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Umbellulone is a headache-inducing monoterpene ketone found in the leaves of the tree Umbellularia californica, sometimes known as the "headache tree".
It is hypothesized to cause headaches by influencing the trigeminovascular system via TRPA1.
Botanist Archibald Menzies was the first to collect the oil at the end of the 18th century. In 1826 this tree was classified as a laurel, Laurus regia, by botanist David Douglas.
In 1833 the tree received another classification by Hooker and Arnott, Tetranthera californica. Shortly after that the present name was given by Nuttal, Umbellularia californica. In 1875 Heaney obtained a colorless liquid (oreodaphenol) via fractionation under reduced pressure. This oil of the California laurel possess a pungent odor.
Stillman (1880) did a fractionation at 215-216 °C. He discovered that inhalation of its fumes can lead to a painful cold sensation and severe headaches. In earlier times the leaves of the tree were used for cures for headaches or stomachaches and even toothaches.
Powers and Lee did in 1904 another fractionation on the oil of the tree at 217-222 °C. This yielded different compounds: pinene, Eucalyptol, eugenol, methyl eugenol and a ketone called umbellulone. Umbellulone is the chemical responsible for the headaches induced by the tree. They gave umbellulone the following structural formula:
In 1908 the structural formula was adapted by Tutin, which was corrected later that year by Semmller to give the structural formula which is accepted today:
Activation of TRPA1 by umbellulone results in the opening of this ion channel. Calcium will enter the cell and the cell membrane will be depolarized. Depolarization of the membrane will result in the release of CGRP1. Released CGRP can bind to its CGRP-receptor. This will induce a CGRP-dependent local vasodilation of the cerebral blood vessels. Vasodilation of the cerebral blood vessels will increase the blood flow to the brain's outer membranes. CGRP binding to its receptor will also promote mast cell degranulation and infiltration by neutrophils and other immune cells. The increase in immune cells and its inflammatory response is thought to be the main cause of the occurrence of migraine. It is still being discussed if vasodilation of the cerebral blood vessels contributes to the cause of the migraine and headaches. Still, the vasodilatory effect and the blood flow increase can be used as an indirect indication for the release of CGRP and therefore for the presence of the migraine and headaches.
Umbellulone can induce the conversion of hemoglobin to methemoglobin. Methemoglobin is a globin protein in the blood that mainly consists of ferric (Fe3+) hemoglobin, instead of the usual ferrous (Fe2+) hemoglobin. Methemoglobin has a decreased ability to bind oxygen, but, in combination with the three other ferrous ions on the hemoglobin unit, the oxygen release is also decreased. Red blood cells will be less able to nurture organs with oxygen, therefore, the probability for hypoxia increases. Methemoglobinemia is a potentially life threating condition when methemoglobin levels exceed 40%.
Umbellularia californica should not be mistaken for the conventional bay leaf ( Laurus nobilis), which is devoid of these toxic effects.
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