CHEMISTRY, PHARMACOLOGY, AND TOXICOLOGY OF SMOKED DRUGS OF ABUSE

RELEASE DATE:  April 3, 2002

PA NUMBER:  PA-02-095

EXPIRATION DATE:  April 20, 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 Mechanism(s) 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 National Institute on Drug Abuse (NIDA) encourages research that will 
further the understanding of the chemical composition of smoked drugs of 
abuse, and the resulting pharmacological and toxicological effects associated 
with such exposure.  This PA solicits nonclinical basic research efforts 
aimed at chemical isolation/identification, metabolic studies, 
pharmacokinetics, and in vitro cellular and in vivo animal 
pharmacology/toxicology studies of condensates or extracts of volatile 
materials and particulates produced in a smoking process.  The drugs of abuse 
of interest include marijuana, tobacco, crack cocaine, heroin, PCP, and 
methamphetamine hydrochloride.

RESEARCH OBJECTIVES

Background

According to the Substance Abuse and Mental Health Services Administration 
(SAMHSA) Household Survey on Drug Abuse (2000), it is estimated that 
approximately fifty-five million Americans use cigarettes with varying 
frequency, while marijuana remained the most commonly used illicit drug in 
the United States among adults and adolescents, followed by crack cocaine and 
methamphetamine, and to a lesser extent, heroin and PCP.  Smoking is the 
preferred route of administration for many abused substances, including 
tobacco, marijuana, and crack cocaine.  Other abused agents are smoked to 
avoid intravenous injection.  Marijuana, PCP, cocaine, and methamphetamine 
are often consumed in addition to tobacco products, or mixed together with 
tobacco in cigars ("blunts").  The complexity and number of products present 
in the particulate phase of smoke resulting from the burning/pyrolysis of 
tobacco, marijuana, and to a lesser extent, cocaine and PCP, have been 
examined to some degree and discussed in the scientific literature.  These 
products include, for example, tobacco-specific N-nitrosamines, aldehydes, 
phenols, polycyclic aromatic hydrocarbons, and specific products of 
cannabinoid and cocaine pyrolysis. 

Some constituents of smoked drugs have been studied and characterized.  For 
example, the carcinogenicity of some tobacco smoke products has been 
established, however, more research is needed.  Some of the products of 
marijuana smoke have shown mutagenic activity when activated by enzymes.  The 
products from PCP, cocaine, or methamphetamine smoke have been less 
thoroughly studied for their carcinogenic potential.  Clearly, however, 
additional research is needed in this area. 

Finally, it has also been recognized that many of these agents have a health 
risk potential because of their effects on respiratory system responsiveness 
and function, including exacerbation of asthma, pulmonary edema, dyspnea, 
bronchoconstriction, and release of proinflammatory mediators. 

This PA will encourage research aimed at:  (1) determining the chemical 
composition of smoked drugs of abuse, (2) understanding the biological 
consequences resulting from exposure to these chemicals, and (3) determining 
the mechanism(s) of action of volatilized compounds using in vivo and in 
vitro models.  The research approaches that would be appropriate to address 
these issues are varied.  The following is just a partial list of possible 
strategies, approaches, and questions that need to be addressed in this area:

(1) Methods to identify chemical components

o  Develop procedures to obtain and isolate materials from the smoking 
process, such as vapor phase condensation and chromatographic fractionation, 
and the extraction of residues, particulates, filters, and solvent/buffer 
systems. 

o  Design of aerobic/anaerobic pyrolysis systems, smoking devices, and flow 
systems to expose cells or whole animals to vapor phases.

o  Develop methods for identification and analytical characterization of 
individual components of the smoking process, particularly new compounds not 
previously reported, that may have potential carcinogenic, immunological, 
medicinal, or other biological effects.  Of particular interest are compounds 
produced when various drugs are mixed or volatilized with tobacco, such as 
can occur with a mixture of methamphetamine and tobacco.

o  Evaluate the effect of pyrolysis/burning temperature on chemical 
composition, including mechanism of compound formation and decomposition.

o  Conduct chemical characterization of bulk materials and delivery devices 
such as processed tobacco leaf, bulk marijuana, cigars, and marijuana and 
tobacco cigarettes from domestic and foreign sources. 

(2) Biological consequences of smoked substances 

o  Determine inhalation toxicity of volatilized substances during and 
following acute/subacute animal exposure, including 
pathological/histopathological findings.

o  Determine the effects of exposure of bronchial/lung epithelial cells 
(primary cells and cell lines) to smoke or materials condensed from smoke, 
which could include genotoxicity and cytotoxicity assays, measures of DNA 
adduct formation, changes in cellular enzymes, proteins, or receptor 
expression. 

o  Conduct mutagenicity testing of condensates or the extracts of smoke 
particulates 

(3) Mechanisms of action 

o  Conduct pharmacokinetic studies of individual compounds found in smoked 
substances that have putative or potential biological, toxicological, or 
addictive properties.

o  Conduct metabolic studies to determine the metabolites of individual 
compounds associated with the smoking process.

o  Identify new biomarkers for detecting inflammatory and malignant or 
premalignant processes in bronchial/lung cells and tissues.

o  Conduct studies that examine, identify, and determine the role of enzymes 
that activate or detoxify smoked compounds, such as cytochrome P450s, 
peroxidases, and sulfotransferases.

MECHANISMS OF SUPPORT

This PA will use the NIH research project (R01), small grant (R03), and 
exploratory/developmental grant (R21) award mechanisms.  As an applicant, you 
will be solely responsible for planning, directing, and executing the 
proposed project.  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, and the 
exploratory/developmental grant program (R21) at 
http://grants.nih.gov/grants/guide/pa-files/PA-01-012.html.  

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 two 
areas:  scientific/research, and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Paul Hillery, Ph.D.
Division of Neuroscience and Behavioral Research
National Institute on Drug Abuse
6001 Executive Boulevard, Room 4282   MSC 9555
Bethesda, MD  20892-9555
Telephone:  (301) 443-6275
Email: [email protected]

o Direct your questions about financial or grants management matters to:

Gary Fleming, J.D., M.A.
Grants Management Branch, OPRM
National Institute on Drug Abuse
6001 Executive Boulevard, Room 3131   MSC 9541
Bethesda, MD  20892-9541
Telephone:  (301) 443-6710
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 the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study, 

2) Obtain agreement from 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 
or board
 
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.

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 

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.

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 see
http://grants.nih.gov/grants/guide/pa-files/PA-02-015.html. 

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