“if you drink too much absinthe, you suddenly realize why van Gogh cut his ear off.”
Johnny Depp: Expressen (Sweden)
Johnny Depp drinking absinthe in “From Hell”
Marijuana, absinthe and the central nervous system.
by J. Del Castillo, M. Anderson, G. M. Rubottom
THERE are striking similarities between the psychological actions of the liqueur absinthe and the experiences frequently reported by users of marijuana. We have therefore compared the properties of thujone and tetrahydrocannabinol (THC), which are believed to be the active principles of Artemisia absinthium and Cannabis sativa, respectively. Both substances are terpenoid, derived from the essential oils absinthol and cannabinol, and are formed by similar biosynthetic mechanisms.
Absinthe: The Price of Creativity : Solano (2002)
Thujone has a molecular structure similar to that of another terpenoid essential oil, tetrahydrocannabinol (THC). THC is the chemical in marijuana that induces its notorious ‘high’. Its functional side groups, which resemble those of THC, are thought to act at the same specific receptor sites in the central nervous system as those occupied by THC.
Thujone appears to effect chloride ion channels in the central nervous system. In neurobiology, ion channels are protein channels in cell membranes that allow ions to pass from extracellular solution to intracellular solution and vice versa. Most ion channels are selective and only allow certain ions to pass through. Each neuron has ion channels with various ion selectivities. Each nerve cell’s parallel conductivity of “information” down its axon is contingent upon the opening and closing of ion channels along its cell membrane. At the end of a neuron, at its synapse, neurotransmitters are released based upon the “information” passed down by the changing concentration gradient and charge.
Neurotransmitters are chemical substances that cross the synapse between a presynaptic nerve ending and a post synaptic nerve ending. At the membrane of the post synaptic neuron the transmitter substances interacts with a receptor. Depending on the type of receptor, the result may be an excitatory or an inhibitory effect on the postsynaptic nerve cell.
GABA is the neurotransmitter substance gamma-aminobutyric acid. A GABA receptor is any of several membrane proteins that bind GABA and mediate its channels. GABA type A receptors produce an inhibitory effect on postsynaptic nerve cell membranes. Studies show that alpha-thujone in absinthe is a rapidly-acting and readily detoxified modulator of the gamma-amino butyric acid-gated chloride ion channel. Thujone also acts as a GABA-type A receptor antagonist. Thujone competitively inhibits the binding of the radioactive convulsant [(sub3)H] ethynylbicycloorthobenzoate to the known convulsant site linked to GABA-type A receptors in mammalian brain membranes. Without access to GABA, a natural inhibitor of nerve impulses, neurons fire too easily and their signaling goes out of control. Perhaps this explains the state of psychosis and high sensitization described by the creative individuals who were addicted to the effects of absinthe.
Scientists had documented thujone’s effects by 1916, but “nobody had ever figured out exactly where the toxin was working,” says Hold. The original concentration of Old absinthe was about 260 parts per million of alpha-thujone. Though today the drink, which is still made in the Czech Republic, Spain, and most recently Great Briton, typically contains less than 10 parts per million. This is below the maximum concentration permitted by European beverage guidelines.
Another possible explanation for van Gogh’s xanthopsia was his excessive ingestion of absinthe. Van Gogh’s taste for absinthe (a liqueur) may have also influenced his style of painting. The drink’s effect comes from the chemical thujone. Distilled from plants such as wormwood, thujone poisons the nervous system. Van Gogh had a pica (or hunger) for unnatural “foods,” craving the entire class of fragrant but dangerous chemicals called terpenes, including thujone. As van Gogh recovered from cutting off his ear, he wrote to his brother: “I fight this insomnia with a very, very strong dose of camphor in my pillow and mattress, and if ever you can’t sleep, I recommend this to you.” Camphor is a terpene known to cause convulsions in animals when inhaled. Van Gogh had at least 4 such fits in his last 18 months of life.
Van Gogh’s friend and fellow artist Paul Signac described an evening in 1889 when he had to restrain the painter from drinking turpentine. The solvent contains a terpene distilled from the sap of pines and firs. Van Gogh tried more than once to eat his paints, which contained terpenes as well. Signac also wrote that van Gogh, returning after spending the whole day in the torrid heat, would take his seat on the terrace of a cafe, with the absinthe and brandies following each other in quick succession. Toulouse-Lautrec drank absinthe from a hollowed walking stick. Degas immortalized absinthe in his bleary-eyed painting, Absinthe Drinker. Van Gogh nursed a disturbed mind on the aquamarine liqueur, which may have encouraged him to amputate his ear.
Paul L. Wolf, MD from the Department of Pathology and Laboratory Medicine at the University of California, San Diego, in Archives of Pathology and Laboratory Medicine: Vol. 129, No. 11, pp. 1457-1464. November 2005)
Curious Brain Effects, UC Berkeley Scientists Discover
Science Daily — BERKELEY (3/22/00) — Long suspected to have contributed to psychoses, fits and hallucinations in such famous artists and writers as van Gogh, Poe and Baudelaire, the liqueur absinthe they cherished contained a potent toxin that UC Berkeley scientists now say causes neurons to seriously malfunction.
The researchers report their findings in this week’s edition of the journal, Proceedings of the National Academy of Sciences.
“Based on what we’ve discovered, large consumption of old absinthe would have greatly disrupted the nervous system,” said scientist John Casida, a UC Berkeley professor of environmental chemistry and toxicology. “Our findings could explain many of the symptoms described in the literature.”
Casida said it was not previously known how the neurotoxin alpha-thujone, found not only in absinthe but also in many popular herbal medicines, acted on the body to bring about poisoning or whether the mechanism could account for strange behaviors noted in many 19th century absinthe drinkers. Vincent van Gogh, Edgar Allen Poe and Charles Baudelaire were among them.
The UC Berkeley researchers discovered that alpha-thujone acts on the same brain receptor responsible for a form of epilepsy. The receptor controls the chloride channel that regulates excitation and keeps neurons under control.
“Basically, alpha-thujone blocks the channel and allows the neurons to fire too easily,” said UC Berkeley postdoctoral researcher Karin Höld, co-author of the study along with Casida; fellow UC Berkeley postdoc Nilantha Sirisoma; and two collaborators at Northwestern University Medical School, Tomoko Ikeda and Toshio Narahashi.
“In light of the findings on how alpha-thujone works, it’s not surprising that absinthe had such a remarkable effect,” Casida said.
Symptoms described, for instance, in Wilfred Niels Arnold’s 1992 book on Vincent van Gogh and others who consumed quantities of the popular 19th- and early 20th-century liqueur included forms of bizarre and psychotic behavior, hallucinations, sudden delirium, convulsions, and even suicide and death.
“The question has been sitting around for a century waiting for someone to say how absinthe and alpha-thujone might work,” Casida said. “We decided to take a look at it in terms of where the toxin goes in the body and what happens to it.”
Absinthe is made from grain alcohol and the common herb wormwood. The herb yields a bitter oil used to produce various formulations of absinthe. This liqueur was very popular until it was banned broadly in the early 20th century.
While the historical aspects are interesting, Casida said he is more concerned about herbal concoctions consumed today that contain alpha-thujone. Many have not been subjected to rigorous toxicology tests, he said, including wormwood oil and cedarleaf oil, which are readily available at herbal medicinal outlets and contain quantities of the neurotoxin. Wormwood oil often is used to treat loss of appetite and stomach, liver and gall bladder disorders. The National Institutes of Health, which funded Casida’s study, have slated alpha-thujone products for further scientific review next year.
Absinthe itself isn’t the health threat it used to be, said postdoc Nilantha Sirisoma. Still banned in some countries but easily available over the Internet, today’s version of the emerald-green alcoholic beverage tends to have very low alpha-thujone levels, although there is a great variation among brands and home brew can be particularly dangerous.
At the moment, “absinthe seems like it’s getting more popular,” said Höld, who monitors some of the Internet traffic on the subject. “It seems to be kind of an ‘in’ thing.”
Note: This story has been adapted from a news release issued by University Of California At Berkeley.
“You are here to learn the subtle science and exact art of potion-making,” he began….”As there is little foolish wand-waving here, many of you will hardly believe this is magic. I don’t expect you will really understand the beauty of the softly simmering cauldron with its shimmering fumes, the delicate power of liquids that creep through human veins, bewitching the mind, ensnaring the senses….I can teach you how to bottle fame, brew glory, even stopper death….”“Potter!” said Snape suddenly. “What would I get if I added powdered root of asphodel to an infusion of wormwood?””For your information, Potter, asphodel and wormwood make a sleeping potion so powerful it is known as the Draught of Living Death. A bezoar is a stone taken from the stomach of a goat and it will save you from most poisons. As for monkshood and wolfsbane, they are the same plant, which also goes by the name of aconite.
What is thujone you may ask? It is the terpene found in Artemisia absinthium. Sound boring? ..think again. It has had a controversial history, and even today can cause a furious response! Most recently wicked old thujone created outrage amongst the relgious right simply because of it’s inclusion in JK Rowling’s Harry Potter books.
“Harry Potter and his wizard friends lie, steal, break rules, disobey authority figures, and take revenge. Harry Potter also makes and uses drug potions, including the psychedelic drug thujone, which has been banned in the United States since 1915“ Here we go
“The wizards practice Hindu-type meditation “to clear the Inner Eye.” There is swearing and violence. A three-headed dog mangles the leg of a professor; a mysterious figure drinks blood from a unicorn carcass; children are attacked and paralyzed; a dead cat is hung upside down by its tail. There are creatures called Dementors that “suck out people’s souls.” There are ghosts who haunt bathroom toilets.”
Here is the pasage:
“I don’t expect you will really understand the beauty of the softly simmering cauldron with its shimmering fumes, the delicate power of liquids that creep through human veins, bewitching the mind, ensnaring the senses … I can teach you how to bottle fame, brew glory, even stopper death – if you aren’t as big a bund of thunderheads as I usually have to teach. – The Potions Master.”
Harry Potter and the Sorcerer’s Stone, p. 137
Did I forget to mention that thujone is the reason why absinthe is banned in the USA?
British book chain WH Smith has seen over 20,000 copies of a back catalogue paperback fly out of its 600 stores in five hours following the release of the final Harry Potter novel. To the surprise of staff, copies of Wormwood by GP Taylor, which had been chosen as “The perfect partner for Harry Potter,” disappeared from the shelves
‘While Wormwood hath seed get a handful or twaine
To save against March, to make flea to refraine:
Where chamber is sweeped and Wormwood is strowne,
What saver is better (if physick be true)
For places infected than Wormwood and Rue?
It is a comfort for hart and the braine
And therefore to have it it is not in vaine.’
Written in 1557 by Tusser
The major constituent of wormwood is an oil, which is usually dark green, or sometimes blue in colour. The oil contains thujone. Do not drink this oil neat as it can cause renal failure.
Absinthe and gamma -aminobutyric acid receptors
Richard W. Olsen
Department of Molecular and Medical Pharmacology, University of California School of Medicine, Los Angeles, CA 90095-1735
Absinthe is an emerald-green liqueur that achieved fantastic popularity at the close of the 19th century. It was associated with the Bohemian lifestyle and was credited with the inspiration of famous artists and poets. Because of its widespread abuse and the associated toxicity of its content of oil of wormwood, absinthe was made illegal in most countries in the 1910s. The most likely ingredient responsible for toxicity is believed to be the terpenoid alpha -thujone . Oil of wormwood has convulsant activity as well as activity in killing worms and insects. The mechanism of action of thujone has remained speculative until now. In a recent issue of PNAS, Hold et al. provided evidence that thujone acts as a gamma -aminobutyric acid type A (GABAA) receptor chloride channel blocker, much like the plant convulsant picrotoxin, and related synthetic analogs.
Absinthe use is ritualistic, involving a special glass and perforated spoon and adding cold water by pouring it over sugar cubes, at which time the liqueur turns white because of precipitation of alcohol-soluble herbal ingredients. Its magical powers worshiped by the masses, absinthe became the national drink of France in the late 19th century, with workers and artists alike awaiting l’heure verte, 5-7 p.m., when they all headed for the cafes of Paris for their glass of absinthe, drinking 36-221 million liters per year around 1910 . In 1906, Paris had 33,330 bars (and drink sellers) for 2,601,000 people, compared with 17,000 bakers. Alcohol was a major economic force. The major supplier was the Swiss factory Pernod, established in 1787, and the original French connection was probably in Algeria.
Many Parisians adopted the Bohemian lifestyle in the Belle Epoque, among them many creative artists and writers. De Musset was so often hung over from absinthe that his students found him to “absinthe himself too much from his lectures.” Beaudelaire was an habitual user of absinthe. Verlaine abused absinthe in a self-destructive overindulgence, in the midst of a homosexual affair with Rimbaud. Other big fans included Zola, Oscar Wilde, Gaugin, Toulouse-Lautrec, van Gogh, and Picasso. But the wild and destructive lifestyle led to a negative reaction and major support for prohibition in France and elsewhere. One can see the negative side of absinthe drinking in many of the poems written about it and the pictures drawn about it, as in Degas (Fig. 1). The “madness in a bottle,” i.e., absinthe, was doubly attacked for its reputation for inducing insane and criminal acts, as well as convulsions and other toxicity. However, statistics showed that in France in 1907, only about 1/40th of the inmates of insane asylums were absinthe drinkers, and many of those would actually drink anything alcoholic.
Finally, military and civilian leaders entering into World War I discouraged alcohol abuse and absinthe in support of the war effort. Absinthe was outlawed in most countries in 1910-1915, and all alcohol became illegal shortly after in many. Pernod, an anise-flavored, green-colored analog of absinthe lacking the oil of wormwood, has remained available. Absinthe can still be purchased in certain lands, including Czechoslovakia, and you can make your own with readily available and legal ingredients (check the web).
Absinthe was widely regarded as imparting pharmacological effects beyond those of alcohol alone, such as stimulating the imagination and aphrodisiac action, as well as producing hallucinations. Except for the toxicity, there is little research evidence supporting this view and more study is needed.
As noted, oil of wormwood had ancient herbal medicinal uses, primarily for digestion. It is an extract of the common European woody bush, the wormwood plant, Artemisia absinthium. Other members of the Artemisia genus include sagebrush. The natural product thujone is found in plants of the Thuja genus, which is arborvitae and cedar. They are in the conifer family Cupressacae, which also includes Juniperus (the source of gin), and nutmeg; the related Tsuga genus is hemlock (a well-known poison).
The newly noted connection with GABAA receptor channel antagonism should not be surprising in light of previous observations. The major pharmacological effect of oil of wormwood is seizures. The active agent is thujone and its only pharmacological action listed in the Merck index is “convulsant”. Many naturally occurring and synthetic convulsive agents are blockers of GABA-mediated inhibition (. The prototypic GABA channel blocker picrotoxinin is isolated from plants of the moonseed family, Menispermaceae, and its close relatives tutin and coriamyrtin, from the New Zealand tutu plant Coriaria arborea known as a “loco weed” that caused occasional poisonings in cows, and even in people.
The senior author of this thujone report, Dr. John Casida, has synthesized and studied a major category of synthetic potent neurotoxic chemicals, the cage convulsants, which were discovered to be noncompetitive GABAA receptor antagonists acting at the picrotoxinin site . One of these drugs, t-butyl bicylcophosphorothionate (TBPS), is a major research tool used to assay GABA receptors by radioligand binding. Synthetic butyrolactones with convulsant and anticonvulsant actions also have been described for the picrotoxinin site. In addition, this drug target appears to be the site of action of the experimental convulsant pentylenetetrazol and numerous polychlorinated hydrocarbon insecticides, including dieldrin and alpha -endosulfan, mentioned in Hold et al. This was demonstrated independently by both Dr. Casida and another author of the report, Dr. Toshio Narahashi , who has been a pioneer in mechanism studies on many drugs and toxins.
The report of Hold et al. convincingly demonstrates that thujone acts as a GABAA receptor antagonist by four lines of evidence: (i) the symptoms of poisoning and protection by benzodiazepines and barbiturates resemble those of other GABA blockers like picrotoxinin; (ii) a strain of insects resistant to picrotoxin and GABA-blocking insecticides like dieldrin is resistant to thujone; (iii) thujone competitively inhibits the binding of a radioactive cage convulsant to the picrotoxin/convulsant site on GABAA receptors in mammalian brain membranes; and (iv) thujone reversibly blocks GABAA receptor chloride currents in mammalian neurons. These actions are shown not to be caused by ethanol. In addition, the authors demonstrate the nature and activity of the major metabolites of thujone in mammalian brain and liver. They demonstrate that alpha -thujone is 2.3 times more active than beta -thujone in binding and that 7-hydroxy-alpha -thujone and dehydro-alpha -thujone are toxic but not as potent as alpha -thujone. It would have been nice to have additional biological potencies for beta -thujone because it is more abundant than alpha -thujone in wormwood and active in the binding test. If the two stereoisomers had differed in activity it would have provided even stronger evidence that the GABAA receptor is the drug target. It is possible or likely that both isomers have some activity. Likewise, the high abundance of the metabolite 7-hydroxy thujone suggests the possibility that some of the pharmacological actions may ensue from this substance.
Now why would a drug with toxic and convulsant actions possibly be considered pleasant or at least desirable? A speculation that thujone might behave in a manner similar to tetrahydrocannabinol, the active ingredient of marijuana, was ruled out : thujone has a low affinity for cannabinoid receptor binding sites but none of the pharmacological actions, such as locomotor activity (open field test), immobility (ring stand test), and analgesia (hot plate test). Thus cannabinoids, but not thujone, are central nervous system depressants, like a sleeping pill. Thujone, like picrotoxin, is excitatory on the brain (analeptic). Such an agent may produce mood elevation and antidepressant effects. One may note the anxiogenic and possibly alerting effect of GABA antagonists, as opposed to the anxiolytic, sedative, but also amnestic effects of GABA-enhancing drugs like benzodiazepines and ethanol . Do not forget, however, that in absinthe one is balancing the effect of thujone with the intoxicating, disinhibitory, and depressant effects of ethanol, not to mention those of the other herbal ingredients of oil of wormwood and others added to the myriad recipes for absinthe now in existence.
I will leave with this quote of Oscar Wilde about absinthe: “After the first glass, you see things as you wish they were. After the second, you see them as they are not. Finally, you see things as they really are, which is the most horrible thing in the world”.
SAGE MAY BE BENEFICIAL IN ALZHEIMER’S DISEASE
The herb sage (Salvia Lavendulaefolia) possesses properties that may be beneficial in the treatment of Alzheimer’s Disease, according to research presented at the British Pharmaceutical Society Conference.
Researchers from Kings College, London, reported exciting results showing that one compound extracted from essential oil of sage blocked the activity of an enzyme which has been implicated in Alzheimer’s Disease – acetylcholinesterase. Blocking the enzyme stops the breakdown of one of the chemical messengers in the brain – acotyl choline. Low levels of this chemical lead to the gradual loss of short-term memory and the ability to carry out every day tasks characteristic of Alzheimer’s Disease.
The findings suggest that sage really lives up to its name. Dr Peter Houghton, senior lecturer in pharmacognosy at Kings College, explained: ”As long as 400 years ago, English herbals were reporting that sage was good for improving the memory. Our research may explain why.”
Thujone bearing Salvia officinalis
Sage may also be useful in other aspects of Alzheimer’s disease as it has previously been shown to have anti-inflammatory and antioxident properties. It is too early to suggest that eating plenty of sage in food may protect against Alzheimer’s. ‘But it shouldn’t do any harm.’ suggests Dr Houghton.
However, it is important to eat the right type of sage. The most common type of sage using in cooking – Salvia officinalis – contains a compound called thujone, which is toxic in large quantities. The species of sage used in the latest research (Salvia lavandulaefolia) does not contain thujone.
The researchers now plan to carry out further investigations with sage oil extract and its compounds, in the hope of developing a product to help in the fight against Alzheimer’s, which is set to become a major problem as the population ages. However, Dr Houghton is wary about overpurifying the active ingredient too much. ”In many herbal products there are other agents present which boost or complement the activity of the active component,’ he pointed out.
Opinion of the Scientific Committee on Food on Thujone
(expressed on 2 December 2002)
Terms of Reference
The Committee is asked to advise the Commission on substances used as flavouring substances or present in flavourings or present in other food ingredients with flavouring properties for which existing toxicological data indicate that restrictions of use or presence might be necessary to ensure safety for human health. In particular the Committee is asked to advise the Commission on the implications for human health of thujone in the diet.
Thujone occurs in nature as a mixture of a-(-)- and b-(+)-diastereoisomers, the proportions varying with the source (Micali & Lanuza, 1995; Pinto-Sconamiglio, 1967). Synthetic a-thujone is also available commercially. Data on both isomers, or mixtures, are considered in this opinion.
Council of Europe (CoE):
Thujone has been evaluated by the CoE which allocated a TDI of 10 mg/kg bw/d based on a NOEL for convulsions of 5 mg/kg bw in the female rat, dosed by gavage on 6 days per week for 14 weeks, to which a safety factor of 500 was applied (Council of Europe, 1999).
Current Regulatory Status
Annex II of Directive 88/388/EEC (EEC, 1988) on flavourings sets the following maximum levels for thujone (a and b) in foodstuffs and beverages to which flavourings or other food ingredients with flavouring properties have been added: 0.5 mg/kg in foodstuffs and beverages with the exception of
5 mg/kg in alcoholic beverages with not more than 25% volume of alcohol
10 mg/kg in alcoholic beverages with more than 25% volume of alcohol
25 mg/kg in foodstuffs containing preparations based on sage
35 mg/kg in bitters.
Thujone may not be added as such to food.
United States of America:
Thujone is not authorized for use as a flavouring substance in the USA.
In 1979, the Codex Committee on Food Additives recommended restricting the use of a- and b-
thujone to the following maximum levels in final products for consumption:
0.5 mg/kg in food and beverages
5 mg/kg in alcoholic beverages containing < 25% alcohol
10 mg/kg in alcoholic beverages containing > 25% alcohol
35 mg/kg in bitters (Codex Alimentarius Commission 1979)