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OCR for page 47
3
PSYCHOCHEMICALS
BACKGROUND
Military interest in paychochemicals stems from the late 1940~.
L. Wilson Green of the Chemical Corps Technical Com~nd at Edgewood
proposed that modern military use of paychochemicale might permit
the conquerls~g of an enemy without the need for weapons of mass des-
truction. Such use, he suggested, might reduce the wholesale
killing, hen misery, and property destruction normally experienced
in warfare. He proposed a search for a stable chemical with the
capacity to produce mental abnor~alitles of military importance; 61
chemicals were suggested as a starting point for this search.1
Over the next few decades. scientists at Ed~ewood encased in
.~
toxicologic and clinical e~raluatlons of the biologic effects of a
wide variety of chemicals that could alter the state of mind or mood,
largely by affecting the brain. Among those tested on h''m-n volus~-
teers were LSD, a hallucinogen; BZ (3-quinuclidinyl benzilate) and
related anticholinergic compounds; phencyclidlue, an anesthetic with
marked disorienting after-effecta; and dibenzopyra=, CNS depres-
sants with powerful capacity to produce orthostatlc hypotension.
LSD and the anticholinergice were the subjects of earlier exten-
sive evaluations.2~3 This chapter is concerned only with phency~
clidine and dimethylheptylpyran (dibenzopyran) and its isomers.
Table 3-l li8t8 the Compounds tested, approximate embers of sub-
jects, routes of admini Stratton, and dosages.
REFERENCES
i. Taylor, J.R., and Johnson, W.N. Research Report Concerning the
Use of Volunteers in Chemical Agent Research. DAIG-IN 21-75.
Department of the Army, Office of the Inspector General and
Auditor General, Washlogton, D.C. 1976.
2. McFarling, D.A., Project Director. LSD Follow~Up Study Report.
U.S. Army Medical Department. U.S. Army Health Services
Con - A rue . 1980.
47
OCR for page 48
3. National Research Council. Committee on 'rosicologg.. Possible
Los~g-Term Health Effects of Short-Term Exposure to Chemical
A8ente. Vol~e I. Anticholinesterases and Antlcholinerglcs.
Washington, D.C.: National Academy Presse 1982. 87 p.,
Appendices.
VOLUNTEER SCREENING, SELECTION, AND CLASSIFICATION
In the clinical charts at Edgewood, severe adverse psychologic
reactions to SNA or to the ca~abinoide appeared less common than
one might expect from experience in civilian laboratories. If these
findings were valid, they might be accounted for by subject selection
procedures and special characteristics of the experimental milieu.
Studies of workers of tern find that workers are hew thier than the
general population. This "healthy~worker effect" is generally
ascribed to the fact that the working populat ion is in better overall
health than the general population, which includes the very alck, the
elderly, and the hypersusceptib'e.
The selection of volunteers for testing at Edgewood moat likely
introduced a "healthy-test-sub ject effect" into the study. In fact,
those Bet ected for exposure to the test chew cals were healthier than
those used as controls or used in nond rug tests of equipment. The
control groups consisted of those who were rejected for drug testing
and thus possibly less healthy. Because the exposed subjects were
healthier at the start than the nonexposed sub] ects, comparisons bet-
ween these two groups may well yield results that understate the rel-
ative risk to the esposed subjects. For the study of neurologic pro-
cesses and paychologic functioning, subtle effects in the exposed
subjects would not be readily evident in a comparison of them with
the less healthy, nonesposed subjects.
In addition, there was a great deal of preselection, in that all
the subjects were soldiera--healthy enough and functioning well
enough to meet the criteria for entry into the Army. A detailed set
of guidelines, most completely spelled out in a document dated August
I2, 196B, described a standard operas ing procedure in the clinical
research department (Appendix A, part 2) for forming the exposure
group. Multiple criteria were used in the paychologic screening of
volunteers. A "yes" answer on any of various items in the medical
history without explanations based on further examination by a medi-
cal officer would routinely be cause for rejection. When General
Test (GT) scores were in the very low range (below 90 or BO), the
volunteer was rejected.
Minnesota Multiphasic Personality Inventory (MMPI) prof iles were
used as approximate guidelines or rules of thumb, rather than to pro-
48
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vice firm cutof f points. In general, any prospective sub ject who had
five or more clinical scales on the MMPI above 65 units was not
included in the experiments. A volunteer with high L and K scales
was considered Dutiable for the experiments only after careful
review of family history and of other indication of possible paycho-
logic problems. Any sub ject with high PI), PA, and SC Scales (pays
chotici~m) was rejected, as was a subject with high ED, ME, and MA
patte`-.ls (sociopathic deviation), particularly if there was a history
of "acting out." Careful review of the overall clinical picture,
history, etc., took place if the HS, D, HY, PT, and SI patterns
~ neuroticism) were high. Apparently, exceptions were made--for
example, if an ambitious college graduate had high ED and MA scales,
but no history of acting out. In doubtful cases, corroborating e~ri-
dence from the family history was reviewed. Particular attention was
paid to the family and developmental histories of prospective volun-
teers, especially a history of trouble in school, contact with a pay-
chiatrist for anything other than routine acreeDlug, fighting in
association with drinking, and overt expreselons of hostility.
Screeni ng of the histories and MMPI profiles took place before
arrival at Edgewood. After arrival, volunteers were interviewed by
of ricers in the Psychopharmacology Branch. On the basis of further
testing (Sentence Completion and Picture Frustration teSts), physi-
cal examination, and interview, sub Sects were classif fed on a four-
point scale. Those rated A were considered suitable for paychochem-
ical test ing; tho &e rated B were suitable f or low~dose paychochemi-
cals only; those rated C were not suitable for paychochemicala; those
rated D were suitable for equipment testing only. The main criteria
for an A or B rating were absence of evidence of psychologic prob-
leme, absence of a tendency to somaticize or act out intrapsychic
tension, good ego strength, flexibi] ity, maturity, good sense of
identity, normal ~PI, and fami] y history. Sub jects who seemed to be
particularly at ease when handling anxiety and hostile or aggressive
impulses were rated A+--suitable for psychochemical tests considered
to be of greater than usual stress. Those rated B were similar to
the A group, but had had occasional experiences that suggested less
control or minor personality disturbances. Arty subject who showed a
tendency toward psychosomatic reaction or aggressive acting out, who
appeared to be dull or nonverbal, or who had obvious neurotic traits,
immaturity, or rigidity was not included in any psychochemical exper-
iments.
The criteria described in the standard operas ing procedure appear
deco be those used either consciously or deliberately in many civilian
laboratories that conduct research with psychoactive drugs with
normal volunteers. It appears that the subjects actually given pay-
chochemicals in these experiments were selected from an optimal pool
of mentally and physically hea lthy persons .
50
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Apparently, the precise configuration and staffing of the re-
search unit changed over the years during which these experiments
occurred. Facilities for the subjects included a controlled environ-
ment with padded rooms ~ to protect sub jects from harm from hypoten
sign) and an ad jacent communal area. During the f irat hours of the
experiment, each subject was in his own padded area with a padded
stool. Each subject had a nurse or aid in the room during his pro-
gress. Later, the sub jects were an owed access to dayroom facili-
ties, where they played cards . When further along in recovery, they
could play table tennis. Throughout the entire recovery process,
they could be observed through a window.
The notes, comments, and data in ache charts reflected what must
have been a supportive and well-staffed research unit. The only neg-
atl~re comments from subjects in the charts had to do with the quality
or preparation of the food . Many posit ive comments ref. lect ing care-
ful attic ion, support, and, in general, informed part icipation in
the experiments occurred throughout the charts over the years.
Retropecti~re chart reviews always involve guessing and specular ion.
A best guess is that a supportive atmosphere and careully screened
aDd well-informed (with respect to experimental procedures, goals,
pitfalls, etc.) subjects were important in determining how well these
volunteer sub] ects tolerated the experiments.
It is difficult to generalize about the experimental design used
in studies of multiple drugs and spanning 10 yr or more. Some gener-
alizations are relevant in assessing the quality of data, pattern of
effects, and possible consequences. In the usual sequence of exper-
iments, the effects of Jow doses were investigated first in a few
volunteers, particularly when the route of administration was being
changed or when a compound that had been studied previously only in
animals ~ such as the car nAbinoide) was being studied. These, depend-
ing on the pattern and duration of effects, a small to moderate-sized
group of subjects were tested with a few doses in what appeared to be
a safe but pharmacological ly active range. Later studies followed up
on interesting or possibly worrisome side effects, such as borderline
changes in hepatic or renal function. Particularly in later studies
based on earlier observations, interventions were made with assumed
antidotes or antagonista; for example, drugs that increased blood
pressure were given in conjunction with or after dimethy~heptylpyran
to investigate the intriguing and important posture' hypotension.
The protocols appeared to be flexible and generally conserva-
tive, with variatlone often following up preliminary observations. A
critical and skeptical reviewer, in retrospect, might say that there
was too great emphasis on browsing and that the changes in protocol,
with seal 1 groups tested under any single protocol, precluded defini-
tive conclusions. These e~cperimer~ts were anal ogous to the Phase 1
clinical trials in human beings now conducted with therapeutic drugs,
51
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in which esa~nati~ of amass groups, attention to borderline bio-
chc~ical abnormalities, revision of protocols, and attention to
hunches about mechanisms of drug action, 608e, etc., are appropriate
research strategies.
Placebo controls were not used and were probably not appropriate,
glared the goals of the research. One must remember that when these
studies began, in the early 1960s, psychopharmacology, particularly
opting research strategy and design as we know them today, was truly
in its infancy. Not until the mid-1960e was there a general consen-
sus in a mlaimally acceptable design for studying paychochemlcals,
aM ever now there may be disagreement. lithe experimental design used
in the experiments at Edgewood compares favorably with the phaneaco-
logic research at other research centers.
In the Edgewood studies, SNA was administered intravenously,
orally, aM by inhalation.
Intravenous doses of 0.l mg/kg given to 10 volunteers produced
onset of physiologic and paychologic effects within 3-5 min of indec-
Lion that peaked about 10 min to 1 h after injection. Most of the
symptoms were no~measurable 5-6 h later. As in all studies with SNA,
individual variation was great. For example, of the 10 volunteers
given intravenous SNA, four became withdrawn and drowsy and answered
when spoken to, but otherwise were silent. The effects on proprio-
ception were manifested by limb numbness, vertigo, ataxia, and a
feeling of detachment. Various degrees of amnesia regarding the
events after the first hour after injection were common. Nausea was
common, but considered to be less than expected by the investigators,
possibly because the subjects were nonambulatory. Increases in
systolic and diastolic blood pressure of up to 20 or 30 mm He
occurred soon after injection and lasted for 2-3 h. It was judged by
subjects and observers alike that SNA would impair performance in a
mili tary f ield situation.
After oral doses of up to 30 mg (0.48 mg/kg), similar signs and
symptoms appeared in a single test subject. At 30 ma, approximately
the first plane of stage three anesthesia was produced. The one sub-
ject used was unreeponsive to sensory stimuli, although corneal
reflexes were intact. Blood pressure was slightly increased. An
hour after the drug administration, he was responsive to stimuli, but
still groggy; a h later, he had recovered almost totally, but was
Emetic regarding the events of the hours after the drug was adminis-
tered. Two volunteers given a combination of SNA (20 ma) arid alcohol
had intense "manic" reactions, with much agitation and restleasnes~.
Perceptual and cognitive effects lasted 4 d ire one and 2 ~ in the
other. At lower oral doses (5 and. 10 mg), volunteers described their
subs ective feelings as similar to those of alcohol intoxication.
Skin temperature and heart rate increased slightly. Vertigo, atasla,
52
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wea]~Ue88, and nausea were mild and not sufficient to interfere with
treadmill exercises that were part of the experiment. Subjects
appeared Slow to think and Slow to make declaiona and reported a sub-
jective slowing don of time. The subjective effects peaked at about
2-4 h after oral administration and, after the 10-mg dose, were still
present to a slight degree at 13-14 h. After the 5-mg dose, effects
were generally milder, and subjective symptoms were gone in about
h. Perceptual motor functioning, as Judged by Purdue pegboard and
Minnesota rate manipulation tests, was definitely impaired after the
10-mg oral dose, markedly impaired after 15 ma, and nearly abeen~c
after 5 ma.
REVIEW OF AVAIIABLE INFORMATION ON PHENCYCLIDINE
CHEMISTRY
Phencyc' idine (Sernyl, SNA)--~-~-pheny~cyclohe~yI)plperidine,
C17H2,N (molecular weight, 243.38~--1s an ar~ricyclohe~ylamine.
It is used as the hydrochloride, C~7H2sN HC] (molecular weight,
279.84), which is crystalilne with a melting point of 214-218°C.
Its hydrobromide salt is also crystalline with a melting point of
214-218°C. The hydrochloride is soluble in water, methanol, etha-
nol, aniline, and methylene chloride, and the base is almost insol-
uble ln water and soluble in toluene, methanol, ethyl acetate, kero-
aene, and methylene chloride. The base (SNB) is crystalline with a
melting point of 46-46.5°C.
The chemical structures of SNA, ketamine, and SHB are show in
Figure 3-1.
9~'NHCH3
a Onto
~~e (it)
FIGURE 3-1 Structure of ketauine, SILA, aDd SNB.
_ _
T;
hydrochionde (SNA)
~-
at
SNA Was originally synthesized and developed as an anesthetic
agent for human use by Parke, Davis and Co. under the name
SernyI.~3~~5 Itch human use was soon abalones, because it some-
times produced postoperative thought disturbances and agitation. It
is currently used, under the name Sernylan, as an immobilizing agent
in veterinary medicine.
In pharmaceutically pure fore, SNA is a white powder that d1~-
8Olve8 readily ire water. When distributed illicitly, phencycildine,
53
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often called PCP, is highly variable in appearance ( powder or tablets
in many colors or as liquid), contains many impurities, is often
adulterated, and quite often is misrepresented as another drug, such
as ~arl~uana constituents, mescaline, pailocybin, lysergic acid
diethylamide (LSD ), or even amphet~mi ne or cocaine .
lithe compost cested at Edgewood was pure phencyclidine provided
by a pharmaceutical manufacturer and should not be confused with the
substance 80~6 0D the street as PCP.
The structure of SNA was modified by replacement of its pheny1,
cyclohesyl, and piperidine rings and by introduction of subetltuents
onto those rings. Replacement of the phenyl ring with a thienyl rlag
increased central activity, but bulkier aromatic rings were inac-
tive.39 Replacement of the piperidine ring by NHCH3 and some
substitutions in ache other rings led to the development of ketamine,
an ef fective dissociative anesthetic agent .
ABSORPTION, FATE, AND ELIMINATION
Two recent reviewa3~22 contain considerable information on the
absorption, distribution, metabolism, and excretion of phencyclidine.
Absorp tion
Early studies in experimental animal 8 and hen subjects46
established that SNA is well absorbed when administered by inhala-
tion, percutaneously, irltraocularly, orally, intramuscularly, tntra-
venoualy, and intraperi toneally . Dogs esposed to aerosols generated
from a 15% aqueous solution of SNA developed prostration, hypersali-
vation, and exophthalmos; approximately 50Z of ache dogs had tremors
and convulsions. SNA and SNB were dissolved in a number of vehicles,
and these preparations were applied to the skin of rabbits. Ataxia
confirmed the percutaneous penetration of the drug. This clinical
sign also occurred after art alcoholic solution of the base or the
salt was instl-~led in the eye n of rabbits. A human volunteer given
SNA orally at 0.48 mg/kg reached plane ~ of stage 3 anesthesia ~ h
after admir~istratlon. Intravenous admiMstratlon of SNA at 0.01
mg/kg is 10 male volunteers resulted in onset of mental and physical
effects within 3-4 min. Nineteen men were given aerosolized SNA in
methylene chloride solution. At an exposure as low as 250
ma. min/m3, one sub ject developed visual disturbances and light-
headednese in 7 min and perioral and distal paresthesias within 10
min. Inadvertent exposures by inhalation have been reported-.
Aniline en al.4 found SNB.in the blood of a 65~ old woman who
occupied a secor~d-floor apar~cment directly above a clandestine labo-
ratory making SNB by an open-vat process. Pitts et al.52 reported
54
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intoxication in two chemists, employed in a law enforcement labora-
tory, who hamiled confiscated samples of SNA.
Absorption through the placenta has been shown in mice and
rabbite50 and is likely to occur in htonana.30 In the mouse, SNA
concentration was 10 times higher in fetal tissue than in maternal
blood. Furthermore, SNB appeared rapidly in the milk, reaching con-
centrations 10 ti - s those in maternal plasma. Fetal SNA concentra-
tions in the rabbit peaked 12 h after parenteral administration to
the dam. A neonatal infant whose mother had used SNA during preg-
nancy manifested abnormal behavior consistent with effects often seen
with this drug. However, blood SNB concentrations were not measured
in either child or mother. Aniline and Pitts studied three women who
used SNA during pregnancy;3 blood and urine SNB concentrations were
determined. Concentrations in cord blood were 2-3 times higher than
those in the mother in all cases.
Distribution
In Spragu - Dawley rats given SNA at 50 mg/kg intraperitoneally,
concentrations in adipose tissue 1 h after injection were 13 times
higher than those in brain and more than 20 times higher than those
in blood. 34 Thus, SNB is highly lipophi ~ c in its distribution;
indeed, SNB remained in fat at approximately 10 Agog 48 h after
injection--that is equivalent to the highest blood concentration
attained (3 h after injection). Brain and blood concentrations were
virtually parallel. In one case of an SNB-related death in a human
subjects the brain:blood ratio of SNB concentration was 6:l, and
the liver:blood ratio was 2:~. In a second case in which it was
established that the deceased had smoked SNB, concentrat ion rat ios
were as follows: liver:blood, 46:~; lung: brood, 2:~; and kidney:
blood, I:~. In a third case, in which latravenous use of SUB was
documented, the liver:blood and bile:blood ratios were 4:1 and ~ :l,
respectively. A knee synovlAl fluid:plama ratio of 9:l was found in
a living subject who had inhaled ("anorted") SNB.
Receptor sites specific for binding SNB have been found in rat
brain aM other organe.66 The greatest specific birthing was found
in the cerbral cortex and the corpus striatum. Bindlug was less in
the thalaeus arid hippocampus and least in the medulla oblongata,
pons, olfactory bulb, hypothalamus, and cerebellum; none was f ound
in the spinal cord. Specific binding ~s also found in heart, liver,
lung, and kidney.
Distribution studies of ~ 3H]SNB in selected brain regione68
revealed concentrations from 10.4 Prolog in cerebellum to 16.4 nmol/g
in anterior cingulate cortex. Another study37 showed that radio-
activity from administration of [3H]SNA was distributed almost
55
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every over ~ aJor anatomic areas of the brain; only the hypothal-
asme had a high concentration. Most of the radioactivity was associ-
ated with the soluble cell fraction, and very little was detected in
nuclear and mltochondrial fractions. Chronic adminlatratlon of SNA
altered the distribution of ~ 3H] SNB and its metabolizes in the cen-
tral nervous system; radioactivity in the cortex was 7-31% ie88 than
that in the whole brain. Other areas, particularly the hypothalamus,
had a higher concentration relative to that in whole brain. A recent
report44 indicated that 30 min after intravenous or oral adminis-
tration of [3H]SNA to mice the highest concentration was in the
stomach. The nest highest concentrations were in fat (by the intra-
venous route) aM in liver an intestine (oral route) aM the lowest
in brain and plasma (either route).
Metabolism
A proposed scheme of the metabolism of SNB in man was reported by
~ r
Jasinski _ al.~'
After mice became tolerant to SNB, hepatic microsomal cytochrome
P~450, cytochrame b5, nicotinamide adenine dinucleotide phosphatase,
and NADPH-cytochrome c reductase activities were increased and thus
presumably involved in SN8 metabollam.49 These findings confirmed
previous observations that chronic SNB administration to the mouse
increased liver Microsoft hydrosylation of aniline, pentobarbital,
and hexobarbital and the N-demethylation of aminopyrine and ethyl-
morphine.32 4-PhenyI-4-piperidinocyclohesanol ( PPC), one of the
major metabolizes of SNB, can exist in cis and bans isomers. Both
isomers were found to be biologically active in the mouse, producing
atria and seizure activity (the latter at high doses). The bans
isomer was only slightly more active than the cis isomer.li The
presence of an additional me~cabolite in the urine of human subjects
ualug SNB has recently been confirmed ;~6 the metabolite had been
found in rat an rabbit liver and in dog urine. This metabolite was
identified as 5-~-phen~ricyclohesylamlao~valeric acid. In man, PPC
is highly conjugated as the glucuro - de and is excrete] fairly in
that form.35 Details of the biotransformation of SNB have been
ester y re~rlewed.40
Eli mi nation ~ Phar~acokinet ice
-
It was recognized many years ago tha~c SNB had a prolonged
action,46 A huff volunteer given SNB orally at 0.48 mg/kg was not
responsive deco stimuli until 4 h after testament, at which time he was
stuporous, aM his anes an legs refined in any position in which
they were placed. full recovery required about 7 h. In Sprague-
Dawley rata, half-lives of SN8 were approximately ~ h in blood, 2 h
56
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in brain, and 3~4 h in adipose tissue.34 Plan half-lives of 2.4
h (monkey) and 2.9 h (dog) have been reported. 69 The half-life in
human varies considerably from subject to subject. Acidification of
urine results in a markedly decreased half-~;ife.24 Some indication
of the slow eliotinatioct of SNB is found in an lnveatigation of coro-
nerst cases of persons who died of accidental causes; the highest
concentratione of SNB in brain and other organs were noted 7-10 d
ricer single high doses of the drug. In brains of S]JB-tolerant mice,
the fife was much shorter than that in control an~ale.49 SN11
me~cabolites revalued in the liver of mice up to 14 d Add in the lung
up to 21 d.44 Measurable concentrations of She persisted In a
hear subject for at least 6 ma after the last known exposure.52
All available ir~for~tion indicates that the phar~acoklnetice of SNB
are highly dose-re~ated.
The recently reported findings of Cook et al.~9 on the biodis-
position of phencyclidine after oral or intravenous administration of
trace amounts of radiolabeled o~aterlal are presented in Table 3-2.
Quantitatively similar dispoaltional kinetics in the dog were
recently published;71 again, there was a wide variability in half-
life, as well as a very small renal clearance.
These results indicate that, in addition to effectiveness by
inhalation and parenteral administration, SNA is wen absorbed in man
when administered orally. The drug is 60~701 bound to plasma pro-
teins, the Solve of distribution is high (approximately 500 L in an
SO~kg man), clearance is largely a result of metabolic processes, the
half-life is quite variable from one person to another, and the drug
and its metabolites are excreted principally in the urine, regardless
of whether it is given orally or in~cravenously.
ANIMAL TOXICOLOGY
Several animal species (mouse, goat, cat, dog, guinea pig, rab-
bit, and rat) were given graded doses of SNA intravenously to deter-
mine its LDso an its median effective dose (EDso) for several
gross manifestatione--ataxia, salivation, prostration, and convul-
sions. Table 3 - 3 lists the LD,os and EDsos for these effects.
It shade that in various species the LD,os ranged from ll.7 to 17.9
mg/l~g, and the pharmacologic dose ranged from 50 to SO ug/kg; thus,
the margin of safety of this compo~md was high. Atasla, Privation,
and prostra~cion occurred wi~chin I-5 min. arid convulsions developed
within l-40 mire. Death usually occurred in less than 15 min in the
guinea pig, rabbit, and cat; in I-3 h in the mouse; and in 5 min to
24 h in the dog. At 3-5 mg/kg intravenously, SNA caused a decrease
in blood pressure, a decrease in heart rate, and mluor cardiac irreg-
ularities in cats. It also algM ficantly depressed respiration, but
57
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sense of hunger, tachycardia, and drowsiness . 31 ~ 38 Postural hypo-
tension is immediately reversed and blood pressure returned to normal
by lying down.
Death due to inhalation or ingestion of marl juana has not been
reported. Nor are there lasting ill effects from the acute use of
marl juana,45 except that the acute or chronic use of marl juana
occasional! y precipitates or exacerbates a -schizophrenic state .43
Isomer 2 is the most potent of the DEEP acetate isomers ~ being active
at intravenous doses of 0. 5-2. ~ ~g/kg. Postural hypotension was reg-
ularly noted, but euphoric responses were infrequent . DMHP has been
the no st extensively studied of these analogues .44 At toxic doses
roof 50 Vg/kg or more, postural hypotension, tachycardia, hypothermia,
and lethargy were noted. Fatigue, thirst, and headaches were associ-
ated symptoms. Prolonged or delayed effects of a Oman number of
acute doses were not mentioned in the literature.
The literature on THC is much more voluminous and may be used in
this evaluation, because DMHP and the DIP acetate isomers and THC
are related chemically and pharmacologically. This ca~binoid also
produces no known long-term or delayed effects, except when admin-
istered chronically in large doses . 3
The doses of the dibenzopyrans used at Edgewood were similar to
those used by other invest igators . Lemberger e t al .30 used DROP at
200 fig per 70 kg intravenously, for example. The severe postural
hypotension that occurs when the drug is taken intravenously, intra-
muscularly, or orally is a limiting factor in giving hallucinogenic
amounts of DbIHP isomers.
Iwo long-term ef fects are theoretical considerations. One is
that exposure to the cannabinoids may somehow have caused a chronic
or delayed posttraumatic stress disorder. In the dosage and fre-
quency used, this is unlikely. The postexperimental effect that was
most undesirable was postural hypotension. 'This resulted in dizzi-
ness and faintness, from which all subjects recovered. Such a stress
is insuf ficient to provoke a delayed or chronic pos~traumatic stress
syndrome, rigor is there any evidence that any such syndrome occurred .
A second consideration is that exposure to DMHP at Edgewood may have
produced a tendency toward abuse of cannabinoids ire later years.
This is not possible to assess.
The target organs that may be involved in prolonged or delayed
effects are the brain and the cardiovascular system. The mental
ef feet consists of a transient or reversible psychosis, which may in
rare instances result in activation of a schizophrenic process. The
cardiovascular effects are postural hypotension and tachycardia.
These are tranaltory and leave no permanent residue.
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Given the absence of followup information on the effects of DAMP,
ache Committee cannot evaluate the possibility that the exposures at
Edgewood produced delayed or long-Berm effects. However, information
on THE suggests that such effects are unlikely to be associated with
the exposures tested. In addition, clinical evaluations immediately
after test administration did not indicate any acute effects likely
to presage future complications or long-term sequelae.
A review of the epidemiologic aspects of DMHP is in Appendix C.
EFFECTS ON VOLUNTEERS
This review of acute effects on volunteers is based on clinical
records at Edgewood. When the cannabinoid studies began at Edgewood
in November 195B, much less was known about the pharmacology of DMHP
than about the pharmacology of phencyclidine (SNA). The Studies of
the DMHP series in humane spared the period from ~ 958 through 196B,
wi th concentration in 196 3-1966 .
Although they are generally more potent, the DAMP derivatives had
ef fects in the normal volunteers at Edgewood that were very similar
to those later described over the ~ ast 15 yr by many research labora-
tories working with cannabis and THC. After administration of DMHP,
there was more orthostatic hypotension than with THC or cannabis and
possibly fewer subjective and mood effects. The time course appeared
more variable, arid DAMP' ~ ef facts were of ten slower or more erratic
in onset, particularly when it was given orally, than were those of
THC. DEEP' s ef fects also persisted longer.
In some of the earliest studies, beginning about November 195B,
racemic mixtures of DAMP were given to approximately 35 volunteers at
0.5-4 mg per 70 kg of body weight. At 0.5 mg per 70 kg, fatigue,
drowsiness, mild headache, and occasionally increased thirst deve-
loped. At 1 and 2.5 me per 70 kg, postural hypotension was common,
and faintness on standing was observed often. Blood pressure in a
supine or prone position was normal or slightly increased. Weakness,
ataxia, a feeling of giddiness, and general slowing of motor activity
were common. At the highest doses, the subjects often showed marked
psychomotor retardation, sluggishness, difficulty in concentrating,
and blurred vision lasting for as long as 48 h after a single dose.
Fewer comments were made about postural hypotension, probably because
at this dose volunteers were unwilling or unable to get out of bed.
Volunteers given over 2 mg of DMHP were judged to be incapable of
performing their regular military duties. The intensity and duration
of the hypotension, tachycardia, decrease in oral temperature, visual
disturbance, sub jective symptoms of thirst and dry mouth, and
decreases in motor performance were generally dose-related, but their
intensity varied among subjects . Thus, many of the signs and symp-
toms of DMHP intoxication were similar to those reported ire recent
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years in many car~nAbia and THE studies of volunteers, except that
DMHP was more potent and probably had more effects an the cardiovas-
cular system.
The most extensive experiments at Edgewood were done in 1963-1966
with DIP acetate. Approximately 100 volunteers were given doses of
a DMHP acetate racemic mistune during this period. Oral, intramuscu-
lar, and intravenous routes of administration were used. Oral doses
ranged from 3 to about 60 ~g/kg. Intravenous doses ranged from 0.5
~g/kg to (in a few subjects) 5 ~g/kg. Intramuscular doses were
between 0.5 and 5 ug/kg. Most sub jects received only one drug expo-
sure, and a few had multiple exposures, but rarely more than two.
Cardiovascular effects were most vocable. Tachycardia and ortho-
static hypotension were seen in some subjects at almost all doses.
ECGs occasionally showed such nonspecific changes as inverted ~
waves. ECGs documented the 6- to 10-s lag in heart-rate increase
caused by DliHP acetate after standing. Many subjects felt light-
headed and faint on standing. As the studies progressed and the
relationship between dose and orthostatic hypoter~sion was better
appreciated, this ef feet was less likely to occur . In general, oral
doses produced changes ire heart rate and blood pressure at 1 or 2 h
and peak ef fects at 6-10 h. Ma jor effects on the cardiovascular ~ys-
tem disappeared in most subjects after 24 h, but persisted for sev-
eral days in a few subjects in whom hypotension and increased heart
rate occurred.
As is often observed with cannabis, conjunctival blood vessel
injection was common. Body temperatures decreased, sometimes by
3-4°F. These changes were generally dose-dependent. Dryness of
the mouth and throat, nasal stuffiness, apathy, and nausea were com-
mon. and their intensity was dose-related.
Psychomotor impairments were measured by such test batteries as
the numerical facility, speed of closure, Purdue pegboard, and Strom-
berg manual dexterity tests. Anecdotal reports, both by sub jects and
by staff, of changes in behavior and mood general y paralleled the
other symptoms . lithe spectrum of the ef facts and their intensity i s
similar to that corona y reported in the recent literature on canna-
bis studies in other volunteer populations. However, UMHP acetate
seemed deco elicit more orthostatic hypotension, and cannabis, a
greater degree of mental effects.
The lack of evidence of severe mental or emotional disturbances,
even is volunteers who were observed to experience intense and per-
sistent cardiovascular effects, is noteworthy. Although DMHP acetate
elicits far greater cardiovascular consequences than other canna-
binoids, it appears to induce less severe mental impairment. I t is
possib] e that careful screening and a supportive test milieu tend to
mi nimize the occurrence of adverse mental ef fects .
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The acute of facts of eight op tical isomers of DEEP acetate giver
Singly or in combluseion were assessed in about 125 volunteers.
Several of these subjects had participated or were participating con-
currently in other DMHP esperimente. The isomers were given intra-
muscularly or intravenously. Some of the intravenous injections were
given with the isomer diluted in propylene glycol and others with
alcohol as the vehicle. Isomers I, 3, 5, 6, 7, and ~ appeared to
have 1itt1 e biologic activity (generally at about 0.5-10 ~g/kg) .
Apart from nonspecific symptoms, such as pain at the injection site,
subjects appeared unaffected subjectively and objectively. In one
sense, this series of experiments provides some index of placebo
responsi~reness-~inimal. Many subjects commented (as recorded in the
charts) that they generally en joyed the experiments, thought we11 of
the stat f support, and, in general, had few complaints other than
about the food.
Isomers 2 and 4 and mixtures thereof had significant biologic
activity. Intravenous doses of l-2 me of isomer 2 produced fairly
intense tachycardia and orthostatic hypotension in the volunteers, an
already described. The postural hypotension was marked, increases in
heart rate were present but less intense, and feelings of impaired
cognition and concentration and altered mood were present and dose-
dependent . The volunt eers seemed able to function reasonably weU--
if they were able to get out of bed and walk around. However, during
the first few hours of intoxication, this was virtually impossible in
many cases, because of hypotension. Dryness of the mouth, increased
thirs t and hunger, mi 1 d sleepiness, in jec ted conjunctival, and wild
to severe hypotension are consistent with the effects of cannabis.
Some~charts contain comments about such observations as skin pallor
on standing. These are understandable in the light of the circum-
stances .
During the DMHP studies, hepatic function and renal function were
assessed. Although occasional borderline-aboorma1 results were noted
af ter exposure, these were generally followed up and did not appear
to be clinically significant. Some attention was given to EEG and
ECG assessments to follow the intensity and duration of any drug-
induced changes in cardiovascular and brain functions. In no
instances of followup, did the ef fects appear to be particularly
specific or clinically significant for acute or long-term toxicity.
In awry, DMHP and some of its acetate isomers produced vari-
ous degrees of physical incapacitation due largely to the moderate to
marked and prolonged orthostatic hypotension. Blood-pre~sure was
normal in the supine position. Mental effects of DRIP were much less
severe than tho se of THC or cannabi ~ at doses that produced similar
degrees of or~chostatlc hypoteasion. Individual dif ferences in inten-
si ty of response were coD.siderable: some sub jects showed little or no
response at doses that produced intense symptoms in other subjects.
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This pattern of variability has been commented on in the extensive
civilian literature on cannabinoid research. Duration of effects
also varied. With most doses and subjects, the majority of measur-
able ef fects disappeared in 24 h, although in a few instances they
persisted for 2 or 3 d. DEEP and biologically actl~re isomers of its
acetate cause greater and longer-lasting orthostatic hypotension and
fewer paychologic ef fee to than THC; otherwise, they are very similar
on the measures recorded during these experiments. The potencies of
DMHP acetate and DMHP itself seemed relatively similar. The eight
isomers of DMHP acetate varied greatly in potency. Those with bi o-
logic activity seemed similar to DRIP in their effects.
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CONCLUSIONS
The Committee found the evidence on the long-term health effects
of the tested psychoche~ cals to be sparse.
The target organs that may be involved in prolonged or delayed
ef fects of phencyclidine are the brain and cardiovascular system.
Mental or cardioyasc~tar effects were not observed, however, within
one week of exposure to the drug at Edgewoocl.
One measure of the margin of safety of a drug can be estimated by
considering the ratio of the lethal dose to the pharmacologically
effective dose (the dose at which some detectable biologic effect
occurs). On this basis, the margin of safety is large for acute
intravenous, intragastric, intraperitoneal, and subcutaneous adminis-
tration of pher~cyclidine ire armada. It is somewhat smaller for
inhalation of the aerosolized form.
On the basis of the Scientific literature alone, it is not pos-
sibie to predict whether any long-term effects would be associated
wi th the expo sure s to pher~cyclidine used . However, at the sma t 1
doses arid low frequencies of administration used at Edgewood in a
small number of test subjects, it is not likely that any detectable
long-term or delayed ef fects have occurred.
Acute admi nistrati~ of the dibenzopyrans ( dimethy~heptylpyran
and congenera) produced various degrees of physical incapacitation
in Edgewood sub] ects, ma inly because of moderate to marked and pro-
longed orthostatic hypo~cension. The duration and intensity of
effects varied among doses and sub Sects. Despite these variations,
there is a large pharmacologic margin of safety in the use of these
compo~mds in armada . The d iber~zopyrans produced more pa tent long-
lasting orthostatic hypotension and weaker (but otherwise similar)
psychologic effects than A-9-tetrahydrocann~binol during the Edge-
wood experiments . There is no information on chronic ef fects of
d ibenzop yrarm .
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Evaluation of the toxicity literature and the Edgewood studies
led the Cocci thee to conclude that at the doses and frequencies of
administra~cion of phencyclidine and dibenzopyrans used at Edgewood
i t is not likely that detec table long-term or delayed ef fee ts have
occurred or will occur. Specific information to support this con-
clusion is, however, lacking.
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Representative terms from entire chapter:
rat brain
