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    THUJONE

    Explanation

         Thujone is a terpenoid ketone which exists in two stereolsomeric
    forms, viz:

    CHEMICAL STRUCTURE 2

         (+)-3-thujone is also known as alpha-thujone and (-)-3-isothujone
    as ▀-thujone. The two isomers occur widely in essential oils, most
    notably in Artemisia spp., Salvia spp., Juniperus, Tanacetum (tansy),
    Thuja spp. and Cedris spp. in varying proportions.

         Studies on the pharmacological and toxicological properties of
    the thujones are complicated by the fact that many experiments
    involved the use of ill-defined mixtures of the two isomers. Since the
    isomers differ markedly in toxicity and convulsant activity,
    quantitative data on mixtures of unspecified composition have to be
    interpreted with caution.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         Thujone (isomer not specified) was a weak inhibitor of
    acyl-CoA:lysophosphatidylcholine acyltransferase activity in mouse
    brain synaptosomes compared to psychoactive cannabinoids (Greenberg et
    al., 1978).

         Thujone was without effect on respiratory activity of the
    cerebral cortex of rats pretreated with single oral doses of
    10-100 mg/kg or repeated daily doses of 10 mg/kg for up to 15 days
    (Pinto-Scognamiglio, 1968).

    TOXICOLOGICAL STUDIES

    Special studies on oil of tansy (Tanacetum vulgare)

         The principal constituents of tansy oil are alpha- and ▀-thujone,
    camphor and borneol, the average content of thujones is approximately
    50%.

         The acute oral LD50 in rats was reported as 1.15 g/kg and the
    acute dermal LD50 in rabbits as >5 g/kg. When tested on dogs with
    intestinal helminths, tansy oil was toxic at oral doses of 300 mg/kg.
    Oil of tansy causes convulsions and signs of poisoning (stated to be
    due to thujone) include vomiting, gastroenteritis, flushing, cramps,
    loss of consciousness, rapid breathing, cardiac arrhythmia, enteric
    bleeding and hepatitis. Death occurs from circulatory or respiratory
    arrest and degenerative organ changes, and human fatalities have been
    reported.

         Undiluted tansy oil was not a skin irritant in hairless mice or
    swine, was slightly irritating to rabbit skin in a 24-hour patch test
    but was non-irritant in a 48-hour patch test in human subjects. No
    sensitization reactions were seen in a maximization test on 25
    volunteers and no phototoxic effects were observed in mice and swine
    (Opdyke, 1976).

    Special studies on oil of wormwood (Artemisia absinthium)

         Artemisia oil contains mainly thujone (Guenther, 1952). The acute
    oral LD50 in rats was reported as 960 mg/kg; the acute dermal LD50 in
    rabbits exceeded 5 g/kg. Undiluted oil was not a skin irritant to
    hairless mice, was mildly irritating to rabbit in a 24-hour patch test
    and produced no irritation in a 48-hour patch test on human subjects.
    No sensitization reactions were observed in a maximization test on 25
    volunteers and no phototoxic effects were reported in hairless mice
    and swine (Opdyke, 1975).

    Special studies on pharmacological activity

         The convulsant properties of thujone, and of thujone-containing
    plant extracts, have been recognized for a long time (see review by
    Pinto-Scognamiglio, 1967). The doses required to produce convulsions
    are tabulated below:

                                                                        

                  Product              Convulsive dose
    Animal     administered     Route    (mg/kg bw)        Reference
                                                                        

    Mouse       (alpha + ▀)     i.p.         590       Wenzel & Ross,
                thujone                                1957

                ▀-thujone       i.p.a        260       Le Bourhis &
                                i.p.b         72       Soenen, 1973
                                p.o.b        250

    Rat         (alpha + ▀)     i.p.         100       Sampson &
                thujone                                Fernandez, 1939

    Rabbit      ▀-thujone       i.v.           4       Keith & Stavaky,
                                                       1935

    Cat         ▀-thujone       i.v.           7       Keith & Stavaky,
                                                       1935

                                                       Opper, 1939

                ▀-thujone       i.v.          20       Keith & Stavaky,
                                                       1935
                                                                        

    a    Administered as a solution in olive oil.
    b    Administered as an aqueous emulsion in 1% Tween 20.

         The thujone-induced convulsions are epileptiform in character and
    are preceded by general vaso-dilation, fall in blood pressure, slowing
    of cardiac rhythm and augmentation of respiratory amplitude (Pinto-
    Scognamiglio, 1967).

         (-)-3-isothujone and (+)-3-thujone were examined for
    antinociceptive activity using the hot-plate and Nilsen tests. In the
    hot-plate test, (-)-3-isothujone was found to be codeine-like (ED50 =
    6.5 mg/kg) and equipotent with (-)delta-tetrahydrocannabinol while the
    racemic mixture was essentially half as potent as isothujone;
    (+)-3-thujone was inactive in both tests. Less antinociceptive
    activity was observed in the Nilsen test (ED50 = 14.1 mg/kg) than in
    the hot-plate assay (Rice & Wilson, 1976).

         (+)-3-thujone was examined for psychotropic activity in mice
    using a series of coordination and behavioural tests, and for
    analgesic and hypnotic properties. At low, sub-convulsive doses,
    thujone produced a slight augmentation of motility at a dose of

    3 mg/kg i.p. and a depression of activity and exploratory behaviour at
    24 mg/kg i.p. Thujone did not reinforce the convulsant activity of
    pentetrazol or electric shocks and had no effect on barbiturate
    sleeping time. On the other hand, barbiturates (10 mg/kg) or
    trans-anethole (200-300 mg/kg i.p.) protected mice against the
    convulsant action of thujone (150 mg/kg i.p.) (Le Bourhis & Soenen,
    1973).

         Pinto-Scognamiglio (1968) studied the effects of repeated oral
    doses of thujone (10 mg/kg daily for 25 days) on spontaneous activity
    and ability to learn conditioned behaviour of rats. Thujone did not
    qualitatively modify either spontaneous activity or conditioned
    behaviour but produced an improvement in coordination. Previous work
    had indicated that thujone given to rats at doses of 50 mg/kg s.c.
    produced a marked increase in activity equivalent to that seen after a
    dose of 2 mg amphetamine/kg bw (cited from Pinto-Scognamiglio, 1967).

         It was suggested (Castillo et al., 1975) that thujone and
    tetrahydrocannabinol exert psychomimetic effects by interacting with a
    common receptor but this hypothesis is not supported by the work of
    Greenberg et al. (1978).

    Acute toxicity
                                                                        

                                               LD50
    Animal            Isomer        Route   (mg/kg bw)       Reference
                                                                        

    Mouse        Not specified      Oral        230       Margaria, 1963
                 (+)-3-thujone      Oral        250       Le Bourhis &
                                                          Soenen, 1975

                 (+)-3-thujone      i.p.        260a      Le Bourhis &
                                                          Soenen, 1973

                                                 72b

                 (+)-3-thujone      s.c.        442       Rice et al.,
                                                          1976
                 (-)-3-isothujone   s.c.        134

    Rat          Not specified      Oral        192       Margaria, 1963
                                    i.p.        140       Sampson &
                                                          Fernandez, 1939

    Guinea-pig   Not specified      Oral        396       Margaria, 1963

    Dog          (-)-3-isothujone   Oral        250       Ionescu et al.,
                                                          1958
                                                                        

    a    Administered as a solution in olive oil.
    b    Administered as a suspension in aqueous 1% Tween 20.

    Short-term studies

    Rat

         Four groups of 10 male and 10 female rats received thujone in
    doses of 0, 5, 10 or 20 mg/kg by gavage on six days per week for 14
    weeks. The isomeric composition of the material was not specified.
    Convulsions were observed after dosing in many instances in nine
    female and six male animals in the top dose group; only one female
    animal from the 10 mg/kg dose group had one convulsion on the thirty-
    eighth day. The ED50 for both sexes lay between 10 and 20 mg/kg daily
    for three months. Three female and one male rat of the top dose group
    died in convulsions.

         At termination, no significant differences were observed between
    groups with respect to weight gain, haematology (Hb, RBC, WBC), or
    weights of heart, liver, spleen, kidney and adrenals. No treatment-
    dependent gross pathological or histopathological lesions were
    observed. The no-effect level was 5 mg/kg/day for females and
    10 mg/kg/day for males (Margaria, 1963).

         A commercial mixture of alpha- and ▀-thujone was administered by
    gavage to groups of 20 male and 20 female weanling rats at doses of 0,
    12.5, 15.0 and 50.0 mg/kg/day for 13 weeks. The dose was given in five
    increments daily as a suspension in aqueous agar. Five rats (four male
    and one female) died during acclimatization and three others (one male
    from each of the low and middle dose groups; one female control) died
    during treatment from a viral infection.

         No dose-related deaths occurred in the rats receiving 12.5 or
    25.0 mg/kg bw but 37% of the males and 60% of the females in the
    50.0 mg/kg dose group died under test. Post-treatment convulsions were
    frequently observed and the number of animals affected was as follows:

                                                             

                                         Animals affected
       Dose                                                  
    (mg/kg/day)     Sex                    Months
                                  1           2          3
                                                             

       12.5         Male        0/18        0/16       0/16
                    Female      0/20        1/20       0/20

       25.0         Male        0/18        3/18       0/18
                    Female      2/20        6/20       7/18

       50.0         Male        7/19       13/17      10/12
                    Female     11/15        8/10        7/8
                                                             

         The convulsive ED50 was estimated as 35.5 mg/kg/day for males
    and 26.3 mg/kg/day for females. No correlation was seen between the
    number of convulsions in an animal and death; in the extreme, one
    survivor had 10 convulsions and one animal died without convulsions.

         No effects were observed on body weight gain, or haematology, and
    histopathological examination at termination did not reveal any dose-
    related lesions.

         The no-effect level for males was 12.5 mg/kg/day; a no-effect
    level cannot be established for female rats since one rat in the
    lowest dose group displayed convulsions on two occasions.

    Comments

         No data from metabolic, reproductive or long-term studies were
    available. Much of the information reported related to unspecified
    isomers or mixtures thereof. It appears that ▀-thujone is
    significantly more toxic than the alpha-isomer and that female animals
    are more sensitive to the toxic effects than males. It is not possible
    to establish an ADI for man on the information available.

    REFERENCES

    Castillo, J. del, Anderson, M. & Rubottom, G. M. (1975) Marijuana,
         absinthe and the central nervous system, Nature (Lond.), 253,
         365-366

    Greenberg, J. H., Mellors, A. & McGowan, J. C. (1978) Molar volume
         relationships and the specific inhibition of a synaptosomal
         enzyme by psychoactive cannabinoids, J. Med. Chem., 21, 1208

    Guenther, E. (1962) The essential oils, Vol. V, p. 487, Van Nostrand:
         Princeton, New Jersey

    Ionescu, C. N. et al. (1958) Extragerea principiilor activi din
         Tanacetum vulgare, Communie Acad. Rep. pop. rom., 8, 279
         (cited by Opdyke, 1976)

    Keith, H. M. & Stavaky, G. W. (1935) Experimental convulsions induced
         by administration of thujone. A pharmacologic study of the
         influence of the autonomic nervous system on these convulsions,
         Arch. Neurol. Psych., 34, 1022-1040

    Le Bourhis, B. & Soenen, A.-M. (1973) Recherches sur l'action
         psychotrope de quelques substances aromatiques utilisÚes en
         alimentation, Fd. Cosmet. Toxicol., 11, 1-9

    Margaria, R. (1963) Acute and sub-acute toxicity study on thujone.
         Unpublished report of Istito di Fisiologia, UniversitÓ di Milano

    Opdyke, D. L. J. (1975) Monographs on fragrance raw materials -
         artemisia oil (wormwood), Fd. Cosmet. Toxicol., 13 (suppl.),
         721-722

    Opdyke, D. L. J. (1976) Monograph on fragrance raw materials - tansy
         oil, Fd. Cosmet. Toxicol., 14 (suppl.), 869-871

    Opper, L. (1939) Pathologic picture of thujone and monobrominated
         camphor convulsions: comparison with pathologic picture of human
         epilepsy, Arch. Neurol. Psych., 41, 460

    Pinto-Scognamiglio, W. (1967) Connaissances actuelles sur l'activitÚ
         pharmacodynamique de la thujone, aromatisant naturel d'un emploi
         entendu, Boll. chim. farm., 106, 292-300

    Pinto-Scognamiglio, W. (1968) Effeti del tujone sull'attivitÓ
         spontanea e sul comportamento condizionato del ratto, Boll.
         chim. farm., 107, 780-791

    Rice, K. C. & Wilson, R. S. (1976) (-)-3-isothujone, a small non-
         nitrogenous molecule with antinociceptive activity in mice,
         J. Med. Chem., 19, 1054-1057

    Sampson, W. L. & Fernandez, L. (1939) Experimental convulsions in the
         rat, J. Pharm. exptl. Therap., 65, 275

    Wenzel, D. G. & Ross, C. R. (1957) Central stimulating properties of
         some terpenones, J. Amer. pharm. Ass., 46, 77
    


    See Also:
       Toxicological Abbreviations
       THUJONE (JECFA Evaluation)