NEUROSCIENCE RESEARCH ON DRUG ADDICTION

RELEASE DATE:  March 18, 2002

PA NUMBER:  PA-02-085

February 21, 2007 - This PA has been reissued as (PA-07-226) for R01's and (PA-07-227)
 for R21's and (PA-07-228) for R03's.

EXPIRATION DATE:  March 31, 2005, unless reissued.

National Institute on Drug Abuse (NIDA) 
 (www.nida.nih.gov)

THIS PROGRAM ANNOUNCEMENT (PA) CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanisms of Support 
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

PURPOSE OF THIS PA

The intent of this program announcement is to continue to encourage 
investigator interest in the wide range of neuroscience research relevant to 
drug abuse, drug dependence, and drug addiction supported by the National 
Institute on Drug Abuse (NIDA).  Of particular interest are new areas of 
neuroscience that may be applied to questions of drug abuse and addiction. 

This PA replaces PA-99-033, which was published in the NIH Guide, December 
23, 1998 at http://grants.nih.gov/grants/guide/pa-files/PA-99-033.html.

RESEARCH OBJECTIVES

The goals of the research areas outlined below are to understand the 
neurobiological mechanisms underlying: (1) drug abuse, addiction and the 
transition process from abuse to addiction, (2) the neurobiological and 
neurobehavioral consequences of drug abuse and addiction (e.g., physical and 
functional neuroadaptations, neurotoxicity, altered cognition, drug 
psychoses, developmental deficits), and (3) antecedents (vulnerability) and 
resistance factors to drug addiction and relapse (e.g., stress, individual 
differences in responses to drugs of abuse, resiliency, effects of 
pharmacotherapy).  In addition, since the opiates (e.g., heroin, 
hydromorphone) are prominent drugs of abuse and are also essential in the 
therapy of severe pain, major research objectives outlined in this PA include 
efforts to understand the neurobiological bases of pain and its alleviation 
by opiates, other types of analgesics and adjunctive medications, as well as 
alternative therapies (e.g., acupuncture, virtual reality).  The scientific 
understanding gained by this research is anticipated ultimately to be 
applicable to improved treatment and prevention of drug abuse and drug 
addiction and their consequences.  The specific research topics emphasized in 
this program announcement are: 

(1)  Animal Models to Study the Neurobiology of Addiction
(2)  Vulnerability to Drug Addiction 
(3)  Neuroadaptation and Neurotoxicity
(4)  Developmental (Ontogenetic) Neurobiology
(5)  Drugs and Learning, Memory, and Cognition
(6)  Pain and Analgesia 
(7)  Drug Abuse Effects on Sensory and Perceptual Systems
(8)  Drugs of Abuse, Sleep and Circadian Rhythms 
(9)  Neuropsychopharmacology of Drugs of Abuse 
(10) Drugs of Abuse and CNS Interaction with Other Systems
(11) Neural Cell Biology
(12) Computational Neuroscience 
(13) Translational and Technical Research
(14) Prescription Drug Abuse
(15) NeuroAIDS
(16) Clinical (Human) Neuroscience

The following examples and topics are illustrative and not meant to encompass 
all research areas supported by this Institute. They represent major 
portfolios of research activity in the area of drug abuse and addiction.  The 
research opportunities outlined below involve laboratory animal models, 
including non-human primates as well as human subjects.  Inasmuch as research 
has begun to show sex differences in many of the areas of research outlined 
below (e.g., vulnerability, developmental neurobiology, learning, pain and 
analgesia, aggression, etc.), investigators may wish to consider conducting 
research with both male and female animals and to examine gender differences 
in outcomes.

1.  Animal Models to Study the Neurobiology of Addiction

The drug self-administration paradigm has been a mainstay in research on the 
behavioral neurobiology of drug abuse and addiction.  From that has evolved 
the brain reward hypothesis of addiction.  A need exists to expand that model 
to include the functional role of brain structures beyond the nucleus 
accumbens, both dopaminergic and non-dopaminergic, such as the ventral 
pallidum, prefrontal cortex, and amygdala and other neurotransmitters, 
including the cholinergic, peptidergic, serotonergic, GABAergic and 
glutamatergic systems.   Investigations of extra-dopaminergic systems are of 
interest in order to encompass complex neurocircuits and interacting 
transmitter systems involved in drug abuse and addiction.  Using these 
approaches, there has been progress made in studies concerned with the neural 
mechanisms underlying the development of salient associations to the drug 
experience.  It is important to focus in on this avenue because a possible 
cause of relapse may be exposure to environmental cues that have been 
associated with drug taking or seeking.  Other aspects of addictive behaviors 
in need of further study and modeling, including an understanding of the 
associated underlying brain mechanisms, include:  (1) drug craving, (2) 
switch in state, i.e., from voluntary to uncontrolled intake in spite of 
increasing negative consequences, (3) loss of control/narrowing of behavioral 
repertoire, and (4) the role of stress and other variables in reinstatement 
of drug taking behavior. In addition to using standard neuroimaging 
techniques, NIDA also encourages the development of new techniques to study 
the neurobiology of addiction, particularly those that can elucidate brain 
and behavior interactions. 

Animal models might also be used to examine the degree of overlap between 
neural circuitry maintaining drug seeking among the various classes of 
addictive drugs.  For example, we know much less about what maintains the 
smoking habit than we do about cocaine. Is the same circuitry involved in the 
addiction to cigarettes as cocaine? Are the mechanisms responsible for drug-
related associations (smoking and cues versus cocaine and cues) the same or 
different? 

Also of interest is the use of neuroethological models of naturalistic or 
specific-specific behavior (e.g., parenting, ingestive or foraging behavior, 
affiliative responses, etc) in understanding brain mechanisms underlying 
compulsive or goal-directed behavior.  The study of feeding behavior is 
relevant to drug seeking as it will provide information on the circuitry 
involved in motivation or drive to locate primary rewards and the role of 
structures such as the nucleus accumbens or endogenous substances in 
signaling relevant stimuli or mediating states such as satiation or 
deprivation. 

2.  Vulnerability to Drug Addiction

Current research suggests that there may be certain predisposing factors that 
account for individual differences in drug preference and drug initiation, 
the development of tolerance and sensitization, abstinence signs, reinforcing 
efficacy, rate of acquisition of drug taking, maintenance, resistance to 
extinction, and reinstatement of drug taking.  NIDA solicits research to 
determine the neurobiological antecedents to compulsive drug abuse (i.e., to 
identify and evaluate the neurobiological factors that influence the 
continuation, escalation, and/or relapse of drug-seeking and drug self-
administration).  There is also a need to examine the neural basis of 
individual differences in the subjective drug response (e.g., altered 
affective state), addiction liability, relapse vulnerability, and dependence 
potential including tolerance and sensitization.

One of the vulnerability factors of interest to NIDA is the genetic 
influence, which might be involved in variations in various neural 
substrates, the reinforcing efficacy of drugs and the sensitivity to negative 
or toxic consequences of drug taking such as:  negative attributes, 
disturbances to the sensorium, seizures, cognitive decline, or frank 
neurotoxicity.  Genetic studies may use, for example, inducible knock-out and 
other transgenic mice, mutagenesis screens, recombinant inbred strains, 
determination of genotypes linked to differences in drug self-administration, 
or the relationship between differences in drug effects and differences in 
drug metabolism or receptor subtypes.  It is expected that these studies 
would be driven by specific hypotheses concerning genetic vulnerability.  In 
addition to investigations in rodents, investigators are encouraged to employ 
model genetics systems such as zebrafish, drosophila, and C. elegans for the 
genetic analysis of addiction.

Other predisposing factors that may influence a person"s decision to use 
drugs include critical periods of development (particularly adolescence), 
gender, immunological status, stress, environmental stimulation, expectation, 
previous drug use (possibly involving cross sensitization within and between 
classes of drugs), and comorbidity with psychiatric disorders.   In addition, 
certain social or hierarchical situations, and the side effects of other 
drugs (e.g., anabolic steroids) can influence the decision to use drugs.  
Further study with animal models is required to identify the neurobiological 
substrates that underlie these phenomena and to characterize how drugs of 
abuse modify these substrates.

3.  Neuroadaptation and Neurotoxicity

Scientific evidence indicates that repeated drug intake can lead to transient 
and persistent neural adaptations in adult animals. Research is solicited on 
the relationships between drug-induced long-lasting neural adaptations and 
behaviors, such as tolerance, sensitization, and the somatic and motivational 
aspects of dependence.  The study of the adaptations unmasked by drug 
withdrawal following continuous or intermittent drug intake, especially those 
neuroadaptations that can lead to reinstatement of drug seeking and self-
administration (i.e., relapse), is encouraged.  Some neurochemical substrates 
have been uncovered only during a period of withdrawal from drug 
administration and are subjects of further study as well.  Such adaptations 
may occur as modification of the actual proteins that influence 
neurotransmission, such as receptors and transporters, and in functional 
changes that occur within the neuron, such as drug-induced alterations in the 
intracellular trafficking of proteins to regulatory intracellular 
compartments.  The neurotoxicology of drugs of abuse, especially the 
relationship of neurotoxicity to behavioral toxicity (e.g., animal models of 
drug-induced psychoses, cognitive impairment, or affective disturbances such 
as anxiety or anhedonia) is also an under-studied area of investigation.  
Also needed are investigations of residual effects of drug exposure that may 
contribute to the onset or progression of diseases not usually linked to drug 
abuse, especially neurodegenerative disorders, e.g., Parkinson"s and 
Alzheimer"s diseases.  Investigations of the mechanisms of structural and 
functional recovery from drug-induced neuropathology and of interventions 
that might improve recovery are encouraged. 

Recent research has established a major role for chemokines in neurotoxicity, 
including dementia resulting from viral infection. More recently, chemokines 
have been shown to be involved in "fast glutaminergic signaling" in the 
brain.  As the effects of glutamate are regulated by uptake by neurons and by 
glia, research into the glial regulation of neural glutaminergic actions is 
also encouraged.  The dual activity of activation and inhibition of certain 
neural processes by chemokines is a recent advance which requires further 
research and an understanding of functional interactions with the endogenous 
and exogenous opiate peptides, for example, is important because both classes 
of compounds profoundly regulate the immune system by regulating a common 
biochemical pathway. 

Research on mechanisms underlying neuropathology may include cellular and 
molecular examinations of transcription factors, neurotrophic factors, 
neuropeptides, neurosteroids, and intracellular signaling pathways, 
mechanisms of cell death, and alterations in the binding, density, and 
trafficking of receptors.  Such research may also include studies of the 
regulatory elements of neurotransmission, including neuronal membrane 
channels, enzymes, synaptic connectivity in well-defined neural circuits, and 
other factors that may mediate long-term neural and behavioral plasticity.  
Regulation of neurotransmission by changes in the neural milieu such as those 
engendered by stressors and reproductive steroids are also of interest as is 
the effect of drugs of abuse on cellular processes of endothelial cells that 
form the blood-brain barrier.  The Institute is especially interested in 
studies on persistent adaptations within and beyond the mesolimbic dopamine 
system and comparisons with neuroadaptations  (e.g., supersensitivity, 
hyposensitivity) seen in other situations.

4.  Developmental (Ontogenetic) Neurobiology

Investigators are encouraged to examine the ontogenetic consequences of 
exposure to drugs of abuse using neuroanatomical, neurophysiological, 
neurochemical, or neurobehavioral methodologies.  The use of laboratory 
animal models to determine the neural bases for drug-induced developmental 
behavioral and cognitive effects is encouraged.

Studies may focus on the direct effects of a given drug on the developing 
brain or on the role of indirect CNS effects, such as drug-influenced 
maternal malnutrition, maternal behavior, blood flow to the fetal brain, and 
other neurobehavioral factors associated with prenatal development or 
rearing.  Studies are also needed on the developmental effects of treatment 
drugs (e.g., methadone) and potential treatment drugs.  Studies examining 
possible differential drug-induced effects in male and female offspring would 
also be of interest.  Other crucial areas include studies on the stage of 
development and the drug effect/response and investigations into the 
influence of perinatal exposure to drugs on abuse liability in adulthood.

Investigators interested in NIDA programs that support studies on the 
molecular and cellular mechanisms of development of brain structures that 
mediate addiction should consult PA-02-015, "ROLE OF LIMBIC SYSTEM AND BRAIN 
ONTOGENY IN DRUG ABUSE" (http://grants.nih.gov/grants/guide/pa-files/PA-02-
015.html.)

5.  Neurobiology of Learning, Memory and Cognition

The process of becoming addicted to drugs often begins with noncompulsive or 
occasional use, which, over time, progresses to uncontrollable drug taking, 
the narrowing of behavioral repertoires, and the "ritualization" of behavior.  
Moreover, "drug craving" and relapse to drug use following long periods of 
abstinence are common and may result from stress and/or from re-exposure to a 
drug or to environments and stimuli previously associated with drug use.  
These facts suggest that associative learning and explicit and implicit 
memory processes are involved in drug addiction.  Research is needed to 
understand the nature of associations and memory representations formed 
during drug exposure, how the drug experience itself is represented in the 
brain, and how drugs affect the neural representation of other events.  
Research is needed also to determine whether drugs potentiate associative 
learning by engaging molecular mechanisms of long-term memory to facilitate 
the transition from drug use to abuse.  Similarly, how the effect of drugs on 
learning mechanisms may contribute to a shift from evaluative, higher-order 
decision making to automatic stimulus-response habits needs to be explored.

Studies have shown that the mesocorticolimbic "reward" system, which includes 
brainstem dopamine neurons, the striatum, and areas of frontal cortex, is 
necessary for the acquisition of self-administration of many drugs of abuse.  
Comparatively less is known about the involvement of the brain"s other 
multiple memory systems in addiction.  In addition, although drugs of abuse 
are known to modulate memory formation in the hippocampus, striatum and 
prefrontal cortex, the contribution of these effects to the addiction process 
is not understood.

Molecular studies have indicated that activation of various signaling 
molecules, such as protein kinases and transcription factors, in neurons of 
the nucleus accumbens, the ventral tegmental area, and other areas 
accompanies the development of tolerance, dependence, craving, and/or 
withdrawal produced by chronic administration of abused drugs.  Many of these 
molecules play an important role in synaptic plasticity and longer-term 
memory, but there is much to be understood about how changes in cellular 
processes produced by these molecules utilize or modify the brain"s learning 
mechanisms to produce compulsive drug taking and drug seeking behavior.

Drugs of abuse can also impair cognitive processes and performance.  Basic 
research is needed to characterize the chronic and residual neural effects of 
abused drugs on attention, learning, memory, awareness, judgment, and 
performance.  Cognitive neuroscience research has the potential to identify 
neurobiological mechanisms that underlie the cognitive antecedents of drug 
abuse.  Also needed are animal laboratory studies that examine the 
interaction between cognitive and emotional processes that influence 
decision-making and increase vulnerability to drug abuse.

Thus, neurobiological investigations at the systems, cellular/molecular, and 
behavioral/cognitive level are all relevant to understanding learning, memory 
and other cognitive processes involved in drug abuse.

6.  Pain and Analgesics

Many analgesics have abuse liability, and the potential development of drug 
dependence is a significant consideration when various analgesics are used 
for the treatment of chronic pain.  NIDA is supportive of a variety of 
research related to pain and analgesia, including studies of the neural 
adaptations that occur during the short- and long-term pain state, studies of 
how the resulting data might be applied to treatment of chronic pain, and how 
these adaptations compare to the general adaptation syndrome.

The Institute encourages studies to develop and examine new compounds which 
are analgesic in nature but have little or no abuse or dependence liability, 
or to evaluate the of modifications of existing compounds for an enhancement 
of their efficacy and reduction in their abuse potential.

Investigations on basic pain mechanisms employing multidisciplinary system 
approaches are sought to dissociate mechanisms of pain perception or 
analgesia from those associated with addiction or dependence. Also, studies 
on the neurobiological substrates of non-pharmaceutical pain treatments 
(e.g., acupuncture, virtual reality) are of interest.  In addition, research 
with humans would be appropriate for certain aspects of pain and analgesia 
research (see Section 16J for further details).

7.  Drug Effects on Sensory and Perceptual Systems

Little is known about effects of drugs of abuse on sensory systems (with the 
exception of those mediating pain).  For example, the mechanisms of 
hallucinogen-induced alterations in perception are in need of study. Also, 
little attention has been given to research regarding puritus (itch) that is 
induced by several drugs of abuse (e.g., heroin) and is a symptom of numerous 
diseases. These studies could focus on either transient drug-induced sensory 
changes or more permanent sensory impairments and mental/cognitive disorders 
that may be the result of neural damage.  For example, neural damage has been 
described in the somatosensory cortex following exposure to certain drugs 
(e.g., methamphetamine).  The functional consequence of this type of damage 
could be examined.  In addition, the role of these sensory and perceptual 
changes in drug-taking behavior and relapse needs study.  This research could 
help determine to what degree drug-induced alterations in sensation and 
perception can affect drug-taking behavior.

Studies are encouraged on a variety of neuroanatomical circuits responsible 
for sensation and perception, ranging from the primary afferents to sensory 
cortex, with the goal of correlating molecular, cellular and circuit changes 
with behavioral changes during and following drug use.

8.  Drugs of Abuse, Sleep and Circadian Rhythms

There are gaps in knowledge regarding changes in sleep patterns and in 
circadian rhythms resulting from drug abuse, addiction, and from 
pharmacological and other treatments for drug abuse and comorbid conditions.  
NIDA encourages research on the relationship of drugs of abuse to sleep 
disturbances including the neurochemical mechanisms responsible, how these 
relate to chronic sleep disturbances that have been shown to promote 
depressive symptoms, and whether sleep disturbances may be a contributing 
factor to relapse.  The Institute also encourages studies to determine (1) 
the patterns of sleep associated with vulnerability or resilience to drug 
abuse during all phases of addiction, and (2) the kinds and patterns of sleep 
that are associated with drug abuse treatment.  As appropriate, research 
could also be conducted with human volunteers (see Section 16I of this 
announcement for details).

9.  Neuropsychopharmacology of Drugs of Abuse

Neuropharmacological studies of the mechanisms underlying the behavioral 
effects of specific abused drugs or drug classes and of potential treatment 
drugs are encouraged.  Areas of interest include, but are not limited to, the 
following:  (1) physiological/functional roles of specific receptors for 
drugs of abuse and their natural ligands (e.g., roles of cannabinoid 
receptors and their endogenous ligands in states of health and disease, roles 
of cholinergic receptors in nicotine addiction, effects of the so-called 
"club drugs" and MDMA), (2) functional relationships between opioid and non-
opioid peptides and classical transmitters, (3) the cellular or systems level 
locus of drug interactions (e.g., interactions between cocaine and ethanol, 
abused drug and treatment drug), and effects of neuromodulators such as 
stressors, steroids and neuropeptides on neuroregulation at the level of the 
neural circuit as well as the individual neural cell, and (4) roles of the 
blood-brain barrier (BBB) in drug abuse phenomena (e.g., changes in BBB 
structure, development, or function caused by drug abuse, role of BBB in 
regard to the neurotoxicity of abused substances, strategies for targeting 
treatment drugs to the brain and for limiting the bioavailability of drugs of 
abuse), and (5) components of a broader circuit which are related to abuse 
liability or are modified as a result of addiction.

Also appropriate are studies of neural mechanisms underlying disruptions of 
complex behaviors induced by drugs of abuse, drug withdrawal, or potential 
treatment drugs.  Examples include studies of:  (1) preclinical models of 
drug-induced aggressive and fighting behavior (e.g., studies of the neural 
mechanisms underlying aggression following phencyclidine or anabolic steroid 
administration, or of anxiety and anhedonia seen during withdrawal), (2) 
neuronal substrates through which drugs can alter social behavior in animals 
(e.g., parental and other affiliative behaviors, or responses to social 
stimuli), and (3) neuropharmacological mechanisms underlying drug-induced 
psychoses, hallucinations and flashbacks. 

10.  CNS Interaction with Other Systems

Through its direct effects on the CNS, drug abuse can influence other systems 
of the body.  Likewise, the CNS may be affected by drug actions on peripheral 
systems.  Therefore, research is solicited involving: (1) interactions 
between drugs of abuse and classical neurotransmitters and neuropeptides 
(e.g., corticotropin-releasing factor, cholecystokinin, neurotensin, 
neuropeptide Y), cytokines (e.g., the interleukins), and chemokines, (2) 
neuromodulation of the endocrine, reproductive, immune, cardiovascular, 
respiratory, and gastrointestinal systems, and (3) feedback from peripheral 
organs impacting on CNS functions.  Studies on the allostatic regulation of 
these systems, especially with regard to aspects of stress and drug-taking, 
are particularly encouraged.

11.  Neural Cell Biology

NIDA supports studies of addiction at the cellular level are encouraged and 
these include research on cell membrane and protein trafficking, signal 
transduction pathways, cytoskeletal rearrangement, protein-protein 
interactions, synaptic vesicle formation, cellular and molecular mechanisms 
underlying mRNA localization and targeting, local protein synthesis in 
neurons, and ion movements.  The Institute is also interested in 
developmental studies of neural pathways and brain structures relevant to 
drug abuse are of interest when they involve stem cell and progenitor cell 
induction, pattern formation, specification of neuronal and glial cell fate, 
programmed cell death, guidance of glial and neuronal migration, regulation 
of dendritic and axonal outgrowth, target selection, and synapse formation.

The Institute supports studies into the cellular aspects of memory and 
learning as well as neural adaptation.  Such studies might include research 
on the role played by transcription factors, scaffolding proteins, adhesion 
molecules, signaling molecules, and cytoskeletal proteins.  Studies could 
examine glial mechanisms of synaptic plasticity and modulation.  Other 
mechanims involved in learning might include signal transduction effectors of 
morphological changes in dendritic spines.

The genetic studies at the molecular/cellular level which are of interest 
include model organism genomics, functional genomics, proteomics, gene 
expression studies, and mutagenesis.  Also supported are new statistical 
methods for the analysis of complex genetic traits.

12.  Computational Neuroscience

Current neurobiological, cellular, and genetic research approaches alone will 
not likely account for all possible aspects of the addiction process or make 
predictions about possible interactions among biological processes involved 
in drug addiction.  Computational and theoretical models are needed to 
provide a framework for the design of experiments and the generation of new 
hypotheses that can help explain phenomena related to drug abuse, such as the 
addiction process, transition to addiction from casual use to compulsive 
drug-taking, consequences of drug abuse and other related phenomena.  The 
process of model development will need to involve protracted refinement and 
intense interaction between computational and theoretical modelers and 
researchers and continued and sustained interaction as new experimentally-
based information becomes available, and as models begin to shape future 
experimentation.

Model development and implementation might use a variety of approaches 
including, but not limited to:  (1) modeling network properties of the brain, 
(2) developing mathematical models describing intracellular signaling, using 
conductance-based models to describe neuronal activity, (3) applying 
connectionist and/or dynamical approaches to model cognitive processes, or 
(4) applying mathematically-based principles of economics, decision-making 
and judgment to behavioral data.

13. Translational and Technical Research

NIDA seeks research that facilitates the translation of basic research data 
into clinical tools for intervention, research instruments and medications. 
Ideally the research would use promising data from one level of analysis as 
the basis for further research at a more applied or clinical level. For 
example, the use of molecular, proteomic, in silico or chemistry data to 
suggest agents to test in animal models, and the use of data from animal 
models to develop preclinical human testing. Small Business Innovation 
Research (SBIR) and Small Business Technology Transfer Research (STTR) 
programs are especially suited, but not required, to fulfill this gap (see:  
http://165.112.78.61/Funding/SBIR_STTR.html)

Of special interest are studies concerned with the design and testing of 
potential new treatment drugs at the basic/preclinical level.  This area 
includes development of innovative neurochemical probes. These might be new 
chemical moieties designed to identify potential medications, new imaging 
agents for brain studies, and receptor selective ligands, novel neuropeptide 
analogs for basic research and structure-activity relationship studies.  Also 
needed are biophysical studies to determine the three dimensional structure 
of a ligand, receptor, or enzyme though structure-function analysis, studies 
of ligand-receptor interactions, crystallization of receptors and signaling 
molecules, and X-ray crystallographic studies. 

14.  Abuse of Prescription Drugs and Prescription Drug Substitutes 

Much of NIDA"s supported research involves illicit drugs.  However, there is 
concern about the abuse of medications that is otherwise targeted toward 
treating disease and their symptoms.  While diversion of prescription drugs 
is the major problem, there are still basic questions that need to be 
answered.  For example, how does the neuropsychopharmacology of the 
prescription drug compare in health and disease (e.g., is the dependence 
liability of opiates different in the pain patient than in the pain-free 
individual)?  Would a prescription drug, with slight stimulant properties, 
trigger relapse in an abstinent cocaine addict?  What is the abuse liability 
of some of the over-the-counter formulations or their key ingredients (e.g., 
phenylephrine, dextromethorphan, or pseudoephedrine)?  Can over-the-counter 
formulations trigger relapse or maintain continued drug use via mechanisms in 
common to abused drugs or learned associations?  Another question of interest 
is whether animals will self-administer drugs to "self-medicate."

In addition to prescription drug abuse, non-prescription preparations 
available (e.g., ma-huang, ginseng) have abuse potential. These preparations, 
which are available through a variety of sources, may precipitate relapse, 
may interact with other drugs, including drugs of abuse, and/or may have some 
misuse and abuse potential in their own right.  Studies of the 
psychopharmacological characteristics of these drugs, sometimes sold as 
"supplements" are of interest. 

15.  NeuroAIDS

It is well established that drug abuse is a major risk factor for contracting 
HIV/AIDS.  In addition, drugs of abuse produce neurodegenerative changes in 
some of the same areas seen following HIV/AIDS.  Also, some of the neurotoxic 
mechanisms of HIV/AIDS and psychomotor stimulants overlap.  NIDA encourages 
studies to determine the neurological, immunological, behavioral, and 
cognitive consequences potentially caused by the combined effects of the 
virus, drugs of abuse, drug abuse pharmacotherapies, and/or anti-HIV 
medications. HIV can cause a cascade of neuroimmune processes that have 
profound and potentially toxic effects on the brain.  Because drugs of abuse 
can also have adverse effects on neuronal and immune function and, in some 
cases, can cause cell death, it is important to characterize the changes in 
neuronal and neuroimmune function and the related cognitive and behavioral 
changes associated with disease progression and drug abuse.  Development of 
new models to study the interaction between HIV/AIDS and substance abuse are 
particularly welcome.  In addition, under certain circumstances, studies 
conducted with human subjects would also be appropriate.  (See Section 16H 
for details.)

16.  Clinical Neuroscience Research

In addition to NIDA"s extensive neuroscience program using animal models and 
more basic approaches, a large program exists to study the interactions of 
drugs of abuse on human neurobiological processes.  With the tremendous 
advances in brain imaging methods, it is now possible to examine directly 
brain-behavior interactions in the human.  This program supports a wide range 
of research issues and methods dealing with the biological etiology and 
clinical neurobiology of drug addiction.  Note that the research proposed 
need not be conducted in drug-abusing populations or involve drug 
administration, however, a potential relevance to understanding drug 
abuse/addiction needs to be established.  General illustrations of the types 
of research involved in this program include, but are not limited to, the 
following:

A.  Neurobiology of Addiction

This program focuses on characterizing neurobiological processes involved 
with drug abuse and addiction in humans.  Neuroadaptive alterations occur in 
the brain in response to the presence of a drug, and these changes involve 
several integrated neural systems and processes.  NIDA encourages studies to 
determine alterations of the structure and/or function of the human central 
nervous system following either acute and/or chronic exposure to drugs of 
abuse.  Also needed are studies to characterize changes in brain sites and 
circuits throughout the course of the addiction process, from drug initiation 
throughout the course of drug addiction and relapse.  Also important are 
studies characterizing the time course of transition to addiction in 
neurobiological terms with particular emphasis on individual differences.  
This program also supports studies to determine neurobiological predictors of 
relapse or treatment success, as well as studies assessing vulnerability to 
relapse. Also needed are studies to elucidate underlying neurobiological 
mechanisms and functional characteristics of brain systems in drug abuse and 
addiction states.

B. Cognitive Neuroscience

Over the past decade research at the intersection of cognitive science and 
neuroscience has undergone rapid development that has been facilitated in large 
part by technological developments in functional and structural neuroimaging.  
Despite rapid advances made in the last decade in understanding the neural basis 
of cognition, research into cognitive influences on the addiction process, and 
reciprocal influences of drugs and addiction on cognitive processes are in a 
relatively early stage.  In this context, cognition refers to the approach to 
human behavior and brain function that emphasizes the flow and transformation of 
information through the nervous system.  Drug addiction encompasses the 
initiation of use, responses to acute drug administration, sequelae of repeated 
use followed by addiction, and discontinuation of drug use.  Although studies of 
brain systems involved in the basic mechanisms of reward and reinforcement are 
fundamental to the study of addiction, examples of cognitive approaches to drug 
addiction include the following: 1) the influence of motivational systems on 
memory formation and retrieval as well as on attention and basic sensory 
processing, 2) decision-making when outcomes are uncertain or include 
simultaneous rewards and punishments, 3) the ability of cognitive manipulations 
("framing") to bias emotional responses and decision making, and 4) the 
transition in behavioral control from deliberate action to habits (automaticity) 
or from habits to deliberate actions.  Such studies could focus on normative 
cognitive processes in drug-naive subjects or alterations in cognitive processes 
in drug users, currently abstinent drug users or populations at risk for 
substance abuse.

C. Neurobiology of Treatment

Major advances have been made in understanding how drugs of abuse alter 
various brain processes and systems both structurally and functionally.  
Further, many of these changes can be very persistent, even in long-term 
abstinence from drugs.  However, relatively little is known of the brain"s 
response to detoxification and protracted abstinence, as well as the specific 
role of treatment in the recovery of neurobiological systems altered by 
repeated drug exposure.  NIDA encourages studies that investigate the central 
nervous system status in patients undergoing treatment or in protracted 
abstinence.  Particularly important are studies comparing therapeutic 
approaches (e.g., pharmacologic and behavioral) in "normalizing" brain 
structure/function as well as to determine the combination of therapeutic 
approaches.  Also, studies are needed to determine if changes that occur in 
neural systems translate into functional improvements.  Examination into the 
interaction of specific drug-dependent neurobiological deficits and other 
pre-existing risk factors (e.g., polydrug use, neurological disorders, 
comorbid mental disorders, HIV status) and treatment outcome are encouraged, 
as well as investigations to determine neurobiological markers of predictors 
of treatment outcome.  

D.  Neurodevelopment and Maturation

A large body of animal data exists revealing the effects of drugs on 
neurodevelopment with less information on the developmental processes in 
humans.  Neuroimaging and other neurodevelopmental methods now allow for the 
characterization of the neurobiological effects of drug abuse on human 
development across the life span.  Studies on pre- and perinatal exposure are 
needed to establish the interaction between drugs of abuse and developing 
neural systems.  Also, important are studies assessing the effects of early 
(child and adolescent) drug exposure on brain development and neurobehavioral 
processes.  NIDA also encourages neurobiological studies on how drugs affect 
the aging central nervous system or how drug abuse and addiction might affect 
(e.g., accelerate) the aging of brain systems.  Investigations characterizing 
the interactions between drug abuse/addiction and the onset and development 
of neurological diseases and disorders (e.g., Parkinson"s disease, cognitive 
deficits/dementias, cerebrovascular disease) are also needed.

E. Biological Etiology

Individuals differ in their tendency to seek and abuse psychoactive 
substances as well as their vulnerability to continue to abuse and become 
dependent or addicted to these substances once experienced.  While individual 
differences can be attributed to environmental factors, such as peer group or 
community influences, there are also underlying neurobiological factors.  
These factors may act alone to increase vulnerability or interact in concert 
with environmental factors to produce increased risk of drug abuse.  Such 
factors would include, for example: 1) biological underpinnings of pleasure-
seeking, 2) reward gratification/drug reward salience, 3) impulsivity, and 4) 
comorbid disorders such as antisocial personality disorder, post-traumatic 
stress disorder, pathological gambling, depression, anxiety disorder, or 
schizophrenia.  Studies are encouraged that examine the neurobiological 
etiologies conferring increased risk to seeking drugs of abuse, and impelling 
increased use to become dependent or addicted.

F. Comorbid Mental and Addictive Disorders

Comorbidity of drug abuse/addiction and other psychiatric disorders.  Because 
drugs of abuse act through the same modulatory transmitter systems believed 
to underlie other psychiatric disorders, a pre-existing psychiatric disorder 
may predispose an individual to developing a drug abuse disorder.  Illicit 
drug use also may start as a means of self-medication for psychiatric 
disorders and then rapidly progress to abuse and addiction.  Alternatively, 
illicit drug use may also precipitate or exacerbate psychiatric disorders.  
Understanding the interactions within the brain between drug addiction and 
other psychiatric disorders is critical for the development of new approaches 
for the prevention and treatment of drug dependence.  Increased attention to 
underlying neurobiological factors may also be helpful in providing a 
rational basis for diagnosis of mental and drug abuse disorders.  Studies on 
this topic may focus the underlying neurobiological factors that could 
contribute to comorbidity of substance abuse any number of psychopathologies.  
Of particular interest are studies of comorbid substance abuse with Post-
Traumatic Stress Disorder, depression, anxiety disorders, and schizophrenia, 
personality disorders (e.g., psychopathy, impulsive and borderline 
personality) as well as neurological disorders such as injury to the frontal 
lobe.  Subpopulations of children, adolescents, women, and minorities 
experiencing comorbid mental and addictive disorders are of particular 
interest.

G. Effects of Stress on Brain and Behavior

Stress is an important contributor to the etiology of drug abuse.  It affects 
a number of homeostatic systems including the immune system and the 
hypothalamic-pituitary-adrenal (HPA) system regulating body state.  It has 
been shown that stress acts acutely causing individuals to seek immediate 
pharmacological relief from environmental stressors by ingesting psychoactive 
substances.  Additionally, stress acts on brain development whereby early 
stressors (both pre- and post-natally) act to modify neuronal 
interconnections and receptor characteristics which, when mature, mediate the 
physiological and psychological effect of psychoactive substances.  Because 
relatively little work exists in this area in humans, NIDA encourages studies 
characterizing neurobiological relationships between stress and relapse or 
treatment outcome.

H. Neurobiology of HIV/AIDS

A clear relationship exists between substance abuse and HIV/AIDS.  NIDA 
encourages the use of state-of-the-art neuroimaging techniques related to HIV 
disease progression, HIV-induced CNS degeneration and dysfunction, and 
neurobehavioral/neurocognitive performance with various drugs of abuse.  
Also, mechanistic studies are sought to elucidate how drug-induced modulation 
of CNS control of susceptibility, disease onset and morbidity occur (i.e., 
through direct action on the immune system or indirectly via the 
neuroendocrine system) in order to identify potential common approaches to 
prevent or treat the neurotoxic process.  Many HIV-positive individuals, who 
are undergoing antiretroviral therapy (e.g., HAART) and are using 
pharmacotherapeutic agents for other conditions, continue to abuse drugs. 
Studies are needed to understand the neurobiological interactive effects of 
concurrently halting the virus and treating addiction and/or a psychiatric 
disorder among abusers who continue abusing drugs.  Studies are needed to 
explore the mechanism of action of drugs of abuse on the progression of 
HIV/AIDS dementias (HAD), as well as to investigate the nature of viral 
damage to specific functional brain regions or circuits especially relevant 
to drug abuse (e.g., mesocortical limbic system, hippocampus, cortical 
association areas, cerebellum).  Other areas of study could include: 
investigations of the blood-brain-barrier permeability in HIV-positive, 
substance abusing individuals, antemortem and postmortem studies of the 
association between neurocognitive dysfunction, neuroprotective effects and 
anatomic/functional brain changes in drug abusers, longitudinal imaging 
studies evaluating changes in neuropsychological patterns and 
neuropsychological deficits in drug abusing HIV-infected individuals, 
structural and/or functional neuroimaging techniques to characterize brain 
changes over the course of infection in drug-abusing, HIV-positive 
individuals, as well as over the course of treatment, investigations that 
assess brain activation in drug users with a history of single versus 
polydrug exposure using neuroimaging techniques and neurocognitive tasks to 
determine effects of HIV infection as a function of disease progression and 
drug status, and investigations that assess the direct correlation between 
brain changes and neurobehavioral (e.g., neuropsychological/neurocognitive) 
status in drug-abusing, HIV-positive individuals.

I.  Neurobiology of Sleep

Individuals who are heavy users of, or addicted to, any one of a variety of 
psychoactive substances experience modifications in their sleep architecture 
including changes in the quality, quantity, patterns and type of sleep.  Even 
following withdrawal, where the usual symptoms have subsided, sleep 
disturbances remain.  This means that psychoactive substances are affecting 
some of the same brain mechanisms that control the onset and maintenance of 
sleep.  In short, researchers who study the cerebral mechanisms of sleep are 
also studying the cerebral mechanisms involved in drug addiction and 
dependence, and vice-versa.  For the most part, researchers fail to recognize 
this.  Therefore, studies are encouraged that combine the study of sleep with 
that of drug addiction.  Collaboration between of sleep researchers and drug 
abuse researchers could foster a powerful alliance in understanding the 
neuromechanisms underlying both drug addiction and altered sleep. 

J.  Neurobiology of Human Pain and Analgesia

This program builds on a broad, basic research program focusing on the long-
term treatment of chronic pain with minimal drug dependence.  Studies are 
encouraged to investigate the neurobiology of pain systems and the production 
of analgesia in human and clinical populations.  Investigations are needed to 
define the role of opioid and other analgesics in control of pain, either by 
reducing dependence liability or enhancing the efficacy of the analgesic.  
These studies include investigations into the development of tolerance and 
dependence, the role of neurotransmitter and receptor systems in the 
modulation of pain, and the events that result from chronic pain with an 
ultimate goal of finding effective treatments.  Alternative (e.g., 
acupuncture, cognitive-behavioral approaches, virtual reality) and adjunctive 
therapies that interact with neuronal systems involved in pain and analgesia 
to reduce the potential for drug dependence and tolerance are encouraged.  
Neuroimaging studies are particularly welcome, and these include analytical 
methods for the study of structural and functional correlates of pain 
perception, not only for diagnostic purposes but also for understanding the 
cognitive versus the sensory control mechanisms.  Further, NIDA encourages 
studies to characterize directly structural and functional aspects of 
pathways and CNS systems involved in pain (both acute and chronic) and their 
alterations with pharmacologic and/or behavioral therapies.

MECHANISMS OF SUPPORT

Support mechanisms include:  research project grant (R01), small grant (R03) 
exploratory/developmental grant (R21).  Refer to the guidelines for the 
specific eligibility requirements for the small grant program (R03) at 
http://grants.nih.gov/grants/guide/pa-files/PAR-00-059.html, the 
exploratory/developmental grant program (R21) at 
http://grants.nih.gov/grants/guide/pa-files/PA-01-012.html.  Because the 
nature and scope of the research proposed in this program announcement may 
vary, it is anticipated the size of an award will vary also.  Consultation 
with NIDA program staff is encouraged prior to application.  

As an applicant, you will be solely responsible for planning, directing, and 
executing the proposed project

This PA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  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.

ELIGIBLE INSTITUTIONS 

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

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

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.  

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA 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:

o Direct your questions about basic scientific/research issues (areas 1-15 
  above)to:

Roger M. Brown, Ph.D.
Associate Director for Neuroscience Coordination
Division of Neuroscience and Behavior Research
6001 Executive Boulevard, MSC 9555
Bethesda, MD 20892-9555
Telephone: (301) 443-1887
FAX: (301) 594-6043
Email: [email protected]

o Direct your questions about human neuroscience to:

Joseph Frascella, Ph.D.
Chief, Clinical Neurobiology Branch
Division of Treatment Research and Development
6001 Executive Boulevard, MSC 9551
Bethesda, MD 20892-9551
Telephone: (301) 443-4877
FAX: (301) 443-6814
Email: [email protected]

o Direct your questions about financial or grants management matters to:
 
Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
6001 Executive Boulevard, MSC 9541
Bethesda, MD  20892-9541
Telephone:  (301) 443-6710
FAX:  (301) 594-6847
Email:  [email protected]

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 
Email: [email protected].

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

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 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 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: 
Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application. 

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

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

2) Obtain agreement from NIDA staff that NIDA 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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

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 on or 
before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  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.

PEER REVIEW PROCESS

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 
(http://www.csr.nih.gov/refrev.htm) 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 score
o Receive a second level review by the appropriate national advisory council
	
REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss the following 
aspects of 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 technologies?

(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)

DATA SHARING:  The adequacy of the proposed plan to share data. 

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

AWARD CRITERIA

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

REQUIRED FEDERAL CITATIONS 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components 
involving Phases 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: http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

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 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 (http://grants.nih.gov/grants/guide/notice-
files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are 
available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.   
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 differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 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, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

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 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 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC):  Criteria for federal funding of research 
on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review. 

PUBLIC 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 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 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

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.

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 
http://www.health.gov/healthypeople.

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 services.  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 
http://grants.nih.gov/grants/guide/notice-files/NOT-DA-01-001.html.

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

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

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.279 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 
http://grants.nih.gov/grants/policy/policy.htm 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.

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