Expired PA-14-162: Effects of Cannabis Use and Cannabinoids on the Developing Brain (R21)

Part 1. Overview Information

Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute on Drug Abuse (NIDA)
Funding Opportunity Title	Effects of Cannabis Use and Cannabinoids on the Developing Brain (R21)
Activity Code	R21 Exploratory/Developmental Grant
Announcement Type	New
Related Notices	January 09, 2018 - Notice of Plans to Allow 13 NIDA Program Announcements to Expire Without Renewal and Guidance to Applicants on how to Apply for Research Grants in Those Topic Areas. See Notice NOT-DA-17-065. May 10, 2017 - New NIH "FORMS-E" Grant Application Forms and Instructions Coming for Due Dates On or After January 25, 2018. See NOT-OD-17-062. April 10, 2017 - Notice of Change in the Expiration Date for PA-14-162. See Notice NOT-DA-17-017. NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015) June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
Funding Opportunity Announcement (FOA) Number	PA-14-162
Companion Funding Opportunity	PA-14-163, R01 Research Project Grant and PA-14-164, R03 Small Research Grant
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.279
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) encourages exploratory/developmental grant (R21) applications from institutions and organizations that propose to study the effects and functional consequences of cannabis and cannabinoid exposures on the developing brain, from pre-, peri-, post-natal development through young adulthood in animal models and humans. Topics of interest pertaining to this PA include, but are not limited to: molecular and cellular mechanisms of cannabis/cannabinoid effects on the developing brain; long term functional consequences of cannabis/cannabinoid exposure on learning and memory, cognitive and emotional development.

Key Dates

Posted Date	March 26, 2014
Open Date (Earliest Submission Date)	May 16, 2014
Letter of Intent Due Date(s)	Not Applicable
Application Due Date(s)	Standard dates apply, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Standard AIDS dates apply, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	New Date January 8, 2018 per issuance of NOT-DA-17-017. (Original Expiration Date: May 8, 2017)
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

Note: This Exploratory/Developmental Grant (R21) FOA, accompanying the Research Project Grant (R01) FOA, PA-14-162, solicits two-year research project applications for the studies of effects of cannabis use and cannabinoids on the developing brain. Exploratory/developmental applications are encouraged to test novel scientific ideas, emerging new hypotheses or model systems, and develop tools and technologies that have the potential for significant impact on the effects of cannabis use and cannabinoids on the developing brain. An R21 grant application need not have preliminary data, but should reflect high-risk-high-impact qualities. The goal of this FOA is to accelerate early stage development of promising concepts, hypotheses and facilitate the progress in overcoming technical challenges.

NIDA supports research to understand, prevent, and treat substance use disorders and mitigate their consequences to improve the public s health. Current epidemiological survey data on cannabis and cannabinoids use among adolescents over the last five-years show significant increases in past-year and past-month (current) cannabis use across 8th, 10th and 12th grades. And rates of daily or nearly daily cannabis and cannabinoids use among 12th graders are at 6.5%. These increases parallel softening attitudes about the perceived risk of harm and disapproval associated with cannabis and cannabinoid use. These data, coupled with evolving policies on cannabis and cannabinoid use are likely to impact the use of cannabis and cannabinoids by different segments of the population (especially youth), strengthening the need to fully understand and address the potential risks of exposure. Particularly important is understanding how and when the brain is most vulnerable to insult or injury, e.g., during fetal development, childhood, and adolescence periods of active maturation. Information from animal models as well as human studies is needed on the impact of chronic, as well as acute, cannabis/cannabinoid exposure on a variety of outcomes, spanning molecular, cellular, and neurobiological approaches; brain imaging (e.g., anatomy and connectivity); and behavior.

Exposure to cannabis and cannabinoids during prenatal, perinatal, postnatal, childhood and adolescent development may produce enduring neurobiological and neurodevelopmental effects that could have wide-ranging impact extending into adulthood, including the possibility of cognitive impairments and heightened vulnerability to drug addiction. In animal models, early (i.e., prenatal, postnatal, adolescent) cannabis exposure leads to specific neuronal alterations, especially in the nucleus accumbens enkephalin/D2 striatopallidal neurons, as well as dysregulation of repressive epigenetic marks, and impaired synaptic plasticity, and these may translate to altered behavioral endpoints, such as increased impulsivity, among others.

Yet, in humans, both cannabis and cannabidiol (CBD; one of ~85 cannabinoids found in cannabis) have been suggested as treatments for a variety of indications, without a detailed understanding of either their beneficial or adverse effects, especially on the developing (and vulnerable) brain. Given that some states have legalized the use of cannabis for medical or recreational purposes, a better understanding of how cannabis and its components affect brain function, especially during neurodevelopmental periods, is warranted. We would expect there to be different effects of cannabis/cannabinoid exposure based on the precise timing (e.g., developmental stage), frequency of exposure, dosages, constituent(s) etc; therefore, experiments designed to address these aspects are of interest.

Purpose and Objectives

The purpose of this FOA is to support research that will examine whether chronic, intermittent and/or acute exposure to cannabis and cannabinoids (e.g., delta9-THC, cannabidiol) during active periods of brain development (e.g., fetal, adolescent) can cause long term changes in brain function. Emerging evidence suggests that THC exposure leads to a spectrum of behavioral effects, dependent on age, sex/gender, genetic, and environmental factors (and their interactions). However, there are surprisingly few basic research studies assessing cannabinoid exposure on neurodevelopment or neurobiology and the impact on subsequent behavioral or biological outcomes.

Studies in humans have suggested adverse psychiatric, cognitive, and behavioral consequences of cannabis use in both adults and children, often dependent on time of exposure; frequency of use; and genetic or other factors. For example, early and frequent cannabis use has been associated with decreases in IQ, heightened risk of substance abuse in later life, and psychiatric disorders in genetically vulnerable individuals. Most of these findings come from epidemiological studies conducted in humans, which are by their nature, observational and correlational, making it difficult to attribute causality to reported consequences of cannabis exposure. Thus, research is needed to provide a deeper mechanistic and causal understanding of cannabis effects.

Neurocognitive assessments along with functional neuroimaging measures, such as task-based fMRI, resting-state fMRI, as well as positron emission tomography (PET) indicate that cannabis/cannabinoid use and abuse can alter brain activity, executive function, intelligence, and possibly risky behavior and impulsivity. Similarly, findings from other animal and human studies have reinforced that cannabis and cannabinoid exposure is associated with defective neurogenesis in hippocampus and reduction of hippocampal and amygdaloidal volume, respectively. Since the endocannabinoid system is involved in neurogenesis, neuronal migration, axon guidance, and synaptic plasticity, research is needed to understand the biologic and neurobehavioral consequences of cannabis exposure on brain function.

While research to understand the long-term neurobehavioral consequences of early exposure is important, there is also a need to better understand the neurobiology of the rewarding or reinforcing effects of specific cannabinoids in cannabis, especially ?9-THC. Animal models of self-administration are lacking and this is a current challenge in the field. Prior studies of experimenter-administered THC (i.e., passive exposure) do not model drug-taking or seeking behavior in the human user. Moreover, much prior research has been conducted with THC concentrations that may not adequately reflect the potency and constituency of cannabis/cannabinoids used today. Animal models need to be developed so that higher potency cannabis/cannabinoids can be used to explore questions, such as effects on cognition, emotion, and motivation over the course of prenatal, adolescent and young adulthood development.

Studies of sex/gender specific outcomes that show differences in brain morphology, age-dependent changes in cannabinoid receptor binding, pharmacokinetics, pharmacodynamics, and variation of behaviors such as acquisition, withdrawal, reinstatement of cannabinoids dependence and effects on learning and memory should be expanded as applicable.

The research areas of interest of this FOA include, but are not limited to the following:

Animal or Human Research on the Impact of Cannabis and Cannabinoids on the Developing Brain, such as:

The cellular and molecular mechanisms of cannabis or cannabinoid exposure on known and yet to be discovered endocannabinoid and cannabinoid receptor signaling in neurogenesis, migration, and neuronal and glial differentiation
Effects on dendritic and axonal outgrowth, navigation, target selection and synaptogenesis
Effects on the cellular and molecular mechanisms during neural circuit formation and connectivity, synaptic modulation, pruning and neural plasticity during fetal, perinatal and adolescent period
Interactions with neuroimmune function in the developing brain
Effects on chromatin remodeling, gene transcription, post transcriptional RNA processing and protein translation
Identification and characterization of single nucleotide polymorphisms of cannabinoid receptors, FAAH, co-activators and other molecules, known or to be identified, that affect physiology in the presence of cannabis and cannabinoids
Impact of exposure on brain energetics and metabolism during development
Changes in brain structure and dynamic activity as a function of cannabis/cannabinoids use, either alone or more commonly in conjunction with other substances (i.e. nicotine, alcohol)
Molecular imaging of changes in gene expression and epigenetic factors as the consequence of cannabis and cannabinoid exposure in the developing brain
Research to identify and characterize the behavioral consequences of genetic, cellular and neuroanatomical changes induced by cannabis/cannabinoids exposure during development, such as:
- Effects of early cannabis and cannabinoid exposures on critical aspects of cognitive processes (attention, memory, decision-making, impulsivity, etc.) in later life
- Effects of cannabinoids, especially ?9-THC, on cognitive, emotional and motivational processes at different stages of development
- Vulnerability changes produced by early life cannabis/cannabinoid exposure, on subsequent drug sensitivity or the motivation for administering other drugs of abuse, and studies on the neurobiological mechanisms for cross-sensitization

Technology and Methods Development for Studying Cannabis and Cannabinoid Effects

Using iPS cells derived from chronic cannabis users for the studies of neuronal differentiation, neural circuit formation, synaptic modulation and functional analyses
Site and tissue specific gene mutation or knock out of cannabinoid receptors or co-activators in developing brains in hippocampus, amygdala and prefrontal cortex for the study of roles of endocannabinoids as well as consequences of cannabinoid exposure
Development of methods for assessing self-administration of ?9-THC and cannabis smoke of various cannabinoid compositions

Note: For functional genomics studies of cannabis and cannabinoid effects and consequences, applicants are encouraged to respond to PA-14-014 "Functional Genetics, Epigenetics, and Non-coding RNAs in Substance Abuse (R01)".

All projects must adhere to a core set of reporting standards for rigorous study design. The standards are described fully in www.nature.com/nature/journal/v490/n7419/full/nature11556.html.

Randomization

Animals should be assigned randomly to the various experimental groups, and the method of randomization reported.
Data should be collected and processed randomly or appropriately blocked.

Blinding

Allocation concealment: the investigator should be unaware of the group to which the next animal taken from a cage will be allocated.
Blinded conduct of the experiment: animal caretakers and investigators conducting the experiments should be blinded to the allocation sequence.
Blinded assessment of outcome: investigators assessing, measuring or quantifying experimental outcomes should be blinded to the intervention.
Sample-size estimation
An appropriate sample size should be computed when the study is being designed and the statistical method of computation reported.
Statistical methods that take into account multiple evaluations of the data should be used when an interim evaluation is carried out.
Data handling
Rules for stopping data collection should be defined in advance.
Criteria for inclusion and exclusion of data should be established prospectively.
How outliers will be defined and handled should be decided when the experiment is being designed, and any data removed before analysis should be reported.
The primary end point should be prospectively selected. If multiple end points are to be assessed, then appropriate statistical corrections should be applied.
Investigators should report on data missing because of attrition or exclusion.
Pseudo replicate issues need to be considered during study design and analysis.
Investigators should report how often a particular experiment was performed and whether results were substantiated by repetition under a range of conditions.

Special Considerations

HIV/AIDS Counseling and Testing Policy for the National Institute on Drug Abuse: In light of recent significant advances in rapid testing for HIV and in effective treatments for HIV, NIDA has revised its 2001 policy on HIV counseling and testing. NIDA-funded researchers are strongly encouraged to provide and/or refer research subjects to HIV risk reduction education and education about the benefits of HIV treatment, counseling and testing, referral to treatment, and other appropriate interventions to prevent acquisition and transmission of HIV. This policy applies to all NIDA funded research conducted domestically or internationally. For more information see https://grants.nih.gov/grants/guide/notice-files/NOT-DA-07-013.html.

National Advisory Council on Drug Abuse Recommended Guidelines for the Administration of Drugs to Human Subjects: The National Advisory Council on Drug Abuse (NACDA) recognizes the importance of research involving the administration of drugs with abuse potential, and dependence or addiction liability, to human subjects. 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 Web site at http://www.drugabuse.gov/funding/clinical-research/nacda-guidelines-administration-drugs-to-human-subjects.

Points to Consider Regarding Tobacco Industry Funding of NIDA Applicants: The National Advisory Council on Drug Abuse (NACDA) encourages NIDA and its grantees to consider the points it has set forth with regard to existing or prospective sponsored research agreements with tobacco companies or their related entities and the impact of acceptance of tobacco industry funding on NIDA's credibility and reputation within the scientific community. Please see http://www.drugabuse.gov/about-nida/advisory-boards-groups/national-advisory-council-drug-abuse-nacda/council-statements/points-to-consider-regarding- for details.

Data Harmonization for Substance Abuse and Addiction via the PhenX Toolkit: NIDA strongly encourages investigators involved in human-subjects studies to employ a common set of tools and resources that will promote the collection of comparable data across studies and to do so by incorporating the measures from the Core and Specialty collections, which are available in the Substance Abuse and Addiction Collection of the PhenX Toolkit (www.phenxtoolkit.org). Please see NOT-DA-12-008 for further details.

Section II. Award Information

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New Resubmission Revisions The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget	Direct costs are limited to $275,000 over an R21 two-year period, with no more than $200,000 in direct costs allowed in any single year.
Award Project Period	The maximum period is 2 years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education
Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

Hispanic-serving Institutions
Historically Black Colleges and Universities (HBCUs)
Tribally Controlled Colleges and Universities (TCCUs)
Alaska Native and Native Hawaiian Serving Institutions
Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

Small Businesses
For-Profit Organizations (Other than Small Businesses)

Governments

State Governments
County Governments
City or Township Governments
Special District Governments
Indian/Native American Tribal Governments (Federally Recognized)
Indian/Native American Tribal Governments (Other than Federally Recognized)
Eligible Agencies of the Federal Government
U.S. Territory or Possession

Other

Independent School Districts
Public Housing Authorities/Indian Housing Authorities
Native American Tribal Organizations (other than Federally recognized tribal governments)
Faith-based or Community-based Organizations
Regional Organizations
Non-domestic (non-U.S.) Entities (Foreign Institutions)

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) 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.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed

Required and Optional Components

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover