Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 256
GUIDELINES FOLLOWED IN THE PROTECTION OF SUBJECTS
The Nuremburg and Helsinki guidelines were regarded by the
investigators and their supervisors as appropriate constraints in
studies performed on volunteers, although this was not clearly arti-
culated in official memoranda until the mid 1960~. The provision of
accurate, informative explanations of what was planned and what might
be expected was regarded as essential to the continuance of the pro-
gram. Written consents, witnessed by medical staff members, were
required from the outset and became more elaborate with time. How-
ever, minutes of hearings conducted by the U.S. Senate Subcommittee
on Health and Subcommittee on Administrative Practice and Procedure,
September 10-12, 1975, stated that the consent information was
inadequate by current standards.
INVESTIGATORS
When BZ studies were begun in 1960, the need for a psychiatrist
with biologic training and interest was recognized and one was
assigned to the program in January 1961. Physicians trained in
internal medicine, anesthesiology, cardiology, surgery, dermatology,
ophthalmology, neurology, and other specialities were assigned as the
program proceeded. Many were research-oriented and have since gained
excellent reputations in academic medicine at leading universities.
SELECTION OF DOSES FOR ~ TESTS
Subthreshold doses based on estimates from animal potency stu-
dies were used in the first few subjects. For example, the earliest
exposures to BZ, one of the anticho~ nergic test compounds, were at
doses between 0.l and 0.5 ~g/kg, which was less than one-tenth the
incapacitating dose (ID) ultimately established at approximately 5.5
~g/kg. The intravenous route was preferred initially, but other
routes of administration were also used. Inhalation studies were
sometimes undertaken after a compound had been thoroughly studied by
one of these parenteral routes. Oral and percutaneous studies were
performed when effectiveness via these routes was of interest.
As the program developed, it became customary to test agents at
dose increments of 40 percent, once the approximate effects of the
lower doses were known. Placebos were used in some studies, but the
cost with respect to subject confinement time, staff workload, and
delay in achieving estimates of potency made this impractical except
in special casses ~ e . g., evaluation of antagonists ~ . Instead , low
and high doses were assigned in a randomized manner by someone not
involved in an experiment. Placebo responses were minimal. Signs
of drug effects at all but the lowest doses were sigh ficant and
made the value of placebo or "no treatment" inconsequential.
-256-
OCR for page 257
RANGE OF DOSES
Rarely did the intramuscular or intra~rer~ous doses exceed l. 5
times the incapacitating dose. Inhalation doses were higher, but
potencies were lower by this route (usually about 60 percent of that
by the intravenous or intramuscular route). Compared with doses
de scribed in the scient if ic literature on atropine coma therapy i8-23
or Scopolamine therapy,\9 the BZ doses to which volunteers were
exposed appear modest. As much as 20 times the IDso of atropine and
30-40 times the ID,o of scopolamine have been administered in the
past by c~inicians--often to older and less robust patients. Many
patients received multiple exposures of this magnitude over a period
of days or weeks. These therapeutic procedures, reported several
decades ago in refereed journals, actually stressed and advocated the
benef its of such treatment, despite occasional deaths (most of which
appear to have been caused by hyperthermia).
SAFETY MARGIN
The safety margin of a drug is defined as the ratio of the
lethal dose (LD) to the effective dose (ED) . Sometimes, ratio of
the LDso to EDEN is used, although a more Conservative approach
favors the use of the ratio of LD, to EDgg ~ standard margin of
safety) . In the case of incapacitating agents, much reliance is
placed on extrapolation from animal experimentation, and estimation
of the LD1 is generally unreliable.
Many other extrapolation techniques have been used in manipu~a-
tion of animal lethality data in an effort to generate a reasonable
human estimate. By taking a conservative approach with data on
deaths at low doses, one can derive estimates for man that are modest
and in keeping with clinical judgement. Such methods depend on pro-
cedures developed and applied in toxico] ogy.
-257—
OCR for page 258
APPENDIX A
Part 2. Clinical Research Department, SOP No. 5, August 12, 1968
(Revised)
VOLUNTEER SCREENING AND SELECTION
The purpose of this SOP is to provide guidelines for the psycho-
logical/paychiatric selection of volunteers. There are several
standard forms used for this purpose and each will be discussed.
I. Screening Data form (medical history). A "yes" answer on
any item without a recommendation of a medical officer for
acceptance will reject the individual.
2. When the GT score is available a very low score (below 90 or
80) will reject the individual.
3. HOPI. These are "rules of thumb." Lacking a scientific
basis for choosing, these represent advice rather than
dogma, but should be followed if possible.
A. Clinical Scales (Hs, D, Hy, Pd. Mf, Pa, Sc, Ma and Si)
I. Operas profile. Reject if any five of the above
scales are over 65.
2. Mark profiles borderline and carefully examine
family history for indication of psychological
problems if-
a. L and K both exceed F by at least 15 scale
points.
b. F exceeds both L and K by at least 15 scale
points.
3. P&, Pa, Sc Pattern (psychoticism)
a. Reject if any two of these three are among the
two highest Scores on the clinical scales.
b. If Pa or Sc is above SO, and mark as border-
1ine if either exceeds 70.
c. Reject if Pa and Sc are both above 65 and are
also both above Ha, D, and Hy.
-258-
OCR for page 259
4. Pd. Mf, Ma Pattern (Sociopathic Deviate; "Acting
Out")
a. Reject if Pa and Ma are both above 65, and
there is a history of "acting out."
b. Re ject if Pa is above 70, and there is a
history of "acting out." -
c.
Reject of Mf is above 80 in combination with
P6, Pa, or Sc above 65.
5. Ha, D, Hy, Pt. Si Pattern (neuroticism)
a. Reconsider overall picture, history, etc., if any
four of these are above 70.
b. Reconsider overall picture, history, etc., if any
two of these are above 80.
c.
Reconsider overall picture, history, etc., if Pt
is above 80.
The most common exception to these rules is the active, ambi-
tious, college graduate with Ed and Ma above 65, but no history of
acting out. In all but the most extreme cases it is well to obtain
corroborating evidence from the Family History.
4. Family arid Developmental History. The Family History
(SMIJEA Form 6-85) contains information about a wide range
of the potential volunteer's activities, as well as
tapping various levels of consciousness. For routine
screening certain items are useful.
Troub1 e in school, with the civilian police, or
Article 15~. A pattern of this sort is indicative
of an "acting out" type of person.
2. Interviews with a psychiatrist for anything other
than routing screening, e.g., peace corps selection,
etc.
3. A history of fighting after heavy drinking, especially
with a bad temper.
4. Blatant and diffuse expressions of hostility on the
Picture Frustration Test pp 15-16.
Other items: Blow rate of promotion, lack of clear cut goals,
excessive depreciation of self value, and generally bizarre answers
-25g-
OCR for page 260
on the Sentence Completion may be clues but must be interpreted to
relation to other information available.
The screening on the basis of the MMPI is usually done by the
psychologist or psychiatrist. The Family Histories are read by the
Medical Officers in Psychopharmacology with each officer reading his
share. Durlug this phase of the screening only those histories that
have survived the preceding steps are read. lthe purpose of this
screening is to pick those volunteers chosen to come to Edgewood for
any type of test.
Af ter all this material has been read and the volunteers rated ,
a list is furnished the administrative office of about SO first
choice names and SO alternates. These names are usually given to
the administrative office by the tenth of the month which precedes
the month they are to report to Edgewood.
When the volunteers arrive at Edgewood they are interviewed by
the officers in the Psychopharmacology Branch.
At the time of the screening interview, on the basis of the
interview, history, questionnaire (sentence completion and Picture
Frustration tests) and MMPI scores a rating will be applied to each
candidate to separate out the following groups and an entry will be
made upon the Physical Examination sheet opposite the heading
"Psychiatric" characterizing the candidates qualification for drug
testing, as follows:
Rating
A
B
C
D
Qualification (on PE form)
l
OK for psychochemical testing
Low-dose psychochemicals only
No p~ychochemicals
Equipment only
The ratings are to be defined as follows:
A. No apparent or overt paychologic problems and no tendency to
somatize or act-out intra-paychic tension. Many assets, few liabi-
lities. Flexible. Good ego strength. Age - appropriate maturity
and responsibility. A clear sense of identity. Such conflicts as
are evidenced are few in number, situational, and usually conscious.
Normal MMPI and Family History.
An exceptionally well adjusted candidate who impresses the
interviewer by his flexibility and ease in handling anxiety and
hostile or aggressive imputes should be rated A+. These men will
be used for such psychochemical tests as are considered to be of
greater than usual stress.
-260-
OCR for page 261
/
B.
well.
. . .
Adequate, flexible, good ego strength. Gets along fairly
An appropriately mature and responsible person. History is
good out may nave one or more negative items such as: a very minor
offense for which an Article 15 is given or a civilian arrest for a
minor, non-occurring matter (symptomatic of immaturity). Minor per-
sonality distortions which do not interfere with optimum functioning.
These men are not optimal candidates for psychochemical testing but
the interviewer expects they would suffer at most negligible psychic
trauma from experience with the effects of psychochemicala.
C. Any tendency to psychosomatic reactions or aggressive physi-
cal acting-out should drop a candidate at least to this group. These
men are good cooperative subjects who, however, are not candidates
~ ~ ~ . ~ . . ~ ~ _.
: :or _
may be somewhat dull or non-verbal, have obvious neurotic traits,
immaturity, rigidity or other apparent liabilities, but with good
reality assessment and no borderline or psychotic tendencies at pre-
sent or at any time in past history does not include bizarre circum-
stances or severe and cont inued traumatization.
_
Psycuocnem~ca1 tests out may De used for other drum tests. they
D. These men fall into the lower end of a scale of group whose
characterization agrees roughly with those rated as C. Some definite
emotional pathology is tolerated in this group as well as some
bizarre or unusual responses on the questionnaire tests and border-
line or aberrent scores on some MMPI scales. Numerous but minor
offenses (2 or 3 Article 15~. These men may be used for equipment
testing and at the discretion of the responsible medical officer may
be used for local drug testing but should not be subjected to any
systematic drug. Hysterical, or schizoid personalities and any but
minor tendencies towards somatization should drop a candidate to this
group. Some men who arrive at Edgewood with diagnosible physical or
emotional disorder may be allowed to participate in the program but
with D rating and their participation in any particular test must be
OK'd by the responsible physician.
Such mere who are untrustworthy, sociopathic, grossly disturbed
or pathologic or have criminal history or a history of recurrent,
severe or recent psychotic episodes should not be selected as
volunteers and if they arrive at Edgewood, should be returned to
their home station. This decision should ordinarily be made during
the initial screening upon the basis of severe distortion of MMPI
scores or very bizarre or unappropriate items on the history or
questionnaire tests.
Under no circumstances should this SOP be construed to supplant
or replace the judgement of the medical officers in the selection
procedures, who may deviate from these guidelines at their discre-
tion. Deviation from the SOP may et so be done in a systematic way
—261—
OCR for page 262
if adherence would interfere with the accomplishment of a particular
investigation, as, for example, a study of the effects of psycho-
chemicals upon depressed subjects. But the conditions of such an
experiment would demand an unusual attention to the safety and well-
being of the volunteers selected.
-262-
Representative terms from entire chapter:
psychochemical testing
