Aspirin

• 1. Introduction

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  Every year, people swallow an estimated 40000 tonne of aspirin, somewhere between 50 and 120 billion pills. In the United States alone, doctors wrote more than 14 million prescriptions for it in 2023, which made it the 46th most commonly prescribed medicine there. The World Health Organization lists it among its Essential Medicines. In most countries, anyone can buy it without a prescription, under a brand name or as a plain generic tablet. Yet the small white pill in the medicine cabinet is stranger than it looks. Where did a drug this common come from, and how did its name end up belonging to almost everyone? How can one small molecule ease a headache, thin the blood, and keep researchers arguing for decades? And why do doctors now disagree about whether healthy people should take it at all?

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• 2. Willow Bark Beginnings

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  Clay tablets from ancient Sumer and the Ebers Papyrus of ancient Egypt both record medicines made from willow and other plants rich in salicylates. Around 400 BC, Hippocrates described a salicylic tea for bringing down fevers. Willow bark preparations then stayed in the medical tradition of classical antiquity and the Middle Ages. The key ingredient is salicin, a compound in willow bark that the human gut converts into salicylic acid. People have used it for its health effects for at least 2,400 years.

  The mid-eighteenth century brought a sharper idea in Chipping Norton, Oxfordshire. The Reverend Edward Stone noticed that willow bark tasted bitter, just like the bark of the cinchona tree. That bark was called Peruvian bark, because it had been used successfully in Peru against a range of ailments. Stone reasoned that a similar taste might mean a similar power. He tried powdered willow bark on people in Chipping Norton for five years and found it as effective as Peruvian bark, and a cheaper domestic version. In 1763, he sent a report of his findings to the Royal Society in London.

  By the nineteenth century, pharmacists were experimenting with and prescribing a variety of chemicals related to salicylic acid, the active component of willow extract. Pharmacology, in short, was now looking for a synthetic alternative to the bark.

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• 3. Bayer and the Name

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  In 1853, the chemist Charles Frédéric Gerhardt treated sodium salicylate with acetyl chloride and produced acetylsalicylic acid for the first time. Over the following fifty years, other chemists, mostly at the German company Bayer, worked out its chemical structure and devised more efficient ways to make it.

  An earlier discovery supplied the drug's name. In 1839, salicylic acid had been extracted from the herb meadowsweet, whose German name is Spirsäure.

  Bayer, a firm that made both drugs and dyes, began studying acetylsalicylic acid in 1897 as a less irritating replacement for the standard salicylate medicines. The company's scientists also identified a new way to synthesize it. That year, Felix Hoffmann, or perhaps Arthur Eichengrün, was the first to produce it in a pure, stable form. By 1899, Bayer had dubbed the drug Aspirin and was selling it around the world. The word blends the prefix a(cetyl), the spir from Spirsäure, and the ending -in, a common drug suffix of the late nineteenth century.

  Between 1918 and 1921, Bayer lost its trademark for the name in the United States and some other countries. The company had failed to use the name correctly for its own product. For years it had also allowed other manufacturers to use it without defending its rights. In many countries, aspirin is now a generic term. With a capital A, it remains a registered Bayer trademark in Germany, Canada, Mexico, and over 80 other countries, sold in different packaging in each market.

  Popularity grew over the first half of the twentieth century and brought fierce competition among brands and formulations. Then acetaminophen, also called paracetamol, arrived in 1956 and ibuprofen in 1962, and aspirin's popularity declined. Sales revived considerably in the final decades of the century and remain strong today, driven by its use in preventing heart attacks and strokes. Just as rivals were pushing it aside, researchers in London were about to explain how it actually worked.

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• 4. How It Works

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  In 1971, the British pharmacologist John Robert Vane, then employed by the Royal College of Surgeons in London, showed that aspirin suppresses the production of prostaglandins and thromboxanes. He won the 1982 Nobel Prize in Physiology or Medicine for the discovery, sharing it with Sune Bergström and Bengt Ingemar Samuelsson.

  Prostaglandins are a type of hormone with diverse jobs. They carry pain information to the brain, adjust the thermostat in the hypothalamus, and drive inflammation. Thromboxanes make platelets clump together to form blood clots. Aspirin cuts off both at the source by disabling an enzyme called cyclooxygenase, or COX. It does this by attaching an acetyl group to a serine residue in the enzyme's active site. The damage is permanent, which sets aspirin apart from other anti-inflammatory drugs such as diclofenac and ibuprofen, whose blocking can be reversed.

  Platelets live only 8-9 days, and they cannot build replacement enzymes. A low dose of aspirin therefore blocks thromboxane A2 in a platelet for the rest of its life. A mere 40 mg a day inhibits a large proportion of the maximum thromboxane A2 release. That is why aspirin helps people who have already had a heart attack, unstable angina, an ischemic stroke, or a transient ischemic attack.

  The enzyme comes in at least two forms, COX-1 and COX-2. Aspirin irreversibly inhibits COX-1 and modifies COX-2, which normally makes mostly proinflammatory compounds. Aspirin-modified COX-2 makes epi-lipoxins, most of which are anti-inflammatory. Newer drugs called coxibs were designed to block only COX-2, hoping to spare the stomach. Several of them, including rofecoxib, sold as Vioxx, were withdrawn after evidence that they raise the risk of heart attack and stroke. The proposed reason is that blocking COX-2 in the cells lining small blood vessels lowers prostacyclin, a clot-fighting compound, while platelet COX-1 keeps making thromboxane.

  High doses add a twist. Aspirin can uncouple oxidative phosphorylation in mitochondria, releasing heat, so very large amounts may cause fever instead of curing it. In 2012, researchers found that salicylic acid activates AMP-activated protein kinase, an enzyme that may explain further effects. The acetyl group also modifies other cellular proteins, and those reactions may account for effects that were previously unexplained.

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• 5. The Heart Question

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  Adult aspirin tablets come in standardised sizes, 300 mg in Britain and 325 mg in the United States, with smaller doses of 75 mg and 81 mg based on them. The 81 mg tablet is called baby aspirin, even though it is no longer meant for infants or children. The dose that works appears to depend on body weight. For people under 70 kg, a low dose is effective against cardiovascular disease, while heavier patients seem to need more.

  The evidence is strongest for people who have already had a cardiac event. The ISIS-2 trial found that 160 mg daily for one month cut mortality by 21% among people with a suspected heart attack, measured over the first five weeks. The 2009 Antithrombotic Trialists' Collaboration, published in The Lancet, found that daily low-dose aspirin brought a 19% relative reduction in serious cardiovascular events in people with a prior ischaemic stroke or heart attack. The price was a 0.19% absolute increase in gastrointestinal bleeding, and the benefits outweighed that hazard. After a coronary artery stent, a US Agency for Healthcare Research and Quality guideline recommends aspirin indefinitely. It is often paired with a second antiplatelet drug such as clopidogrel, prasugrel, or ticagrelor.

  The picture for healthy people is murkier. The ASCEND study followed diabetics with no prior cardiovascular disease for 7.4 years. Low-dose aspirin cut serious vascular events by 12% but raised gastrointestinal bleeding by 29%, so there was no overall clinical benefit. The ARRIVE study found no benefit for people at moderate risk over 5 years. In April 2022, the United States Preventive Services Task Force advised that adults aged 40 to 59 with a 10% or greater 10-year cardiovascular risk should decide with a clinician, since the net benefit is small. For adults 60 or older, it recommended against starting aspirin to prevent a first heart attack or stroke.

  The early evidence had its own flaw. Large studies of low-dose aspirin published in the 1970s and 1980s included only men, yet people drew general conclusions that did not hold true for women. Those studies helped spur reform in clinical research ethics, in guidelines for research on human subjects, and in US federal law. The WHI study of postmenopausal women later reported a 25% lower risk of cardiovascular death. The 2021 ADAPTABLE study then found no significant difference in cardiovascular events or major bleeding between 81 mg and 325 mg doses.

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• 6. Beyond the Heart

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  For colorectal cancer, the evidence for aspirin is substantial, but the benefit shows up only after taking it for at least 10-20 years. A meta-analysis through 2019 linked aspirin use to a lower risk of cancers of the colorectum, esophagus, and stomach. The United States Preventive Services Task Force recommended against aspirin for colorectal cancer prevention in average-risk people in 2007. Nine years later it issued a grade B recommendation for low-dose aspirin, 75 to 100 mg a day, for adults aged 50 to 59 who met several conditions, including a 10% or greater 10-year cardiovascular risk. In 2021, the same body raised new questions, noting that in the 2018 ASPREE trial, cancer-related death was higher in the aspirin group than in the placebo group.

  In 2025, scientists at the University of Cambridge reported that aspirin stimulates the immune system to reduce cancer metastasis. A protein called ARHGEF1 suppresses the T cells that attack metastatic cancer cells. Aspirin appeared to counter this by targeting thromboxane A2, the clotting factor that activates ARHGEF1. The researchers called it a "Eureka moment". An earlier experiment by Gasic and co-workers had shown that mice given aspirin in their drinking water developed far fewer lung metastases. The Cambridge team stressed that people should not self-medicate with aspirin for this purpose until clinical trials are held.

  A 2022 systematic review pooled three studies and concluded that aspirin exposure reduced the risk of depression. Reviewers still say that longer, double-blind randomized trials are needed to show whether aspirin helps in bipolar depression. Cohort studies suggested low-dose aspirin might reduce dementia, but numerous randomized controlled trials have not confirmed it.

  Some uses are older and narrower. Aspirin is a first-line treatment for the fever and joint pain of acute rheumatic fever, usually for one to two weeks. Kawasaki disease remains one of the few indications for aspirin in children, despite a lack of high-quality evidence. Low-dose aspirin also has moderate benefits in preventing pre-eclampsia, and the benefit is greater when it is started in early pregnancy. In tuberculous meningitis, adding aspirin reduced the risk of new cerebral infarction. There are even anecdotal reports that aspirin helps plants grow and resist stress, though most research has used salicylic acid instead.

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• 7. The Costs

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  Between 1981 and 1997, 1207 cases of Reye syndrome in people younger than 18 were reported to the US Centers for Disease Control and Prevention. The illness, which brings acute encephalopathy and fatty liver, is rare but severe. Of those patients, 93% had been ill in the three weeks before, most often with a respiratory infection, chickenpox, or diarrhea. Salicylates were detectable in 81.9% of the children whose test results were reported. In 1986, the US Food and Drug Administration required warnings on aspirin-containing medicines against use in children and teenagers. Use by children then fell considerably in the United States, as did reported cases, and the United Kingdom saw a similar decline after its own warnings. The UK National Health Service says children under 16 should not be given aspirin except on a doctor's advice.

  The stomach takes the most common damage. Aspirin raises the risk of upper gastrointestinal bleeding, and drinking alcohol, taking other anti-inflammatory drugs, or taking warfarin or clopidogrel raises it further. Manufacturers have tried several fixes. Enteric coating, which delays release until the small intestine, does not reduce bleeding and may make aspirin less effective at preventing clots. Buffering agents show no clear advantage either, though Bufferin uses magnesium oxide and Alka-Seltzer uses sodium bicarbonate. Vitamin C is more promising, since aspirin combined with vitamin C caused less stomach damage in trials.

  Overdose is far more dangerous than a normal dose. Acute poisoning, from a single large dose, has a mortality rate of 2%. Chronic poisoning, from higher than normal doses over time, is more commonly lethal, with a mortality rate of 25%. High doses of salicylate can also cause temporary ringing in the ears. Animals are at risk too. Cats metabolize aspirin slowly because they lack the glucuronide conjugates that help excrete it, so the recommended veterinary dose is 10 mg/kg only every 48 hours.

  Not everyone gets the same effect from a tablet. A study of 2,930 people found 28% were resistant to aspirin's effect on platelets. In a study of 100 Italian people, 31% appeared resistant, yet only 5% truly were, and the rest had not taken the drug as directed. Among 400 healthy volunteers, no one was truly resistant, but some showed what the researchers called "pseudoresistance, reflecting delayed and reduced drug absorption".

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• 8. Chemistry and Crystals

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  Factories that make aspirin tablets share a hazard with flour mills, because airborne powder mixed with air can explode. The United States National Institute for Occupational Safety and Health recommends an exposure limit of 5 mg/m3 as a time-weighted average. In 1989, the Occupational Safety and Health Administration set a legal limit at the same figure, but the AFL-CIO v. OSHA decision vacated it in 1993.

  Students meet the drug in laboratories, because the standard way to make it is commonly demonstrated in undergraduate courses. Salicylic acid is treated with acetic anhydride, which turns a hydroxyl group into an ester group and leaves acetic acid as a byproduct. A little sulfuric acid, and occasionally phosphoric acid, acts as the catalyst. Using acetic acid instead is possible, but the reaction is reversible and water breaks the product down again. That is why an anhydrous reagent is preferred.

  The same water problem explains a smell. Strong aspirin preparations often smell of vinegar, because moisture slowly splits the molecule back into salicylic and acetic acids. In its pure form, aspirin is a white, crystalline, weakly acidic substance. It melts at 136 C and decomposes around 140 C.

  For most of its history, chemists knew only one crystal form of aspirin, called form I. A 1981 report noted weak extra peaks in its diffraction pattern, but they were dismissed as impurity. Looking back, that was form II. It was properly reported in 2005, after an attempt to co-crystallize aspirin with levetiracetam from hot acetonitrile. Form III followed in 2015, made by compressing form I above 2 GPa, but it reverts to form I once the pressure is released. Form IV was reported in 2017 and is stable at ambient conditions, so the crystal structure of this familiar tablet was still being revised in the 2010s.

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