The Willow Tree

White willow (Salix alba) is justly famous as the precursor of aspirin. The bark contains heavy concentrations of the glycoside salicin from which salicylates are derived. White willow and closely related species have been used for thousands of years in Europe, Africa, Asia and North America to relieve joint pain and manage fevers. Dioscorides, a Greek physician in the 1^st century AD, suggested taking "willow leaves, mashed with a little pepper and drunk with wine" to relieve lower back pain. In the Indian subcontinent, willow has been used for centuries as a remedy for fever (1).

White willow is a tree that is native to Europe, but it is also found in North Africa and Asia. It thrives in damp areas, such as on riverbanks, and grows up to 25 m (80 ft), with green tapering leaves and catkins in spring.

White willow is astringent and was formerly used to staunch internal bleeding. In his Herbal (1652), Nicholas Culpeper advised that the burnt ashes of the bark be "mixed with vinegar, [to] take away warts, corns and superfluous flesh" (1).

Willow is listed in herbal remedies of ancient Egypt, in the Ebers papyrus (1534 BC). Known in Egyptian as tjeret, Ebers 293 recommends an unidentified part of the tree for internal use "to cause the heart to receive bread." (2). It appears that the ancient Egyptians used willow to treat certain heart conditions. This is intensely fascinating and intriguing since current medical knowledge has shown that aspirin dramatically reduces mortality from acute myocardial infarction and can even prevent its occurrence (3). The preparation was not mentioned, but willow was otherwise used for surface application.

It was not until the mid-18^th century, however, that the first written account of its analgesic properties was made. In the summer of 1758 in England, a man named Edward Stone was suffering from another of his bouts of fever and rheumatic attacks. Frustrated, he accidentally chewed on a twig of the white willow tree. He was amazed that despite its "extraordinary bitterness", it relieved his arthritic pain. He devised a method of drying and pulverizing the bark, and then experimented to discover the best dosage. Over the next five years, he gave his remedy to 50 others, and "it never failed in the cure." Enthusiastic at his discovery, he wrote to the President of the Royal Society of London, but was ignored (4).

White Willow Tree (Salix Alba) It has been used for thousands of years to relieve joint pain and manage fevers	The bark contains heavy concentration of salicin, from which salicylic acid was prepared in 1893.	Meadowsweet (Spirea Ulmaria) It was called "meadwort" in the Middle Ages, as it was used to flavored mead - an alcoholic drink of fermented honey and water	The flowering tops and leaves of meadow sweet containsalicylates. Salicylic acid was isolated from the leaves in the 1920s and its molecular structure was discover in 1853

The Meadowsweet Herb

The flowers and leaves of meadowsweet (Spirea ulmaria) contain salicylates that reduce inflammation, and has been a longstanding folk remedy in much of Europe. It was a favorite stewing herb in medieval times. Gerard wrote in his Herball (1597) that "the smell thereof makes the heart merry and joyful and delighteth the senses" (1). Meadowsweet is a perennial reaching 1.5 m (5 ft), with toothed leaves and clusters of creamy scented flowers.

The herb is well known as a pain-reliever in European folk medicine. Nicholas Culpeper wrote in1652 that "it helpeth speedily those that are troubled with the cholic being boiled in wine; and stayeth the flux in the belly" (1).

Research has found that the combination of salicylates, tannins and other constituents in meadowsweet acts to protect the inner lining of the stomach and intestines while providing the anti-inflammatory benefit of the salicylates (1). It was not until the early 19^th century that salicylic acid was extracted from the leaves of the plant, and in 1853, Karl Gerhardt, a chemistry professor at France's Montpellier University, discovered its molecular structure. Although effective in alleviating pain, salicylic acid caused painful irritation of the stomach lining. He tried to modify it to eliminate its rather severe side-effect, but he found the procedure so time consuming that he abandoned the drug as "of no further significance" (4).

Only people whose pain was worse than that caused by the drug itself then used salicylic acid. One of these was a Mr. Hoffman, who was crippled by arthritis. He lived in the German town of Elberfield. His son, Felix, worked as a chemist at the huge Bayer drug plant nearby. Felix, in an effort to end his father's suffering, experimented changing salicylic acid, and in 1895, came up with acetylsalicylic acid. Hoffman gave the new compound to his father, who after taking it became pain-free.

Bayer laboratories conducted animal tests and clinical trials and published their result in 1899. The compound was indeed effective in controlling pain and inflammation in rheumatism and other conditions, and in reducing fever as well. Bayer patented the production process and named the new drug Aspirin: a for acetyl, spir for the spirea plant family and in to round it off (4). Aspirin became their best-selling drug.

Aspirin Wars

In 1914, Britain in anticipation of the outbreak of war and fearing a halt in supplies from Germany, offered a prize of 20,000 pounds to anyone in Britain or the British Commonwealth who could come up with a new formulation of aspirin that would circumvent Bayers patents. Australia added another 5000 pounds as an incentive. George Nicholas, a British chemist who was almost totally blind due to an ether explosion at his laboratory, took up the challenge. He succeeded in processing exceptionally pure aspirin _ and won the prize.

Following Germany's defeat, the British Alien Properties Custodian confiscated the name "aspirin", and Bayer Company lost its exclusive rights to both the name and manufacture of the drug. Among the firms that began to make the compound was Nicholas's; his product Aspro became the biggest selling aspirin outside the United States. The Sterling drug company in the United States _ even though no longer connected with the original German enterprise _ continued to market their aspirin as "Bayer", with its well known cross trademark (4).

But Mr. Stone's discovery of the willow bark all those years before, did not completely go unnoticed. Italian chemists found the bark's active ingredient was salicin, and successfully prepared salicylic acid from salicin in 1839. From then on the active ingredient in aspirin could be obtained from both the willow and the meadowsweet. It is now made synthetically from phenol.

Aspirin eventually became part of a group known as non-steroidal anti-inflammatory drugs (NSAIDs), which now includes the more recent drug, ibuprofen. Aspirin became the most popular painkiller for all ages. Manufacturers exploited it as a cure-all for a variety of illnesses. It was even widely believed that the drug prevented illness; people sprinkled its powder form over their food. In the1980s however, aspirin was superceded by paracetamol _ first used in 1893 but first marketed in 1953 _ as a favorite painkiller.

In an effort to boost lagging sales and restore public confidence in the drug's curative powers, manufacturers funded research grants to study the mechanisms of action of aspirin. The fruit of this financially motivated enterprise led to a revolutionary shift in medical thinking as new research revealed unprecedented insights into the molecular mechanisms of action of aspirin.

How Aspirin Works

For centuries the pharmacokinetics of aspirin remained unknown. It was only in 1971 that researchers in Britain came up with at least one reason why aspirin works. Prostaglandins, a group of hormone-like substances found in virtually all tissues of the body, seems to increase the sensitivity of nerve endings at sites of inflammation _ and aspirin appears to interfere with the effective action of these substances.

In the late 1980s, a series of secondary prevention trials documented that regular use of aspirin lowered the risk for myocardial infarction and nonfatal strokes in persons with cardiovascular disease (3). Subsequently, a large randomized trial demonstrated that regular use of aspirin decreased the risk of myocardial infarction by approximately half in healthy male physicians with no history of cardiovascular disease (5). It is now known that its protective effects are largely due to its anti-platelet action through inhibition of cyclooxygenase-dependent platelet activation (6). In 1989, the U.S. Preventive Services Task Force (USPSTF) recommended that regular low-dose aspirin should be considered for men aged 40 years or more who were at substantially increased risk for myocardial infarction and who lacked contraindications to the drug.

A Lesson From History

The medical uses of aspirin continue to evolve as scientists gain more insight into its molecular action. Today, it occupies a preeminent place in the management of cardiovascular diseases. The story of aspirin underscores the value of scientifically evaluating so-called folk remedies. The wisdom behind many folk remedies rests on the accumulated weight of empiric experience throughout the millennia. Aspirin is neither the first, nor will it be the last folk remedy to be vindicated by science. The story of aspirin illustrates the evolutionary pattern of medical progress. Medicine can benefit from folk wisdom only if the very highest clinical standards are maintained. As Sir William Osler so aptly put it in1902: "The philosophies of one age become the absurdities of the next, and the foolishness of yesterday has become the wisdom of tomorrow."

© Rachel Hajar, MD 1998