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Scientist who gets sick from poisonous toads in the rain forest is cured through natural herbs and ceremonial rites performed by local natives.

The ritual of healing with herbal medicines brings a scientist back from the brink of death.

"Who better, then, to demonstrate that his ailments could be cured by the natural herbs of the jungle and by the natural wisdom of the only Brazilians who know how to respect the rain forests?"

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Credit... The New York Times Archives

This is a digitized version of an article from The Times's print archive, before the start of online publication in 1996. To preserve these articles as they originally appeared, The Times does not alter, edit or update them.

Occasionally the digitization process introduces transcription errors or other problems; we are continuing to work to improve these archived versions.

An evil toad poisons a good naturalist and the nation watches helplessly as he begins dying slowly. The President becomes alarmed and calls in an Indian shaman, who magically extracts the venom - and the naturalist is saved.

But, as in all good fairy tales, some moralizing is first called for, with the naturalist denouncing the devastation of rain forests and the shaman demanding justice for the country's dwindling Indian tribes. Only then do things end happily.

For the best part of 10 days last month, the story of an ailing 70-year-old expert in hummingbirds and orchids, Augusto Ruschi, and a Txucarramae Indian chief, Raoni, captured Brazil's imagination in a way that no news has done in months.

It was a real-life melodrama more incredible than the television soap operas that are so popular here. It appealed to this country's strong penchant for the mystical, psychic and supernatural. And the President, under attack for rising inflation, saw an opportunity to adopt a popular cause. A Lesson for the White Man

Whether Mr. Ruschi has in fact been cured of severe liver poisoning will not be known for months but, looking much healthier after three days of Indian medicine, he told reporters here the other day: ''I feel as I have never felt before. White men can learn a lot from Indians.''

He was the ideal person to be cast in this role. Having dedicated his life to studying the flora and fauna of the vanishing Atlantic Coast rain forests of his native Espirito Santo State, Mr. Ruschi has constantly prodded the conscience of a country that, until now, has paid little heed to protecting the environment and conserving nature.

Who better, then, to demonstrate that his ailments could be cured by the natural herbs of the jungle and by the natural wisdom of the only Brazilians who know how to respect the rain forests? And what clearer moral than that both nature and the Indians should be protected?

The story began with a front-page report Jan. 12 in the Rio de Janeiro daily Jornal do Brasil that carried the headline, ''Nature condemns a man who protected her.'' It recounted how Mr. Ruschi was dying as a result of having touched poisonous Dendrobates toads while carrying out research in the Amapa region of the Amazon in 1975. The Power of the Poet

Other papers and television and radio immediately caught onto the story, but it was three days later that President Jose Sarney was reportedly moved by a newspaper column written by a prominent Brazilian poet, Affonso Romano de Sant'Anna. The column took its title from a novel by the Colombian Nobel laureate, Gabriel Garcia Marquez, ''Chronicle of a Death Foretold.''

In it, the poet appealed to the President to order a search for an antidote not only in the United States and the Soviet Union but also among the Indian tribes of the Xingu National Park. ''Brazil cannot afford to lose a man of Ruschi's stature just because some shameless toads declared him to be their enemy,'' Mr. Sant'Anna wrote.

Mr. Sarney immediately told his Interior Minister, Ronaldo Costa Couto, to contact Raoni, the middle-aged cacique, or chief, of the 4,000-strong Txucarramae tribe, who is also recognized as a spokesman for Brazil's 180,000 surviving Indians. And a few day later, an unusual sight in his feathered headdress and with the huge protruding lower lip that members of his tribe develop through wearing a disk, Raoni was received by the President in his office in Brasilia.

Raoni told Mr. Sarney that he had dreamed of Mr. Ruschi struggling in a pond full of toads and, after looking at photographs of the naturalist, he proclaimed: ''He already has the face of a toad. He has become a toad. We have to take the toad from inside or he will soon die.'' The Treatment Begins

A Brazilian Air Force plane flew to the Xingu, 500 miles northwest of Brasilia, to collect herbs as well as Sapaim, a shaman from the nearby Caimura tribe. And, in the middle of last week, in the presence of newspaper reporters and television crews, Raoni and Sapaim met Mr. Ruschi in Rio de Janeiro.

The naturalist recounted that for more than a year he had suffered intense pain, nausea, fevers and nose bleeding and could rarely sleep for more than two or three hours at a stretch. Further, reporters noted, he was barely able to climb a short stairway and his eyes and mouth looked swollen and red.

The treatment, which was witnessed by a reporter from Jornal do Brasil and by Mr. Ruschi's wife, Marilande, first involved Raoni and Sapaim smoking 10-inch hallucinogenic herbal ''cigars'' and exhaling over the patient while chanting in their own language.

Raoni then massaged Mr. Ruschi's body and appeared to extract a green strong-smelling pasty substance that he identified as the toad poison. While blowing smoke, the Indian chief rubbed it between his palms and it disappeared, the reporter said. Finally, the naturalist took a herbal bath. He Is Pronounced Cured

For three days, with the entire nation's attention focused on the house where the treatment was taking place, the ritual was repeated, with Mr. Ruschi claiming that he was feeling steadily better. By last Saturday, Raoni said all the poison had been removed and Mr. Ruschi was pronounced cured.

Before completing the ritual, though, Raoni indicated that tradition required he be given a present by the person who had called on him - in this case, President Sarney. The present could be a clay pot or, he added more pointedly, land for the Indians. Raoni and Sapaim then went on a shopping spree in Rio de Janeiro and, with Interior Ministry officials paying the bills, acquired $800 worth of beads and trinkets.

The final act will take place in Brasilia when President Sarney presents his gift to Raoni in the presence of Mr. Ruschi, with all three expected to use the occasion to appeal for greater preservation of the natural and native patrimony of this vast land. Then only an epilogue will still have to be written, describing whether Mr. Ruschi was indeed permanently cured.

Not surprisingly, some skepticism has already been heard from physicians. Wallace Magalhaes, who treated Mr. Ruschi last year, said his liver was poisoned from excessive self-medication taken to combat chronic malaria. Haity Moustatche, a scientist at the Fundacao Oswaldo Cruz medical research center, said, ''We have to determine whether, in all the ritual, there was also some treatment.''

But, for the moment at least, with patient and shaman as well as public and press delighted with the present happy ending, Mr. Ruschi seemed to offer the best closing words for the fairy tale. He said that, when he died, he wished to be buried in the rain forest near his home. ''And I have the hope,'' he added, ''that the hummingbirds will lead me to the Kingdom of God.''

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SHAMAN AND THE DYING SCIENTIST: A BRAZILIAN TALE (Published 1986)

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This is a digitized version of an article from The Times's print archive, before the start of online publication in 1996. To preserve these articles as they originally appeared, The Times does not alter, edit or update them. Occasionally the digitization process introduces transcription errors or other problems; we are continuing to work to improve these archived versions.

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Do herbal medicines altar the brain?

Science has come a long way, but is still in the infant stages in studying natural herbs as a source of healing. The research is promising with many benefits from Alzheimer's prevention to relief from depression.

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Swan, Tiffiny
Personal Interview
doTerra essential oil specialist

Notes from interview
April 30, 2021

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Stoneroad, J.C.
Personal Interviews 1998-2011

Here's an example of his writing about the sweat lodge, offered as a teaching of the traditions.

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A history of the evolution from Sumarian use of willow to scientific application in asprin.

No matter the culture or approach, application of willow to support and heal was in place long before science brought a deeper understanding to it.

"Willow bark has been used as a traditional medicine for more than 3500 years.

Unknown to the ancient Sumerians and Egyptians who made use of it, the active agent within willow bark was salicin, which would later form the basis of the discovery of aspirin.”

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Corresponding Author

NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK

Oxford Clinical Research in Transfusion Medicine, Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, UK

Correspondence: Dr Michael J. R. Desborough, NHS Blood and Transplant, John Radcliffe Hospital, Oxford OX3 9DU, UK.

E‐mail: michael.desborough@ouh.nhs.uk
Search for more papers by this author

Summary

The story of the discovery of aspirin stretches back more than 3500 years to when bark from the willow tree was used as a pain reliever and antipyretic. It involves an Oxfordshire clergyman, scientists at a German dye manufacturer, a Nobel Prize‐winning discovery and a series of pivotal clinical trials. Aspirin is now the most commonly used drug in the world. Its role in preventing cardiovascular and cerebrovascular disease has been revolutionary and one of the biggest pharmaceutical success stories of the last century.

Weeping willow to salicylic acid

Willow bark has been used as a traditional medicine for more than 3500 years. Unknown to the ancient Sumerians and Egyptians who made use of it, the active agent within willow bark was salicin, which would later form the basis of the discovery of aspirin (Fig 1).

Evidence for this early use of willow as an analgesic and antipyretic first surfaced in 1862. Edwin Smith (1822-1906), an American trader living in Cairo purchased a pair of ancient documents, the provenance of which was unknown. These scrolls dated back to around 1500 BC and are amongst the most important historical documents in medicine (Bryan, ). One of these is now known as the Edwin Smith Surgical Papyrus and details 48 surgical cases and their management. The other is now known as the Ebers Papyrus. This was an Egyptian record of around 160 herbal and vegetable remedies. One of these remedies is the first written record of the use of tjeret or salix (now known as willow) for treatment of non‐specific pains. This herbal knowledge was passed on as empires rose and fell. The use of willow bark for pain relief continued through ancient Greece, where it was recommended by Hippocrates to relieve the pain of childbirth, through to Roman times, when its use was recorded by Pliny the Elder (Jeffreys, ).

Many traditional therapies were used for pain relief over the following centuries but were not studied systematically. The study of natural remedies received a boost with the discovery that the bark of the cinchona tree had fever‐relieving properties. This bark was imported at great expense from South America. Although it was unclear at the time, we now know that cinchona is a source of quinine, the first treatment for malaria. It was with this background that in 1763 the Reverend Edward Stone (1702-1768), an Oxfordshire clergyman and fellow of Wadham College at the University of Oxford, investigated the use of willow bark. His letter to the president of the Royal Society outlining his findings survives today. He described using willow bark as a treatment for aguish (fever and shivering): ' There is a bark of an Englifh tree that, which I have found by experience to be a powerful aftringent, and very efficacious in curing aguifh and intermitting diforders'. Reverend Stone left the willow bark to dry on the outside of a baker's oven for 3 months then pounded and sifted it into a powder. He reported: ' It hath been given I believe to fifty perfons, and never failed in the cure, except in a few autumual and quartun agues, with which the patients have been long and feverely afflicted ' (Stone, ). This letter is likely to be the driving force behind the use of willow bark to treat fevers by many physicians of the time.

The active ingredient in willow bark was not discovered until 1828 when Johann Buchner (1783-1852) first refined willow bark into yellow crystals and named it Salicin (after Salix, the genus of the willow tree) (Schindler, ). In 1829, the process was further refined by Pierre‐Joseph Leroux (1795-1870) in France (Leroux, ) and taken a step further in 1838 when Raffaele Piria (1814-1865) produced a stronger compound from the crystals isolated from willow bark, which he named salicylic acid (Piria, ) (Fig 2).

In 1852, the French chemist, Charles Gerhardt (1816-1856), was the first to modify salicylic acid with the introduction of an acetyl group in place of a hydroxyl group, but the compound was not stable (Gerhardt, ). Gerhardt has one of the first true claims to be the person to discover aspirin but the lack of stability of his newly derived compound stopped him from developing it further. Acetylation of salicylic acid later proved to be the key step in reducing its irritant properties.

Early evidence for salicin

In 1876, the first clinical trial of salicin was published by Thomas Maclagan (1838-1903) a Scottish physician at the Dundee Royal Infirmary (MacLagan, ,,). He investigated the effects of salicylate in relieving the symptoms of rheumatic fever. His first step was to take salicin himself: ' I determined to give salicin; but before doing so, took myself first five, then ten, then thirty grains without experiencing the least inconvenience or discomfort '. He proceeded to treat eight patients with rheumatic fever with 12 grains of salicin every 3 h, demonstrating its antipyretic and anti‐inflammatory effects (MacLagan, ,,). Despite the clear antipyretic benefits of salicin, it was not taken up more widely due to complications with gastritis.

A breakthrough produces aspirin

In 1890, the German dye manufacturer, Bayer, set up a pharmaceutical division with research facilities for scientists. This followed early success deriving antipyretic medications from waste products of the dye manufacturing process. The establishment of this unit resulted in rapid development of a large number of drugs.

Three key figures in the discovery of aspirin at Bayer were Arthur Eichengrün (1867-1949) (the head of the pharmaceutical division, which was responsible for developing new drugs, Fig 3), Felix Hoffmann (1868-1946) (a chemist working for Eichengrün, Fig 4) and Heinrich Dreser (1860-1924) (the head of the pharmacology section, which was responsible for clinical trials). There is ongoing controversy over how the credit for the discovery of aspirin should be distributed.

In 1897, Eichengrün decided to develop a form of salicylate that did not cause gastric irritation. He allocated this task to Hoffmann. Hoffmann had studied as a pharmaceutical chemist at Munich University and in 1894 was hired by Farbenfabriken vormals Frederich Bayer & Company. Upon being allocated this task by Eichengrün, Hoffmann set to work trying to manipulate the salicylic acid that he extracted from dry meadowsweet leaves. He was able to acetylate a phenol group of salicylic acid, producing acetylsalicylic acid (Schmidt, ). His breakthrough was recorded in his laboratory book on 10 August 1897:

'When salicylic acid (100.0 parts) is heated with acetic anhydride (150.0 parts) for 3 hours under reflux, the salicylic acid is quantatively acetylated.......By its physical properties, e.g. its sour taste without being corrosive, the acetylsalicylic acid differs favourably from salicylic acid, and is now being tested in this respect to test its usefulness.' (Jeffreys, ).

The acetylsalicylic acid (soon to be known as aspirin) was put through clinical trials by Dreser's pharmacology division. Initial reports were that it was a successful antipyretic but Dreser rejected it on the grounds that it may cause tachycardia and palpations. Ten days after his discovery of acetylsalicylic acid, Hoffmann produced a second famous drug: diacetylmorphine, also known as heroin. This drug was extraordinarily effective for pain relief and there was great hope that it would prove to be a non‐addictive form of morphine.

Controversy over the discovery of aspirin

Eichengrün did not accept the rejection from the head of the pharmacology division and pushed ahead to run his own clinical trials, including taking the drug himself. These trials demonstrated it was an effective analgesic and had no apparent adverse effects on the heart. Dreser was not impressed and wrote a famous note in the margin of Eichengrün's report: 'This is the usual Berlin boasting. The product has no value' (Jeffreys, ). However following the intervention of the head of the unit who ordered further trials, Dreser accepted that the drug should be produced.

The name aspirin was agreed by a committee of those who had discovered the drug. The name was derived from a combination of acetyl and spiraea (the Latin name for meadowsweet). Although the uptake of aspirin in the medical community was initially slow, it soon took off and aspirin rapidly became known worldwide as one of the first analgesics. While Hoffmann and Eichengrün received no royalties for the development of aspirin, Dreser was paid royalties on every medication in his laboratory, and went on to make a personal fortune from the development of aspirin (Jeffreys, ).

Although Felix Hoffman is widely credited with the discovery of aspirin, there is some controversy over his claim (Sneader, ). At the time of the discovery, Bayer was producing large numbers of new drugs and no individual was specifically credited with the discovery. This changed in 1934, when Schmidt wrote a history of the discovery of aspirin after trawling through the Bayer archives (Schmidt, ). Notably, Eichengrün's contribution to the discovery was omitted. Eichengrün was a Jew and the rise of the Nazi party in Germany may have limited his ability to make a claim to a role. He had, by this time, left Bayer to set up his own company but was faced with heavy restrictions on his work. In 1938 he was forced to sell his business and in 1944 he was sent to the Theresienstadt concentration camp where he remained until the Russians liberated it in 1945 (Sneader, ).

In 1949, 15 years after the publication of the report attributing the discovery to Hoffmann, Arthur Eichengrün, published a manuscript emphasising that the work was performed under his direction. He went on to point out that he identified acetylsalicylic acid as the best compound they had isolated and was the first to call for clinical trials. He reported he had tested it on himself and had initiated the first trials. These trials demonstrated the antipyretic and analgesic effects of acetylsalicylic acid as well as its favourable side effect profile (Eichengrün, ).

The rise of aspirin

Within 3 years of its release onto the market, more than 160 scientific papers had been published extolling the virtues of aspirin. It went on to become enormously successful around the world. In 1918 following World War I, the world was hit by another tragic event, a worldwide outbreak of influenza. Approximately 50 million people died from the outbreak: more than died from fighting in the whole of World War I (Shanks, ). No cure could be found and vaccination was unsuccessful. Aspirin became widely used and was efficacious in relieving the symptoms of influenza, although it was not effective in reducing mortality. Its popularity was maintained thereafter and aspirin went on to be considered by the public and the medical profession as an effective antipyretic and analgesic, with few side effects when taken at standard doses (Lancet Editorial, ).

Aspirin slowly falls out of favour

Aspirin suffered a number of setbacks over the following years. After the invention of the gastroscope in 1932 it soon became apparent that aspirin use was associated with gastritis (Douthwaite, ; Douthwaite & Lintott, ). The development of new analgesic agents without these side effects, such as paracetamol in 1956 and ibuprofen in 1962, further dented aspirin's popularity. Further problems were identified in 1962 when aspirin was proposed to be associated with Reye syndrome in children (Mortimer, ). This condition is associated with an acute encephalopathy and fatty infiltration of the viscera and can be fatal. Over the following years, there was mounting evidence for this association (Linnemann et al, ) and aspirin is no longer recommended for anyone under the age of 16 years, although there are some exceptions, such as the treatment of Kawasaki disease.

A Nobel Prize for understanding how aspirin worked

While aspirin was an extraordinarily successful product, little was known about its mechanism of action. This started to become clearer later in the 19th century as scientific techniques improved.

One of the first manuscripts hypothesising how aspirin worked was published in 1960 by Harry Collier (1912-1983) (Collier & Shorley, ), a scientist working for Allen and Hanburys, a pharmaceutical company. He demonstrated that aspirin prevented bronchoconstriction in guinea pigs following administration of bradykinin. Aspirin did not exert an effect if it was given after bradykinin, leading him to hypothesise that aspirin inhibited bradykinin (Collier & Shorley, ). In 1963, Priscilla Piper (d. 1995), a PhD student from the University of London, joined Harry Collier to work on the mechanism behind the effects of aspirin. They pressed ahead with experiments for the next 5 years but struggled to make further inroads. At this point, Collier recommended that Piper should join John Vane's laboratory as a postgraduate student to learn new laboratory techniques and to take the investigation of the mechanism of aspirin further.

John Vane (1927-2004) is a key figure in the history of aspirin (Fig 5). He was born in Birmingham, United Kingdom in 1927 and went on to study chemistry at the University of Birmingham in 1944, before moving to the University of Oxford in 1946 to read pharmacology. His career went on to take him to the University of Sheffield and Yale in the United States before he returned to the United Kingdom to work in the University of London in 1955 where he developed the 'blood‐bathed organ cascade'. This was a technique where blood was passed over two strips of tissue. The first 'upstream' strip was treated to induce it to release cytokines. He could then observe the effects on the downstream smooth muscle to see if it contracted in response to the cytokine that was released. He used this technique to dynamically measure levels of blood hormones, such as angiotensin and bradykinin (Flower, ).

Priscilla Piper worked with John Vane using this technique to examine how aspirin interacted with different cytokines. They were using a variant of the blood‐bathed organ cascade where rabbit aorta was used as the 'downstream' tissue. They were able to demonstrate that aspirin antagonised an unknown cytokine that they named 'rabbit aorta contracting factor'. They went on to repeat Collier's experiments to demonstrate that injecting rabbit aorta contracting factor into the guinea pig induced anaphylaxis which was antagonised by aspirin (Piper & Vane, ). Vane was able to go on to demonstrate that rabbit aorta contracting factor was a prostaglandin and that aspirin inhibited its synthesis (Vane, ). The demonstration that aspirin inhibited prostacyclin synthesis paved the way for the future development of nonsteroidal anti‐inflammatory drugs (NSAIDs) and other cyclooxygenase (COX) inhibitors and earned John Vane the Nobel Prize for Physiology or Medicine in 1982. He went on to be knighted in 1984.

The effect of aspirin on platelets

Platelets were first identified in 1865 by Max Schultze (1825-1874) (Schultze, ) and were found to be key to normal haemostasis in 1882 by Giulio Bizzozero (1846-1901) (Bizzozero, ). In 1961, with the role of platelets in pathological thrombus formation becoming increasingly clear, two Oxford scientists, John Poole and John French, postulated that inhibiting platelet function might be key to treating pathological thrombus formation. At the time, they were not aware of any agents that could successfully inhibit platelet function in vivo (Poole & French, ) and it would be several more years before the value of aspirin for preventing platelet aggregation was realised. In 1966, Armand Quick (1894-1978) noted that aspirin prolonged the bleeding time and noted that this was particularly pronounced amongst people with von Willebrand disease leading him to hypothesise that aspirin and von Willebrand disease may have similar effects (Quick, ).

A new technique, light transmission aggregometry, was developed in the early 1960s (Born, ; O'Brien, , ) and this provided a tool to investigate aspirin's effects on platelets. In 1967, the US physicians, Harvey Weiss and Louis Aledort, reported that aspirin inhibited platelet function (Weiss & Aledort, ). They treated ten normal volunteers with either ten 300 mg capsules of aspirin, taken in divided doses, or the equivalent volume of lactulose. Bleeding time increased and platelet aggregation decreased in those treated with aspirin compared to controls.

It was known that arachidonic acid could induce platelets to release rabbit aorta contracting factor and, using the new tests of platelet function, it was shown that this resulted in platelet aggregation. In 1975, work led by Bengt Samuelsson (1934-) in Sweden demonstrated that rabbit aorta contracting factor was thromboxane A2 and that this was antagonised by the effects of aspirin and indomethacin (Hamberg et al, ). This work was augmented by the discovery of cyclo‐oxygenase in 1976, which we now know to be the enzyme inhibited by aspirin, leading to impaired synthesis of thromboxane (Hemler et al, ).

Thromboxane A2 was known to induce vasodilation and aspirin antagonised this, suggesting a potentially prothrombotic effect. However its antiplatelet effect, which was becoming apparent, outweighed the effects of any vasoconstriction (Patrono et al, ).

Bengt Samuelsson went on to share the 1982 Nobel Prize for Medicine of Physiology with John Vane and Sune Bergstrom (1916-2004) (the first person to report the existence of prostaglandins). The mechanism of action of aspirin was finally proven more 70 years after its discovery.

Re‐incarnation as an anti‐platelet agent for the prevention of cardiovascular disease

In the early 1950s, long before aspirin's mechanism had been unravelled, a Los Angeles family doctor called Lawrence Craven (1883-1957) wrote to several American journals outlining his experience of using aspirin (Craven, ,, , ). Initially he prescribed a chewing gum impregnated with aspirin to his patients to relieve post‐operative pain from tonsillectomies. He noted that many of his patients used far more chewing gum than he had prescribed and often had serious bleeding complications. He deduced that aspirin might prevent thrombotic events. Craven went on to recommend aspirin to his patients and claimed to have treated more than 6000 people in this way. In 1957, Craven died from a myocardial infarction, which may have led many to question the value of his methods. His reports of the value of aspirin for prevention of myocardial infarction and stroke were largely forgotten for the next decade.

Through the 1970s there was an increased interest in the use of aspirin as an antiplatelet agent. The first randomised controlled trial using aspirin was published by Elwood et al (). A total of 1239 men discharged from hospitals in the UK with a myocardial infarction were identified. Participants were visited at home by the trial team and provided with either aspirin 300 mg daily or a matching gelatine capsule. While fewer participants treated with aspirin died in the following 6 months, the difference was not statistically significant and the trial was considered inconclusive. However, as further randomised controlled trial evidence accumulated, the overall benefit from the introduction of aspirin in this setting was a 25% reduction in recurrent myocardial infarction.

By 1980, six randomised controlled trials assessing the use of aspirin had been completed. In one of the first uses of meta‐analysis, Sir Richard Peto (1943-) combined the results of these trials to demonstrate that aspirin reduced the risk of re‐infarction by 21% (Peto, ). There were ongoing concerns about the risks of aspirin, with the incidence of a fatal bleed much more obvious to clinicians than the prevention of a myocardial infarction (Smith et al, ).

The Second International Study of Infarct Survival (ISIS‐2 trial) recruited 17 187 patients, who were randomised to aspirin (160 mg/day), placebo, streptokinase or a combination of aspirin and streptokinase within 24 h of presenting with symptoms of myocardial infarction. When published in 1988, the clear reduction in mortality associated with aspirin therapy led to its widespread adoption (relative risk reduction 20% at 5 weeks) (ISIS‐2 Collaborative Group, ) (Fig 6).

Early randomised controlled trial evidence in the setting of myocardial infarction was followed by evidence for aspirin in the treatment of stroke (relative risk reduction 31%) (The Canadian Cooperative Study Group, ). Two trials in 1991 clearly demonstrated that 30 mg (The Dutch TIA Trial Study Group, ) and 75 mg (The SALT Collaborative Group, ) per day were as effective as higher doses in prevention of cerebral ischaemia.

In 1994 the British Medical Journal devoted 50 pages to 'The aspirin papers' (Antiplatelet Trialists' Collaboration, ,,). A meta‐analysis by the Antiplatelet Trialists' Collaboration showed a reduction on vascular events by about one quarter (Antiplatelet Trialists' Collaboration, ). Aspirin is now in widespread use for the prevention of cardiovascular disease. It is recommended at the time of acute myocardial infarction (National Institute for Health and Care Excellence, ; O'Gara et al, ) or ischaemic stroke as secondary prophylaxis (National Institute for Health and Care Excellence, ; Kernan et al, ). For those at high risk of cardiovascular disease, aspirin is recommended as primary prophylaxis (National Institute for Health and Care Excellence, ; Bibbins‐Domingo, ).

Aspirin for the prevention of venous thromboembolism

Two recent studies examined the role of aspirin for secondary prophylaxis following initial treatment for venous thromboembolism (Becattini et al, ; Brighton et al, ). These studies demonstrated a 32% reduction in recurrence of venous thromboembolism compared to placebo. Although aspirin was not compared to anticoagulants, the reduction in venous thromboembolism was considerably less than would be expected with an anticoagulant and the use of aspirin in this setting is not routinely recommended.

The potential of aspirin as primary thromboprophylaxis in surgical and medical patients had been shown by the third of 'The aspirin papers' (Antiplatelet Trialists' Collaboration, ), which showed a 26% reduction in deep venous thrombosis (DVT). The Pulmonary Embolism Prevention (PEP) Trial found a 28% reduction in symptomatic DVT in major orthopaedic surgery (Pulmonary Embolism Prevention Trial Collaborative Group, ). However, thromboprophylaxis with anticoagulants gives larger reductions in thrombosis risk and so they are preferred (despite no head‐to‐head comparisons).

Aspirin is used for primary prophylaxis against venous thromboembolism in the small group of patients with multiple myeloma who are treated with lenalidomide or thalidomide (Lyman et al, ). Both of these chemotherapeutic agents are associated with a substantial increase in the incidence of venous thromboembolism and some form of venous thromboprophylaxis is recommended alongside their use. It should be noted that in each trial, there were fewer thrombotic events with low molecular weight heparin than with aspirin (Palumbo et al, ; Larocca et al, ).

Aspirin for stroke prevention in atrial fibrillation

Meta‐analysis comparing aspirin to placebo found aspirin was associated with a non‐significant lower risk of stroke [odds ratio (OR) 0·70, 95% confidence interval (CI) 0·47-1·07] (Aguilar & Hart, ). However when aspirin was compared to warfarin there was a lower risk of stroke with warfarin than aspirin (OR 0·68, 95% CI 0·54-0·85) (Aguilar et al, ). Although aspirin has been widely used in stroke prevention in atrial fibrillation, the National Institute for Health and Care Excellence concluded antiplatelet therapy to have limited benefits for patients with atrial fibrillation for preventing strokes and made a strong recommendation that aspirin should not be offered to patients at increased risk of stroke (National Institute for Health and Care Excellence, ).

Aspirin and haematological conditions

Myeloproliferative diseases

Aspirin is recommended for the prevention of cardiovascular events for patients with myeloproliferative diseases, such as polycythaemia vera and essential thrombocythaemia. The basis for this recommendation was the European Collaboration on Low‐Dose Aspirin in Polycythaemia Vera (ECLAP1) trial, which randomised 518 patients with polycythaemia vera to aspirin or placebo. The risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis or death from cardiovascular causes was significantly lower in the group treated with aspirin (Landolfi et al, ). This has now become part of standard care for both patients with polycythaemia vera and essential thrombocythaemia (Harrison et al, ).

Thrombotic thrombocytopenic purpura and antiphospholipid syndrome

Due to the rarity of thrombotic thrombocytopenic purpura (TTP), randomised controlled trials are very difficult to perform, so management is extrapolated on the basis of observed clinical outcomes. Aspirin is recommended for TTP following treatment when the platelet count rises above 50 × 10 ⁹/l (Scully et al, ), following the observation that following the introduction of aspirin and low molecular weight heparin thromboprophylaxis there was a lower incidence of thrombotic events compared to historical controls (Scully et al, ).

Thrombotic events associated with the acquired thrombophilia, antiphospholipid syndrome, are most commonly treated with anticoagulation. However there is evidence that people with antiphospholipid syndrome with a previous arterial event, such as a stroke, benefit equally from an anticoagulant or aspirin (Levine et al, ). For those who also have recurrent pregnancy loss, aspirin is recommended alongside low molecular weight heparin and also for those with previous pre‐eclampsia or fetal growth restriction (Keeling et al, ).

Aspirin and acute bleeding

Approximately one quarter of patients with acute upper gastrointestinal bleeds (Hearnshaw et al, ) or haemorrhagic strokes are taking an antiplatelet agent (Lovelock et al, ) and the management is unclear.

For some time, platelet transfusion was recommended in a number of guidelines (Ferraris et al, ; Makris et al, ) on the basis of in vitro data (Vilahur et al, ; Li et al, ) and one small single arm study suggesting that the effects of aspirin could be reversed with the administration of 2-3 units of platelets (Thiele et al, ).

These findings have been called into doubt by the findings of a recent trial in patients with spontaneous intracranial haemorrhage who were taking an antiplatelet agent (most of whom were taking aspirin) (Baharoglu et al, ). Patients were randomly allocated to receive either one to two units of platelets or standard care (without platelet transfusions). Platelet transfusion failed to reduce new bleeding or expansion of the haematoma. More worryingly, it resulted in an increased risk of the composite endpoint of death and disability after 3 months. There are few other options at present; although some guidelines recommend consideration of desmopressin acetate, this is on the basis of little evidence (Kozek‐Langenecker et al, ; American Society of Anesthesiologists ; Rossaint et al, ). The optimal management of patients with these severe bleeding complications associated with aspirin is still unclear.

The future

Overall, despite aspirin being more than 100 years old, it continues to occupy a prominent place in the treatment of cardiovascular disease and there are no clear signs at present of it being displaced in the near future. There is, however, inter‐individual variation in the response to aspirin, leading some to speculate on the existence of aspirin resistance. This is often defined as a failure to inhibit arachidonic acid‐induced platelet aggregation by at least 95% (Reilly & FitzGerald, ). However there are problems with achieving consistency in testing for aspirin resistance and there are dramatically different rates of 'aspirin resistance' between studies (Le Quellec et al, ). The position of most guideline groups is that, at present, testing for aspirin resistance is a research tool only (Patrono et al, ; Michelson et al, ), but it remains to be seen if, using more consistent techniques, it is possible to identify individuals who will benefit most (or least) from aspirin. Several ongoing trials are assessing whether it is possible to personalise antiplatelet treatment according by using platelet function tests (NCT01959451) or point‐of‐care genetic tests (NCT01742117) to personalise the choice of antiplatelet agents.

A potential role for the regular use of aspirin to reduce the long‐term risk of several cancers (Rothwell et al, ; Algra & Rothwell, ) could open up a whole new era of aspirin use.

Conclusion

Aspirin has come a long way since the use of willow bark by the ancient Sumerians and Egyptians. It is now the most commonly used drug in the world and has proved life saving in the prevention of cardiovascular disease. It is unclear what the future will bring for aspirin with the development of new antiplatelet medications. However, we owe an enormous debt to all those who discovered aspirin, identified its mechanism, and demonstrated how it reduces the risk of cardiovascular death.

Author contributions

MD prepared the first draft of the manuscript and DK and MD revised the manuscript to produce the submitted article.

Conflict of interest

The authors have no conflicts of interest to declare.

Summary

The story of the discovery of aspirin stretches back more than 3500 years to when bark from the willow tree was used as a pain reliever and antipyretic. It involves an Oxfordshire clergyman, scientists at a German dye manufacturer, a Nobel Prize‐winning discovery and a series of pivotal clinical trials. Aspirin is now the most commonly used drug in the world. Its role in preventing cardiovascular and cerebrovascular disease has been revolutionary and one of the biggest pharmaceutical success stories of the last century.

Weeping willow to salicylic acid

Willow bark has been used as a traditional medicine for more than 3500 years. Unknown to the ancient Sumerians and Egyptians who made use of it, the active agent within willow bark was salicin, which would later form the basis of the discovery of aspirin (Fig 1).

Evidence for this early use of willow as an analgesic and antipyretic first surfaced in 1862. Edwin Smith (1822-1906), an American trader living in Cairo purchased a pair of ancient documents, the provenance of which was unknown. These scrolls dated back to around 1500 BC and are amongst the most important historical documents in medicine (Bryan, ). One of these is now known as the Edwin Smith Surgical Papyrus and details 48 surgical cases and their management. The other is now known as the Ebers Papyrus. This was an Egyptian record of around 160 herbal and vegetable remedies. One of these remedies is the first written record of the use of tjeret or salix (now known as willow) for treatment of non‐specific pains. This herbal knowledge was passed on as empires rose and fell. The use of willow bark for pain relief continued through ancient Greece, where it was recommended by Hippocrates to relieve the pain of childbirth, through to Roman times, when its use was recorded by Pliny the Elder (Jeffreys, ).

Many traditional therapies were used for pain relief over the following centuries but were not studied systematically. The study of natural remedies received a boost with the discovery that the bark of the cinchona tree had fever‐relieving properties. This bark was imported at great expense from South America. Although it was unclear at the time, we now know that cinchona is a source of quinine, the first treatment for malaria. It was with this background that in 1763 the Reverend Edward Stone (1702-1768), an Oxfordshire clergyman and fellow of Wadham College at the University of Oxford, investigated the use of willow bark. His letter to the president of the Royal Society outlining his findings survives today. He described using willow bark as a treatment for aguish (fever and shivering): ' There is a bark of an Englifh tree that, which I have found by experience to be a powerful aftringent, and very efficacious in curing aguifh and intermitting diforders'. Reverend Stone left the willow bark to dry on the outside of a baker's oven for 3 months then pounded and sifted it into a powder. He reported: ' It hath been given I believe to fifty perfons, and never failed in the cure, except in a few autumual and quartun agues, with which the patients have been long and feverely afflicted ' (Stone, ). This letter is likely to be the driving force behind the use of willow bark to treat fevers by many physicians of the time.

The active ingredient in willow bark was not discovered until 1828 when Johann Buchner (1783-1852) first refined willow bark into yellow crystals and named it Salicin (after Salix, the genus of the willow tree) (Schindler, ). In 1829, the process was further refined by Pierre‐Joseph Leroux (1795-1870) in France (Leroux, ) and taken a step further in 1838 when Raffaele Piria (1814-1865) produced a stronger compound from the crystals isolated from willow bark, which he named salicylic acid (Piria, ) (Fig 2).

In 1852, the French chemist, Charles Gerhardt (1816-1856), was the first to modify salicylic acid with the introduction of an acetyl group in place of a hydroxyl group, but the compound was not stable (Gerhardt, ). Gerhardt has one of the first true claims to be the person to discover aspirin but the lack of stability of his newly derived compound stopped him from developing it further. Acetylation of salicylic acid later proved to be the key step in reducing its irritant properties.

Early evidence for salicin

In 1876, the first clinical trial of salicin was published by Thomas Maclagan (1838-1903) a Scottish physician at the Dundee Royal Infirmary (MacLagan, ,,). He investigated the effects of salicylate in relieving the symptoms of rheumatic fever. His first step was to take salicin himself: ' I determined to give salicin; but before doing so, took myself first five, then ten, then thirty grains without experiencing the least inconvenience or discomfort '. He proceeded to treat eight patients with rheumatic fever with 12 grains of salicin every 3 h, demonstrating its antipyretic and anti‐inflammatory effects (MacLagan, ,,). Despite the clear antipyretic benefits of salicin, it was not taken up more widely due to complications with gastritis.

A breakthrough produces aspirin

In 1890, the German dye manufacturer, Bayer, set up a pharmaceutical division with research facilities for scientists. This followed early success deriving antipyretic medications from waste products of the dye manufacturing process. The establishment of this unit resulted in rapid development of a large number of drugs.

Three key figures in the discovery of aspirin at Bayer were Arthur Eichengrün (1867-1949) (the head of the pharmaceutical division, which was responsible for developing new drugs, Fig 3), Felix Hoffmann (1868-1946) (a chemist working for Eichengrün, Fig 4) and Heinrich Dreser (1860-1924) (the head of the pharmacology section, which was responsible for clinical trials). There is ongoing controversy over how the credit for the discovery of aspirin should be distributed.

In 1897, Eichengrün decided to develop a form of salicylate that did not cause gastric irritation. He allocated this task to Hoffmann. Hoffmann had studied as a pharmaceutical chemist at Munich University and in 1894 was hired by Farbenfabriken vormals Frederich Bayer & Company. Upon being allocated this task by Eichengrün, Hoffmann set to work trying to manipulate the salicylic acid that he extracted from dry meadowsweet leaves. He was able to acetylate a phenol group of salicylic acid, producing acetylsalicylic acid (Schmidt, ). His breakthrough was recorded in his laboratory book on 10 August 1897:

'When salicylic acid (100.0 parts) is heated with acetic anhydride (150.0 parts) for 3 hours under reflux, the salicylic acid is quantatively acetylated.......By its physical properties, e.g. its sour taste without being corrosive, the acetylsalicylic acid differs favourably from salicylic acid, and is now being tested in this respect to test its usefulness.' (Jeffreys, ).

The acetylsalicylic acid (soon to be known as aspirin) was put through clinical trials by Dreser's pharmacology division. Initial reports were that it was a successful antipyretic but Dreser rejected it on the grounds that it may cause tachycardia and palpations. Ten days after his discovery of acetylsalicylic acid, Hoffmann produced a second famous drug: diacetylmorphine, also known as heroin. This drug was extraordinarily effective for pain relief and there was great hope that it would prove to be a non‐addictive form of morphine.

Controversy over the discovery of aspirin

Eichengrün did not accept the rejection from the head of the pharmacology division and pushed ahead to run his own clinical trials, including taking the drug himself. These trials demonstrated it was an effective analgesic and had no apparent adverse effects on the heart. Dreser was not impressed and wrote a famous note in the margin of Eichengrün's report: 'This is the usual Berlin boasting. The product has no value' (Jeffreys, ). However following the intervention of the head of the unit who ordered further trials, Dreser accepted that the drug should be produced.

The name aspirin was agreed by a committee of those who had discovered the drug. The name was derived from a combination of acetyl and spiraea (the Latin name for meadowsweet). Although the uptake of aspirin in the medical community was initially slow, it soon took off and aspirin rapidly became known worldwide as one of the first analgesics. While Hoffmann and Eichengrün received no royalties for the development of aspirin, Dreser was paid royalties on every medication in his laboratory, and went on to make a personal fortune from the development of aspirin (Jeffreys, ).

Although Felix Hoffman is widely credited with the discovery of aspirin, there is some controversy over his claim (Sneader, ). At the time of the discovery, Bayer was producing large numbers of new drugs and no individual was specifically credited with the discovery. This changed in 1934, when Schmidt wrote a history of the discovery of aspirin after trawling through the Bayer archives (Schmidt, ). Notably, Eichengrün's contribution to the discovery was omitted. Eichengrün was a Jew and the rise of the Nazi party in Germany may have limited his ability to make a claim to a role. He had, by this time, left Bayer to set up his own company but was faced with heavy restrictions on his work. In 1938 he was forced to sell his business and in 1944 he was sent to the Theresienstadt concentration camp where he remained until the Russians liberated it in 1945 (Sneader, ).

In 1949, 15 years after the publication of the report attributing the discovery to Hoffmann, Arthur Eichengrün, published a manuscript emphasising that the work was performed under his direction. He went on to point out that he identified acetylsalicylic acid as the best compound they had isolated and was the first to call for clinical trials. He reported he had tested it on himself and had initiated the first trials. These trials demonstrated the antipyretic and analgesic effects of acetylsalicylic acid as well as its favourable side effect profile (Eichengrün, ).

The rise of aspirin

Within 3 years of its release onto the market, more than 160 scientific papers had been published extolling the virtues of aspirin. It went on to become enormously successful around the world. In 1918 following World War I, the world was hit by another tragic event, a worldwide outbreak of influenza. Approximately 50 million people died from the outbreak: more than died from fighting in the whole of World War I (Shanks, ). No cure could be found and vaccination was unsuccessful. Aspirin became widely used and was efficacious in relieving the symptoms of influenza, although it was not effective in reducing mortality. Its popularity was maintained thereafter and aspirin went on to be considered by the public and the medical profession as an effective antipyretic and analgesic, with few side effects when taken at standard doses (Lancet Editorial, ).

Aspirin slowly falls out of favour

Aspirin suffered a number of setbacks over the following years. After the invention of the gastroscope in 1932 it soon became apparent that aspirin use was associated with gastritis (Douthwaite, ; Douthwaite & Lintott, ). The development of new analgesic agents without these side effects, such as paracetamol in 1956 and ibuprofen in 1962, further dented aspirin's popularity. Further problems were identified in 1962 when aspirin was proposed to be associated with Reye syndrome in children (Mortimer, ). This condition is associated with an acute encephalopathy and fatty infiltration of the viscera and can be fatal. Over the following years, there was mounting evidence for this association (Linnemann et al, ) and aspirin is no longer recommended for anyone under the age of 16 years, although there are some exceptions, such as the treatment of Kawasaki disease.

A Nobel Prize for understanding how aspirin worked

While aspirin was an extraordinarily successful product, little was known about its mechanism of action. This started to become clearer later in the 19th century as scientific techniques improved.

One of the first manuscripts hypothesising how aspirin worked was published in 1960 by Harry Collier (1912-1983) (Collier & Shorley, ), a scientist working for Allen and Hanburys, a pharmaceutical company. He demonstrated that aspirin prevented bronchoconstriction in guinea pigs following administration of bradykinin. Aspirin did not exert an effect if it was given after bradykinin, leading him to hypothesise that aspirin inhibited bradykinin (Collier & Shorley, ). In 1963, Priscilla Piper (d. 1995), a PhD student from the University of London, joined Harry Collier to work on the mechanism behind the effects of aspirin. They pressed ahead with experiments for the next 5 years but struggled to make further inroads. At this point, Collier recommended that Piper should join John Vane's laboratory as a postgraduate student to learn new laboratory techniques and to take the investigation of the mechanism of aspirin further.

John Vane (1927-2004) is a key figure in the history of aspirin (Fig 5). He was born in Birmingham, United Kingdom in 1927 and went on to study chemistry at the University of Birmingham in 1944, before moving to the University of Oxford in 1946 to read pharmacology. His career went on to take him to the University of Sheffield and Yale in the United States before he returned to the United Kingdom to work in the University of London in 1955 where he developed the 'blood‐bathed organ cascade'. This was a technique where blood was passed over two strips of tissue. The first 'upstream' strip was treated to induce it to release cytokines. He could then observe the effects on the downstream smooth muscle to see if it contracted in response to the cytokine that was released. He used this technique to dynamically measure levels of blood hormones, such as angiotensin and bradykinin (Flower, ).

Priscilla Piper worked with John Vane using this technique to examine how aspirin interacted with different cytokines. They were using a variant of the blood‐bathed organ cascade where rabbit aorta was used as the 'downstream' tissue. They were able to demonstrate that aspirin antagonised an unknown cytokine that they named 'rabbit aorta contracting factor'. They went on to repeat Collier's experiments to demonstrate that injecting rabbit aorta contracting factor into the guinea pig induced anaphylaxis which was antagonised by aspirin (Piper & Vane, ). Vane was able to go on to demonstrate that rabbit aorta contracting factor was a prostaglandin and that aspirin inhibited its synthesis (Vane, ). The demonstration that aspirin inhibited prostacyclin synthesis paved the way for the future development of nonsteroidal anti‐inflammatory drugs (NSAIDs) and other cyclooxygenase (COX) inhibitors and earned John Vane the Nobel Prize for Physiology or Medicine in 1982. He went on to be knighted in 1984.

The effect of aspirin on platelets

Platelets were first identified in 1865 by Max Schultze (1825-1874) (Schultze, ) and were found to be key to normal haemostasis in 1882 by Giulio Bizzozero (1846-1901) (Bizzozero, ). In 1961, with the role of platelets in pathological thrombus formation becoming increasingly clear, two Oxford scientists, John Poole and John French, postulated that inhibiting platelet function might be key to treating pathological thrombus formation. At the time, they were not aware of any agents that could successfully inhibit platelet function in vivo (Poole & French, ) and it would be several more years before the value of aspirin for preventing platelet aggregation was realised. In 1966, Armand Quick (1894-1978) noted that aspirin prolonged the bleeding time and noted that this was particularly pronounced amongst people with von Willebrand disease leading him to hypothesise that aspirin and von Willebrand disease may have similar effects (Quick, ).

A new technique, light transmission aggregometry, was developed in the early 1960s (Born, ; O'Brien, , ) and this provided a tool to investigate aspirin's effects on platelets. In 1967, the US physicians, Harvey Weiss and Louis Aledort, reported that aspirin inhibited platelet function (Weiss & Aledort, ). They treated ten normal volunteers with either ten 300 mg capsules of aspirin, taken in divided doses, or the equivalent volume of lactulose. Bleeding time increased and platelet aggregation decreased in those treated with aspirin compared to controls.

It was known that arachidonic acid could induce platelets to release rabbit aorta contracting factor and, using the new tests of platelet function, it was shown that this resulted in platelet aggregation. In 1975, work led by Bengt Samuelsson (1934-) in Sweden demonstrated that rabbit aorta contracting factor was thromboxane A2 and that this was antagonised by the effects of aspirin and indomethacin (Hamberg et al, ). This work was augmented by the discovery of cyclo‐oxygenase in 1976, which we now know to be the enzyme inhibited by aspirin, leading to impaired synthesis of thromboxane (Hemler et al, ).

Thromboxane A2 was known to induce vasodilation and aspirin antagonised this, suggesting a potentially prothrombotic effect. However its antiplatelet effect, which was becoming apparent, outweighed the effects of any vasoconstriction (Patrono et al, ).

Bengt Samuelsson went on to share the 1982 Nobel Prize for Medicine of Physiology with John Vane and Sune Bergstrom (1916-2004) (the first person to report the existence of prostaglandins). The mechanism of action of aspirin was finally proven more 70 years after its discovery.

Re‐incarnation as an anti‐platelet agent for the prevention of cardiovascular disease

In the early 1950s, long before aspirin's mechanism had been unravelled, a Los Angeles family doctor called Lawrence Craven (1883-1957) wrote to several American journals outlining his experience of using aspirin (Craven, ,, , ). Initially he prescribed a chewing gum impregnated with aspirin to his patients to relieve post‐operative pain from tonsillectomies. He noted that many of his patients used far more chewing gum than he had prescribed and often had serious bleeding complications. He deduced that aspirin might prevent thrombotic events. Craven went on to recommend aspirin to his patients and claimed to have treated more than 6000 people in this way. In 1957, Craven died from a myocardial infarction, which may have led many to question the value of his methods. His reports of the value of aspirin for prevention of myocardial infarction and stroke were largely forgotten for the next decade.

Through the 1970s there was an increased interest in the use of aspirin as an antiplatelet agent. The first randomised controlled trial using aspirin was published by Elwood et al (). A total of 1239 men discharged from hospitals in the UK with a myocardial infarction were identified. Participants were visited at home by the trial team and provided with either aspirin 300 mg daily or a matching gelatine capsule. While fewer participants treated with aspirin died in the following 6 months, the difference was not statistically significant and the trial was considered inconclusive. However, as further randomised controlled trial evidence accumulated, the overall benefit from the introduction of aspirin in this setting was a 25% reduction in recurrent myocardial infarction.

By 1980, six randomised controlled trials assessing the use of aspirin had been completed. In one of the first uses of meta‐analysis, Sir Richard Peto (1943-) combined the results of these trials to demonstrate that aspirin reduced the risk of re‐infarction by 21% (Peto, ). There were ongoing concerns about the risks of aspirin, with the incidence of a fatal bleed much more obvious to clinicians than the prevention of a myocardial infarction (Smith et al, ).

The Second International Study of Infarct Survival (ISIS‐2 trial) recruited 17 187 patients, who were randomised to aspirin (160 mg/day), placebo, streptokinase or a combination of aspirin and streptokinase within 24 h of presenting with symptoms of myocardial infarction. When published in 1988, the clear reduction in mortality associated with aspirin therapy led to its widespread adoption (relative risk reduction 20% at 5 weeks) (ISIS‐2 Collaborative Group, ) (Fig 6).

Early randomised controlled trial evidence in the setting of myocardial infarction was followed by evidence for aspirin in the treatment of stroke (relative risk reduction 31%) (The Canadian Cooperative Study Group, ). Two trials in 1991 clearly demonstrated that 30 mg (The Dutch TIA Trial Study Group, ) and 75 mg (The SALT Collaborative Group, ) per day were as effective as higher doses in prevention of cerebral ischaemia.

In 1994 the British Medical Journal devoted 50 pages to 'The aspirin papers' (Antiplatelet Trialists' Collaboration, ,,). A meta‐analysis by the Antiplatelet Trialists' Collaboration showed a reduction on vascular events by about one quarter (Antiplatelet Trialists' Collaboration, ). Aspirin is now in widespread use for the prevention of cardiovascular disease. It is recommended at the time of acute myocardial infarction (National Institute for Health and Care Excellence, ; O'Gara et al, ) or ischaemic stroke as secondary prophylaxis (National Institute for Health and Care Excellence, ; Kernan et al, ). For those at high risk of cardiovascular disease, aspirin is recommended as primary prophylaxis (National Institute for Health and Care Excellence, ; Bibbins‐Domingo, ).

Aspirin for the prevention of venous thromboembolism

Two recent studies examined the role of aspirin for secondary prophylaxis following initial treatment for venous thromboembolism (Becattini et al, ; Brighton et al, ). These studies demonstrated a 32% reduction in recurrence of venous thromboembolism compared to placebo. Although aspirin was not compared to anticoagulants, the reduction in venous thromboembolism was considerably less than would be expected with an anticoagulant and the use of aspirin in this setting is not routinely recommended.

The potential of aspirin as primary thromboprophylaxis in surgical and medical patients had been shown by the third of 'The aspirin papers' (Antiplatelet Trialists' Collaboration, ), which showed a 26% reduction in deep venous thrombosis (DVT). The Pulmonary Embolism Prevention (PEP) Trial found a 28% reduction in symptomatic DVT in major orthopaedic surgery (Pulmonary Embolism Prevention Trial Collaborative Group, ). However, thromboprophylaxis with anticoagulants gives larger reductions in thrombosis risk and so they are preferred (despite no head‐to‐head comparisons).

Aspirin is used for primary prophylaxis against venous thromboembolism in the small group of patients with multiple myeloma who are treated with lenalidomide or thalidomide (Lyman et al, ). Both of these chemotherapeutic agents are associated with a substantial increase in the incidence of venous thromboembolism and some form of venous thromboprophylaxis is recommended alongside their use. It should be noted that in each trial, there were fewer thrombotic events with low molecular weight heparin than with aspirin (Palumbo et al, ; Larocca et al, ).

Aspirin for stroke prevention in atrial fibrillation

Meta‐analysis comparing aspirin to placebo found aspirin was associated with a non‐significant lower risk of stroke [odds ratio (OR) 0·70, 95% confidence interval (CI) 0·47-1·07] (Aguilar & Hart, ). However when aspirin was compared to warfarin there was a lower risk of stroke with warfarin than aspirin (OR 0·68, 95% CI 0·54-0·85) (Aguilar et al, ). Although aspirin has been widely used in stroke prevention in atrial fibrillation, the National Institute for Health and Care Excellence concluded antiplatelet therapy to have limited benefits for patients with atrial fibrillation for preventing strokes and made a strong recommendation that aspirin should not be offered to patients at increased risk of stroke (National Institute for Health and Care Excellence, ).

Aspirin and haematological conditions

Myeloproliferative diseases

Aspirin is recommended for the prevention of cardiovascular events for patients with myeloproliferative diseases, such as polycythaemia vera and essential thrombocythaemia. The basis for this recommendation was the European Collaboration on Low‐Dose Aspirin in Polycythaemia Vera (ECLAP1) trial, which randomised 518 patients with polycythaemia vera to aspirin or placebo. The risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis or death from cardiovascular causes was significantly lower in the group treated with aspirin (Landolfi et al, ). This has now become part of standard care for both patients with polycythaemia vera and essential thrombocythaemia (Harrison et al, ).

Thrombotic thrombocytopenic purpura and antiphospholipid syndrome

Due to the rarity of thrombotic thrombocytopenic purpura (TTP), randomised controlled trials are very difficult to perform, so management is extrapolated on the basis of observed clinical outcomes. Aspirin is recommended for TTP following treatment when the platelet count rises above 50 × 10 ⁹/l (Scully et al, ), following the observation that following the introduction of aspirin and low molecular weight heparin thromboprophylaxis there was a lower incidence of thrombotic events compared to historical controls (Scully et al, ).

Thrombotic events associated with the acquired thrombophilia, antiphospholipid syndrome, are most commonly treated with anticoagulation. However there is evidence that people with antiphospholipid syndrome with a previous arterial event, such as a stroke, benefit equally from an anticoagulant or aspirin (Levine et al, ). For those who also have recurrent pregnancy loss, aspirin is recommended alongside low molecular weight heparin and also for those with previous pre‐eclampsia or fetal growth restriction (Keeling et al, ).

Aspirin and acute bleeding

Approximately one quarter of patients with acute upper gastrointestinal bleeds (Hearnshaw et al, ) or haemorrhagic strokes are taking an antiplatelet agent (Lovelock et al, ) and the management is unclear.

For some time, platelet transfusion was recommended in a number of guidelines (Ferraris et al, ; Makris et al, ) on the basis of in vitro data (Vilahur et al, ; Li et al, ) and one small single arm study suggesting that the effects of aspirin could be reversed with the administration of 2-3 units of platelets (Thiele et al, ).

These findings have been called into doubt by the findings of a recent trial in patients with spontaneous intracranial haemorrhage who were taking an antiplatelet agent (most of whom were taking aspirin) (Baharoglu et al, ). Patients were randomly allocated to receive either one to two units of platelets or standard care (without platelet transfusions). Platelet transfusion failed to reduce new bleeding or expansion of the haematoma. More worryingly, it resulted in an increased risk of the composite endpoint of death and disability after 3 months. There are few other options at present; although some guidelines recommend consideration of desmopressin acetate, this is on the basis of little evidence (Kozek‐Langenecker et al, ; American Society of Anesthesiologists ; Rossaint et al, ). The optimal management of patients with these severe bleeding complications associated with aspirin is still unclear.

The future

Overall, despite aspirin being more than 100 years old, it continues to occupy a prominent place in the treatment of cardiovascular disease and there are no clear signs at present of it being displaced in the near future. There is, however, inter‐individual variation in the response to aspirin, leading some to speculate on the existence of aspirin resistance. This is often defined as a failure to inhibit arachidonic acid‐induced platelet aggregation by at least 95% (Reilly & FitzGerald, ). However there are problems with achieving consistency in testing for aspirin resistance and there are dramatically different rates of 'aspirin resistance' between studies (Le Quellec et al, ). The position of most guideline groups is that, at present, testing for aspirin resistance is a research tool only (Patrono et al, ; Michelson et al, ), but it remains to be seen if, using more consistent techniques, it is possible to identify individuals who will benefit most (or least) from aspirin. Several ongoing trials are assessing whether it is possible to personalise antiplatelet treatment according by using platelet function tests (NCT01959451) or point‐of‐care genetic tests (NCT01742117) to personalise the choice of antiplatelet agents.

A potential role for the regular use of aspirin to reduce the long‐term risk of several cancers (Rothwell et al, ; Algra & Rothwell, ) could open up a whole new era of aspirin use.

Conclusion

Aspirin has come a long way since the use of willow bark by the ancient Sumerians and Egyptians. It is now the most commonly used drug in the world and has proved life saving in the prevention of cardiovascular disease. It is unclear what the future will bring for aspirin with the development of new antiplatelet medications. However, we owe an enormous debt to all those who discovered aspirin, identified its mechanism, and demonstrated how it reduces the risk of cardiovascular death.

Author contributions

MD prepared the first draft of the manuscript and DK and MD revised the manuscript to produce the submitted article.

Conflict of interest

The authors have no conflicts of interest to declare.

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The aspirin story - from willow to wonder drug

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Corresponding Author NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK Oxford Clinical Research in Transfusion Medicine, Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, UK Correspondence: Dr Michael J. R. Desborough, NHS Blood and Transplant, John Radcliffe Hospital, Oxford OX3 9DU, UK.

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Through willow bark derivatives, experiments performed to combine or compare with anti-depressants already on market.

Willow brings an anti-inflammatory element to complement the anti-depressants already on market.

“Inflammatory processes

are increasingly recognized to contribute to neurological and neuropsychiatric disorders such as depression… These findings contribute to our understanding of the link between inflammation and neurological functions and may also support the scope for the development of co-medications from salicylate…”

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Abstract

Inflammatory processes are increasingly recognised to contribute to neurological and neuropsychatric disorders such as depression. Thus we investigated whether a standardized willow bark preparation (WB) which contains among other constituents salicin, the forerunner of non-steroidal antiphlogistic drugs, would have an effect in a standard model of depression, the forced swimming test (FST), compared to the antidepressant imipramine. Studies were accompanied by gene expression analyses. In order to allocate potential effects to the different constituents of WB, fractions of the extract with different compositions of salicyl alcohol derivative and polyphenols were also investigated. Male Sprague Dawley rats (n=12/group) were treated for 14 days (p.o.) with the WB preparation STW 33-I (group A) and its fractions (FR) (groups FR-B to E) in concentrations of 30 mg/kg. The FRs were characterized by a high content of flavone and chalcone glycosides (FR-B), flavonoid glycosides and salicyl alcohol derivatives (FR-C), salicin and related salicyl alcohol derivatives (FR-D) and proanthocyanidines (FR-E). The tricyclic antidepressant imipramine (20 mg/kg) (F) was used as positive control. The FST was performed on day 15. The cumulative immobility time was significantly (p<0.05) reduced in group A (36%), group FR-D (44%) and by imipramine (16%) compared to untreated controls. RNA was isolated from peripheral blood. RNA samples (group A, group FR-D, and imipramine) were further analysed by rat whole genome microarray (Agilent) in comparison to untreated controls. Quantitative PCR for selected genes was performed. Genes (>2 fold, p<0.01), affected by WB and/or FR-D and imipramine, included both inflammatory (e.g. IL-3, IL-10) and neurologically relevant targets. Common genes regulated by WB, FR-D and imipramine were GRIA 2 ↓, SRP54 ↓, CYP26B ↓, DNM1L ↑ and KITLG ↓. In addition, the hippocampus of rats treated (27 d) with WB (15-60 mg/kg WB) or imipramine (15 mg/kg bw) showed a slower serotonin turnover (5-hydroxyindol acetic acid/serotonin (p<0.05)) depending on the dosage. Thus WB (30 mg/kg), its ethanolic fraction rich in salicyl alcohol derivatives (FR-D) (30 mg/kg) and imipramine, by being effective in the FST, modulated known and new targets relevant for neuro- and immunofunctions in rats. These findings contribute to our understanding of the link between inflammation and neurological functions and may also support the scope for the development of co-medications from salicylate-containing phytopharmaceuticals as multicomponent mixtures with single component synthetic drugs.

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Prediction of adverse events by in vivo gene expression profiling exemplified for phytopharmaceuticals containing salicylates and the antidepressant imipramine.

Ulrich-Merzenich G, Koptina A, Kelber O, Freischmidt A, Heilmann J, Müller J, Sadeghlar F, Zeitler H, Wagner H. Ulrich-Merzenich G, et al. Phytomedicine. 2012 Feb 15;19(3-4):322-9. doi: 10.1016/j.phymed.2011.09.078. Epub 2011 Nov 25. Phytomedicine. 2012. PMID: 22119042

In vitro anti-proliferative effects of the willow bark extract STW 33-I.

Bonaterra GA, Kelber O, Weiser D, Metz J, Kinscherf R. Bonaterra GA, et al. Arzneimittelforschung. 2010;60(6):330-5. doi: 10.1055/s-0031-1296296. Arzneimittelforschung. 2010. PMID: 20648923

Willow species and aspirin: different mechanism of actions.

Vlachojannis J, Magora F, Chrubasik S. Vlachojannis J, et al. Phytother Res. 2011 Jul;25(7):1102-4. doi: 10.1002/ptr.3386. Phytother Res. 2011. PMID: 21226125

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national center for biotechnology information

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Novel neurological and immunological targets for salicylate-based phytopharmaceuticals and for the anti-depressant imipramine - PubMed

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Inflammatory processes are increasingly recognised to contribute to neurological and neuropsychatric disorders such as depression. Thus we investigated whether a standardized willow bark preparation (WB) which contains among other constituents salicin, the forerunner of non-steroidal antiphlogistic drugs, would have an effect in a standard model of depression, the forced swimming test (FST), compared to the antidepressant imipramine.

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Originating from the Bursa family of trees, Copal has been used for centuries to stabilize emotions, cleanse, and purify.

Age old remedy for depression and balance.

“its properties determine a series of very interesting benefits: Balance the state of the mind. Increase concentration and relaxation. Powerful channeling of energies, ideal to enter into states of meditation. Fight stress and insomnia.”

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Benefits and uses about the peruvian Copal Incense

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Of the raw materials used to make incense, copal is possibly one of the most historical and magical. Copal incense dates back to pre-Hispanic times.

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Thought to be a food for the gods, Copal had many uses, including to treat insomnia and anxiety.

The power of Copal is like that of the sun and moon, useful for supporting a healthy body and mind.

“Known for its ability to elicit mentally uplifting and calming effects, Copal is rich in triterpenes that have been shown to significantly reduce anxiety. Burning this resin is thought to activate “ion” channels in the brain, helping to alleviate stress

and anxiety.”

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Derived from the sap of native trees of the Buresa family in South America, Copal is a smoky, sweet incense used by the indigenous tribes of the Americas for ceremonies and rituals. Trees in the Buresa family were seen as medicinal trees that were traditionally used to combat disease and repel mosquitos and other biting insects.

The word Copal is from the Aztec word "copalli" and was considered the sacred blood of the trees. This resin was also used as a binder for pigments used on Mayan murals and in a jewellery making technique that has been lost to the annals of history.

Copal Benefits
Insomnia/Anxiety
Known for its ability to elicit mentally uplifting and calming effects, Copal is rich in triterpenes that have been shown to significantly reduce anxiety. Burning this resin is thought to activate "ion" channels in the brain, helping to alleviate stress and anxiety.

These calming effects of Copal also allow the body to wind down and destress in readiness for sleep. It has long been used by the ancients to promote emotional balance and to calm down the nervous system.
Meditation
Copal is a powerful incense to use during meditation. It is linked with the crown chakra, deepening connection to the mystical and encouraging pure thoughts during meditation. Copal also helps to strengthen the auric body, helping to remove stagnant energy.

It is believed that Copal unites the energising force of the sun with the grounding properties of the earth, drawing out and transmuting negative energy on every level.
Energetic Cleansing
In line with most other incenses, Copal has a long history of traditional use as a space clearer, eradicating negative energy from places and objects.

It's clean, light and woody scent is said to bring a positive and loving energy that will fill the home with peaceful energies.

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Copal is referenced in the Mayan book the "Popol Vuh", which includes a long passage describing how the sun, moon, and stars arrived on earth bringing Copal with them. The 16th-century Spanish friar Bernardino de Sahagun reported that the Aztec people used Copal as makeup, adhesive for masks, and in dentistry where Copal was mixed with calcium phosphate to affix precious stones to teeth.

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Burning frankincense supports ion channels in brain to relieve depression and anxiety.

Frankincense helps our brains relax and open to bring relief and relaxation.

“Burning frankincense (resin from the Boswellia plant) activates poorly understood ion channels in the brain to alleviate anxiety or depression.”

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Religious leaders have contended for millennia that burning incense is good for the soul. Now, biologists have learned that it is good for our brains too. An international team of scientists, including researchers from Johns Hopkins University and the Hebrew University in Jerusalem, describe how burning frankincense (resin from the Boswellia plant) activates poorly understood ion channels in the brain to alleviate anxiety or depression. This suggests that an entirely new class of depression and anxiety drugs might be right under our noses.

"In spite of information stemming from ancient texts, constituents of Bosweilla had not been investigated for psychoactivity," said Raphael Mechoulam, one of the research study's co-authors. "We found that incensole acetate, a Boswellia resin constituent, when tested in mice lowers anxiety and causes antidepressive-like behavior. Apparently, most present day worshipers assume that incense burning has only a symbolic meaning."

To determine incense's psychoactive effects, the researchers administered incensole acetate to mice. They found that the compound significantly affected areas in brain areas known to be involved in emotions as well as in nerve circuits that are affected by current anxiety and depression drugs. Specifically, incensole acetate activated a protein called TRPV3, which is present in mammalian brains and also known to play a role in the perception of warmth of the skin. When mice bred without this protein were exposed to incensole acetate, the compound had no effect on their brains.

"Studies of how those psychoactive drugs work have helped us understand modern neurobiology," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "The discovery of how incensole acetate, purified from frankincense, works on specific targets in the brain should also help us understand diseases of the nervous system. This study also provides a biological explanation for millennia-old spiritual practices that have persisted across time, distance, culture, language, and religion -- burning incense really does make you feel warm and tingly all over!"

According to the National Institutes of Health, major depressive disorder is the leading cause of disability in the United States for people ages 15 -- 44, affecting approximately 14.8 million American adults. A less severe form of depression, dysthymic disorder, affects approximately 3.3 million American adults. Anxiety disorders affect 40 million American adults, and frequently co-occur with depressive disorders.

Journal Reference:

Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain. Arieh Moussaieff, Neta Rimmerman, Tatiana Bregman, Alex Straiker, Christian C. Felder, Shai Shoham, Yoel Kashman, Susan M. Huang, Hyosang Lee, Esther Shohami, Ken Mackie, Michael J. Caterina, J. Michael Walker, Ester Fride, and Raphael Mechoulam. Published online before print May 20, 2008 as doi: 10.1096/fj.07-101865. [abstract]

Cite This Page:

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mental health research; nervous system; psychology research; psychiatry; anxiety; disorders and syndromes; mice; biology; biochemistry research

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Burning incense is psychoactive: New class of antidepressants might be right under our noses

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Religious leaders have contended for millennia that burning incense is good for the soul. Now, biologists have learned that it is good for our brains too. An international team of scientists, including researchers from Johns Hopkins University and the Hebrew University in Jerusalem, describe how burning frankincense (resin from the Boswellia plant) activates poorly understood ion channels in the brain to alleviate anxiety or depression.

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Summary:
An overview of the myriad of ways the brain functions and develops.
Interpretation:
A birds eye perspective of the capacity of the brain and how it perceives reality
Quote:
"It was about chemical imbalances in her (Elyn Saks) brain that subtly changed the pattern of signals."

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Locked in the silence and darkness of your skull, your brain fashions the rich narratives of your reality and your identity. Join renowned neuroscientist David Eagleman for a journey into the questions at the mysterious heart of our existence. What is reality? Who are "you"? How do you make decisions? Why does your brain need other people? How is technology poised to change what it means to be human? In the course of his investigations, Eagleman guides us through the world of extreme sports, criminal justice, facial expressions, genocide, brain surgery, gut feelings, robotics, and the search for immortality.

"A magical, mystical tour of the brain showing how life shapes your brain and your brain shapes your life." - Parade

"He is a gifted educator with considerable communication skills... Eagleman is a convincing tour guide, and his unstated goal of being an ambassador of neuroscience - a public intellectual taking on subject matter some may consider too esoteric or controversial for widespread dissemination - is laudable in a time when so much new knowldge may prove valuable to society." - Neurology Today

"In the fine tradition of Carl Sagan, Eagleman shows that science is captivating without hyped embellishment, and, if you pay attention, you'll find yourself immersed in it." - Forbes

"An ideal introduction to how biology generates the mind.... structured around crucial and wide-ranging questions, saturated with personal and social relevance. And Eagleman's answers are consistently clear, engaging and thought-provoking." - Nature

"An intellectual thrill-ride. Plus, Eagleman isn't merely a brilliant guide, he can turn a phrase, too." - Newsday

"The show and its companion book by Eagleman, "The Brain: The Story of You," are testaments to the neuroscientist's fervent belief in the relevance of his field to ordinary people." - NY Magazine

"This ranks as the most fascinating and unsettling science series of the year, setting out the state of contemporary research into the human brain in terms that any interested layperson can comprehend." - OC Register

"David Eagleman's wide-ranging roundup of the current state of knowledge about the brain is concise, accessible and often very surprising. It's a strange new world inside your head." - Brian Eno

"David Eagleman's The Brain its an astonishing read. On every page there is a revelation so fantastic as to make one gasp. It would be impossible to take in if we didn't all possess that impossibly extraordinary thing, a brain. Eagleman comes closer than anyone to solving the mystery of how to find the self inside the grey electric mush between our ears." - Stephen Fry

"David Eagleman makes it easy to comprehend the most complex collection of cells in the Cosmos - our brain. If neuroscience had a rock legend this would be him." - Ruby Wax

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Brain and Behavior: A Cognitive Neuroscience Perspective addresses the central aims of cognitive neuroscience, seeking to examine the brain not only by its components but also by their functions. It highlights the principles, discoveries, and remaining mysteries of modern cognitive neuroscience.

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Oxidative stress contributes to causing Alzheimer’s disease (AD), Parkinson’s disease, and schizophrenia.  Three strains of sage were used in testing with various ways of extracting and various solvents used in handling these extractions, creating the results of two strains demonstrating strength in minimizing toxicity as well as creating a protective anti-oxidants to repair damage.

Molecular and environmental stress cause brain degenerative diseases that sage can not only counteract against but protect from further damage.

“This study shows the protective effects of Artemisia extracts… suggested that these

species could be also considered as promising neuroprotective agents in treatment of different neurodegenerative diseases.”

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Treatment of MS found that Frankincense reduces bio-reactive responses which lower episode occurances.

Frankincense supports those with auto-immune diseases.

“Oral treatment with an SFE [standardized frankincense extract] significantly reduces bioactive … derived LMs [Lipid Mediator], MRI disease Activity...”

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Stress alters the neural systems causing symptoms of chronic depression, altered moods, and cognitive functions.  Artemisia capillaris Thunb. has proven effective as an antidepressant.

As a resource, Artemisia capillaris Thunb. has proven to support brain function and increase brain and mood balance.

“The expression of the pituitary gland and hypothalamic… endorphin levels were increased by extract of Artemisia capillaris.  …shows a potent antidepressant effect.”

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The anti-inflammatory aspect of acetyl salicylic acid proves to be effective in preventing Alzheimer's Disease.

The use of anti-inflammatory medications can prevent the decay of the brain.

“ASA may generate messengers that are counter-proinflammatory signals and may shed new light on how the brain modulates its response to Alzheimer’s injury.”

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Can ceremony heal the brain?  Before and after MRI show, yes, it absolutely does.

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A sweat lodge gives woman a second chance at life

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An ancient tradition, burning sage is to purify and cleanse.

There are a multitude of cultures as well as benefits for burning sage.

“…white prairie sage…an important traditional remedy for treating anxiety, depression, and mood disorders.”
And:
“noted that evidence for Salvia’s cognitive-enhancing benefits are promising — perhaps to treat dementia and Alzheimer’s disease.”

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Where did the practice originate?

Burning sage - also known as smudging - is an ancient spiritual ritual.

Smudging has been well established as a Native American cultural or tribal practice, although it isn't practiced by all groups.

We have the traditions of many Native American peoples to thank for its use. This includes the Lakota, Chumash, Cahuilla, among others.

Many other cultures around the world share similar rituals.

Read on to learn more about the benefits of burning sage and how you can use it to improve your overall well-being.

The most-used types of sage have antimicrobial properties. This means they keep infectious bacteria, viruses, and fungi at bay.

White prairie sage ( Artemisia ludoviciana) is both antimicrobial and antibacterial. White sage ( Salvia apiana) is also antimicrobial. And both have been shown to repel insects.

Beliefs that burning sage clears out spiritual impurities, pathogens, and even insects have been fundamental to the practice of smudging.

It turns out that sage may help clear the air of lots more than bugs and bacteria.

Though scientifically unproven, burning sage is thought to release negative ions. This is said to help neutralize positive ions.

Common positive ions are allergens like:

If this is the case, burning sage may be a blessing for those with asthma, allergies, bronchitis, and other respiratory conditions. But inhaling the smoke during the smudging can aggravate any respiratory condition. Wait until the smoke clears before going into the room.

Smudging has long been used to connect to the spiritual realm or enhance intuition.

For healers and laypeople in traditional cultures, burning sage is used to achieve a healing state - or to solve or reflect upon spiritual dilemmas.

This may have some scientific basis, too. Certain types of sage, including salvia sages and white prairie sage, contain thujone.

Research shows that thujone is mildly psychoactive. It's actually found in many plants used in cultural spiritual rituals to enhance intuition.

Smudging may also be used as a ritual tool to rid yourself - or your space - of negativity. This includes past traumas, bad experiences, or negative energies from others.

This may help you establish a positive environment for meditation or another ritual. Choosing to sit and let go of negative thoughts in a ritual like this sets your intention and dedication to self-improvement. Choosing to engage in ritual can be the beginning of your change in mindset.

Burning sage creates fragrant smoke central to smudging's benefits. You can use this incense to smudge yourself or specific spaces. Or according to some sources, you can smudge specific objects.

This can be useful with new purchases, gifts, or secondhand items. However, any item can be smudged.

If you have any concern with negative history or energy attached to a new or unfamiliar object, smudging may help bring peace of mind and make the object more sacred to you.

Tradition suggests that smudging can literally lift one's spirits to banish negativity. Some research supports this.

A 2014 study documented white prairie sage (also known as estafiate) as an important traditional remedy for treating anxiety, depression, and mood disorders in certain cultures.

If burning sage can lift one's mood, it could also be a great ally against stress.

A 2016 research project for the University of Mississippi established that white sage ( Salvia apiana) is rich in compounds that activate certain receptors in the brain. These receptors are responsible for elevating mood levels, reducing stress, and even alleviating pain.

Smudging has been traditionally used to safeguard against negativity that could interfere with sleep.

Some research suggests that sage contains compounds that could help ease insomnia.

Classic garden sage ( Salvia officinalis) is sometimes burned like white sage. It's also been used to improve sleep and soothe anxiety.

In addition to dissipating negative energy, improving mood, and strengthening intuition, smudging with sage might improve your memory and focus.

A 2016 review of studies noted that evidence for Salvia 's cognitive-enhancing benefits are promising - perhaps to treat dementia and Alzheimer's disease. Still, more research is needed.

Ridding the body, objects, and spaces of bad energy can help welcome in newer, fresher, and more positive energies. In a way, this could have an energizing effect and help with fatigue.

Some sagelike species closely related to white prairie sage are also used for smudging. Many have documented antifatigue uses.

For some, this may be the best of all benefits: Sage is a lovely incense with a divine aroma, pure and simple.

It also works great as a chemical-free air freshener or odor controller.

The practice of burning sage or smudging is fairly simple, with few necessary tools.

Basic tools include:

a sage bundle (or smudge stick)

some recommend a seashell or bowl of ceramic, clay, or glass to hold burning sage or capture ash

some recommend matches over a manufactured lighter

optional feather or fan for fanning smoke

There are many types of sage usable for smudging. Traditional examples include:

white sage (Salvia apiana)

other Salvia species

white prairie sage or estafiate (Artemisia ludoviciana)

other Artemisia species

To support and respect the cultures that developed the practice, purchase sage from native gatherers, crafters, and artists.

Before burning sage, some recommend setting intentions if smudging for spiritual, energetic, and negativity clearing purposes. Remove animals or people from the room.

It's also important to leave a window open before, during, and after smudging. This allows smoke to escape.

Some believe smoke also takes impurities and negative energy with it - so don't skip this step.

These steps apply whether you're smudging yourself, your home, or an object. You can smudge any of these as often as you'd like.

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1. Light the end of a sage bundle with a match. Blow out quickly if it catches on fire.

2. The tips of the leaves should smolder slowly, releasing thick smoke. Direct this smoke around your body and space with one hand while holding the bundle in the other.

3. Allow the incense to linger on the areas of your body or surroundings you'd like to focus on. Using a fan or feather can also help direct the smoke, though this is optional.

4. Allow the ash to collect in a ceramic bowl or shell.

Smudge your home or living space

In this instance, direct sage smoke over all surfaces and spaces in your home or living area. Be thorough.

Some recommend working in a clockwise direction around your home, ending back where you started, especially for spiritual purposes. Others recommend counterclockwise.

Do what feels best for your situation and follow your intuition.

Smudge an object

Direct smoke around and over the object of your choice.

This can be done to a new item, such as jewelry, furniture, or clothing, to protect or dispel it of negative energy. Items related to negative experiences or memories may also be smudged.

Some people burn sage over special objects, to acknowledge the object with sacred meaning.

Aromatherapy

You can also light and burn sage to improve odor, fragrance, and mood.

Simply waft sage smoke in and around your home. You can place the bundle in a fireproof bowl or burner and allow it to smoke for a while.

Make sure your smudge stick is completely extinguished. You can do this by dabbing the lit end into a small bowl of ash or sand.

Check the end closely to make sure there are no more embers burning. Once it's completely put out, store it in a safe, dry place out of the sun.

When done correctly and respectfully, smudging is completely safe and the effects last after the smoke clears.

Be careful with sage when it's lit. If you aren't careful, burns and even fire is possible. Have water nearby.

Never leave burning sage unattended. Make sure to put your sage bundle out completely after every use.

Setting off smoke alarms is common. Consider this if smudging in a public building.

People with asthma and other respiratory conditions may be more sensitive to the smoke and have adverse reactions.

Always leave a window open while smudging. Inhaling smoke can be hazardous to your health.

Burning sage has many benefits as a spiritual practice. Some research supports certain health benefits of sage, such as antimicrobial properties and enhanced alertness, but more research is needed.

There is very little research on smudging as a practice beyond the cultural practice of the ritual.

Keep in mind: Burning sage is a sacred religious practice in some Native American cultures. Treat the ritual with respect.

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11 Benefits of Burning Sage, How to Get Started, and More

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Burning sage (also known as smudging) is an ancient spiritual ritual. The most-used sage types have antimicrobial properties. Read on to learn more about this benefit and others, the tools you need to get started, when to smudge, and more.

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It is questionable if burning sage is appropriate for those of the Christian faith.  Through exploration, it is compared with incense which is referenced in the bible.

Depending on intention behind the burning of sage, if done with a good heart, it is approved by the church.

“Smudging may have mental health benefits as well. A 2016 study found that white sage has receptor-activating compounds that work with receptors in the brain to elevate mood levels, reduce stress, and even alleviate pain. Some research has shown that sage may be effective against insomnia and anxiety. There is also evidence that it may boost cognition and help with Alzheimer’s and dementia.”
And:
“the intent behind the burning determines the acceptability of the practice.”

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The burning of organic material and incense has been practiced by people all over the world since ancient times. Creating fragrant smoke has been used for spiritual purposes, medicinal purposes, and just to make things smell good for millennia.

Today, some controversy surrounds the subject of burning a particular kind of fragrant herb: sage.

Burning sage, also known as smudging, is used for a variety of purposes. Some of these purposes are occult in nature, while others are for supposed healing properties.

But is this practice acceptable for Christians?

Some Christians are vehemently against burning sage, citing biblical warnings against witchcraft. Others advocate the practice, sometimes pointing to the familiar ritual of the burning of incense in Catholic and Eastern Orthodox churches. Others still are in favor of some aspects of smudging, but not others.

Like many such things, burning sage is not inherently good or bad, as it is neither good nor bad to burn any dried plant. However, the intent behind the burning determines the acceptability of the practice.

Photo Credit: ©GettyImages/karandaev

What Is Sage and Is It in the Bible?

Sage is of the genus Salvia, part of the Lamiaceae family that includes mint. It can be found all over the world, from Salva officinalis, or garden sage, around the Mediterranean, to S alvia apiana, white sage or bee sage, a shrub native to the southwestern United States and northwestern Mexico.

Sage has long been used as an herb in Mediterranean cuisine, used for medicinal purposes, or grown ornamentally. The white sage of the American Southwest is a common, fragrant shrub that has been used for food and ritual practices by many Native American tribes for just as long.

Sage is not specifically mentioned in the Bible, though incense is a common theme. You can read several biblical passages about incense here.

What Is the Purpose and Practice of Burning Sage or Smudging?

Cultures all over the world have practiced the burning of herbs for millennia. Some Native American tribes would burn white sage in a practice that has become known as smudging.

Today, smudging has become popular in the mainstream as well. There are two main reasons people smudge: for spiritual purification, and for health benefits. We will explore each in turn.

It's difficult to give a single explanation of how smudging is used for spiritual purposes, as the practice is diverse. Native American smudging ceremonies might be performed before or after a significant event, before meditation, or to ward off illness. In general, those who smudge for spiritual purposes, whether as an ancient practice, a New Age ritual, or for other reasons, do so to drive out negativity or evil spirits, cleanse the area, and increase healing and positive energy.

Burning sage is also done for medicinal reasons. Sometimes this is mixed with spiritual intentions, but for others, smudging is just part of natural healing methods.

Though studies are inconclusive on the effectiveness of burning sage, it is known to have antimicrobial and antibacterial properties, as well as drive away insects.

Another potential medical benefit, though unproven, is that burning sage can release negative ions, neutralizing positive ions in allergens like pet dander, dust, and mold. Thus, some claim that burning sage is helpful for those with allergies, asthma, and other respiratory issues-as long as the smoke is cleared from the room before the affected person returns.

Smudging may have mental health benefits as well. A 2016 study found that white sage has receptor-activating compounds that work with receptors in the brain to elevate mood levels, reduce stress, and even alleviate pain. Some research has shown that sage may be effective against insomnia and anxiety. There is also evidence that it may boost cognition and help with Alzheimer's and dementia.

Smudging with sage is accomplished by acquiring a sage bundle or smudge stick. The end is lit into a slow smolder, releasing thick smoke. The smoke may be waved with a hand or a feather to direct it. In some cases, when used spiritually, a person will move clockwise (or counterclockwise) around the house, starting at the front door, giving special attention to corners. The smoke may also be directed over a person or object. It can also be left to smolder in a bowl or burner. Ash is caught in a receptacle such as a ceramic bowl or shell.

Why Burning Sage Is Considered an Occult or Witchcraft Ritual

When reading studies that examine this practice only as a natural curative in the vein of using essential oils or taking supplements, burning sage seems innocuous at first glance. However, its other uses are what can make it problematic.

Smudging, though it was believed to have curative properties, was not historically used from a purely medical, scientific standpoint. Like most healing practices until very recent times, it was based on some guesswork, some trial and error, some luck, and some superstition.

We now know sickness is brought by germs, not evil spirits or negative energy, and medicine has advanced accordingly. However, some still perceive smudging as beneficial for ridding themselves of both.

For those that follow New Age ideations, smudging can be used to purge their "auras" of negative energy or a space of bad vibes. Sometimes, smudging can be used in a ritualistic fashion to bless certain body parts, for example to open one's ears or eyes to the spirit world. The smoke is supposed to attract good energy and drive out bad energy or evil spirits. Smudging may even be used on objects to purge them of the past.

Vibes, auras, and energy aren't biblical ideas. Nor is the idea that smoke can drive out evil spirits. Anything having to do with the spiritual realm that is not approached from the basis of trusting in Jesus Christ is dangerous.

Are There Christian Ways to Use Sage for Healing or Cleansing?

We can't chase off Satan with some fragrant smoke. The Bible is clear that God is the one that protects us from evil ( 2 Thessalonians 3:3). The Bible also teaches us that the world isn't ruled by capricious "energies," but rather by our Father God, in whom we can trust ( Psalm 89:11).

Smoke does not cleanse our "aura," or our soul. We are cleansed by the blood of Christ alone ( Ephesians 1:7). Sage will not save us.

We don't need pagan rituals to help us connect to God or experience spiritual growth. Witchcraft, pagan rituals, and sorcery are called an "abomination" and "detestable" by God in the Bible ( Deuteronomy 10:9-13). He strictly prohibits His people from engaging.

On the other hand, there is nothing inherently bad about burning a nice-smelling plant. It's also possible, though not proven, that sage may have some health benefits.

Sage should not be used for spiritual purposes. However, it is permissible for Christians to use the plant God created to enjoy its scent.

Photo Credit:©GettyImages/fotomem

Biblical Practices with Herbs

Herbs and incense are frequently used positively in the Bible. Two of the three gifts from the wise men to Jesus were used for incense: frankincense and myrrh. Among other uses, myrrh was an ingredient in the anointing oil used in the Temple. Frankincense was frequently used as incense burned for worship before the Lord, directly commanded by God in Exodus 30.

Our prayers to the Lord are often compared to incense (e.g. Revelation 8:3-5, Psalm 141:2, Acts 10:4). Herbs, spices, and incense are mentioned frequently in the Bible, from Jesus' parable of the mustard seed ( Matthew 13:31-32) to the hyssop used to sprinkle blood on the doorframes of Hebrew homes to protect them during the tenth plague ( Exodus 12).

The Bible does not demonstrate anywhere that God hates herbs, spices, and incense, and they are in fact sometimes used in the Temple to worship Him. However, these uses were carefully regulated and instated by God Himself.

Clearing Up the Confusion around Burning Sage

Burning sage is not inherently bad. The Bible does not mention sage, but other herbs and spices were used for food, incense, perfume, and even worship.

However, putting our trust in a ritual to save us, heal us, or drive out evil is foolhardy and contrary to God's will. Instead, we are to put our trust in Him and His power to drive out sin and evil.

Sage might have healing properties. Some people may find that it smells nice. There is no harm in these things specifically, taken separately from occult practice.

However, it is important to remember Paul's words in 1 Corinthians 10:23: "'I have the right to do anything,' you say-but not everything is beneficial. 'I have the right to do anything'-but not everything is constructive."

Just because we can do something doesn't necessarily mean that we should. Just because something is not w rong doesn't mean it is good.

Burning sage may not have any occult ties for you. It may feel no different than lighting a candle. As you exercise your freedom to do this, let us recall Paul's words, "Be careful, however, that the exercise of your rights does not become a stumbling block to the weak" ( 1 Corinthians 8:9). Let us be cognizant of the feelings and struggles of other believers and act in ways that are uplifting and urge one another forward toward Christ.

At the end of the day, the Lord knows our hearts. May we proceed with honoring Him as our foremost goal.

Photo Credit: ©GettyImages/RobertPetrovic

Alyssa Roat studied writing, theology, and the Bible at Taylor University. She is a literary agent at C.Y.L.E., the publicity manager at Mountain Brook Ink, and a freelance editor with Sherpa Editing Services. She is the co-author of and has 200+ bylines in publications ranging from The Christian Communicator to Keys for Kids. Find out more about her here and on social media @alyssawrote.

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Is Burning Sage a Biblical Practice or Witchcraft?

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Sage might have healing properties and smell nice. There is no harm in these things separate from the occult practice of burning sage to cleanse people or places of evil. However, 1 Corinthians 10:23 reminds us, "'I have the right to do anything,'...