and AUD, and the potential for common origins or pathways of SUD and AUD and these comorbidities, it seems reasonable to predict that CAM therapies intended for the treatment of psychiatric and neurological disorders might be beneficial in the treatment of SUD and AUD. In the case of biologically-based therapies, for example, several controlled studies showed that omega-3 fatty acids and Hypericum can be are beneficial in the treatment of depression; melatonin and Valerian for anxiety and insomnia; Ginkgo biloba, phosphatidylserine and L-carnitine for memory impairments; mega doses of vitamin E for slowing down the progression of Alzheimer's dementia. Mind-body therapies such as biofeedback or meditation are effective for treating anxiety and for stress management. Novel neurotechnologies such as TMS have shown beneficial effects in the treatment of depression, and a potential in the treatment of OCD, PTSD, epilepsy, Parkinson's disease, memory impairments, and hallucinations. Some of these disorders, such as depression, OCD, PTSD, cognitive deficits, are comorbid with drug dependence, hypodopaminergia is common for Parkinson's disease and stimulant dependence, and hallucinations are common for schizophrenia and for intoxications with certain drugs. By alleviating these neuropsychiatric disorders/symptoms, such neurotechnologies may also aid drug abuse therapies.

Research topics of interest include, but are not limited to:

Combinations of different CAM therapies with each other, or with conventional treatments for SUD and AUD that are expected to enhance their efficacy, may also be tested. Such combinations may target simultaneously several biological and clinical aspects of SUD and AUD. Because treatment of SUD and AUD usually requires a multidisciplinary approach, it is expected that proposals, which assess effects of biologically based CAM therapies will use - when appropriate - some behavioral intervention platform (i.e., psychotherapy).

Certain CAM therapies may require INDs and FDA approval. With biologicals and natural products quality certificates will be required. For information and guidance on NIH policy on the quality of natural products, please refer to NCCAM instructions. ( For guidance on designing clinical trials of NCCAM therapies determining dose ranges, please refer to the NCAM site. (

For studies developing, adapting, reverse-engineering, and/or testing behavioral therapies and other non-biologically-based therapies for the treatment of SUD and AUD drawing from CAM therapies traditions such as mindfulness, meditation, martial arts, tai chi, yoga, dance and others, or using virtual reality as a way to help improve the efficacy of a therapy, applicants should refer to the Behavioral Therapies Development Program Announcement, which can be found at:

Because clinical and preclinical studies have documented that males and females respond differently to drugs of abuse, alcohol, and to various pharmacological and behavioral treatments, the investigators are encouraged to evaluate, if feasible, sex/gender differences in response to their selected CAM therapies.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism of Support

This FOA will use the NIH Exploratory/Developmental Research Grant (R21) award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses just-in-time concepts. It also uses the modular budget formats (see the Modular Applications and Awards section of the NIH Grants Policy Statement. Specifically, if you are submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs), use the PHS398 Modular Budget component provided in the SF424 (R&R) Application Package and SF424 (R&R) Application Guide (see specifically Section 5.4, Modular Budget Component, of the Application Guide).

Exploratory/developmental grant support is for new projects only; competing renewal (formerly competing continuation ) applications will not be accepted. Up to two resubmissions (formerly revisions/amendments") of a previously reviewed exploratory/developmental grant application may be submitted. See NOT-OD-03-041, which was published in the NIH Guide on May 7, 2003.

2. Funds Available

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIH Institutes and Centers (ICs) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

The total project period for an application submitted in response to this funding opportunity may not exceed 2 years. Although the size of award may vary with the scope of research proposed, it is expected that applications will stay within the budgetary guidelines for an exploratory/developmental project; direct costs are limited to $275,000 over an R21 2-year period, with no more than $200,000 in direct costs allowed in any single year. Applicants may request direct costs in $25,000 modules, up to the total direct costs limitation of $275,000 for the combined 2-year award period. NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this Program Announcement funding opportunity.

Facilities and Administrative (F&A) costs requested by consortium participants are not included in the direct cost limitation. See NOT-OD-05-004, which was published in the NIH Guide.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

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

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the Project Director/Principal Investigator (PD/PI) is invited to work with his/her organization 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 support.

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement.

3. Other-Special Eligibility Criteria

Applicants may submit more than one application, provided each application is scientifically distinct.

Section IV. Application and Submission Information

Registration and Instructions for Submission via

To download a SF424 (R&R) Application Package and SF424 (R&R) SBIR/STTR Application Guide for completing the SF424 (R&R) forms for this FOA, link to and follow the directions provided on that web site.

A one-time registration is required for institutions/organizations at both:

PDs/PIs should work with their institutions/organizations to make sure they are registered in the eRA Commons.

Several additional separate actions are required before an applicant institution/organization can submit an electronic application, as follows:

1) Organizational/Institutional Registration in Started

2) Organizational/Institutional Registration in the eRA Commons

3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.

Note that if a PD/PI is also an NIH peer-reviewer with an Individual DUNS and CCR registration, that particular DUNS number and CCR registration are for the individual reviewer only. These are different than any DUNS number and CCR registration used by an applicant organization. Individual DUNS and CCR registration should be used only for the purposes of personal reimbursement and should not be used on any grant applications submitted to the Federal Government.

Several of the steps of the registration process could take 4 weeks or more. Therefore, applicants should immediately check with their business official to determine whether their institution is already registered in both and the Commons. The NIH will accept electronic applications only from organizations that have completed all necessary registrations.

1. Request Application Information

Applicants must download the SF424 (R&R) application forms and SF424 (R&R) Application Guide for this FOA through

Note: Only the forms package directly attached to a specific FOA can be used. You will not be able to use any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA), although some of the "Attachment" files may be useable for more than one FOA.

For further assistance, contact GrantsInfo; Telephone: 301-710-0267, E-mail:

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Prepare all applications using the SF424 (R&R) application forms and in accordance with the SF424 (R&R) Application Guide (MS Word or PDF).

The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. There are fields within the SF424 (R&R) application components that, although not marked as mandatory, are required by NIH (e.g., the Credential log-in field of the Research & Related Senior/Key Person Profile component must contain the PD/PI’s assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see Tips and Tools for Navigating Electronic Submission on the front page of Electronic Submission of Grant Applications.

The SF424 (R&R) application is comprised of data arranged in separate components. Some components are required, others are optional. The forms package associated with this FOA in will include all applicable components, required and optional. A completed application in response to this FOA will include the following components:

Required Components:
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information

Research & Related Senior/Key Person
Research & Related Budget
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist
PHS398 Modular Budget

Optional Components:
PHS398 Cover Letter File
Research & Related Subaward Budget Attachment(s) Form

Note: While both budget components are included in the SF424 (R&R) forms package, the NIH R21 uses ONLY the PHS 398 Modular Budget. (Do not use the detailed Research & Related Budget.)

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.

3. Submission Dates and Times

See Section IV.3.A for details.

3.A. Submission, Review and Anticipated Start Dates
Opening Date: May 19, 2006 (Earliest date an application may be submitted to
Letters of Intent Receipt Date(s): Not applicable.
Application Submission Date(s):
Peer Review Date:
Council Review Date:
Earliest Anticipated Start Date:

3.A.1. Letter of Intent

A letter of intent is not required for the funding opportunity.

3.B. Sending an Application to the NIH

To submit an application in response to this FOA, applicants should access this FOA via and follow steps 1-4. Note: Applications must only be submitted electronically

3.C. Application Processing

Applications may be submitted on or after the opening date and must be successfully received by no later than 5:00 p.m. local time (of the applicant institution/organization) on the application submission/receipt date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the receipt date(s) and time, the application may be delayed in the review process or not reviewed.

Once an application package has been successfully submitted through, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two business days to view the application image.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Incomplete applications will not be reviewed.

There will be an acknowledgement of receipt of applications from and the Commons. Information related to the assignment of an application to a Scientific Review Group is also in the Commons.

The NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of an application already reviewed with substantial changes, but such application must include an Introduction addressing the previous critique. Note such an application is considered a "resubmission" for the SF424 (R&R).

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See the NIH Grants Policy Statement.

6. Other Submission Requirements

The NIH requires the PD/PI to fill in his/her Commons User ID in the PROFILE Project Director/Principal Investigator section, Credential log-in field of the Research & Related Senior/Key Person Profile component. The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with For additional information, see Tips and Tools for Navigating Electronic Submission on the front page of Electronic Submission of Grant Applications.

Renewal (formerly competing continuation or Type 2 ) applications are not permitted.

All application instructions outlined in the SF424 (R&R) application are to be followed, with the following requirements for R21 applications:

Note: While each section of the Research Plan needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.

Do not use the Appendix to circumvent the page limitations of the Research Plan. An application that does not observe these limitations may be delayed in the review process.

Plan for Sharing Research Data

Not applicable.

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (see the NIH Grants Policy Statement at Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each Non-Competing Grant Progress Report (PHS 2590). See Section VI.3., Reporting.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications submitted for this funding opportunity will be assigned to the ICs on the basis of established U.S. Public Health Service (PHS) referral guidelines.

Appropriate scientific review groups convened in accordance with the standard NIH peer review procedures ( will evaluate applications for scientific and technical merit.

Applications that are complete will be evaluated for scientific and technical merit by an appropriate review group convened by the NIH Center for Scientific Review in accordance with the review criteria stated below.

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

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

The NIH R21 exploratory/developmental grant is a mechanism for supporting novel scientific ideas or new model systems, tools, or technologies that have the potential to significantly advance our knowledge or the status of health-related research. Because the Research Plan is limited to 15 pages, an exploratory/developmental grant application need not have extensive background material or preliminary information as one might normally expect in an R01 application. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will place less emphasis on methodological details and certain indicators traditionally used in evaluating the scientific merit of R01 applications, including supportive preliminary data. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria 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 an 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.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

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

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the PD/PI and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. See item 6 of the Research Plan component of the SF424 (R&R).

Inclusion of Women, Minorities and Children in Research: 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 will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. See item 7 of the Research Plan component of the SF424 (R&R).

2.B. Additional Review Considerations

Budget and Period of Support: The reasonableness of the proposed budget and the appropriateness of the requested period of support in relation to the proposed research may be assessed by the reviewers. Is the effort listed for the PD/PI appropriate for the work proposed? Is each budget category realistic and justified in terms of the aims and methods?

2.C. Sharing Research Data

Not applicable.

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (see the NIH Grants Policy Statement at Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each Non-Competing Grant Progress Report (PHS 2590), See Section VI.3., Reporting.

Model Organism Sharing Plan: If applicable, reviewers are asked to assess the sharing plan in an administrative note. The sharing plan itself should be discussed after the application is scored. Whether a sharing plan is reasonable can be determined by the reviewers on a case-by-case basis, taking into consideration the organism, the timeline, the applicant's decision to distribute the resource or deposit it in a repository, and other relevant considerations. For the R21 mechanism, the presence or adequacy of a plan should not enter into the scoring of the application.

3. Anticipated Announcement and Award Dates

Not applicable.

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the Notice of Grant Award (NoA). For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General ( and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

For applications focusing on drug abuse and dependence research:

Melissa W. Racioppo, Ph.D.
Division of Treatment Research and Development
National Institute on Drug Abuse/NIH/DHHS
6001 Executive Blvd., MSC 9551
Bethesda, Maryland 20892-9551
Telephone: 301-443-2261
Fax: 301-443-6814

For applications focusing on alcohol abuse and dependence research:

Raye Litten, Ph.D.
Division of Clinical and Prevention Research
National Institute on Alcohol Abuse and Alcoholism/NIH/DHHS
Willco Building, Suite 505
6000 Executive Blvd., MSC-7003
Bethesda, MD 20892-7003
Telephone: 301-443-0636
Fax: 301-443-8774

2. Peer Review Contacts:

Not applicable.

3. Financial or Grants Management Contacts:

For applications to NIDA:

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse/NIH/DHSS
6001 Executive Blvd., MSC 9541
Rockville, MD 20892-9541
Telephone: 301-443-6710
Fax: 301-594-6849
E-mail: GF6S@NIH.GOV

For applications to NIAAA :

Judy Fox
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism/NIH/DHHS
6000 Executive Blvd., MSC 7003
Bethesda, MD 20892-7003
Telephone: 301-443-4704

Section VIII. Other Information

Required Federal Citations

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts,

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide 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 funding opportunity 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.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement). Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
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 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 "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (; a complete copy of the updated Guidelines is 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 SF424 (R&R); 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 differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

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 (

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system ( at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at and view the Policy or other Resources and Tools including the Authors' Manual (

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR Website ( provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at

HIV/AIDS Counseling and Testing Policy for the National Institute on Drug Abuse: Researchers funded by NIDA who are conducting research in community outreach settings, clinical, hospital settings, or clinical laboratories and have ongoing contact with clients at risk for HIV infection, are strongly encouraged to provide HIV risk reduction education and counseling. HIV counseling should include offering HIV testing available on-site or by referral to other HIV testing service for persons at risk for HIV infection including injecting drug users, crack cocaine users, and sexually active drug users and their sexual partners. For more information see

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 of Council before submitting an application that will administer compounds to human subjects. The guidelines are available on NIDA's Home Page at under the Funding, or may be obtained by calling (301) 443-2755.

URLs in NIH Grant Applications or Appendices:
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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

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 at and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at

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.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see:

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