Expired PAR-14-105: Synthetic Psychoactive Drugs and Strategic Approaches to Counteract Their Deleterious Effects (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	Synthetic Psychoactive Drugs and Strategic Approaches to Counteract Their Deleterious Effects (R21)
Activity Code	R21 Exploratory/Developmental Research Grant
Announcement Type	New
Related Notices	December 18, 2017 - This PA has been reissued as PAR-18-509. April 18, 2017 - Notice of Change in the Expiration Date for PAR-14-105. See Notice NOT-DA-17-025. 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. February 27, 2014 - See Notice NOT-DA-14-006. Notice that NIDA's "Synthetic Psychoactive Drugs and Strategic Approaches to Counteract Their Deleterious Effects" Funding Opportunity Announcements Have Been Reposted as PARs.
Funding Opportunity Announcement (FOA) Number	PAR-14-105
Companion Funding Opportunity	PAR-14-106 R01 Research Project Grant PAR-14-104, R03 Small Grant Program
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.279
Funding Opportunity Purpose	The purpose of this FOA is to support research to deepen our knowledge of the use of synthetic psychoactive drugs, their mechanisms of action, their health effects, and development of prevention strategies and strategies to treat patients in emergency departments and long range treatment.

Key Dates

Posted Date	February 20, 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 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-17-025. (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

Synthetic psychoactive drugs (SPDs) are substances that are specifically designed to mimic the actions of known abused drugs, may skirt the legal definition of an illegal substance, and may pose a public health threat. SPD use is particularly alarming with increasing reports of a variety of health consequences, such as heart trouble, vomiting, agitation, confusion, hallucinations, violence, suicidal thoughts, and even death. Still, 11.3% of high school seniors reported use of synthetic psychoactive (SP) cannabinoids in 2012, a rate that is second only to marijuana itself among illicit drugs. Furthermore, over 60% of people admitted to an emergency department in 2011 for their reported SP cannabinoid use were between 12 and 20 years of age.

The illusive marketing strategies deployed by illicit producers of the SPDs and the difficulties associated with identifying and controlling new SPDs are proving challenging for health officials and law enforcement. It is increasingly difficult to predict SPD effects, establish epidemiologic patterns, and prioritize for basic research to gain fundamental knowledge about their pharmacology and toxicology. Nonetheless, the surge of SPD use during the last 8-10 years is a major public health concern and necessitates multiple lines of a research agenda to help counter their increasingly widespread use.

SPDs can be classified as follows: 1) SP Cannabinoids (THC-mimics, e.g. JWH compounds) are usually herbal products that are contain SP additives that produce experiences similar to marijuana, but can be more potent and unpredictable. This class of drugs appears to be the most commonly abused; 2) SP Cathinones (stimulant-mimics, e.g. methylone, e.g. MDPV [3,4-methylenedioxypyrovalerone]) differentially interact with several physiological targets and depending on their individual profile, their pharmacology can range from powerful stimulant to hallucinogenic effects; 3) SP Opiates (opiate-mimics, e.g. acetyl fentanyl) tend to be more potent analgesics than morphine, have euphoric and sedative properties, faster onset of action and a shorter elimination half-life, and higher addictive potential than morphine; 4) SP Hallucinogens are structurally related to mescaline, exhibit hallucinogenic properties and can have severe toxic effects; 5) Other SPDs, such as those currently being used overseas and have potential for abuse in the US; and 6) Designer Cocktails, which generally refer to the mixture and abuse of prescription pharmaceuticals and is not a focus of this FOA.

Among the research needs is to establish and understand the receptor targets, signaling pathways, neurodevelopmental, and neurocircuitry effects of these SPDs. Although little is known about their detailed pharmacology, toxicology and metabolism, some of the SPD compounds have shown potent activity at the monoamine neurotransmitter and endocannabinoid systems. There are reports showing that rats self-administer SP cathinones similar to, or more robustly than, methamphetamine. SPDs also demonstrate addictive properties; they can induce intense cravings, tolerance, dependence, and strong withdrawal symptoms. A number of toxicological symptoms have been reported with synthetic drugs. However, the observed effects cannot be relied upon as the typical toxicological profile is a combined result of the drug compound and the non-drug ingredients (how the drug is synthesized and purified) of the dosage form. Because of the lack of available evidence, epidemiologic data and studies on how to treat SPD intoxication are needed.

This R21 mechanism is for exploratory/developmental research. Applicants with novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research, should consider applying for this mechanism. Alternatively, applicants with small well-defined research ideas should consider the companion R03 small grant mechanism. The R03 supports discrete, well-defined projects that realistically can be completed in two years and that require limited levels of funding. Both the R03 and R21 mechanisms are for two years of support. Preliminary data are not required for R03 or R21 applications; however, they may be included if available.

Research Objectives

The goal of this FOA is to support the necessary science to help inform researchers, clinicians, emergency personnel, and policymakers of the current epidemiologic trends, mechanisms of actions, and the clinical strategies to mitigate the consequences of these dangerous SPD compounds.

Epidemiological data generated will be the main guiding force for research directions, which will consist of basic research into the analysis of the new products and development of detection techniques, methods development and preclinical evaluation. Concomitantly, research on clinical evaluation, determination of toxicological and medical consequences is also needed.

For the purposes of this FOA, priority will be given to research examining the SP cannabinoids and cathinones, although all classes will be considered if well-justified. This FOA will support 4 specific categories of research. Applicants are encouraged to speak with the Scientific/Research contact listed for each category prior to applying.

Where applicable, applicants are encouraged to conduct research to address sex/gender differences.

Category 1. Epidemiological and prevention research

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

Studies that examine rates (e.g., prevalence) and changes over time of use of SPDs and associated medical, social and behavioral consequences in general and specified populations (e.g., adolescents, socially active young adults, athletes and high risk groups such as individuals subject to drug testing) and variations by gender, race/ethnicity and socio-demographic factors.
Studies of patterns of use of SPDs including context or setting of use, types of dosage forms (e.g., incense, candles, fertilizers, sprays, bath salts types, pastes), mode of administration and use of co-ingestants.
Research on factors which influence initiation, continuation and desistance of use of specific SPDs in different populations. Examples include: knowledge, attitudes and perceptions pertaining to synthetic drugs; market and distribution factors; policies; and the role of peer influences, social media and the internet.
Studies of social, cultural, behavioral and environmental factors that influence patterns of use and availability of SPDs.
Studies on the emergence, spread and geographic distribution of SPD use, including development of rapid assessment models and methods to investigate and verify purported new outbreaks of use of SPDs and associated adverse effects.
Examination of SPD marketing and distribution methods.
Development of models and methods for early detection of SPDs using leading or real-time indicators. Examples include data development and implementation of models for rapid dissemination of alerts and information to the public and public health entities (e.g., rates of emergency department use and outcomes, costs of visits, etc) on adverse effects of SPDs, incidence data from poison centers; emergency departments; news media and the internet; and social media such as Facebook and Twitter.
Studies of risk behaviors associated with or co-occurring with SPD use (e.g., sexual risk behaviors, injection, violence).
Investigation of why certain populations have high rates of specific categories/types of SPDs (e.g., high rates of cannabinoid use among high school students), to assist in developing prevention messages.
Strategies for improved communication with DEA and investigators in the field on emerging drugs.
Development and testing of (targeted) prevention messages for populations at-risk for use and abuse of existing and emerging SPDs.
Studies to explore and test the impact of existing evidence-based drug abuse prevention programs and approaches or variants of existing approaches on SPD use and abuse behaviors and patterns.
Research on approaches and strategies for screening, detection, prevention and treatment of SPD use and abuse (i.e., SBIRT models) in emergency departments, primary care, and other health care settings.

Category 2. Basic and preclinical research

Areas of interest include, but are not limited to:

Studies on stability, pharmacokinetic and pharmacodynamic (PK/PD) profiles (depending on route of administration), development of specific and sensitive analytical methods for in vitro and in vivo analysis including, urine, blood, saliva, sweat, etc;
Studies that determine the ligand binding properties of SPDs to receptors; including off-target binding effects; determine agonism/antagonism, structure-activity studies to develop very potent and selective, and ultra-fast antagonists as potential detoxifying treatment drugs;
Studies on neurotransmitter release and uptake following acute and chronic exposure to SPDs;
Development of interaction profiles of common SPD ingredients with receptors, channels, transporters, enzymes, etc as a guide to estimate potential biological activity and toxicity;
Studies in animal behavioral models to determine addiction liability, drug interactions, and the effects of exposure to synthetic drugs on the development of vulnerability to other drugs of abuse, at various developmental stages;
Preclinical studies of acute and longer-term effects on processes such as sensation and perception, cognition, learning and memory, emotion and anxiety, and social interactions, along a developmental continuum, including the identification of novel effects that have not been observed with traditional drugs of abuse;
Comparative investigations of these SPDs versus other abused substances, such as choice behavior, relative reinforcement, and the ability to reinforce associations with environmental stimuli that serve as cues prompting drug-taking behavior;
Development of analytic detection methods to identify the active ingredients present in a given SPD, and to the extent possible, identifying residual solvents, metals and reaction ingredients (cyanides, thiocyanates, diluents, herbals, etc) and account for purity and potential toxicological profiles;
Identification of biomarkers as proxies for detecting SPDs in vitro and in vivo;
Studies on circadian and/or bioenergetics effects of SPDs;
Research to elucidate the mechanisms of both immediate and long range effects of SPDs on CNS and other systems;
Imaging studies to identify the general SPD effects on brain activity, blood flow and circuit connectivity.

Category 3. Human studies and clinical research

Topics of interest include, but are not limited to:

Psychopharmacological studies including measures of subjective drug effects, effects on perceptual, cognitive, and reinforcement processes, either separately or combined with measures of brain structure and/or function. Such studies could include investigations of dose-response functions and/or different routes of administration.
Residual effects in individuals who take the drug on a chronic or intermittent basis after acute or long-term abstinence.
Individual differences related to gender, personality, ethnicity and race, age, other drug use or prior drug history, and/or co-occurring (e.g., psychiatric, psychological, neurologic) conditions.
Effects of SPDs on sleep, wakefulness, and biorhythms.
SPD Effects on complex behaviors, such as driving
Influence of variation in genes involved in the drug’s endogenous transmitter, receptor, or cellular signaling pathways.

Category 4. Medical consequences and therapeutic approaches

Topics of interest include, but are not limited to:

Clinical research to study short- and long-term health consequences associated with consumption of cathinones (bath salts) or SP marijuana. These studies may examine effects on neurological, psychiatric, cardiovascular, or other physiological systems and may examine the pathophysiology or the time course of pathological affects.
Clinical studies examining interventions to ameliorate the toxicological/ pathophysiological consequences associated with consumption of SP marijuana or cathinone derivatives.

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 (https://grants.nih.gov/grants/guide/notice-files/NOT-DA-12-008.html) 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 Revision 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	The combined budget for direct costs for the two year project period may not exceed $275,000. No more than $200,000 may be requested in any single year. Applicants may request direct costs in $25,000 modules, up to the total direct costs limitation of $275,000 for the combined two-year award period.
Award Project Period	The maximum project 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 and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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