1954_fischer_1524_1.pdf

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A_tract
amd file card
M 500 proper_:i,
es
M 377 psychot:ceffect
TI
T_V. NOo3 (§102d)
_
Noo60 (§102a)
_0
_,_ mthedrine(_65g)
rISaHEE_ 2o
(PsychiatoResoUni±_ Deptoof Public
Health
GenoHOSpftal_
_e
Wing ResoLabo Regina_ Saskatchewan_ Canada)
_a_tors involv_roduced
model psychoses°
_r
JoMentoSCo_
London
I00_623(1954) o
_O_EM_
Fibrous wool protein was used as a model of the structural
Surface of receptors possibly involved in the mechanism producing a
_ya_osis
by means of drugs° A study was therefore made of the affiu_
_tty for wool of mescaline, methedrine_ LAE and LSD at pH 5o2o
I_LTS:
lo Affinit Z for wool (i_,eoaverage millimoles x l0_2 of
sorbed by 1 g wool): mescaline 0_ methedrine 0o6_ IAE lol;
'_ 2°6° The increasing affinity of the drugs for wool is attributed
to their different degrees of specificity simulating a reversible
inhibition of an equilibrium involved in the production of hallucin=
_ti@ns o
ao
A common characteristic of drugs with psychotic effects is
_bat _n high doses they act as ad:renergic blocking agents° According
to P, thlin (personal communication_ 1953)_ the peripheral adrenolytic
o
effects of LAE and LSD are about I/_00 to 1/2000 of that of DHEo It
appears that drugs which exhibit central and/or peripheral adrenergic
blocking activity in smaller doses than d_benamine_ and also exhibit
_igh
affinity for wool protein are able to cause hallucinations in
wmry small doses°
3o Chemical structure and biolo_l
activit_
The increasing
i_morption (higher degree of specificity for wool protein) of basic
(_tion_active)
drugs is accompanied by the following structural
t_tures_
lo increased grade of alkylation on the primary amino group_
2% increasing number of such amino groups_
5
o increasing number of C
•bems between the primary amino {_ou_) and the neighbouring N of th<:
nucleus_ 40 the presence of two hidden "I_D tails '_ (N=C-C_C_N), 5_ a
molecular weight around
520°
The following data_ supplied by Rothlin_ indicate that there is
m@ _reat difference in basicity between LA_ and LSD
pKb in H20
of
mescaline
LAE
LSD
4o25
7o17
7o12
and therefore the higher affinity of LSD for wool must be due to
other factors°
The high affinity for wool of basic compounds seems to be associated
with very
potent biological
activity_
eogo the affinity
for
wool of
iargactii is high° The low affinity of atabrine explains why
drug has %o be given in high doses for a prolorged period°
this
4o
_aCtlO_'S
e_KravaTi_dj_re___nduced
s choses_ It is
possib_e
e,)
tha% stress _..__ua o.n_ causing sympathetic stimulation
s _+'"
......
__
"
and ove,.ac_-
'+,
_._-tty_
eog_ the ._hoakplease
of
the general adaptatio_ sym_
....
drome cr administrat:L¢_ of Img atropine prior to LSD (FORRER and
GOLDNER_ LSD _i)_.
migh_ diminish the dosage of a drug required to
produce a psychotic effect_ Analogously_ it is possible to decrease
the intensity of a hallucinatory
experi.ence_ eogo that caused by LS_,
if the volunteer is successfully influenced psychologically so as to
feel free of anxiety prior to the administration
of
the drug (HYDE,
personali communication 1954_ STEFKNIUK_ personal communication 1953')o
A similar freedom from anxiety and the concomitant sympathetic hyper-
tonus may be provided by drugs_ such as Largactil_, which prevent t_
mediation of the stress response and thus result in a _pure _ adrenerg-
ic bloekadeo Stress and adrenergic blockade seem to be essential cOm-
ponents for the precipitation of psychoses°
Thus_, drugs with psyc_tlc
effects may act by producing sympathetic hypertonus and exerting
adrenergic blocking activity°
b) that persisting stress situations_ causing sympathetic and smb-
sequent!y parasympathetic
stimulation may increase the dosage of a
drug required to produce hallucinations_
eogo the variations in th@
response of a schizophrenic to methedrineo
c) that simultaneous administration of one of the four drugs
producing psychotic effects and an adrenergic blocking agent may
intensify
the psychotic
experience°
d) that administration of certain compounds with a high affinitl
for (wool) protein might prevent the LAE_ or LSD, induced hallucina-
tions by means of competitive inhibition° FISCHER and.AGNEW (to be
published) have found that 0_15 g methy.t.ene
blue (administered in_wa-
gluteal.ly prior to LSD)_ a weak adrenolytic agent but with a higher
affinity than LSD for wool_ reduces the intensity of the effects_ @f
80f_g LSD by approx_ aO%o Such experiments are being continued° T@
date_ Diparco]. (dieth_iaminoethy1_.N,_dibenzoparathiazdne HC1) appemzs
to be the most effective compound in blocking out LSD symptoms°
COMMENT_
The observations and speculations contained in this paper
are very intrigu_ngo O_ par_ : 'ular _!mportance is the finding that
"
b,_.u_nd bipar',:ol_
a
can reduce the
intensity of LSD=induced symptoms o However_ confirmation is
essential° The formula given for i_ in the paper is incorrect°
w7 (K6314)
NKT/bh 1054
®_

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