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Nutmeg as a Narcotic. A Contribution to the Chemistry and Pharmacology of Nutmeg (Myristica fragrans)

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[17] K . S. Mazdiyasni, R.7: Dollof, and J . S. Smith 11, J. Amer. Ceram.
Soc 52, 523 (1969);53, 91 (1970).
[18] Dr. G.Bayer, ETH Zurich, private communication.
1191 Aufdampfglas 8329 Schott-Datenblatt; H . D U t Z , H . 0.MuFnger,
andG. Krolla,Belg. Pat. 727217(1969);JenaerGlaswerkSchott undGen.
[20] H . Dislich, P . H i m , and R. Kaufmann, DAS 1941 191 (1969),
Jenaer Glaswerk Schott und Gen.
[213 H . Schroeder in G. Hass: Physics of Thin Films. Academic Press,
New York 1969, Vol. 5, p. 87.
[22] H . Dislich, Glastechn. Ber. 44, 1 (1969).
[23] Dr. H . L Oei, Metallgesellschaft Frankfurt/Main, private communication.
~ 2 4 1 Sack, Chem,-Ing,-Techn.37, 1154 (1965).
[25] J . Petzoldt, French Pat. 1583934 (196% Jenaer Glaswerk Schott
und Gen.
[26] W Sack, H . Scheidler, and J . Petzoldt, French Pat. 1562377(1968),
Jenaer Glaswerk Schott und Gen.
Nutmeg as a Narcotic
A Contributionto the Chemistry and Pharmacology of Nutmeg (Myristicafragrans)
By Dieter Abbo Kalbhen"]
The abuse of nutmeg for narcotic purposes has led to renewed chemical and pharmacological
interest in this drug. Several allylbenzene derivatives whose biological transformation products
have structures resembling mescaline and amphetamine have been identified as psychotropic
constituents. It is suggested that the intensity of the hallucinogenic action of these compounds
is due to the possibility of simulation of LSD-like structural elements.
1. Introduction
Nutmeg has a very checkered history as a medicine. Though
it was used in India and in the Arab countries as a spice
and as a remedy as early as the year 700 BC, this drug was
unknown to the Greeks and Romans, and it was only in
the Middle Ages that it was introduced into Europe by
Arab merchants and later by Portuguese.and Dutch traders.
The product, which came from the Moluccas in the East
Indies, was the monopoly of the Portuguese and Dutch for
a long time. It was not unfil 1843 that the British and
French managed to break this monopoly by growing
nutmeg trees on the islands of the Caribbean. Thus nutmegs
are now available both from the East Indies and from the
West Indies.
Like many other cooking spices, such as ctoves, pepper,
paprika, caraway, fennel, and aniseed, nutmeg was very
important to the ancient Indians and Arabs as a medicine,
and it is still found in the folk medicine of these countries.
Various nutmeg preparations were and are used as analgesics, stomachics, digestives, hypnotics, aphrodisiacs, and
amenorrhea1 agents. The European physicians of the
Middle Ages, who borrowed many recipes and treatments
from their Arab colleagues, prescribed nutmeg for an
equally wide range of indications.
Priv.-Doz. Dr. D. A. Kalbhen
Pharmakologisches Institut der Universitat
53 Bonn, Reuterstrasse 2 b (Germany)
Whereas the use of nutmeg as a spice has persisted to the
present day, its interest and importance in medicine has
declined in Europe since the beginning of the 18th century.
The end of the 19th century saw a brief return to popularity
in the wake of a rumor that nutmeg is an effective abortifacient. Several medical journals at this period reported a
high incidence of nutmeg poisoning in women.
Intoxication due to the benumbing and psychotropic
effects of nutmeg had been described even earlier. Thus the
famous Breslau physiologist Purkinje"' carried out an
experiment on himself; the symptoms that he described as
resulting from the ingestion of three ground nutmegs are
very similar to the effects of hashish. The excessive use of
nutmeg in folk medicine as a stomachic, as an abortifacient,
or in love potions leads in man to intoxication symptoms
that are manifested in outbreaks of sweat, desire to urinate,
headaches, nausea, disequilibrium, hysterical laughter,
hallucinations, and/or stupor.
Though the hallucinogenic action was described repeatedly
around the turn of the century, it was only after the second
world war that nutmeg came to be used as a narcotic, and
this use was mainly, if not exclusiveIy, confined to the USA.
This drug is used particularly by young people, students,
hippies, and convicts to attain an intoxicated state with
hallucinations. Since nutmeg is generally known as a spice,
can be bought anywhere, and has even been used in prison
kitchens, it is readily obtainable by the groups mentioned
above, and is welcomed by them as a substitute for controlAngew. Chem. internat. Edit. / Vol. 10 (1971) / No. 6
led substances such as marihuana, mescaline, and LSD.
(The American government has now stopped the use of
nutmeg spices in the kitchens of penal establishments.)
2. Constituents and Active Ingredients of Nutmeg
The wide availability and use of nutmeg as a spice and also
its psychotropic and toxic effects aroused interest in the
composition of this drug some time ago. A detailed analysis
was reported by Power and SuEwuy in 1907 and 19081293J.
These authors showed by various extraction and distillation methods that nutmeg contains 25-40% of fatty oils
(nutmeg butter), 8-15% of volatile oils, and 45-60% of
structural materials containing cellulose.
The fatty oils from nutmeg have found little interest in
medicine, and therapeutic uses have been concentrated
mainly on the volatile oil. Thus the German Pharmacopeia
valid until the end of 1968 and the Supplement, 6th edition,
contained the nutmeg preparations listed in Table 1. The
7th edition of the German Pharmacopeia, which has been
valid since January 1,1969, no longer contains nutmeg and
its preparations.
In the search for the medicinally active constituents, it was
found that the nuts no longer had any action after the
removal of the volatile oil. It was therefore concluded that
the volatile oil, and particularly the main constituent
myristicin, should be regarded as the active principle.
Though Wurburg14] questioned the contribution of the
volatile oils to the action of nutmeg in 1897, evidence
obtained at the beginning of this century indicated that
myristicin is responsible for the pharmacological and toxic
effects of nutmeg
3. Hallucinogenic Ingredients of Nutmeg
Following repeated confirmation by further investigations
that the volatile oils are the principal cause of the effects of
nutmeg, later work has been concentrated mainly on the
allylbenzene derivatives ( I ) - ( 9 ) (see Table 2).
C H ~ O ~ C H , - C H = C H ~
(1). Myristicin
(2). Elemicin
Table I. Nutmeg preparations listed in the 6th Edition of the German
Pharmacopeia (DAB VI) and the relevant supplement (Suppl. VI).
Oleum nucistae, oleum myristicae, nutmeg butter, DAB VI; oleum
myristicae aethericum, oleum macidis, oil of nutmeg, DAB VI (also as
a constituent of spiritus melissae compositus, DAB VI)
Semen myristicae, nutmeg kernel, Suppl. VI
Mace, Suppl. VI
Nutmeg butter, Suppl. IV
The components listed in Table 2 have been detected qualitatively and quantitatively in the further analytical investigation of the volatile oil of nutmeg, in which excellent
results have recently been obtained, in particular by the
use of gas-chromatographic methods.
Myristicin ( I ) , elemicin (2), and safrole ( 3 ) have been
identified as constituting the greater part (about 80%) of
the group of allylbenzene derivatives.
( 6 ) , Methylisoeugenol
(5), Eugenol
CH30 D C H = C H - C H 3
(7). Isoeugenol
( S ) , Isoelemicin
Table 2. Constituents of the volatile oil of nutmeg.
1) Terpene hydrocarbons
p-mentha-I ,4-diene
p-mentha- 1,8-diene
2) Allylbenzene derivatives [a]
myristicin ( I )
elemicin ( 2 )
safrole (3)
methyleugenol ( 4 )
eugenol I S )
geranyl acetate
methylisoeugenol (6)
isoeugenol (7)
isoelemicin (8)
methoxyeugenol (9)
3) Myristic acid
4) Unidentified substances
[a] See Section 3 for formulas.
Angew. Chem. internat. Edit. J Vol. 10 (1971) No. 6
[9), Methoxyeugenol
Of these allylbenzene derivatives, which are present in the
volatile oil in quantities that vary with the region in which
the nutmeg was grown, only myristicin ( I ) has so far been
investigated pharmacologically as a single substance. Slight
inhibition of monoamine oxidase occurred in mice, and a
distinct psychotomimetic effect (see Section 4) has been
detected in man. It should be mentioned in this connection,
however that the action was always stronger when the
other constituents of the volatile oil were administered at
the same time. It is assumed that the terpene hydrocarbons
do not themselves contribute to the psychotropic action,
but promote the absorption of the allylbenzene derivatives
by irritating the gastrointestinal tract.
4. Hallucinogenic Action Pattern in Man
The use of nutmeg as a narcotic became known to large
numbers, particularly of young people, through the autobiography of racial conflict victim Malcolm XI7], which
has been widely circulated in the USA. Nutmeg preparations have been taken by many people as a substitute for
cannabis, mescaline, or LSD, with the result that considerable knowledge now exists concerning the action pattern
in nutmeg poisoning.
The drug is generally ground, stirred into a drink, and taken
in a quantity of 5 to 30g. The psychotomimetic action,
which may range from a slight change in consciousness to
very intense hallucinations, begins to take effect 2 to 5
hours after ingestion. Whereas visual hallucinations are
less common than in LSD or mescaline intoxication, distinct changes are found in the perception of time and space.
A feeling of soaring and of dissociation of the limbs from
the body is frequently also reported. The main side effects
noted are nausea, headaches, dry mouth, increased pulse
rate, and giddy feeling. All the symptoms of nutmeg intoxication usually disappear after 12 to 48 hours. An occasional
after-effect is a lasting aversion to the taste and/or smell of
nutmeg. For this reason nutmeg is generally used only once
or twice, very rarely more often, as a narcotic.
assume the formation of 3,4,5-trimethoxyamphetamine
(13a) from elemicin (2) and the formation of 3-methoxy4,5-methylenedioxyamphetamine (14a) from myristicin
As can be seen from the formula of 3,4,5-trimethoxyamphetamine (13a), it contains structural elements of amphetamine (12) and of mescaline (10). The compound (13a),
which was synthesized in 1947 by Heyr"], exhibited twice
the hallucinogenetic activity of mescaline in pharmacological tests. It is interesting to note that the stimulatory action
component of amphetamine, which is manifested in increased blood pressure, increased pulse rate, and insomnia,
is no longer present in the trimethoxy derivative (13a).
Shulginr'zl has recently synthesized other isomers of trimethoxyamphetamine and examined them for hallucinogenic action (Table 3).
Table 3. Relative hallucinogenic activities of the isomeric trimethoxyamphetamines (TMA) (13) and methoxymethylene-dioxyamphetamines (MMDA) (14) [activity of mescaline (10) :I].
5. Biotransformation of the Allylbenzene Derivatives
Shulgin has developed an interesting hypothesis to explain
the hallucinogenic action of the allylbenzene derivativesL8!
Comparison of the structural formula of elemicin (2) with
that of mescaline (10) shows a certain similarity. ShulginC8]
Isomer of (13)
Posn. of CH,O
relative activity
< I
< 10
( I ) , Elemicin
( l o ) , Mescaline
assumes that elemicin (2), myristicin (I), and the other
allylbenzene derivatives are transformed into the amino
derivative in the human body by direct transamination or
by oxidation and subsequent transamination. As was dis] , metabolism of allylbenzene
covered by K a ~ a b a t a [ ~the
(11) leads to cinnamic acid, P-hydroxy-P-phenylpropionic
acid, and p-hydroxyphenylacetic acid. Barfknecht"ol later
found that allylbenzene fed to rats is partly also converted
into amphetamine (12). It therefore seems reasonable to
C J 3 3 0 ~ C H . - C H = C H z + CH30o
c H Z - $ E ;
( 1 3 4 . 3 , 4. 5-TMA
Isomer of (14)
Position of
relative activity
Besides the trimethoxy compounds, ShuZgin'121also synthesized and investigated substances in which two methoxy
groups were replaced by a methylenedioxy group, i.e. isomers of (14a) (Table 3).
3-Methoxy-4,5-methylenedioxyamphetamine(14a) thus
corresponds to the metabolite that should be formed in the
body from myristicin (1) by transamination. The other
allylbenzene derivatives in the volatile oil of the nutmeg
could also be converted into the corresponding amphetamine derivatives by biotransformation. Detailed studies
on the biotransformation of these allylbenzene derivatives
are being carried out at present in animal experiments by
Kalbhen and B r a ~ n " ~ ' .
Angew. Chem. iniernai. Edit. Vol. 10 (1971) 1 NO.6
6. Explanation of the Hallucinogenic Action of the
Amphetamine Derivatives
Pronounced quantitative differences are found in a comparison of the hallucinogenic effects of the isomeric trimethoxyamphetamines (13). Since it could be shown that
these substances are degraded and excreted by the body at
the same rate and by the same metabolic pathway, and
that the partition coefficients (between fat and water) of
the isomers do not differ greatly, other explanations were
sought for the difference in their hallucinogenic activities.
Snyder and Richel~on"~]
have developed a hypothesis that
allows an interesting explanation of this phenomenon.
Lysergic acid diethylamide (LSD) is well known to be by
far the most potent of the hallucinogenic drugs discovered
so far; even in a dose of 5-100
pg in man, it causes very
intense hallucinations of long duration. On the basis of
this intense action, the above authors assume that the LSD
structure possesses optimum characteristics for the production of hallucinogenic effects. Its outstanding structural
features are the indole skeleton and the two fused sixmembered rings. For greater clarity in the following discussion, the rings have been labeled A, B, c , and D.
A comparison of the structures of hallucinogenic drugs
containing no indole grouping with the structure of LSD
shows that e.g. mescaline (10) and the amphetamine
derivatives (13) and (14), either formed by the metabolism
of myristicin and elemicin or synthesized, have only the
benzene ring A in common with LSD. In the case of mescaline, it is quite possible to simulate an indole structure by a
change in the conformation of the side chain. This conformation can be stabilized by a hydrogen bond. The extent
to which this intramolecular hydrogen bonding occurs
naturally depends on the magnitude of the negative charge
on C-2 or C-6, and this is determined in turn by the nature
of neighboring substituents on the benzene ring. Because
of the neighboring trimethoxy groups, the negative charge
in mescaIine is in fact greatest on C-2 or C-6; in this case,
therefore, a sort of ring B can be formed, and hence an
indole structure simulated, by intramolecular hydrogen
Examination of the possibility of intramolecular hydrogen
bond formation for the structures of the six isomeric trimethoxyamphetamines (13) yields interesting clues that
contribute to the explanation of the difference in activity.
(13a) can form the ring B, and hence simulate the indole
structure by hydrogen bonding in the same manner as
mescaline (10).This is also possible in (I3e). The latter
substance can also form a hydrogen bond from the amino
hydrogen to the oxygen of the 2-methoxy group, and the
resulting structure approximates to ring C in the LSD
It thus seems possible that 2,4,5-TMA (13e) can simulate
rings B and C of LSD, though a molecule can naturally
exist in only one of the two conformations at any given time.
The formation of ring C also depends on the freedom of
movement of the rnethoxy group on C-2. An adjacent
methoxy group, i. e. in position 3, hinders the free rotation
of the methoxy group on C-2, with the result that ring C
cannot be simulated. This would explain why the 2,3,5trimethoxy derivative (13c) has a weaker hallucinogenic
action than the 2,4,5-trimethoxy derivative (13e), and why
the 2,3,4-trimethoxy derivative (13b) is practically inactive.
The assumption that adjacent methoxy groups hinder the
formation of a ring C conformation is confirmed by the
investigation of compounds of the methoxy(methy1enedi0xy)amphetamine type (14). Whereas (13b) is inactive
and cannot simulate either ring B or ring C, 2-methoxy-3,4methylenedioxyamphetamine (14c) has a strong hallucinogenic action, which can be attributed to the possibility of
formation of a ring C conformation.
J . E. Purkinje, Neue Breslauer Sammlungen aus dem Gebiet der
Heilkunde I, 423 (1829).
[Z] F. B. Power and A. W Salway, J. Chem. SOC.91,2037 (1907).
[3] F. B. Power and A. W Salway, J. Chem. SOC.93,1653 (1908).
[4] 0.Warburg: Die Muskatnuss. Leipzig 1897.
[5] A. R. Cushny, Proc. Roy. Soc. Med. 1908-1,39; H.H. Dale, ibid. 23,
69 (1909); F . Jurns: On Myristicin and Some Closely Related Substances. Reports published by Schimmel & Comp., Leipzig 1904.
161 G . B. Wallace: Contributions to Medical Research. Vaughn, Ann
Arbor, Michigan 1903, p. 351.
[7] Malcolm X with A. Holey: The Autobiography of Malcolm X.
Grove Press, New York 1964.
[8] A . 'i?
Shulgin, Nature 210, 380 (1966).
[9] H . Kawabata, Yakugaku Zasshi (J. Pharmac. SOC.Japan) 65, 9
It is interesting to observe that no hallucinogenic action
could be detected for 2,3,4-trimethoxyamphetamine(I3b),
in which hydrogen bonds of this nature cannot be formed.
Angew. Chem. internat. Edit. 1 Vol. 10 (1971) / No. 6
C. F. Barfknecht, cited by A . Z Shulgin e f al. in D. H. Efron:
Ethnopharmacologic Search for Psychoactive Drugs. Public Health
Service Publication No. 1645, Washington 1967, p. 210.
[illP. Hey, Quart. J. Pharm. Pharmacol. 20,129 (1947).
[I21 A . T Shulgin, Nature 197, 379 (1963).
[13] D. A. Kalbhen and U . Bratm, to be published.
1141 S . H. Snyder and E. Richelson in D. H . Efron: Psychopharmacology. Public Health Service Publication No. 1836, Washington 1968,
p. 1199.
2-Methoxy-4,5-methylenedioxyamphetamine(14 b) can also simulate ring C and/or ring B, whereas 3-methoxy-4,5methylenedioxyamphetamine (14a) can assume only a
ring B conformation, as is also confirmed by the lower
activity of the latter.
methoxy groups, which allow a ring B orland ring C conformation. The methyl group on C-4 prevents rapid
enzymatic degradation of this compound, and this may
help to potentiate the action.
7. Closing Remarks
0 f i C H 3
f N
On examination of the formulas of 2,3-dimethoxy-4,5methylenedioxyamphetamineand 2,5-dimethoxy-3,4-methylenedioxyamphetamine, it can be predicted on the basis
of the above working hypothesis that the second compound
will have a stronger action than the first. This has been
confirmed by pharmacoIogica1 tests.
Finally, mention should also be made of 2,5-dimethoxy4-methylamphetamine (DOM), which has become very
popular in the USA as a psychodelic drug under the name
STP. The very intense psychotomimetic action of this
substance can be explained by the favorable position of the
Though no specific receptor localizations and points of
attack on the molecular level have been established as yet
for LSD and the other hallucinogenic drugs described here,
the above working hypothesis developed by Snyder and
offers a valuable contribution to the elucidation of the mode of action of these psychotomimetics. The
abuse of nutmeg as a narcotic drug has given fresh impetus
to pharmacological research in the testing of psychotropically active components, and this research has led through
structure-action relations to a model possessing unquestionable interest. However, nutmeg is now almost without
significance in practical medicine, and there is little likelihood, in view of its strong taste, that this well-known spice
will remain popular for long as a narcotic drug.
Received: October 20,1970 [A 818 IE]
German version: Angew. Chem. 83,379 (1971)
Translated by Express Translation Service, London
Bis(trimethylsily1)diimine :Preparation, Structure, and Reactivity[']
By Nils Wiberg"'
Based on investigations carried out in collaboration with Wan-Chul Joo,
Gerhard Schwenk, Wilfried Uhlenbrock, and Michael Veith
Dedicated to my father, Professor Egon Wiberg, on the occasion of his 70th birthday
The highly reactive compound bis(trimethylsily1)diimine (BSD), which was first prepared by
oxidation of lithium tris(trimethylsilyl)hydrazide, is light blue, sensitive to thermolysis and
hydrolysis, and ignites spontaneously in air. On the basis of electron transfer, acid-base, or freeradical reactions, it acts in particular as a (preparatively useful) redox system and as an agent
for the introduction of azo groups. Redox reactions lead by oxidation or reduction of the other
reactant through two oxidation stages to hydrazine derivatives or molecular nitrogen, and in the
case of electrochemical reduction, to BSD radical-anions.Azo-group transfers, on the other hand,
yield new inorganic azo compounds with no change in the oxidation state of the diimine group.
1. Introduction
When we succeeded, in 1968, in synthesizing bis(trimethylsilyl)diimine[zl
- ___
[*I Priv.-Doz. Dr. N. Wiberg
Institut fiir Anorganische Chemie der UniversitBt
8 Miinchen 2, Meiserstrasse 1 (Germany)
as the fist diimine completely substituted with silyl
groups131,the unexpectedly long-wave light absorption
and the resulting radiant blue color of the compound
immediately aroused our particular interest. The investigation of this substance, which has lost none of its original fascination, has proved worth while ; it has revealed
a varied, unusual, and interesting chemistry.
Various investigators had attempted to prepare a bis(sily1)diimine. The ability of carbon to fonn azo compounds (Z), which are often surprisingly stable (for
Angew. Chem. internat. Edit. / Vol. 10 (1971) 1 No. 6
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