1954_horita_1533_2.pdf

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Reprinted
from
SCIENCE, December
_pRINTED
31, 1954, Vol. 120, iN•. 313],
IN
U.
S.
A.
_
pages
1100-110l.
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eyretogenic Effect of
Lysergic
Acid Diethylamide
Akira
Horita and James M.
Dille
Department
University
oy
Pharmacology,
School
of Washington,
Seattle
oJ
Medicine,
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Whereas most of the ergot
alkaloids
exhibit oxytocic
or peripheral autonomic effects, lysergic
acid
diethyl-
amide (LSD) shows little or
none
of these actions but
rather a hallucinogenic effect (i,
2).
In
studying the
effects of LSD in intact normal rabbits marked hy-
perpnea was
noted. This
led to
a
consideration of
the
possibility
of
the
existence of increased body
tempera-
ture, which was indeed found to be the
case
(3).
Most experiments were carried out on
unanesthe-
tized and otherwise untreated animals.
The
agent was
supplied in ampuls containing 0.1 mg/ml and was
administered either subcutaneously or intravenously
without dilution. No significant difference was ob-
served in the amount of the
fever,
but
the
time of
onset and duration of action were somewhat shortened
with the intravenous
route
of administration. A rise
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INHOURS
Fig.
2. Effect of the administration of anesthetic doses
of sodium pent•barbital of 30 mg/kg intravenously on
the pyretogenic effect of 50 I_g/kg LSD administered
intravenously. In the curve indicated by triangles the
pent•barbital was given at the height of the LSD effect.
The lower curve is the rectal temperature of a control
rabbit
receiving pent•barbital
only. Sleep
indicates the
period during which righting reflex was
absent.
Preliminary experiments were carried out in an
attemptto clarifythe mechanism the pyretogenic
of
action. In
addition
to
rectal
temperature, surface
tern-
perature of the skin and the ear was measured by
a
MeKesson's model 205 Dermalor in several rabbits.
The
approximately 4 was
measured
of
a
rabbit.
area skin
temperature
in._ on the backfromthe shaved
Figure 1
is a typical response from such
as
experi-
ment. Skin temperature did
not
change significantly
fell markedly. control rabbit, but
persisted
temperature
throughout
from far beyond
This
latter effect effect. This led to
a
and that of
a
the pyretogenie the ear
consideration of the possibility that the
rise
in
rectal
temperature
might be due to
a
vasoconstriction of the
rabbit ear
preventing radiation
and raising the in-
ternal temperature.
To test the
role of
the rabbit
ears
in the control of body temperature, the ears of a nor-
mal
rabbit
were clamped with hem•stats.
There
was
no change in rectal temperature during a period of
6
hr. Hence
the is
not
likely that
the pyretogenic
effect
of LSD is it
result
of this vascular effect.
Attempts were made to lower the LSD-produeed
fever by the administration of antipyrine, dihydro-
ergotamine.
Hydergine,
and dibenamine.
These
were
without effect. Sodium pent•barbital administered in-
travenously in doses of 30 mg/kg did affect the LSD-
induced
fever,
l_igure 2 shows this marked antagon-
ism. Previous administration of this dose of sodium
pent•barbital prevented the pyretogenic response of
LSD for as long as the animal was anesthetized. Ad-
ministration of this dose of pent•barbital at the height
of the temperature rise reduced the
fever
and restored
the temperature to approximately normal.
Reports of the action of LSD in intact animals and
human beings have been conflicting and undepend-
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7,
Fig.
1.
Skin,
ear, and rectal
temperatures
of a
rabbit
receiving 50 !l_g/kg of LSD
subcutaneously
and
a
control
rabbit receiving an equivalent
volume
of saline.
in rectal temperature was produced in rabbits, dogs,
and eats, but the rabbit was most markedly affected
and,
hence, was used for certain subsequent experi-
ments. Subcutaneous injections of 50 _g/kg of LSD
in the rabbit produced a rise in rectal temperature
within 10 to 20 min. The peak effect was reached after
2 to 4
hr. The total
duration of the
pyretogenie
action
was 7 to 9 hr.
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able. Forrer and Goldner (2) report that two of five
patients showed a slight rise in oral temperature after
LSD. Reports of other actions of LSD on the cardio-
vascular system (2), central nervous system (4), and
autonomic system (5) are likewise variable and equiv-
ocal.Thepyretogenicffects
e
reported
herearerepro-
dicible and dependable, and so there is a possibility
of taking advantage of this effect as an end-point in
the investigation of the pharmacology of LSD. On the
one hand,
this effect may be part of the predominant
central
action.
On the other
hand,
it may be simply
a side action
of
this
agent unconnected
with its pre-
dominant
central
being continued
nervous
system
effects.
Studies
are
to determine
the mechanism
of this
Conclusions.
Lysergie acid diethylamide produces _':_
rise in body temperature of normal rabbits, cats, and" •
dogs.
This
rise in temperature is antagonized by the
administration of sodium pentobarbital but not by
antipyrine or adrenergic blocking agents.
Referencesand
Notes
1. A.
Hoffer, H. Osmond,
and
$.
Smythies,
100, 29 (1954).
2. G• R. Forrer and
Neurol. Phychiat.
s. The lysergic acid
investigation
was
:
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J. Menta_ Sci.
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R. D• Goldner,
Am• Med. Assoc• Arch.
65,
581 (1951).
diethylamide was furnished by and this
supported in part by Sandoz Pharma-
Psychiat.
4. J. Delay
et al.,
Sutter
neurol.
86, 81 (1952).
eeuticals,
450
Rev.
St., San
Francisco, Calif•
5. J. H. DeSchon, M.
Rlnkel,
and It. Solomon,
• pyretogenic effect of LSD and
to
explore its useful-
hess in general pharmacologic studies of this agent.
Quart.
26,
33 (1952).
19 July 1954.
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