Jacob Bell
New Member
BY ROGER ADAMS, Ph.D.
The facts on marijuana which I shall present to you this
evening comprise the results of the cooperative efforts of
three laboratories-the chemical investigations at the University
of Illinois, the pharmacology at Cornell Medical College
under the direction of Dr. S. Loewe, and the clinical
experiments at Welfare Island Hospital under the auspices of
the Mayor's Committee on Marijuana and under the immediate
direction of Dr. Samuel Allentuck. All three laboratories
acquired their supplies of raw materials from Dr. H. J.
Wollner of the Narcotics Laboratory of the Treasury Department,
and received much encouragement and stimulation
from him. Dr. J. R. Matchett of the same laboratory contributed
significantly to the general problem by devising a
method whereby a fraction of the red oil of hemp, containing
a very high concentration of the active principle, could be
obtained.
Cannabis sativa, more commonly called hemp, is of peculiar
interest. It has been known for thousands of years as a
product of commerce; the fiber of the plant for clothing and
rope, the seeds for the oil they contain. The presence of an
intoxicating principle in the resin of the plant has also long
been recognized, since the physiological action of hemp
preparations is mentioned in some of the earliest records
available and is described in the first medical treatises. In the
last two thousand years over four hundred articles have been
published describing intoxicating characteristics and the
effects on humans.'
The preparation of the hemp for consumption as an
intoxicant varies in different countries and consequently
several names, such as marijuana, charas, ganja, hashish, and
others, have been adopted, each in a definite locality. It is
significant that the same characteristic phenomenon from
any of these products is observed in man when the doses are
equated.
The clarification of the chemical and medical aspects of
hemp extracts has been extraordinarily slow for a material
known as long and as frequently as marijuana. The reasons
have been several: the failure of chemists to isolate a pure
active principle, the unsuccessful attempts of the pharmacologist
to find an animal test which paralleled the activity in
humans, and finally the lack of controlled clinical experiments.
The recorded medical literature is most confusing. The
reports are contradictory, and the description of the drug
varies from one which is habit-forming and which with
constant use is as harmful to the system as morphine, to one
which is almost completely innocuous with stimulation not
far remote from that of alcohol. Spread of the use of
marijuana in the United States has been due in part to its
ready availability, since hemp grows wild in countless places
all over the country. Newspaper articles have described
marijuana smoking among school children, and magazine
articles have carried vivid accounts of activies encountered in
tea-pads-dens where marijuana is enjoyed by devotees. Marijuana
has been accredited with precipitating premeditated
criminal acts, of lowering morals and releasing inhibitions,
and of serving as a stepping-stone to other drug addictions
such as the use of heroin. Furthermore, the claim has been
made that continued use of marijuana produces mental
deterioration. A "Marijuana Bill" was passed by the United
States Congress in 1934. For purposes of administration,
marijuana is defined essentially as any part of the hemp plant
or extract therefrom which induces somatic and psychic
changes in man. The regulations and penalties in the bill for
use and distribution of marijuana are as rigid as those
imposed for the use and sale of morphine.
In the investigations which are to be described this even
ing, more quantitative data on the chemistry, pharmacology,
and clinical aspects of marijuana has been gathered than
hitherto have been available and present a foundation for the
eventual complete understanding of this interesting natural
product. The chemical investigations, an excellent resume of
which up to 1938 has been published by Blatt,' will be
discussed first. Practically all of the chemical experiments
which have been reported were performed on the resin
present in hemp from various sources and the same general
procedure for isolating the resin has been used by all
investigators in this field. After extraction with an organic
solvent, filtration of the solution thus obtained, removal of
the solvent and vacuum distillation of the residue, a highly
viscous, physiologically active oil results, red in color and
boiling over a wide range. Fractionation of the oil leads to
the concentration of the active components in the portion
boiling from 180-190" (1 mm.) which is commonly known as
"purified red oil." This purified red oil usually used in the
chemical studies has been shown definitely to be a welter of
closely related substances which are very difficult to separate
from each other and which occur in varying proportions
dependent on the sources of the hemp.
Between 1840 and 1895, most of the chemical investigations
consisted in attempts to discover tests which would
provide means of identifying a hemp extract. Numerous color
reactions were reported, only one of which has received
frequent application and until recently general acceptance.
This is the so-called alkaline Beam test which is the purple
color produced by treatment of a hemp extract with 5
percent methanolic potassium hydroxide.3 From our chemical
results and from an extensive investigation of agronomic
varieties of hemp by Dr. Matchett4 it can be concluded that
this test is not indicative of a substance with marijuana
activity.
In 1895 Wood, Spivey, and Easterfield' were able to isolate
from "purified red oil" by means of a treatment with acetic
anhydride, a crystalline acetate, which was removed from the
residual oil and which could be purified in the normal way.
Hydrolysis of this pure acetate resulted in a homogeneous
viscous oil which these investigators called cannabinol. Until
about a decade ago, when the fact was shown to be
erroneous, cannabinol was accepted as the active principle of
hemp. These same investigators performed preliminary experiments
on the structure of the cannabinol molecule.
Further work on its chemistry was impeded by the fact that
in spite of many attempts in different laboratories the
isolation of cannabinol was not repeated until 1932. At that
time Cahn ,6 an English chemist, again obtained this compound
and completed a series of brilliant researches from the
results of which he was able to establish the skeleton and the
substituents in the molecule but was unsuccessful in determining
the orientation of all the groups.
It was with this background that the chemical experiments
were begun at the University of Illinois.* Attempts to isolate
cannabinol from the purified red oil of Minnesota wild hemp
* The experimental work of the series of researches at the University of
Illinois was performed by the following students: B. R. Baker, C. K.
Cain, J. H. Clark, Madison Hunt, Charles F. Jelinek, W. D. McPhee,
D. C. Pease, C. M. Smith, R. B. Wearn and Hans Wolff.
by the procedure described by Cahn failed. Consequently,
attention. was turned to attempts to isolate a phenolic
product, the presence of which was established by qualitative
tests. Of the numerous reagents employed, 3,5-
dinitrobenzoyl chloride reacted to give a crystalline compound
which was readily removed from the residual oil and
purified. It proved to be a &-ester, the hydrolysis of which
by an appropriate method gave a new substance which was
termed "cannabidiol" because of the presence of two
phenolic groups.' It was isolated first as an oil but eventually
was obtained as a crystalline solid. By developing a new
procedure as a substitute for Cahn's method the isolation of
cannabinol from this same oil was also accomplished, and for
the first time cannabinol was induced to crystallize.8 * The
properties of cannabinol and cannabidiol are compared in
Chart 1. Cahn's proposed formula for cannabinol is shown;
his evidence for this structure was conclusive except for the
positions of the hydroxyl and n-amyl groups.
The similarity in the empirical formulas of these two
compounds is striking and led to the belief that these two
sister substances must have structural formulas not too
unrelated. The optical activity of cannabidiol suggested immediately
the probability of partial hydrogenation of one
aromatic nucleus in cannabinol and indeed the left one, since
cannabidiol contains phenolic groups.
Although cannabidiol, like cannabinol, is physiologically
inactive, the study of its structure and its reactions was most
revealing. The results served to determine completely the
structure of cannabinol and led to the formation of tetrahydrocannabinols,
products of high marijuana potency which
are probably active principles in the red oil of hemp.
The complicated and extensive chemical investigations on
the structure of cannabidiol, on the synthesis of cannabinol,
and on the preparation of tetrahydrocannabinol and synthetic
analogs, will be presented in very brief form and only
the more significant facts will be mentioned. The structure of
cannabidiol" will be considered first with the pertinent
* Cannabidiol and cannabinol are the only pure compounds related by
structure to the active constituents which have been isolated from
hemp extracts. Claims have been made for the isolation of other compounds
or their derivatives, but no detailed information is available and
the results require confirmation.
reactions given in logical rather than chronological order.
Typical color tests indicated a phenol group, and formation
of &s-esters and ethers the probable presence of two
such groups. Catalytic reduction resulted in the absorption of
two moles of hydrogen with formation of a molecule which
still retained the two phenolic groups, thus leading to the
deduction that two pyridine hydrochloride caused cleavage
into p-cymene and olivetol (1,3-dihydroxy-5-n-amylbenzene)
both of which were identified by comparison with authentic
samples. This is convincing evidence that cannabidiol is
composed of dihydrocymyl and olivetol residues. The positions
of the linkage between these residues were determined
next. Cannabidiol was first reduced to tetrahydrocannabidiol
and then oxidized; menthane carboxylic acid was isolated,
identical with a specimen obtained by synthesis from l-menthol,
thus demonstrating that the attachment of the dihydrocymyl
residue was adjacent to the isopropyl grouping. From
a comparison of the absorption spectra of various amyl
resorcinols and of cannabidiol and its reduction product, the
dihydrocymyl was postulated as being attached to the oliveto1
between the hydroxyl groups. Direct chemical proof of
this was accomplished by conversion of cannabidiol with
acidic reagents to tetrahydrocannabinol which, upon dehydrogenation,
gave cannabinol. Cannabinol was shown to contain
the linkage between the hydroxyls by synthesis of this
molecule by an unequivocal method.
The structure of the cannabidiol molecule was thus established
except for the orientation of the two aliphatic double
bonds in the dihydrocymyl residue. One of these proved to
be terminal, since ozonization of cannabidiol gave formaldehyde.
This information, along with the fact that tetrahydrocannabinol
was produced from cannabidiol through closure
of a pyran ring, left no doubt that this terminal double bond
must be present as an isopropenyl group. The location of the
second double bond was determined only by indirect means.
Since the arguments are rather involved, they will be omitted
here and merely the positions assigned for the double bonds
will be given. The tetrahydrocannabinol obtained in the
isomerization of cannabidiol, varied in rotation dependent on
the reagent used. Apparently two forms exist which were
isolated as low-rotating and high-rotating isomers. In the
low-rotating tetrahydrocannabinol, which presumably has the
double bond in the same position as in cannabidiol, the
double bond was deduced to be in the y&position between
the unsubstituted carbons; in the high-rotating isomer, the
double bond is probably substituted in the y&position
which includes the ring carbon holding the methyl group.
The establishment of olivetol as a cleavage product of
cannabidiol revealed the probable orientation of the hydroxyl
and n-amyl groups in cannabinol. This supposition
was proven correct by the synthesis of cannabinol by two
different methodsl' as shown in Chart III. The syntheses
served also to prove that the position of the linkage of the
two benzene rings is between the hydroxyl groups and thus
confirmed a similar attachment of the rings in cannabidiol.
2-Bromo4-methylbenzoic acid and dihydroolivetol condensed
in the presence of alkali and a copper salt to 1-keto-3-
n-amyl-9-methyl- 1,2,3,4-tetradydro-6dibenzopyrone; dehydrogenation
gave 1-hydroxy-3- n-amyl-9-methyl-6-dibenzopyrone
which, with excess of methylmagnesium iodide, gave
cannabinol, (1-hydroxy-3- n-amyl-6,6,9-trimethyl-6dibenzo-
pyran). An analogous condensation of 2-bromo4-methylbenzoic
acid with olivetol, followed by treatment with
methylmagnesium iodide, gave the isomeric cannabinol with
the linkage between an hydroxyl and the n-amyl group. The
second method consisted in condensation of ethyl Fmethylcyclohexanone-
2-carboxylate with olivetol in the presence of
phosphorous oxychloride to give 1-hydroxy-3- n-amyl-9-
methyl- 7,8,9,10-tetrahydro- 6dibenzopyrone. Dehydrogenation
to the corresponding 1-hydroxy-3- n-amyl-9-methyl-6-
dibenzopyrone followed by treatment with methylmagnesium
iodide gave cannabinol.
The disappointment accompanying the discovery that cannabidiol
had no marijuana activity was more than compensated
by the observation that both the low-rotating and
high-rotating tetrahydrocannabinols possess very marked
marijuana potency." These two substances, which were
high-boiling oils, have not yet been induced to crystallize. All
attempts to isolate solid crystalline derivatives have failed.
The isomerization of cannabidiol required intensive study
before procedures were found which resulted in products of
constant rotation. Apparently, without very specific conditions,
mixtures of low- and high-rotating forms are obtained
which cannot be converted readily to a product of maximum
rotation. Tetrahydrocannabinol of constant rotation [a] 27 D
-265" can be produced conveniently from cannabidiol
merely by heating the latter in benzene solution with a little
toluene sulfonic acid until the reaction mixture exhibits no
alkaline Beam test. This product was the principal one
selected for pharmacological and clinical investigation.
The acetates of these tetrahydrocannabinols also had
marijuana potency though less than that of the unacetylated
compounds. By catalytic reduction all of the tetrahydrocannabinols
of varying optical activity gave a hexahydrocannabinol
of essentially the same optical activity. This product
was physiologically active though less so than any of the
tetrahydrocannabinols from which it was derived.
The typical marijuana activity manifested by the isomeric
tetrahydrocannabinols constitutes ponderable evidence that
the activity of the plant itself, and of extracts prepared
therefrom, is due in large part to one or the other of these
compounds, or both, and possibly also to their stereoisomers,
of which a number are possible. Confirmation of this supposi
tion is available from an investigation by Wollner, Matchett,
Levine and Loewe,13 the results of which were published just
recently. These authors have described the isolation from
acetylated red oil of a tetrahydrocannabinol acetate of
potency greater than than of either of the tetrahydrocannabinols
prepared by isomerization of cannabidiol. Partition of
the acetylated red oil was accomplished by selective absorption.
Silica gel removed cannabidiol diacetate and unknown
material from a benzene solution of the mixture; alumina
adsorbed substances of lower rotation by two passages, first
in carbon tetrachloride, then in pentane solution. The
product was judged to be stereochemically homogeneous by
failure to effect further separation through selective adsorption
or by careful fractional distillation in a specially designed
high-vacuum fractionating column. Hydrolysis of the
acetate yielded a tetrahydrocannabinol whose structure was
identified through analysis and dehydrogenation to cannabin
01. Its potency was similar to the products prepared by
isomerization of cannabidiol. It would appear that rearrangement
occurred during hydrolysis, since reacetylation failed to
restore either the optical rotation or physiological potency to
the original value.
With the discovery of the character of substances which
possess marijuana activity, attention was directed next to
attempts to synthesize compounds of similar activity. A very
satisfactory procedure was devised for obtaining an isomer of
the natural tetrahydrocannabinol with the double bond
conjugated to the benzene ring. It consisted in the condensat
i o n o f e t h y l Smethylcyclohexanone-2-carboxylate with
olivetol to give 1-hydroxy-3-n-amyl-9-methyl-7,8,9,10-tetrahydroddibenzopyrone
which, with excess methylmagnesium
iodide, yielded 1-hydroxy-3-n-amyl,6,6,9-trimethyl-7,8,9,10-
tetrahydro-6-dibenzopyran.14 The product proved to have
marijuana activity though only about one-tenth that of its
isomer, natural tetrahydrocannabinol. A series of several
closely related synthetic compounds was then prepared by
the same procedure using the same keto ester but homologs
of olivetol. " All of these products were reduced to the
corresponding hexahydro compounds.16 The synthetic tetrahydrocannabinol
was also modified by replacing the 6-methyl
groups by ethyl and propyl groups.i7 (Chart V.)
A provisional synthesis designed to obtain an optically
active tetrahydrocannabinol was sought in the condensation
of pulegone and olivetol. I79 I8 In the presence of phosphorous
oxychloride, a product which analyzes for, and has the
properties of tetrahydrocannabinol is formed. A possible
mechanism by which such a reaction might take place is
shown in Chart VI. The purity of the final product is by no
means established. There is a possibility of contaminants
formed by condensation of the two reactants to give a
partially hydrogenated xanthane or a tetrahydrodibenzofuran,
isomeric with tetrahydrocannabinol. Homologs in
which the olivetol portion was substituted by other 1,3-dihydroxy-
S-alkylbenzenes were synthesized.16 The reduction
product of each was prepared.
Finally in Chart VII are shown molecules in which the
left-hand ring has been modified by removal or by change in
the position of the methyl group.17
The pharmacological studies on hemp extracts have been
equally as meager as the chemical investigations and in the
long history of Cannabis preparations only three tests have
been reported. Liataud" in 1844 observed that motor
incoordination in the dog was a characteristic effect induced
by marijuana preparations; Fraenkel*O in 1903 interpreted
this incoordination as a cataleptic condition. This was followed
in 1928 by the observations of Gayer*' that in various
animals such as cats, rabbits, or dogs, intravenous injection of
marijuana preparations in acetone solution induced cornea1
anesthesia which was characteristic of active fractions of the
resin. In 1937, Munch and Maritz** reported no unequivocal
effects when Cannabis preparations were administered to
albino mice. On the other hand, Loewe noted a definite
increased depressant action when treated mice were given a
hypnotic of the barbiturate series. Pernocton, butyl-bromoally1
barbituric acid, gave the greatest enhancement of any of
the drugs tested.
The Gayer corneal anesthesia test was developed further
by Marx and Eckhardt 24 but neither these investigators nor
Gayer himself went further than to designate that the cornea1
reflex was normal or abnormal. The cornea1 response was
ascertained by tapping with von Frey hairs. Walton*' took
steps in a quantitative direction by counting the number of
responses occasioned by tapping the cornea a given number
of times and by plotting the results over the whole duration
of the effect. By thus locating a definite maximum in the
areflexia-versus-time curve of each experiment, quantitative
comparisons were made possible by determining the ratios of
doses producing equal maxima in different animals. Loewe
developed this procedure further by application of his
method of "Bioassay by Approximation" to overcome as far
as possible the large intra-individual and the large group
variabilities which seem to be inherent in the reaction of all
types of animals to marijuana preparations. His study of the
Gayer test applied to the behavior of rabbits as test animals
showed not only great inter-individual variations in sensitivity
but also enormous intra-individual variations in the same
animal. Using the same animal repeatedly, this investigator
found a consistent decrease in sensitivity to one and the same
dose. Therefore, even though the method of approximation
was applied, the values of potency obtained by this method
are not suitable for anything but qualitative purposes. Moreover,
they do not parallel the dog-ataxia potencies of the
same preparations, the divergence sometimes being tenfold.
This indicates either that the Gayer test is not conclusive for
quantitative measurements or else that an active principle
other than that disclosed by the dog-ataxia test is present in
red oil.
The "mouse sleep prolongation test" may be dismissed
with merely a brief discussion. The Cannabis preparations,
usually red oil, were administered by stomach tube. After a
definite time, pernocton was injected intravenously at a level
just above the threshold of hypnotic action. The synergistic
effect of the Cannabis was measured by the period of
suppression of the righting reflex averaged over all the
animals of a single-dose group. This effect, though typical of
red oil, could not be duplicated with the natural or synthetic
tetrahydrocannabinols which had been shown definitely to
have physiological activity in man. Pure cannabidiol, which is
devoid of the marijuana effect upon man, showed the highest
potency in this test and consequently the action from the red
oil probably is due to its cannabidiol content.
The determination of the cataleptic condition in dogs
reported by Fraenkel, as accepted in former editions of the
United States Pharmacopoeia for bioassay of Cannabis ex
tracts, was developed further by Walton25 to attempt to
make the effect the basis of a quantitative test. The arbitrary
stages of intensity of effects were recognized; first a slight
depression; second, a barely detectable ataxia; third, an
obvious ataxia; fourth, a marked ataxia in which the animal
frequently pitches forward and barely catches itself; fifth,
inability to stand alone; sixth, inability to rise and plunge
about. The ataxia is chiefly a static one and is manifested
particularly by swaying movements. Intravenous doses of red
oil dissolved in acetone always acted within half an hour. A
similar intensity of effect by oral administration required five
to seven times the dose. Walton employed for evaluating
potency the procedure used in most bioassay methods, the
comparison of test and standard doses of equal intensity of
effect. By comparing the results at various levels of dosage
and by repeating the procedure a considerable number of
times, he obtained more accurate results than had hitherto
been reported. About eight trials with the unknown on the
same dog, calibrated in about six trials with the standard,
were used. A single assay required about three weeks or more
for completion.
Loewe applied his principle of "Bioassay by Approximation"
to the ataxia test and has thus been able to obtain a
more decisive method for comparison of active products. The
procedure aims at obtaining from each one of an adequate
number of calibrated dogs, several figures of comparison of a
test dose with the calibration doses. These figures represent
ratios of doses, the response to which is not quantitatively
the same. They are used to approximate the true potency
value from both sides. At the same time the degree of
overlapping marks the range of variation and gives an idea of
the inherent inaccuracy. An entire assay may in this way be
performed in a single day and highly consistent results may
be obtained. The maximum order of accuracy is 10 percent
since this is the minimum of variation in the response of the
same animal at different times. Since parallelism between the
results of the dog-ataxia tests and the effects of different
preparations on humans has been established, it may be
concluded that the ataxia method as developed by Loewe
represents a reliable index of potency.
Using this procedure as just outlined, the comparison of
results on the various natural and synthetic products will be
presented in charts. Each value given represents the result
obtained by the use of several dogs; three or four in the case
of low potency materials, ten to twenty or more for substances
of higher potency.
In Chart VIII is shown a comparison of the potencies of
the series of products analogous to synthetic tetrahydrocannabinol.
The latter was adopted as a standard. The corresponding
hexahydro derivatives were also tested. It is observed
that the modification of the alkyl group results in a
gradual increase in activity with increase in size until a
maximum is reached at the n-hexyl derivative. The point of
maximum potency is the same in the hexahydro compounds,
though all, with the exception of the n-hexyl, exhibit a
decreased effect. There is also presented the potencies of
tetrahydrocannabinols of different optical rotations all derived
from cannabidiol, the potency of an average purified
red oil and of a highly active portion of red oil obtained from
it by extraordinarily careful fractionation. The increased
activity of the optically active natural tetrahydrocannabinols
is striking. The commercial cannabis fluid extracts are of very
low and variable potency.
In Chart IX, the potency of products of questionable
purity produced from pulegone and various olivetol homologs,
together with their hydrogenated derivatives are shown.
The maximum potency appears in the n-octyl molecule, and
the values for the n-heptyl and n-octyl derivatives exceed
those of the corresponding products synthesized by an
unequivocal procedure.
Finally in Chart X, the activities of other analogs are
shown. Each has an activity less than that of the molecule
possessing methyl groups in the 6,6,9-positions.
Recognizing that the indulgence in marijuana in New York
City has constituted a growing problem of major consequence
involving psychiatric, medical, legal, sociological and
civic aspects, a clinical study was undertaken by a committee
appointed by Mayor LaGuardia and supported by funds
allotted by several foundations. The primary objectives were
the determination of the mental and physical actions of marijuana
on the kind of person resorting to its use and the
consequent social implications. Dr. Samuel Allentuck directed
the clinical studies in a unit of the Welfare Island
Hospital, and the facts I am presenting have been summarized
from his report on the results.
An orientation group, the members of which were subjected
to numerous and varied procedures, was used to
determine precisely which tests would best lend themselves
to the solution of the specific problems. From the results a
program was established which consisted in a systematic
study of a group of seventy-seven subjects ranging in age
from twenty-one to forty-five years and from borderline to
superior in intelligence, all of them voluntary recruits from
one prison population. About half had used marijuana previously.
After a physical, neurological, and psychiatric examination,
they were placed in one or more of five categories as
to personality types-normal, antisocial, autistic, cyclothymic
and epileptic. Each individual before and during the period of
action of marijuana was interviewed at regular intervals
throughout the day by various members of the staff. Possible
subjective and objective phenomena resulting from use of the
drug were discussed and elaborated upon in detail. Introspective
reports were obtained in the absence of the drug, under
pseudo-stimulation with placebos and during intoxication
with marijuana or allied synthetics; analysis of the data was
based on the most frequently mentioned phenomena. The
patients were also subjected to periodic tests for blood
pressure or pulse changes, pupillary changes, urinalyses,
blood chemistries, hematological surveys, basal metabolic
rates, electrocardiograms, arterial and venous pressure tracings
and vital capacities. In addition, psychological examinations
before and during the intoxication periods were carried
out, including a wide variety of psychophysical, psychomotor
and clinical tests.
The marijuana was suppplied in the form of a fluid
concentrate which was desolvated and administered in the
form of pills. Pure tetrahydrocannabinol was diluted with a
little olive oil and placed in gelatin capsules holding 15 mg. of
drug, the equivalent in physiological potency of one pill
containing 300 mg. of crude solids from hemp. The l-hydroxy-
3-n-amyl,6,6,9-trimethyl-7,8,9,1O-tetrahydroddibenzopyran
and its 3-n-hexyl homolog were administered in a
similar manner using the equivalent doses which produced
similar activity, namely, 120 mg. per capsule of the former
and 60 mg. per capsule of the latter. It is significant that
these relative amounts are practically identical with those
observed by Loewe for obtaining identical effects in dogataxia
tests.
The patients were started on two marijuana pills or on
equated doses of tetrahydrocannabinol or the two synthetic
analogs. The dose was increased by two pills at a time at
intervals of two days unless toxic symptoms supervened. At
the appearance of toxicity, the patient was returned to the
physiological dose and this was increased one pill at a time.
Thus the maximum tolerated dose for each individual was
determined and at the same time approximately the threshold
at which psychotic changes first appeared. Tetrahydrocannabinol
and the synthetic compounds dissolved in olive
oil were in some cases administered by intramuscular injection.
Other clinical tests were made which involved intoxication
from smoking marijuana cigarettes.
Barbiturates, cold showers and sweet candies were found
to be efficacious in ameliorating any alarming physical or
psychotic symptoms which developed following marijuana
overdosage.
The detailed results of this carefully planned and executed
clinical investigation, the first of its kind on record, must be
left to the complete report when it is published. Merely the
more significant findings which may prove of maximum value
will be presented here. The crude drug in the form of
concentrated marijuana extract, tetrahydrocannabinol derived
from cannabidiol, and the two purely synthetic compounds,
l-hydroxy-3-n-amyl-6,6,9-trimethyl-7,8,9,10-tetrahydro6dibenzopyran
and the corresponding 3n-hexyl
derivative elicited similar clinical and psychiatric phenomena
upon the same subjects. The pharmacological action of these
drugs somewhat resembles atropine and the psychiatric portrait,
alcohol. The effects of marijuana do not vary qualitatively
with the route of administration, whether ingested,
injected or inhaled. By inhalation, however, they are more
prompt in their appearance and disappearance; by ingestion
they appear within one-half to one and one-half hours, reach
their maximum in from three and one-half to five hours and
disappear within seven hours.
The observed physical effects, one or more of which occur
in each patient, are (a) elevation of the pulse rate, the
increase being directly proportionate to the degree of intoxication;
(b) elevation of the blood pressure; this varies with
the individual and usually rises in direct proportion to the
pulse; (c) injection of the conjunctival blood vessels which
varies with the dose; (d) dilation of the pupils and sluggish
reaction to light and in accommodation; vision for proximity,
distance and color changes slightly; (e) circum oral tremors;
tremulousness of the protruded tongue and the extremities;
(f) dryness of the oral and pharyngeal mucous membranes;
(g) increased frequency with decreased amplitude of thoracic
respiratory movements; (h) ataxia; (i) hyperreflexia. The
observed psychiatric effects are (a) apprehension and anxiety,
(b) euphoria, (c) loquaciousness, (d) lowering of inhibitions,
(e) hunger and thirst, (f) feeling of being "high," (g) uncontrollable
bursts of laughter or giggles, (h) drowsiness, languor,
lassitude and a pleasant feeling of fatigue.
Clinical tests revealed that marijuana produces no significant
changes in basal metabolic rates, blood chemistry,
hematological picture, liver function, kidney function or
cardiac electrical conduction. Marijuana delays somewhat
gastric and intestinal motility as gauged by the Carlson
apparatus and x-ray studies; it produces definite increase in
the frequency of the alpha wave in electroencephalographic
recordings thus indicating increased relaxation.
Other observations of a more general character were
recorded. Tolerance for marijuana may be produced by
repeated administration of subtoxic doses over a prolonged
period of time. Thus the same dose elicited progressively
fewer and milder symptoms. Marijuana is unlike opium
derivatives in that it does not give rise to a biological
dependence accompanied by withdrawal symptoms. Neither
does it establish a stro: .3 craving as exists in tobacco smoking
or in alcoholic indulgence. Follow-up of the subjects has
failed to establish existence of any craving for the product.
Many of the unpleasant physical symptoms previously mentioned
appear only as a result of the administration of
excessive doses of drug. It is no more of an aphrodisiac than
alcohol.
Since all the clinical experiments at Welfare Island were
conducted on volunteer prisoners, it was desirable for completeness
or perhaps to satisfy my curiosity to obtain some
results on subjects in another social class. As a consequence, I
have conducted a dozen or more experiments using as test
individuals chemists among whom were two members of the
National Academy of Sciences and two high-ranking and very
successful industrial chemists. In all cases very small doses, 1.5
mg. or 30 mg. of tetrahydrocannabinol, were administered
about one hour before dinner. Each individual reacted differently
with the possible exception of the observed stimulation
of the appetite. They all recognized an intoxication which
they described as in general like, but in detail different from
that induced by alcohol. Thus, one industrial chemist who
shows no outward change under the influence of alcohol,
reported essentially no effect from 15 mg. except a mild
stimulation of his desire for food. A 30 mg.-dose, however, to
this same individual had a pronounced effect. Though he
noticed no particular craving for food before dinner, as soon
as he started eating he became particularly hungry and
consumed a very large meal. He felt intoxicated and dissociated
from his normal self, had a feeling of heaviness in his
head and legs and reported a fogginess which he described as
the inability to focus his eyes on more than a single object at
a time. Since this man desired to get the effect of distorted
time and space which is recorded as a frequent phenomenon
associated with the marijuana user, he tried it a third time,
taking 45 mg. The result was a ravenous hunger which was
not satisfied after eating the equivalent of two hearty meals.
A marked hypergeusia was also noted. The same fogginess
appeared and heaviness in head and legs. During the conversation
which took place among his five associates at the
dinner table, he was able to comprehend a question but by
the time the answer was given, which was immediately, he
couldn't remember the question. In spite of the intoxication
with the resulting phenomena, this subject had no difficulty
in holding his own and then some in a poker game composed
of expert players.
A second industrialist took 15 mg. at five o'clock in the
afternoon and felt the first effects about 6:30 when he lost
coordination in his fingers to the extent that he had to stop
playing the violin, which he was doing at the time. Shortly
thereafter he developed a tremendous appetite which was, if
anything, sharpened by eating an enormous dinner and
popcorn all through the evening. He had a mild lift about like
a cocktail or two on an empty stomach and this and the
hunger left about eleven o'clock.
A chemistry professor who took 30 mg. had a mildly
increased appetite and reported feeling a bit fuzzy during his
dinner, which resulted in difficulty in comprehending what
his associates were saying. This was followed by sleepiness
and lassitude until the effects of the drug disappeared two
hours afterwards. The stimulation was only slight, which
.paralleled the effect of alcohol upon this man.
A fourth subject of high standing in university circles
wrote me in detail concerning his experience. I am quoting
from his letter received two days after the experiment.
This is to report to you on the outcome of my trip
conducted under the powerful guidance of the marijuana
drops. I would be interested some time to know
just how much of what specific material you gave me,
but there is no question but that it gave me a most
terrific wallop. In brief:
5:20 P.M. Took two capsules, went for short swim,
had a highball and began to feel something beyond the
mild glow from the drink about 6:15. By 6:30 felt
bouncy in the knees, a little gay and foolish.
6 :00-8: 30 P.M. Very much in the fog. Had alternate
waves of hilarity and depression. Sat in smoking compartment
looking at myself in the mirror, writing notes
on the experiment, and feeling very silly and stupid.
Would feel the onset of a surge of hilarity and then
break into a raucous, rippling laugh. This gaiety was not
particularly pleasant, however, for throughout I felt
wholly dissociated from myself, knew that I was at the
mercy of the drug, and greatly resented this lack of
control. The feeling was very different from that of
being at one or another stage of intoxication, for I
looked perfectly clear and normal and I could stand
erect without swaying and execute motions with considerable
precision. I could not, to my annoyance and as
I was well aware, speak or write and think coherently.
This bothered me particularly in the waves of depression,
when my lips would feel very parched and salty
and I would long to break the spell and regain my own
consciousness. A very pressing and persistent sensation
was that of extreme hunger, but I had sense enough to
wait until the laughing spells were under control before
going into the diner.
Here are a few excerpts from the log: "7:20. Not so
good; for a few minutes I sat and looked at myself in a
silly way. . . . This is me again. I very suddenly snapped
out of it and am struggling back to normal. Lips are very
dry. Maybe I'm not quite out of it. . . . The above is
true. I am writing here in a serious vein-but quick, I
must write that a minute or two ago I was sitting here in
the men's lounge giggling at myself in the mirror and
saying: This stuff does make you feel pretty gay (gay in
the neese). Isn't that the damndest thing? [I knew the
spelling was wrong but couldn't right it.] . . . 7:42. Yes,
snapping out again. I just had a most jubilant laugh and
feel another coming along. 7 :45, not feeling laughy, feel
like hell. This is really awful stuff. . . . 8:03. I feel like a
fool. Lips bad. Want water, but I am terribly hungry and
wish the experiment were over. I am thinking very much
of eating, for I am very hungry. . . . 8:09. Nearly came
out of it. It is awful. Helpless, awful feeling. Over, over,
when will it be over? When can I eat? . . . 8 : 13. A fellow
just came in to shave. Why now? Why not at this time of
the evening EAT. . . . ha, ha. Now I have been silly.
Looked silly. . . . ha, ha. Of all places to have this-the
train. Bad, bad. Oh I feel like hell, salty lips . . ."
At 8: 30 I devoured an enormous steak dinner with
great rapidity and thoroughness, and left no trace of any
of the fixings, even though I ordinarily do not eat ripe
olives or salad, and although ordinary delicacy would
keep me somewhat below the ten crackers I had with
my cheese. The food tasted no better or worse than
usual, and I had a dissociated feeling that my mouth was
a purely mechanical guide for all that came its way, and
wondered if mine was not very much the same as the
"appetite" of a cat.
At 9:00 I felt myself coming out of the spell, and
again at 9: 15 I felt sane for a minute or two. A little
later the sane periods began to predominate, and by 10
A.M. I was back again in control and could sit down and
write out the details of a new natural product synthesis.
Thus ended the trip. I didn't sleep too well or too
poorly, and the next morning I felt O.K. and had no
hang-over.
It was an interesting experiment, but I can't write too
enthusiastic an endorsement for this drug you fellows
are synthesizing. The feeling of well-being would not, in
my estimation, equal that from about three highballs,
and the penalty seemed to me to be pretty severe. The
outstanding impressions were the feeling of detachment
from myself and the extreme hunger. Are these both
associated with the same part of the molecule? If not,
you might hydrogenate out some of the bad effects and
thereby obtain a wonderful aperitif.
After the Welfare Island study of every phase of the action
of marijuana and the synthetic drugs and after finding no
discernible evidence of any permanent deleterious effects,
either mental or physical, Dr. Allentuck considered the
question of the possible therapeutic value of these substances.
The potential availability of pure synthetics of
standard potency invites such a study, for hitherto merely
hemp extracts were accessible, the clinical activity of which
must be determined for each batch of extracted material.
Since the outstanding manifestation of the marijuana action
is the euphoria which makes its user feel "high," consideration
was given to its possible employment as a drug for
individuals in various stages of mental depression as cyclothymics,
involutionals, reactives, or those with organic
conditions in which dysphoria is a dominant factor. The
invariable characteristic of the drugs to stimulate the appetite,
suggests they might be applicable in psychoneurosis in
which a lack of desire for food exists. Many subjects show an
alcohol-like picture of intoxication following the use of
marijuana. The idea of using these drugs in the treatment of
chronic alcoholic addiction was considered and preliminary
experiments by Dr. Allentuck on private patients and colleagues
were sufficiently encouraging to merit investigation
on a larger scale and over a longer period of time.
The euphoria produced by marijuana is in many ways
comparable to that achieved by the use of opium derivatives.
This suggested the possibility of use in the treatment of
opiate derivative addictions to eliminate or ameliorate the
withdrawal symptoms commonly experienced during previously
so-called "cures." To clarify this question Dr. Allentuck
selected a series of cases among drug addicts undergoing
treatment. One group of thirteen received 1.5 mg. of tetrahydrocannabinol
orally three times daily at 5 :00 A.M., 2:00
P.M., and 10:00 P.M. and a sterile hypodermic injection;
another group of fourteen received the same treatment
without the sterile injection. Subjective and objective findings
were recorded. In general the consensus of subjective
opinions favored the new treatment as compared to previous
cures and the established routine taken by some of these
patients. They felt happier, had a better appetite and wanted
to return to activity sooner. These results served as a basis for
further study of fifty cases in which quantitative criteria were
employed.
Two groups of twenty subjects were selected, one group
receiving the tetrahydrocannabinol up to a maximum of ten
days and the others receiving none. Members of each group
were observed throughout the day. Each morning they were
interviewed and any complaints recorded on a chart. Thus an
attempt was made to arrive at a quantitative comparison of
the withdrawal symptoms. It was found that the tetrahydrocannabinol
treatment was useful in alleviation or elimination
of withdrawal symptoms and in diminishing or eliminating
the accompanying discomfort which follows cessation of
narcotic indulgence. Any withdrawal symptoms under the
tetrahydrocannabinol treatment were of a mild character and
occurred within the first three or four days following which
the patients began to feel much better. The chief complaints
were restlessness, headache and dryness of the throat. They
had an increased appetite and desire for food which diminished
or eliminated such withdrawal symptoms as nausea,
diarrhea and perspiration. They felt physically stronger and
showed psychomotor activity. The feeling of euphoria produced
by the tetrahydrocannabinol helped in rehabilitating
the physical condition and in facilitating social reorientation.
An outstanding result is a subjective feeling of relaxation.
The sleep induced by the drug likewise contributes to the
general improvement in the patients' health. These results are
in contrast to those from the use of Magendie's solution
which produces in the patients contentment for the first
three or four days, after which signs of marked discomfort or
withdrawal effects appear. The patients after this treatment,
upon their discharge were shaky and generally in poor
physical condition. These preliminary results with tetrahydrocannabinol
justify a more exhaustive study of its
possibilities as a means of relieving the withdrawal symptoms
in narcotic addicts.
With this brief picture of the results of the cooperative
program before you, I may conclude by adding a few remarks
about what may be expected from a continuation of the
investigations under way. In the chemical field, repeated
attempts to synthesize a tetrahydrocannabinol with a double
bond in the y, b-position have failed. Just recently, however,
a new approach has appeared and the results have progressed
to the point where I am convinced it is merely a matter of
time before the goal is reached. The physiological reaction of
this product will allow a conclusion in regard to the relative
importance of the position of the double bond in the
alicyclic ring and of the optical activity in the tetrahydrocannabinol
molecule. Other synthetic molecules of a similar
character, which are soluble in aqueous acids or bases and,
therefore, perhaps suitable for intravenous injection, are
being prepared. It is hoped also to clarify the significant
groups and their orientation which induce marijuana activity.
Thorough investigation of the constituents in red oil is
necessary to complete the understanding of hemp extracts.
In pharmacology, there is still much to be done in
cooperation with the chemist to elucidate in more detail
relationship between activity and molecular structure. With
pure chemical substances of marijuana activity, it will now be
possible to determine experimentally what actions are
exerted upon body functions other than those which have
hitherto attracted attention. The relationship between the
mechanism of ataxia action in the dog and the psychic action
in man should be clarified. It has not yet been established
that the structural differences between the various marijuanaactive
substances do not result in a relative prevalence toward
ataxia effectiveness by some, psychic effectiveness by others.
In the clinical field, the practical application of these
substances must be awaited with the usual necessary
patience. The initial experiments of Dr. Allentuck make it
appear likely that some use of this interesting drug or its
synthetic equivalents will be discovered.
In all phases of this work just completed, the groundwork
has been laid so that a wider interest should ensue, and
significant contributions may be anticipated in the chemistry,
pharmacology and clinical aspects of this class of substances.
REFERENCES
1. Brotteaux, P. Hachich; herbe de folie et de r&e. Paris, 1934.
2. Blatt, A. H. A critical survey of the literature dealing with the
chemical constituents of Cannabis sativa, J. Washington Acad. SC.,
1938,28:465.
3. Beam, W. A test for hashish, Wellcome Trop. Research Lab.
Report, 1911,4B:25.
4. Wollner, H. J., Matchett, J. R., Levine, J. and Valaer, P. Report
of the marihuana investigation, J. Am. Pharm. A., 1938, 27: 29.
- Matchett, J. R., Levine, J., Benjamin, L., Robinson, B. B. and
Pope, 0. A. Marihuana investigations, ibid., 1940, 29:399.
- Robinson, B. B. and Matchett, J. R. Marihuana investigations,
ibid., 1940,29:448.
5. Wood, T. B., Spivey, W. T. N. and Easterfield, T. H. Charas; the
resin of Indian hemp, J. Chem. Sot., 1896, 69:539; and Cannabinol,
ibid., 1899, 75:20.
6. Cahn, R. S. Cannabis indica resin, J. Chem. Sot., 1930:286;
1931:630; 1932:1342; 1933:1400.
7. Adams, R., Hunt, M. and Clark, J. H. Structure of cannabidiol, a
product isolated from the marihuana extract of Minnesota wild hemp,
J. Am. Chem. Sot., 1940,62:196.
8. Adams, R., Pease, D. C. and Clark, J. H. Isolation of cannabinol,
cannabidiol and quebrachitol from red oil of Minnesota wild hemp, J.
Am. Chem. Sot., 1940,62:2194.
9. Jacob, A. and Todd, A. R. Cannabidiol and cannabol, constituents
of Cannabis indica resin, Nature, 1940, 14.5:350
Haagen-Smit et al. A physiologically active principle from Cannabis
sativa (marihuana), Science, 1940,91:602.
Powell, G., Salmon, M., Bembry, T. H., and Walton, R. P. The
active principle of marihuana, ibid., 1941,93:522.
10. Adams, R. et al. Structure of cannabidiol, J. Am. Chem. SOC.,
1940,62: 196; 732; 735; 1770; 2215; 2402; 2566,1941,63:2209.
Jacob, A. and Todd, A. R. Isolation of cannabidiol from
Egyptian hashish, J. Chem. Sot., 1940, 1:649.
11. Adams, R. et al. Structure of cannabinol, J. Am. Cbem. SOC.,
1940,62:2197; 2201; 2204; 2208; 2401.
Bergel, F., Todd, A. R. and Work, T. S. Observations on the
active principles of Cannabis indica resin, Cbem. & Ind., 1938, 16~86.
Work, T. S., Bergel, F. and Todd, A. R. The active principle of
Cannabis indica resin, Biocbem. J., 1939, 33: 123.
Todd, A. R. et al. Cannabis indica, J. Cbem. Sot., 1940:649;
1118; 1393; 1941:137.
Powell, G. and Bembry, T. H. Synthesis of cannabinol, J. Am.
Cbem. Sot., 1940,62:2568.
12. Adams, R. et al. Conversion of cannabidiol to a product with
marihuana activity, J. Am. Cbem. Sot., 1940, 62:2245; 2402; 2566;
1941,63:2209.
Russell, P. B. et al. Cannabis indica: the relation between chemical
constitution and hashish activity, J. Chem. Sot., 1941 : 169.
13. Wollner, H. J., Matchett, J. R., Levine, J. and Loewe, S. Isolation
of a physiologically active tetrahydrocannabinol from Cannabis
sativa resin, J. Am. Chem. Sot., 1942, 64:26.
14. Adams, R. and Baker, B. R. Structure of cannabidiol; a method
of synthesis of a tetrahydrocannabinol which possesses marihuana activity,
J. Am. Chem, Sot., 1940,62: 2405.
Todd, A. R., et al., Cannabis indica, J. Chem. Sot., 1942: 1121;
1941: 137; 169.
15. Adams, R., Lotwe, S., Jelinek, C. and Wolff, H. Tetracannabinol
homologs with marihuana activity, J. Am. Chem. SOL, 1941, 63: 1971.
16. Adams, R., Loewe, S., Smith, C. M. and McPhee, W. D. Tetrahydrocannabinol
homologs and analogs with marihuana activity, J. Am.
Chem. Sot., 1942,64:694.
17. Adams, R., Smith, C. M. and Loewe, S. Tetrahydrocannabinol
homologs and analogs with marihuana activity, J. Am. Cbem. Sot.,
1941,63: 1973.
Bembry, T. H. and Powell, G. Compounds of the cannabinol
type; synthesis of some compounds related to tetrahydrocannabinol,
ibid., 1941, 63:2766.
.- 18. Ghosh, R., Todd, A. R. and Wright, D. C. Cannabis indica; a new
h synthesis of cannabinol and of a product of hashish activity, J. Cbem.
sot., 1941:137.
19. Liataud. Memoire sur l'histoire naturelle et les proprietes meditales
du chanvre indien, Compt. rend. Acad. d. SC., 1844, 18: 149.
20. Fraenkel, S. Chemie und Pharmakologie des Haschisch, Arch. fi
exper. Path. u. Pbarm., 1903, 49:266.
2 1. Gayer, H. Pharmakologische Wertbestimmung von orientalischem
Haschisch und Herba cannabis indica, Arch. fi exper. Path. u.
Pbarm., 1928, 129: 3 12.
22. Munch, J. C. and Mantz, H. W. Pennsylvania Pharmacist, July,
1937.
23. Loewe, S. Synergism of Cannabis and butyl-bromallyl-barbituric
acid, J. Am. Pbarm. A., 1940, 29:162.
24. Marx, H. and Eckhardt, G. Tierexperimentelle Untersuchungen
iiber die Wirkung des Haschisch, Arch. fi exper. Path. u. Pbarm., 1933,
170:395.
25. Walton, R. P., Martin, L. F. and Keller, J. H. Relative activity of
various purified products obtained from American grown hashish, J.
Pbarmacol. & Exper. Tberap., 1938,62:239.
26. Loewe, S. Principle of "bioassay by approximation" and its application
to the assay of marihuana (dog) and laxatives (monkey), J.
Pharmacol. & Exper. Tberap., 1939, 66:23, and Bioassay of laxatives
on monkeys (rhesus) and on lower mammahans, J. Am. Pbarm. A.,
1939,28:427.
27. Matchett, J. R. and Loewe, S. On the preparation of an extract
having "marihuana-like" activity from the fruits of Cannabis sativa,
ibid., 1941,30:130.
28. Homologs were prepared in which the n-amyl group was substituted
by C3H7, C4H9, Cd313, C7Hlsr C&17, Cd19; the reduction product
of each was also synthesized.
Source: Marijuana
The facts on marijuana which I shall present to you this
evening comprise the results of the cooperative efforts of
three laboratories-the chemical investigations at the University
of Illinois, the pharmacology at Cornell Medical College
under the direction of Dr. S. Loewe, and the clinical
experiments at Welfare Island Hospital under the auspices of
the Mayor's Committee on Marijuana and under the immediate
direction of Dr. Samuel Allentuck. All three laboratories
acquired their supplies of raw materials from Dr. H. J.
Wollner of the Narcotics Laboratory of the Treasury Department,
and received much encouragement and stimulation
from him. Dr. J. R. Matchett of the same laboratory contributed
significantly to the general problem by devising a
method whereby a fraction of the red oil of hemp, containing
a very high concentration of the active principle, could be
obtained.
Cannabis sativa, more commonly called hemp, is of peculiar
interest. It has been known for thousands of years as a
product of commerce; the fiber of the plant for clothing and
rope, the seeds for the oil they contain. The presence of an
intoxicating principle in the resin of the plant has also long
been recognized, since the physiological action of hemp
preparations is mentioned in some of the earliest records
available and is described in the first medical treatises. In the
last two thousand years over four hundred articles have been
published describing intoxicating characteristics and the
effects on humans.'
The preparation of the hemp for consumption as an
intoxicant varies in different countries and consequently
several names, such as marijuana, charas, ganja, hashish, and
others, have been adopted, each in a definite locality. It is
significant that the same characteristic phenomenon from
any of these products is observed in man when the doses are
equated.
The clarification of the chemical and medical aspects of
hemp extracts has been extraordinarily slow for a material
known as long and as frequently as marijuana. The reasons
have been several: the failure of chemists to isolate a pure
active principle, the unsuccessful attempts of the pharmacologist
to find an animal test which paralleled the activity in
humans, and finally the lack of controlled clinical experiments.
The recorded medical literature is most confusing. The
reports are contradictory, and the description of the drug
varies from one which is habit-forming and which with
constant use is as harmful to the system as morphine, to one
which is almost completely innocuous with stimulation not
far remote from that of alcohol. Spread of the use of
marijuana in the United States has been due in part to its
ready availability, since hemp grows wild in countless places
all over the country. Newspaper articles have described
marijuana smoking among school children, and magazine
articles have carried vivid accounts of activies encountered in
tea-pads-dens where marijuana is enjoyed by devotees. Marijuana
has been accredited with precipitating premeditated
criminal acts, of lowering morals and releasing inhibitions,
and of serving as a stepping-stone to other drug addictions
such as the use of heroin. Furthermore, the claim has been
made that continued use of marijuana produces mental
deterioration. A "Marijuana Bill" was passed by the United
States Congress in 1934. For purposes of administration,
marijuana is defined essentially as any part of the hemp plant
or extract therefrom which induces somatic and psychic
changes in man. The regulations and penalties in the bill for
use and distribution of marijuana are as rigid as those
imposed for the use and sale of morphine.
In the investigations which are to be described this even
ing, more quantitative data on the chemistry, pharmacology,
and clinical aspects of marijuana has been gathered than
hitherto have been available and present a foundation for the
eventual complete understanding of this interesting natural
product. The chemical investigations, an excellent resume of
which up to 1938 has been published by Blatt,' will be
discussed first. Practically all of the chemical experiments
which have been reported were performed on the resin
present in hemp from various sources and the same general
procedure for isolating the resin has been used by all
investigators in this field. After extraction with an organic
solvent, filtration of the solution thus obtained, removal of
the solvent and vacuum distillation of the residue, a highly
viscous, physiologically active oil results, red in color and
boiling over a wide range. Fractionation of the oil leads to
the concentration of the active components in the portion
boiling from 180-190" (1 mm.) which is commonly known as
"purified red oil." This purified red oil usually used in the
chemical studies has been shown definitely to be a welter of
closely related substances which are very difficult to separate
from each other and which occur in varying proportions
dependent on the sources of the hemp.
Between 1840 and 1895, most of the chemical investigations
consisted in attempts to discover tests which would
provide means of identifying a hemp extract. Numerous color
reactions were reported, only one of which has received
frequent application and until recently general acceptance.
This is the so-called alkaline Beam test which is the purple
color produced by treatment of a hemp extract with 5
percent methanolic potassium hydroxide.3 From our chemical
results and from an extensive investigation of agronomic
varieties of hemp by Dr. Matchett4 it can be concluded that
this test is not indicative of a substance with marijuana
activity.
In 1895 Wood, Spivey, and Easterfield' were able to isolate
from "purified red oil" by means of a treatment with acetic
anhydride, a crystalline acetate, which was removed from the
residual oil and which could be purified in the normal way.
Hydrolysis of this pure acetate resulted in a homogeneous
viscous oil which these investigators called cannabinol. Until
about a decade ago, when the fact was shown to be
erroneous, cannabinol was accepted as the active principle of
hemp. These same investigators performed preliminary experiments
on the structure of the cannabinol molecule.
Further work on its chemistry was impeded by the fact that
in spite of many attempts in different laboratories the
isolation of cannabinol was not repeated until 1932. At that
time Cahn ,6 an English chemist, again obtained this compound
and completed a series of brilliant researches from the
results of which he was able to establish the skeleton and the
substituents in the molecule but was unsuccessful in determining
the orientation of all the groups.
It was with this background that the chemical experiments
were begun at the University of Illinois.* Attempts to isolate
cannabinol from the purified red oil of Minnesota wild hemp
* The experimental work of the series of researches at the University of
Illinois was performed by the following students: B. R. Baker, C. K.
Cain, J. H. Clark, Madison Hunt, Charles F. Jelinek, W. D. McPhee,
D. C. Pease, C. M. Smith, R. B. Wearn and Hans Wolff.
by the procedure described by Cahn failed. Consequently,
attention. was turned to attempts to isolate a phenolic
product, the presence of which was established by qualitative
tests. Of the numerous reagents employed, 3,5-
dinitrobenzoyl chloride reacted to give a crystalline compound
which was readily removed from the residual oil and
purified. It proved to be a &-ester, the hydrolysis of which
by an appropriate method gave a new substance which was
termed "cannabidiol" because of the presence of two
phenolic groups.' It was isolated first as an oil but eventually
was obtained as a crystalline solid. By developing a new
procedure as a substitute for Cahn's method the isolation of
cannabinol from this same oil was also accomplished, and for
the first time cannabinol was induced to crystallize.8 * The
properties of cannabinol and cannabidiol are compared in
Chart 1. Cahn's proposed formula for cannabinol is shown;
his evidence for this structure was conclusive except for the
positions of the hydroxyl and n-amyl groups.
The similarity in the empirical formulas of these two
compounds is striking and led to the belief that these two
sister substances must have structural formulas not too
unrelated. The optical activity of cannabidiol suggested immediately
the probability of partial hydrogenation of one
aromatic nucleus in cannabinol and indeed the left one, since
cannabidiol contains phenolic groups.
Although cannabidiol, like cannabinol, is physiologically
inactive, the study of its structure and its reactions was most
revealing. The results served to determine completely the
structure of cannabinol and led to the formation of tetrahydrocannabinols,
products of high marijuana potency which
are probably active principles in the red oil of hemp.
The complicated and extensive chemical investigations on
the structure of cannabidiol, on the synthesis of cannabinol,
and on the preparation of tetrahydrocannabinol and synthetic
analogs, will be presented in very brief form and only
the more significant facts will be mentioned. The structure of
cannabidiol" will be considered first with the pertinent
* Cannabidiol and cannabinol are the only pure compounds related by
structure to the active constituents which have been isolated from
hemp extracts. Claims have been made for the isolation of other compounds
or their derivatives, but no detailed information is available and
the results require confirmation.
reactions given in logical rather than chronological order.
Typical color tests indicated a phenol group, and formation
of &s-esters and ethers the probable presence of two
such groups. Catalytic reduction resulted in the absorption of
two moles of hydrogen with formation of a molecule which
still retained the two phenolic groups, thus leading to the
deduction that two pyridine hydrochloride caused cleavage
into p-cymene and olivetol (1,3-dihydroxy-5-n-amylbenzene)
both of which were identified by comparison with authentic
samples. This is convincing evidence that cannabidiol is
composed of dihydrocymyl and olivetol residues. The positions
of the linkage between these residues were determined
next. Cannabidiol was first reduced to tetrahydrocannabidiol
and then oxidized; menthane carboxylic acid was isolated,
identical with a specimen obtained by synthesis from l-menthol,
thus demonstrating that the attachment of the dihydrocymyl
residue was adjacent to the isopropyl grouping. From
a comparison of the absorption spectra of various amyl
resorcinols and of cannabidiol and its reduction product, the
dihydrocymyl was postulated as being attached to the oliveto1
between the hydroxyl groups. Direct chemical proof of
this was accomplished by conversion of cannabidiol with
acidic reagents to tetrahydrocannabinol which, upon dehydrogenation,
gave cannabinol. Cannabinol was shown to contain
the linkage between the hydroxyls by synthesis of this
molecule by an unequivocal method.
The structure of the cannabidiol molecule was thus established
except for the orientation of the two aliphatic double
bonds in the dihydrocymyl residue. One of these proved to
be terminal, since ozonization of cannabidiol gave formaldehyde.
This information, along with the fact that tetrahydrocannabinol
was produced from cannabidiol through closure
of a pyran ring, left no doubt that this terminal double bond
must be present as an isopropenyl group. The location of the
second double bond was determined only by indirect means.
Since the arguments are rather involved, they will be omitted
here and merely the positions assigned for the double bonds
will be given. The tetrahydrocannabinol obtained in the
isomerization of cannabidiol, varied in rotation dependent on
the reagent used. Apparently two forms exist which were
isolated as low-rotating and high-rotating isomers. In the
low-rotating tetrahydrocannabinol, which presumably has the
double bond in the same position as in cannabidiol, the
double bond was deduced to be in the y&position between
the unsubstituted carbons; in the high-rotating isomer, the
double bond is probably substituted in the y&position
which includes the ring carbon holding the methyl group.
The establishment of olivetol as a cleavage product of
cannabidiol revealed the probable orientation of the hydroxyl
and n-amyl groups in cannabinol. This supposition
was proven correct by the synthesis of cannabinol by two
different methodsl' as shown in Chart III. The syntheses
served also to prove that the position of the linkage of the
two benzene rings is between the hydroxyl groups and thus
confirmed a similar attachment of the rings in cannabidiol.
2-Bromo4-methylbenzoic acid and dihydroolivetol condensed
in the presence of alkali and a copper salt to 1-keto-3-
n-amyl-9-methyl- 1,2,3,4-tetradydro-6dibenzopyrone; dehydrogenation
gave 1-hydroxy-3- n-amyl-9-methyl-6-dibenzopyrone
which, with excess of methylmagnesium iodide, gave
cannabinol, (1-hydroxy-3- n-amyl-6,6,9-trimethyl-6dibenzo-
pyran). An analogous condensation of 2-bromo4-methylbenzoic
acid with olivetol, followed by treatment with
methylmagnesium iodide, gave the isomeric cannabinol with
the linkage between an hydroxyl and the n-amyl group. The
second method consisted in condensation of ethyl Fmethylcyclohexanone-
2-carboxylate with olivetol in the presence of
phosphorous oxychloride to give 1-hydroxy-3- n-amyl-9-
methyl- 7,8,9,10-tetrahydro- 6dibenzopyrone. Dehydrogenation
to the corresponding 1-hydroxy-3- n-amyl-9-methyl-6-
dibenzopyrone followed by treatment with methylmagnesium
iodide gave cannabinol.
The disappointment accompanying the discovery that cannabidiol
had no marijuana activity was more than compensated
by the observation that both the low-rotating and
high-rotating tetrahydrocannabinols possess very marked
marijuana potency." These two substances, which were
high-boiling oils, have not yet been induced to crystallize. All
attempts to isolate solid crystalline derivatives have failed.
The isomerization of cannabidiol required intensive study
before procedures were found which resulted in products of
constant rotation. Apparently, without very specific conditions,
mixtures of low- and high-rotating forms are obtained
which cannot be converted readily to a product of maximum
rotation. Tetrahydrocannabinol of constant rotation [a] 27 D
-265" can be produced conveniently from cannabidiol
merely by heating the latter in benzene solution with a little
toluene sulfonic acid until the reaction mixture exhibits no
alkaline Beam test. This product was the principal one
selected for pharmacological and clinical investigation.
The acetates of these tetrahydrocannabinols also had
marijuana potency though less than that of the unacetylated
compounds. By catalytic reduction all of the tetrahydrocannabinols
of varying optical activity gave a hexahydrocannabinol
of essentially the same optical activity. This product
was physiologically active though less so than any of the
tetrahydrocannabinols from which it was derived.
The typical marijuana activity manifested by the isomeric
tetrahydrocannabinols constitutes ponderable evidence that
the activity of the plant itself, and of extracts prepared
therefrom, is due in large part to one or the other of these
compounds, or both, and possibly also to their stereoisomers,
of which a number are possible. Confirmation of this supposi
tion is available from an investigation by Wollner, Matchett,
Levine and Loewe,13 the results of which were published just
recently. These authors have described the isolation from
acetylated red oil of a tetrahydrocannabinol acetate of
potency greater than than of either of the tetrahydrocannabinols
prepared by isomerization of cannabidiol. Partition of
the acetylated red oil was accomplished by selective absorption.
Silica gel removed cannabidiol diacetate and unknown
material from a benzene solution of the mixture; alumina
adsorbed substances of lower rotation by two passages, first
in carbon tetrachloride, then in pentane solution. The
product was judged to be stereochemically homogeneous by
failure to effect further separation through selective adsorption
or by careful fractional distillation in a specially designed
high-vacuum fractionating column. Hydrolysis of the
acetate yielded a tetrahydrocannabinol whose structure was
identified through analysis and dehydrogenation to cannabin
01. Its potency was similar to the products prepared by
isomerization of cannabidiol. It would appear that rearrangement
occurred during hydrolysis, since reacetylation failed to
restore either the optical rotation or physiological potency to
the original value.
With the discovery of the character of substances which
possess marijuana activity, attention was directed next to
attempts to synthesize compounds of similar activity. A very
satisfactory procedure was devised for obtaining an isomer of
the natural tetrahydrocannabinol with the double bond
conjugated to the benzene ring. It consisted in the condensat
i o n o f e t h y l Smethylcyclohexanone-2-carboxylate with
olivetol to give 1-hydroxy-3-n-amyl-9-methyl-7,8,9,10-tetrahydroddibenzopyrone
which, with excess methylmagnesium
iodide, yielded 1-hydroxy-3-n-amyl,6,6,9-trimethyl-7,8,9,10-
tetrahydro-6-dibenzopyran.14 The product proved to have
marijuana activity though only about one-tenth that of its
isomer, natural tetrahydrocannabinol. A series of several
closely related synthetic compounds was then prepared by
the same procedure using the same keto ester but homologs
of olivetol. " All of these products were reduced to the
corresponding hexahydro compounds.16 The synthetic tetrahydrocannabinol
was also modified by replacing the 6-methyl
groups by ethyl and propyl groups.i7 (Chart V.)
A provisional synthesis designed to obtain an optically
active tetrahydrocannabinol was sought in the condensation
of pulegone and olivetol. I79 I8 In the presence of phosphorous
oxychloride, a product which analyzes for, and has the
properties of tetrahydrocannabinol is formed. A possible
mechanism by which such a reaction might take place is
shown in Chart VI. The purity of the final product is by no
means established. There is a possibility of contaminants
formed by condensation of the two reactants to give a
partially hydrogenated xanthane or a tetrahydrodibenzofuran,
isomeric with tetrahydrocannabinol. Homologs in
which the olivetol portion was substituted by other 1,3-dihydroxy-
S-alkylbenzenes were synthesized.16 The reduction
product of each was prepared.
Finally in Chart VII are shown molecules in which the
left-hand ring has been modified by removal or by change in
the position of the methyl group.17
The pharmacological studies on hemp extracts have been
equally as meager as the chemical investigations and in the
long history of Cannabis preparations only three tests have
been reported. Liataud" in 1844 observed that motor
incoordination in the dog was a characteristic effect induced
by marijuana preparations; Fraenkel*O in 1903 interpreted
this incoordination as a cataleptic condition. This was followed
in 1928 by the observations of Gayer*' that in various
animals such as cats, rabbits, or dogs, intravenous injection of
marijuana preparations in acetone solution induced cornea1
anesthesia which was characteristic of active fractions of the
resin. In 1937, Munch and Maritz** reported no unequivocal
effects when Cannabis preparations were administered to
albino mice. On the other hand, Loewe noted a definite
increased depressant action when treated mice were given a
hypnotic of the barbiturate series. Pernocton, butyl-bromoally1
barbituric acid, gave the greatest enhancement of any of
the drugs tested.
The Gayer corneal anesthesia test was developed further
by Marx and Eckhardt 24 but neither these investigators nor
Gayer himself went further than to designate that the cornea1
reflex was normal or abnormal. The cornea1 response was
ascertained by tapping with von Frey hairs. Walton*' took
steps in a quantitative direction by counting the number of
responses occasioned by tapping the cornea a given number
of times and by plotting the results over the whole duration
of the effect. By thus locating a definite maximum in the
areflexia-versus-time curve of each experiment, quantitative
comparisons were made possible by determining the ratios of
doses producing equal maxima in different animals. Loewe
developed this procedure further by application of his
method of "Bioassay by Approximation" to overcome as far
as possible the large intra-individual and the large group
variabilities which seem to be inherent in the reaction of all
types of animals to marijuana preparations. His study of the
Gayer test applied to the behavior of rabbits as test animals
showed not only great inter-individual variations in sensitivity
but also enormous intra-individual variations in the same
animal. Using the same animal repeatedly, this investigator
found a consistent decrease in sensitivity to one and the same
dose. Therefore, even though the method of approximation
was applied, the values of potency obtained by this method
are not suitable for anything but qualitative purposes. Moreover,
they do not parallel the dog-ataxia potencies of the
same preparations, the divergence sometimes being tenfold.
This indicates either that the Gayer test is not conclusive for
quantitative measurements or else that an active principle
other than that disclosed by the dog-ataxia test is present in
red oil.
The "mouse sleep prolongation test" may be dismissed
with merely a brief discussion. The Cannabis preparations,
usually red oil, were administered by stomach tube. After a
definite time, pernocton was injected intravenously at a level
just above the threshold of hypnotic action. The synergistic
effect of the Cannabis was measured by the period of
suppression of the righting reflex averaged over all the
animals of a single-dose group. This effect, though typical of
red oil, could not be duplicated with the natural or synthetic
tetrahydrocannabinols which had been shown definitely to
have physiological activity in man. Pure cannabidiol, which is
devoid of the marijuana effect upon man, showed the highest
potency in this test and consequently the action from the red
oil probably is due to its cannabidiol content.
The determination of the cataleptic condition in dogs
reported by Fraenkel, as accepted in former editions of the
United States Pharmacopoeia for bioassay of Cannabis ex
tracts, was developed further by Walton25 to attempt to
make the effect the basis of a quantitative test. The arbitrary
stages of intensity of effects were recognized; first a slight
depression; second, a barely detectable ataxia; third, an
obvious ataxia; fourth, a marked ataxia in which the animal
frequently pitches forward and barely catches itself; fifth,
inability to stand alone; sixth, inability to rise and plunge
about. The ataxia is chiefly a static one and is manifested
particularly by swaying movements. Intravenous doses of red
oil dissolved in acetone always acted within half an hour. A
similar intensity of effect by oral administration required five
to seven times the dose. Walton employed for evaluating
potency the procedure used in most bioassay methods, the
comparison of test and standard doses of equal intensity of
effect. By comparing the results at various levels of dosage
and by repeating the procedure a considerable number of
times, he obtained more accurate results than had hitherto
been reported. About eight trials with the unknown on the
same dog, calibrated in about six trials with the standard,
were used. A single assay required about three weeks or more
for completion.
Loewe applied his principle of "Bioassay by Approximation"
to the ataxia test and has thus been able to obtain a
more decisive method for comparison of active products. The
procedure aims at obtaining from each one of an adequate
number of calibrated dogs, several figures of comparison of a
test dose with the calibration doses. These figures represent
ratios of doses, the response to which is not quantitatively
the same. They are used to approximate the true potency
value from both sides. At the same time the degree of
overlapping marks the range of variation and gives an idea of
the inherent inaccuracy. An entire assay may in this way be
performed in a single day and highly consistent results may
be obtained. The maximum order of accuracy is 10 percent
since this is the minimum of variation in the response of the
same animal at different times. Since parallelism between the
results of the dog-ataxia tests and the effects of different
preparations on humans has been established, it may be
concluded that the ataxia method as developed by Loewe
represents a reliable index of potency.
Using this procedure as just outlined, the comparison of
results on the various natural and synthetic products will be
presented in charts. Each value given represents the result
obtained by the use of several dogs; three or four in the case
of low potency materials, ten to twenty or more for substances
of higher potency.
In Chart VIII is shown a comparison of the potencies of
the series of products analogous to synthetic tetrahydrocannabinol.
The latter was adopted as a standard. The corresponding
hexahydro derivatives were also tested. It is observed
that the modification of the alkyl group results in a
gradual increase in activity with increase in size until a
maximum is reached at the n-hexyl derivative. The point of
maximum potency is the same in the hexahydro compounds,
though all, with the exception of the n-hexyl, exhibit a
decreased effect. There is also presented the potencies of
tetrahydrocannabinols of different optical rotations all derived
from cannabidiol, the potency of an average purified
red oil and of a highly active portion of red oil obtained from
it by extraordinarily careful fractionation. The increased
activity of the optically active natural tetrahydrocannabinols
is striking. The commercial cannabis fluid extracts are of very
low and variable potency.
In Chart IX, the potency of products of questionable
purity produced from pulegone and various olivetol homologs,
together with their hydrogenated derivatives are shown.
The maximum potency appears in the n-octyl molecule, and
the values for the n-heptyl and n-octyl derivatives exceed
those of the corresponding products synthesized by an
unequivocal procedure.
Finally in Chart X, the activities of other analogs are
shown. Each has an activity less than that of the molecule
possessing methyl groups in the 6,6,9-positions.
Recognizing that the indulgence in marijuana in New York
City has constituted a growing problem of major consequence
involving psychiatric, medical, legal, sociological and
civic aspects, a clinical study was undertaken by a committee
appointed by Mayor LaGuardia and supported by funds
allotted by several foundations. The primary objectives were
the determination of the mental and physical actions of marijuana
on the kind of person resorting to its use and the
consequent social implications. Dr. Samuel Allentuck directed
the clinical studies in a unit of the Welfare Island
Hospital, and the facts I am presenting have been summarized
from his report on the results.
An orientation group, the members of which were subjected
to numerous and varied procedures, was used to
determine precisely which tests would best lend themselves
to the solution of the specific problems. From the results a
program was established which consisted in a systematic
study of a group of seventy-seven subjects ranging in age
from twenty-one to forty-five years and from borderline to
superior in intelligence, all of them voluntary recruits from
one prison population. About half had used marijuana previously.
After a physical, neurological, and psychiatric examination,
they were placed in one or more of five categories as
to personality types-normal, antisocial, autistic, cyclothymic
and epileptic. Each individual before and during the period of
action of marijuana was interviewed at regular intervals
throughout the day by various members of the staff. Possible
subjective and objective phenomena resulting from use of the
drug were discussed and elaborated upon in detail. Introspective
reports were obtained in the absence of the drug, under
pseudo-stimulation with placebos and during intoxication
with marijuana or allied synthetics; analysis of the data was
based on the most frequently mentioned phenomena. The
patients were also subjected to periodic tests for blood
pressure or pulse changes, pupillary changes, urinalyses,
blood chemistries, hematological surveys, basal metabolic
rates, electrocardiograms, arterial and venous pressure tracings
and vital capacities. In addition, psychological examinations
before and during the intoxication periods were carried
out, including a wide variety of psychophysical, psychomotor
and clinical tests.
The marijuana was suppplied in the form of a fluid
concentrate which was desolvated and administered in the
form of pills. Pure tetrahydrocannabinol was diluted with a
little olive oil and placed in gelatin capsules holding 15 mg. of
drug, the equivalent in physiological potency of one pill
containing 300 mg. of crude solids from hemp. The l-hydroxy-
3-n-amyl,6,6,9-trimethyl-7,8,9,1O-tetrahydroddibenzopyran
and its 3-n-hexyl homolog were administered in a
similar manner using the equivalent doses which produced
similar activity, namely, 120 mg. per capsule of the former
and 60 mg. per capsule of the latter. It is significant that
these relative amounts are practically identical with those
observed by Loewe for obtaining identical effects in dogataxia
tests.
The patients were started on two marijuana pills or on
equated doses of tetrahydrocannabinol or the two synthetic
analogs. The dose was increased by two pills at a time at
intervals of two days unless toxic symptoms supervened. At
the appearance of toxicity, the patient was returned to the
physiological dose and this was increased one pill at a time.
Thus the maximum tolerated dose for each individual was
determined and at the same time approximately the threshold
at which psychotic changes first appeared. Tetrahydrocannabinol
and the synthetic compounds dissolved in olive
oil were in some cases administered by intramuscular injection.
Other clinical tests were made which involved intoxication
from smoking marijuana cigarettes.
Barbiturates, cold showers and sweet candies were found
to be efficacious in ameliorating any alarming physical or
psychotic symptoms which developed following marijuana
overdosage.
The detailed results of this carefully planned and executed
clinical investigation, the first of its kind on record, must be
left to the complete report when it is published. Merely the
more significant findings which may prove of maximum value
will be presented here. The crude drug in the form of
concentrated marijuana extract, tetrahydrocannabinol derived
from cannabidiol, and the two purely synthetic compounds,
l-hydroxy-3-n-amyl-6,6,9-trimethyl-7,8,9,10-tetrahydro6dibenzopyran
and the corresponding 3n-hexyl
derivative elicited similar clinical and psychiatric phenomena
upon the same subjects. The pharmacological action of these
drugs somewhat resembles atropine and the psychiatric portrait,
alcohol. The effects of marijuana do not vary qualitatively
with the route of administration, whether ingested,
injected or inhaled. By inhalation, however, they are more
prompt in their appearance and disappearance; by ingestion
they appear within one-half to one and one-half hours, reach
their maximum in from three and one-half to five hours and
disappear within seven hours.
The observed physical effects, one or more of which occur
in each patient, are (a) elevation of the pulse rate, the
increase being directly proportionate to the degree of intoxication;
(b) elevation of the blood pressure; this varies with
the individual and usually rises in direct proportion to the
pulse; (c) injection of the conjunctival blood vessels which
varies with the dose; (d) dilation of the pupils and sluggish
reaction to light and in accommodation; vision for proximity,
distance and color changes slightly; (e) circum oral tremors;
tremulousness of the protruded tongue and the extremities;
(f) dryness of the oral and pharyngeal mucous membranes;
(g) increased frequency with decreased amplitude of thoracic
respiratory movements; (h) ataxia; (i) hyperreflexia. The
observed psychiatric effects are (a) apprehension and anxiety,
(b) euphoria, (c) loquaciousness, (d) lowering of inhibitions,
(e) hunger and thirst, (f) feeling of being "high," (g) uncontrollable
bursts of laughter or giggles, (h) drowsiness, languor,
lassitude and a pleasant feeling of fatigue.
Clinical tests revealed that marijuana produces no significant
changes in basal metabolic rates, blood chemistry,
hematological picture, liver function, kidney function or
cardiac electrical conduction. Marijuana delays somewhat
gastric and intestinal motility as gauged by the Carlson
apparatus and x-ray studies; it produces definite increase in
the frequency of the alpha wave in electroencephalographic
recordings thus indicating increased relaxation.
Other observations of a more general character were
recorded. Tolerance for marijuana may be produced by
repeated administration of subtoxic doses over a prolonged
period of time. Thus the same dose elicited progressively
fewer and milder symptoms. Marijuana is unlike opium
derivatives in that it does not give rise to a biological
dependence accompanied by withdrawal symptoms. Neither
does it establish a stro: .3 craving as exists in tobacco smoking
or in alcoholic indulgence. Follow-up of the subjects has
failed to establish existence of any craving for the product.
Many of the unpleasant physical symptoms previously mentioned
appear only as a result of the administration of
excessive doses of drug. It is no more of an aphrodisiac than
alcohol.
Since all the clinical experiments at Welfare Island were
conducted on volunteer prisoners, it was desirable for completeness
or perhaps to satisfy my curiosity to obtain some
results on subjects in another social class. As a consequence, I
have conducted a dozen or more experiments using as test
individuals chemists among whom were two members of the
National Academy of Sciences and two high-ranking and very
successful industrial chemists. In all cases very small doses, 1.5
mg. or 30 mg. of tetrahydrocannabinol, were administered
about one hour before dinner. Each individual reacted differently
with the possible exception of the observed stimulation
of the appetite. They all recognized an intoxication which
they described as in general like, but in detail different from
that induced by alcohol. Thus, one industrial chemist who
shows no outward change under the influence of alcohol,
reported essentially no effect from 15 mg. except a mild
stimulation of his desire for food. A 30 mg.-dose, however, to
this same individual had a pronounced effect. Though he
noticed no particular craving for food before dinner, as soon
as he started eating he became particularly hungry and
consumed a very large meal. He felt intoxicated and dissociated
from his normal self, had a feeling of heaviness in his
head and legs and reported a fogginess which he described as
the inability to focus his eyes on more than a single object at
a time. Since this man desired to get the effect of distorted
time and space which is recorded as a frequent phenomenon
associated with the marijuana user, he tried it a third time,
taking 45 mg. The result was a ravenous hunger which was
not satisfied after eating the equivalent of two hearty meals.
A marked hypergeusia was also noted. The same fogginess
appeared and heaviness in head and legs. During the conversation
which took place among his five associates at the
dinner table, he was able to comprehend a question but by
the time the answer was given, which was immediately, he
couldn't remember the question. In spite of the intoxication
with the resulting phenomena, this subject had no difficulty
in holding his own and then some in a poker game composed
of expert players.
A second industrialist took 15 mg. at five o'clock in the
afternoon and felt the first effects about 6:30 when he lost
coordination in his fingers to the extent that he had to stop
playing the violin, which he was doing at the time. Shortly
thereafter he developed a tremendous appetite which was, if
anything, sharpened by eating an enormous dinner and
popcorn all through the evening. He had a mild lift about like
a cocktail or two on an empty stomach and this and the
hunger left about eleven o'clock.
A chemistry professor who took 30 mg. had a mildly
increased appetite and reported feeling a bit fuzzy during his
dinner, which resulted in difficulty in comprehending what
his associates were saying. This was followed by sleepiness
and lassitude until the effects of the drug disappeared two
hours afterwards. The stimulation was only slight, which
.paralleled the effect of alcohol upon this man.
A fourth subject of high standing in university circles
wrote me in detail concerning his experience. I am quoting
from his letter received two days after the experiment.
This is to report to you on the outcome of my trip
conducted under the powerful guidance of the marijuana
drops. I would be interested some time to know
just how much of what specific material you gave me,
but there is no question but that it gave me a most
terrific wallop. In brief:
5:20 P.M. Took two capsules, went for short swim,
had a highball and began to feel something beyond the
mild glow from the drink about 6:15. By 6:30 felt
bouncy in the knees, a little gay and foolish.
6 :00-8: 30 P.M. Very much in the fog. Had alternate
waves of hilarity and depression. Sat in smoking compartment
looking at myself in the mirror, writing notes
on the experiment, and feeling very silly and stupid.
Would feel the onset of a surge of hilarity and then
break into a raucous, rippling laugh. This gaiety was not
particularly pleasant, however, for throughout I felt
wholly dissociated from myself, knew that I was at the
mercy of the drug, and greatly resented this lack of
control. The feeling was very different from that of
being at one or another stage of intoxication, for I
looked perfectly clear and normal and I could stand
erect without swaying and execute motions with considerable
precision. I could not, to my annoyance and as
I was well aware, speak or write and think coherently.
This bothered me particularly in the waves of depression,
when my lips would feel very parched and salty
and I would long to break the spell and regain my own
consciousness. A very pressing and persistent sensation
was that of extreme hunger, but I had sense enough to
wait until the laughing spells were under control before
going into the diner.
Here are a few excerpts from the log: "7:20. Not so
good; for a few minutes I sat and looked at myself in a
silly way. . . . This is me again. I very suddenly snapped
out of it and am struggling back to normal. Lips are very
dry. Maybe I'm not quite out of it. . . . The above is
true. I am writing here in a serious vein-but quick, I
must write that a minute or two ago I was sitting here in
the men's lounge giggling at myself in the mirror and
saying: This stuff does make you feel pretty gay (gay in
the neese). Isn't that the damndest thing? [I knew the
spelling was wrong but couldn't right it.] . . . 7:42. Yes,
snapping out again. I just had a most jubilant laugh and
feel another coming along. 7 :45, not feeling laughy, feel
like hell. This is really awful stuff. . . . 8:03. I feel like a
fool. Lips bad. Want water, but I am terribly hungry and
wish the experiment were over. I am thinking very much
of eating, for I am very hungry. . . . 8:09. Nearly came
out of it. It is awful. Helpless, awful feeling. Over, over,
when will it be over? When can I eat? . . . 8 : 13. A fellow
just came in to shave. Why now? Why not at this time of
the evening EAT. . . . ha, ha. Now I have been silly.
Looked silly. . . . ha, ha. Of all places to have this-the
train. Bad, bad. Oh I feel like hell, salty lips . . ."
At 8: 30 I devoured an enormous steak dinner with
great rapidity and thoroughness, and left no trace of any
of the fixings, even though I ordinarily do not eat ripe
olives or salad, and although ordinary delicacy would
keep me somewhat below the ten crackers I had with
my cheese. The food tasted no better or worse than
usual, and I had a dissociated feeling that my mouth was
a purely mechanical guide for all that came its way, and
wondered if mine was not very much the same as the
"appetite" of a cat.
At 9:00 I felt myself coming out of the spell, and
again at 9: 15 I felt sane for a minute or two. A little
later the sane periods began to predominate, and by 10
A.M. I was back again in control and could sit down and
write out the details of a new natural product synthesis.
Thus ended the trip. I didn't sleep too well or too
poorly, and the next morning I felt O.K. and had no
hang-over.
It was an interesting experiment, but I can't write too
enthusiastic an endorsement for this drug you fellows
are synthesizing. The feeling of well-being would not, in
my estimation, equal that from about three highballs,
and the penalty seemed to me to be pretty severe. The
outstanding impressions were the feeling of detachment
from myself and the extreme hunger. Are these both
associated with the same part of the molecule? If not,
you might hydrogenate out some of the bad effects and
thereby obtain a wonderful aperitif.
After the Welfare Island study of every phase of the action
of marijuana and the synthetic drugs and after finding no
discernible evidence of any permanent deleterious effects,
either mental or physical, Dr. Allentuck considered the
question of the possible therapeutic value of these substances.
The potential availability of pure synthetics of
standard potency invites such a study, for hitherto merely
hemp extracts were accessible, the clinical activity of which
must be determined for each batch of extracted material.
Since the outstanding manifestation of the marijuana action
is the euphoria which makes its user feel "high," consideration
was given to its possible employment as a drug for
individuals in various stages of mental depression as cyclothymics,
involutionals, reactives, or those with organic
conditions in which dysphoria is a dominant factor. The
invariable characteristic of the drugs to stimulate the appetite,
suggests they might be applicable in psychoneurosis in
which a lack of desire for food exists. Many subjects show an
alcohol-like picture of intoxication following the use of
marijuana. The idea of using these drugs in the treatment of
chronic alcoholic addiction was considered and preliminary
experiments by Dr. Allentuck on private patients and colleagues
were sufficiently encouraging to merit investigation
on a larger scale and over a longer period of time.
The euphoria produced by marijuana is in many ways
comparable to that achieved by the use of opium derivatives.
This suggested the possibility of use in the treatment of
opiate derivative addictions to eliminate or ameliorate the
withdrawal symptoms commonly experienced during previously
so-called "cures." To clarify this question Dr. Allentuck
selected a series of cases among drug addicts undergoing
treatment. One group of thirteen received 1.5 mg. of tetrahydrocannabinol
orally three times daily at 5 :00 A.M., 2:00
P.M., and 10:00 P.M. and a sterile hypodermic injection;
another group of fourteen received the same treatment
without the sterile injection. Subjective and objective findings
were recorded. In general the consensus of subjective
opinions favored the new treatment as compared to previous
cures and the established routine taken by some of these
patients. They felt happier, had a better appetite and wanted
to return to activity sooner. These results served as a basis for
further study of fifty cases in which quantitative criteria were
employed.
Two groups of twenty subjects were selected, one group
receiving the tetrahydrocannabinol up to a maximum of ten
days and the others receiving none. Members of each group
were observed throughout the day. Each morning they were
interviewed and any complaints recorded on a chart. Thus an
attempt was made to arrive at a quantitative comparison of
the withdrawal symptoms. It was found that the tetrahydrocannabinol
treatment was useful in alleviation or elimination
of withdrawal symptoms and in diminishing or eliminating
the accompanying discomfort which follows cessation of
narcotic indulgence. Any withdrawal symptoms under the
tetrahydrocannabinol treatment were of a mild character and
occurred within the first three or four days following which
the patients began to feel much better. The chief complaints
were restlessness, headache and dryness of the throat. They
had an increased appetite and desire for food which diminished
or eliminated such withdrawal symptoms as nausea,
diarrhea and perspiration. They felt physically stronger and
showed psychomotor activity. The feeling of euphoria produced
by the tetrahydrocannabinol helped in rehabilitating
the physical condition and in facilitating social reorientation.
An outstanding result is a subjective feeling of relaxation.
The sleep induced by the drug likewise contributes to the
general improvement in the patients' health. These results are
in contrast to those from the use of Magendie's solution
which produces in the patients contentment for the first
three or four days, after which signs of marked discomfort or
withdrawal effects appear. The patients after this treatment,
upon their discharge were shaky and generally in poor
physical condition. These preliminary results with tetrahydrocannabinol
justify a more exhaustive study of its
possibilities as a means of relieving the withdrawal symptoms
in narcotic addicts.
With this brief picture of the results of the cooperative
program before you, I may conclude by adding a few remarks
about what may be expected from a continuation of the
investigations under way. In the chemical field, repeated
attempts to synthesize a tetrahydrocannabinol with a double
bond in the y, b-position have failed. Just recently, however,
a new approach has appeared and the results have progressed
to the point where I am convinced it is merely a matter of
time before the goal is reached. The physiological reaction of
this product will allow a conclusion in regard to the relative
importance of the position of the double bond in the
alicyclic ring and of the optical activity in the tetrahydrocannabinol
molecule. Other synthetic molecules of a similar
character, which are soluble in aqueous acids or bases and,
therefore, perhaps suitable for intravenous injection, are
being prepared. It is hoped also to clarify the significant
groups and their orientation which induce marijuana activity.
Thorough investigation of the constituents in red oil is
necessary to complete the understanding of hemp extracts.
In pharmacology, there is still much to be done in
cooperation with the chemist to elucidate in more detail
relationship between activity and molecular structure. With
pure chemical substances of marijuana activity, it will now be
possible to determine experimentally what actions are
exerted upon body functions other than those which have
hitherto attracted attention. The relationship between the
mechanism of ataxia action in the dog and the psychic action
in man should be clarified. It has not yet been established
that the structural differences between the various marijuanaactive
substances do not result in a relative prevalence toward
ataxia effectiveness by some, psychic effectiveness by others.
In the clinical field, the practical application of these
substances must be awaited with the usual necessary
patience. The initial experiments of Dr. Allentuck make it
appear likely that some use of this interesting drug or its
synthetic equivalents will be discovered.
In all phases of this work just completed, the groundwork
has been laid so that a wider interest should ensue, and
significant contributions may be anticipated in the chemistry,
pharmacology and clinical aspects of this class of substances.
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28. Homologs were prepared in which the n-amyl group was substituted
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of each was also synthesized.
Source: Marijuana
