Full Text PA-96-010
 
MEDICAL AND HEALTH CONSEQUENCES OF DRUG ABUSE
 
NIH GUIDE, Volume 24, Number 42, December 8, 1995
 
PA NUMBER:  PA-96-010
 
P.T. 34

Keywords: 
  Drugs/Drug Abuse 
  Mental Disorders 
  Clinical Medicine, General 
  Epidemiology 

 
National Institute on Drug Abuse
 
PURPOSE
 
The purpose of this program announcement is to stimulate a wide range
of studies on the medical and health consequences of drug abuse,
including mental disorders.  Research on factors, processes and
mechanisms associated with the onset, duration, clinical
manifestations and treatment of medical and health consequences of
drug abuse is encouraged.  This includes general population- based
and clinical epidemiologic, clinical, and laboratory studies that
address issues of morbidity and mortality of drug abuse.  Parallel
animal and human studies, wherever appropriate, are encouraged.
Although HIV/AIDS issues are included within the medical and health
consequences addressed in this announcement, NIDA also has a number
of more specialized  announcements addressing HIV/AIDS.  This is a
reissuance of PA-92-16, published in the NIH Guide, Volume 20, No.
41, November 1, 1991.
 
HEALTHY PEOPLE 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This program
announcement, Medical and Health Consequences of Drug Abuse, is
related to the priority area of alcohol and other drugs.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0 or Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800).
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
Foreign institutions are not eligible for the First Independent
Research and Transition (FIRST) (R29) award.
 
MECHANISM OF SUPPORT
 
Research support mechanisms include the research project grant (R01),
small grant (R03), and FIRST awards (R29).  There are special
requirements for FIRST and R03 mechanisms; applicants intending to
apply utilizing either of these mechanisms, should contact the
program officer listed under INQUIRIES for further information.
 
Because the nature and the scope of the research proposed in response
to this program announcement may vary, it is anticipated that the
size of an award will also vary.
 
RESEARCH OBJECTIVES
 
Summary
 
Research studies are sought on (1) the extent and nature of medical
and health consequences among drug-abusing populations (e.g.,
epidemiology, natural history studies), (2) the underlying
pathophysiology of these consequences, and (3) the impact of
strategies to prevent and/or treat such consequences.  Studies of
pathophysiology should address (1) direct toxic effects of exposure
to drugs of abuse, alone or in frequently used combinations, (2)
mediation effects, such as drug-induced behavioral factors that
interfere with adherence to medical treatment regimens, and (3)
drug-related health/lifestyle variables (e.g., nutritional status),
that affect disease occurrence and course.  Other areas of emphasis
include the development, accessibility to, and utilization of
effective and cost-effective medical treatment for drug-related
medical conditions, and the influence of drug abuse on pre-existing
disease and its treatment.
 
Background
 
Drug abuse and drug-abusing behaviors have been associated with
increased morbidity and mortality, even prior to the advent of the
human immunodeficiency virus (HIV) epidemic.  Drug abuse has been
linked to many medical problems, including infectious diseases,
pulmonary disease, cardiac failure, and mental disorders.  The
longitudinal Drug Abuse Reporting Program (DARP) data, collected
between 1969 and 1985, revealed that mortality rates among opiate
users were three to fourteen times greater than those in age matched
individuals in the general population.  Mortality was due primarily
to violence, drug-abuse-related causes (e.g., overdose, cirrhosis),
and infectious and chronic diseases.  These data do not yet reflect
the burden of HIV disease.  Data collected on polysubstance abusers
in New York City in the early part of the HIV epidemic indicate an
increasing excess mortality from AIDS-associated infectious diseases.
However, given the combined influence of more recent factors such as
the more widely used array of drugs, the more complex patterns of
drug use associated behaviors, the evolution of the HIV epidemic and
the increasing availability of weapons, both morbidity and mortality
require further study.
 
Several physiological systems have been reported to be affected by
one or more legal or illicit drugs.  The following examples
illustrate the range and limitations of existing knowledge and,
hence, the need for further studies.
 
Pulmonary disease is reported to be associated with both tobacco and
marijuana smoking, while lung cancer to date has been reported only
in association with tobacco smoking.  For example, although marijuana
smoke, like tobacco, is mutagenic in the Ames test, produces impaired
pulmonary function, and causes dysplasia in chronic marijuana
smokers, an analogous linkage of cancer attributable to chronic
marijuana smoking has not been similarly investigated.  Smoking of
"crack cocaine" is associated with acute respiratory symptoms, and
may produce alterations in pulmonary function.
 
Cardiovascular complications have been linked to the use of tobacco,
alcohol, marijuana, cocaine, amphetamines, and inhalants.  For
example, the toxic effects of cocaine on cardiac and vascular cells
may be direct and indirect and are enhanced by chemical, physiologic
and environmental factors.  Cocaine in combination with anabolic
steroids has been hypothesized in one study as possibly producing
much more serious cardiotoxicity in athletes who tend to use both
drugs.  Moreover, the epidemiology of use patterns for both of these
substances suggests that both in isolation and taken together, these
drugs are significant risk factors for cardiovascular complications
in younger individuals.
 
Hepatotoxicity associated with alcohol is well-documented.
Similarly, the heroin-associated disruption of endocrine and
neuroendocrine systems (ACTH and cortisol, beta-endorphin, LH and
peripheral gonadal steroids, especially testosterone) has been
characterized.  However, the association of hepatic damage,
gastrointestinal and other endocrine disorders with the use of
marijuana, cocaine, inhalants and other drugs of abuse has been
reported but is less clearly established.
 
Fetal toxicity and related adverse developmental effects have been
reported with in utero exposure to nicotine, alcohol, opiates,
cocaine, and marijuana.  For example, childhood acute
nonlymphoblastic leukemia has been associated with in utero exposure
to marijuana.  Clear causal relationships have not been established
between exposure to illicit drugs during pregnancy and cardiac
disease, intellectual impairment in the child, and reproductive
disorders in the mothers.
 
Many co-morbid mental disorders have been reported among substance
abusers.  Common examples are rebound depression associated with
stimulant use; psychotic episodes precipitated by PCP, LSD, and
amphetamines; depression associated with drug withdrawal; and
suicidal behavior precipitated by substance abuse.  While chronic use
is associated with persistent psychoses or affective disorders, the
mechanisms underlying the associations with drug abuse remain to be
clearly established.  Accordingly, the degree to which the mechanisms
by which drug abuse causes and/or influences the course of
pre-existing mental disorders require further exploration.  For
example, drug abuse has been associated with the early onset of
schizophrenia.  However, schizophrenic patients are also at markedly
elevated risk for drug abuse.  In addition, major depression and
psychosis have been reported with anabolic steroid abuse, but the
underlying pathophysiology of mental illness in chronic anabolic
steroid abusers remains unclear.
 
It is well established that infectious diseases such as hepatitis,
HIV, endocarditis, and cutaneous abscesses are highly prevalent among
injection drug users.  Sexually transmitted diseases (STDs),
tuberculosis, pneumonia and hepatic disease are similarly prevalent
among both injection and non-injection users. However, for a number
of these diseases, the relationship of pathophysiology to continued
drug use remains unclear, and the optimization of treatment in the
active drug user continues to be problematic.
 
Accidental traumatic injury has been linked to alcohol, but the
relationship to drug abuse requires further study.  A survey of
persons with recent spinal cord injuries documented substantial abuse
of a variety of substances (but primarily alcohol, marijuana and
cocaine) both before and after injury.
 
General malaise, illness, diminished physical health and well- being
(quality of life), and increased hospitalizations have been commonly
reported with alcohol abuse.  The extent to which other drugs of
abuse also have similar adverse consequences remains to be
quantified.
 
Case-control and cohort studies are needed to strengthen
interpretations of relationships between drug abuse and reported
medical and health consequences.  In addition, new models and
instruments are needed to identify health and medical consequences,
including mental disorders, associated with drug abuse.  Models that
allow gender-specific consequences and gender differences to be
addressed where appropriate are particularly needed.  New assessments
and innovative research designs may facilitate analysis of clinical
data to detect subtle and long- term effects and to identify causal
relationships between drug abuse and medical consequences.
 
Areas of Interest
 
Areas that examine the question of drug abuse and medical and health
consequences that would be responsive to this program announcement
include, but are not limited to:
 
1.  Documentation of the occurrence of various medical disorders in
drug-abusing populations including the homeless, prostitutes,
minorities, adolescents, the elderly, and women, especially those
disorders not already recognized as associated with drug abuse.
 
2.  Examination of the relationships between behaviors associated
with drug use and acquisition and course of infectious diseases,
including HIV.
 
3.  Elucidation of the mechanisms by which substance abuse affects
cardiovascular, renal, hepatic, pulmonary/respiratory, immunologic,
endocrine, and other organ systems with reference to medical
outcomes.  Identification of the pathophysiological processes
initiated or potentiated by particular substances (e.g., crack
cocaine relative to cardiopulmonary complications), or combinations
of substances (polydrug use); and investigations linking drug
pharmacokinetic or pharmacodynamic parameters to medical outcomes.
Studies to determine gender differences, where appropriate, are
encouraged.
 
4.  Cancer epidemiologic studies to determine relationships between
the long-term abuse of drugs and hepatocellular cancer, lung cancer
and other cancers; studies of oncogenesis caused by drugs alone or in
combination with viral infections.
 
5.  Elucidation of associations between substance abuse during
pregnancy and medical conditions in the mother (e.g.,
obstetrical/gynecological, nutritional) and in the offspring (e.g.,
leukemia), and on child and adolescent development.
 
6.  Study of drug abuse associated endocrine dysfunction (e.g.,
changes in menstrual cycle) in women.
 
7.  Examination of the metabolic, nutritional, immunologic, mental
disorders or other medical/health outcomes that drug abuse may
influence through effects on a pre-existing or ongoing disease
processes, e.g., drug abuse effects in diabetics.  Vulnerability
studies to examine the effects of drug abuse on physiological systems
and later medical/health outcomes also would be appropriate.
 
8.  Evaluation and clarification of feedback loops or reciprocal
causality, where an existing health condition leads to substance
abuse that in turn leads to worsening of the original symptoms (e.g.,
self-medication for mental disorders that leads to exacerbation of
the disorder or delays recovery).
 
9.  Research on the relationship between infectious agent and disease
processes in drug abusers to examine the interplay of host and
pathogen factors and the influence of drugs as co-factors on the
natural history of disease.
 
10.  Examination of the relationship of drugs to the sexual
transmission of disease, including drug-related impairment of
judgment, and both host and viral factors that have an impact on
biological mechanisms of transmission.
 
11.  Development and modification of treatments for diseases
associated with drug abuse, such as alternatives to parenteral
therapy for patients with venous obliteration secondary to injection
drug use, or innovative antibiotic regimens applicable to drug
abusers with infections.
 
12.  Determination of the incidence and prevalence of all types of
hepatitis in drug abusers.  Feasibility and effectiveness studies of
specific health interventions, such as hepatitis B vaccination,
targeted at drug abusers.
 
13.  Research on patterns of clinical use of potentially abusable
prescription drugs (e.g., pain medications) in precipitating or
preventing medical complications, drug abuse relapse, mental
disorders or other conditions.
 
14.  Examination of mechanisms underlying mental disorder and drug
abuse comorbidity, including associations with suicidal ideation,
attempted suicides, and dyscontrol disorders.
 
15.  Exploration of the influence of prior/concurrent drug abuse on
the latency to onset and the course of disorders or conditions in the
elderly, e.g., Alzheimer's Disease; studies of association between
drug abuse and manifestations of aging; degenerative disorders such
as Parkinson's disease; memory impairment; stroke and other
cerebrovascular disease.
 
16.  Characterization of drug-related general health consequences
such as general malaise, fatigue, nonspecific illness and multiple
somatic complaints.
 
17.  Morbidity studies of associations between long-term drug abuse
and accidents and injuries, including those resulting in physical
disabilities or other long term consequences.
 
18.  Studies of the relationships between drug abuse and impairments
of performance, e.g., driving, work or academic performance,
including investigations of the neurological substrates of the
impairments.
 
19.  Examination of the relationships among undetected or known drug
abuse in patients and patterns of behavior by health care providers,
e.g., diagnostic efforts, prescription practices, treatment of pain
and emotional distress.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.
 
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.
 
Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application form
PHS 398 (rev. 5/95) and will be accepted at the standard
application deadlines as indicated in the application kit.
Application kits are available at most institutional offices of
sponsored research and may be obtained from the Office of Grants
Information, Division of Research Grants, National Institutes of
Health, 6701 Rockledge Drive, Room 3032, MSC 7762, Bethesda, MD
20892, telephone
301/435-0714, email:  girg@drgpo.drg.nih.gov.  The title and
number of the program announcement must be typed in Section 2a on the
face page of the application.
 
FIRST award applicants must include at least three sealed letters
of reference attached to the face page of the original
applications.  FIRST award applications submitted without the
required number of reference letters will be considered
incomplete and will be returned without review.
 
The completed original application and five legible copies must
be sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM MSC-7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817-7710 (for express/courier service)
 
REVIEW CONSIDERATIONS
 
Applications that are complete will be evaluated for scientific and
technical merit by an appropriate peer review group convened in
accordance with the standard NIH peer review procedures.  As part of
the initial merit review, all applications will receive a written
critique and undergo a process in which only those applications
deemed to have the highest scientific merit, generally the top half
of applications under review, will be discussed, assigned a priority
score and receive a second level review by the appropriate national
advisory board or council.  Small grants do not receive a
second-level review.
 
Review Criteria
 
o  scientific, technical, or medical significance and originality of
proposed research;
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
o  availability of the resources necessary to perform the research;
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
o  adequacy of the plans to include both genders and minorities and
their subgroups as appropriate for the scientific goals of the
research.  Plans for the recruitment and retention of subjects will
also be evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects, and the safety of the
research environment.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding
decisions:  quality of the proposed project as determined by peer
review, availability of funds, and program priority.
 
INQUIRIES
 
Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Jag H. Khalsa, Ph.D.
Division of Clinical and Services Research
National Institute on Drug Abuse
5600 Fishers Lane, Room 11A-33
Rockville, MD  20857
Telephone:  (301) 443-1801
FAX:  (301) 594-6566
Email:  JKHALSA@AOADA.SSW.DHHS.GOV
 
Direct inquiries regarding fiscal matters to:
 
Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
5600 Fishers Lane, Room 8A-54
Rockville, MD  20857
Telephone:  (301) 443-6710
Email:  GFLEMING@AOADA.SSW.DHHS.GOV
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.279.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78- 410, as
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants policies and Federal Regulations 42 CFR 52 and 45
CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency
review.  Grants must be administered in accordance with the Public
Health Service Grants Policy Statement, (DHHS Publication No. (OASH)
82-50-000 GPO 0017-020- 0090-1 (rev. 10/01/90).
 
The PHS strongly encourages all grant recipients to provide a
smoke-free work place and promote the non-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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