This story has a surprise ending, so stick around for it. The following is a doctor’s explanation of how aspirin works. I’m leaving out the pictures of molecule chains because you won’t understand those without a chemistry degree anyway. Following this story is a pathologist’s short (albeit heavy in technical words) explanation of why it works. That is followed by my one-liner plain language version.

How Aspirin Works

by Lucas Hoffman, MD, PhD

Aspirin is a member of a family of chemicals called salicylates. These chemicals have been known to people interested in medicine for centuries.

One of the first and most influential physicians, Hippocrates, wrote about a bitter powder extracted from willow bark that could ease aches and pains and reduce fevers as long ago as the fifth century BCE. In the 1700s, the scientist Reverend Edmund Stone wrote about the success of the bark of the Willow in the cure of the “agues,” or fevers with aches. With a bit of chemical detective work, scientists found out that the part of willow bark that was (1) bitter and (2) good for fever and pain is a chemical known as salicin.

This chemical can be converted (changed) by the body after it is eaten into another chemical, salicylic acid. It was a pharmacist known as Leroux who showed, in 1829, that salicin is this active willow ingredient, and for many years it, salicylic acid (made from salicin for the first time by Italian chemist Piria), and close relatives, were used at high doses to treat pain and swelling in diseases like arthritis and to treat fever in illnesses like influenza.

The problem with these chemicals was that they upset the user’s stomach fairly badly. In fact, some people had bleeding in their digestive tracts from the high doses of these chemicals needed to control pain and swelling. One of these people was a German man named Hoffmann. His arthritis was pretty bad, but he just couldn’t “stomach” his salicylic acid. Enter this man’s son, German chemist Felix Hoffmann, who worked for a chemical company known as Friedrich Bayer & Co. Felix wanted to find a chemical that wouldn’t be so hard on his dad’s stomach lining. Reasoning that salicylic acid might be irritating because it is an acid, he put the compound through a couple of chemical reactions that covered up one of the acidic parts with an acetyl group, converting it to acetylsalicylic acid (ASA). He found that ASA not only could reduce fever and relieve pain and swelling, but he believed it was better for the stomach and worked even better than salicylic acid.

Unfortunately, Hoffmann had to wait for fame. He finished his initial studies in 1897, and his employers didn’t pay much attention to it because it was new and they were cautious – they didn’t think it had been tested enough. By 1899, though, one of Bayer’s top chemists, a scientist named Dreser, had finished demonstrating the usefulness of the potent new medicine and even gave it a new name: Aspirin. It is believed that the name comes from a plant relative of a rose that makes salicylic acid (several plants make this compound, not just the willow). The Bayer company could then support the tested medicine; they spread the word and marketed the new pill widely.

Over the next hundred years, this medicine would fall in and out of favor, at least two new families of medicines would be derived from it, and innumerable research articles would be published about aspirin. Thousands have been published in the past five years alone! One of the most important pieces of research about aspirin came in the early 1970s, when a British scientist named John Vane and his colleagues showed how aspirin works. His work was so important that he and his colleagues were awarded the Nobel Prize in Medicine in 1982. Dr. Vane was even made a British knight for his work!

What is a Headache?

No one completely understands exactly how pain works. Actually, a lot is known about pain, but the more we find out, the more questions arise. So let’s take a simplified view.

Pain is really something you feel in your brain. For example, let’s say you hit your finger with a hammer (please don’t try this at home). The part of your finger that is damaged has nerve endings in it – these are little detectors in your joints and your skin that feel things like heat, vibration, light touch from things like the mouse you’re holding, and, of course, big crushing shocks like being hit with a hammer. There are different receptors for each of these types of sensations. The damaged tissue in your finger also releases some chemicals that make those nerve endings register the crushing shock even stronger – like turning up the volume on your stereo so you can hear it better. Some of these chemicals are prostaglandins,*1 and working cells in the damaged tissues make these chemicals using an enzyme called cyclooxygenase 2 (COX-2).

Note 1: Prostaglandins are fatty acids that are manufactured by nearly every cell in the human body. These acids serve many biological functions. In particular, a certain prostaglandin known as PGE2 increases the sensitivity of pain receptors and produces discomfort, inflammation, fever and irritation in areas of the body that are injured and/or not functioning properly. PGE2 is also known to constrict blood vessels, which is one of the most common causes of a headache. So aspirin works peripherally, or directly at the source of pain or discomfort, rather than centrally in the brain like morphine does.

Because of the prostaglandins, the nerve endings that are involved now send a strong signal through nerves in your hand, then through your arm, up your neck and into your brain, where your mind decides this signal means, “HEY! PAIN!” The prostaglandins seem to contribute just a portion of the total signal that means pain, but this portion is an important one. In addition, prostaglandins not only help you to feel the pain of the damaged finger, but they also cause the finger to swell up (this is called inflammation) to bathe the tissues in fluid from your blood that will protect it and help it to heal. Remember this is a simplified version of the pain story; lots of chemicals seem to be involved in this process, not just prostaglandins.

This pathway works very well as far as telling you that your finger is hurt. The pain serves a purpose here: It reminds you that your finger is damaged and that you need to be careful with it and not use it until it’s healed. The problem is that, sometimes, things hurt without the hammer or for any other good reason (that you can think of). For example, sometimes you get a headache, probably because your scalp and neck muscles are contracted from stress or because a blood vessel in your brain has a spasm. Many people have arthritis, which is swelling and pain in the joints such as the knuckles or knees, and this problem can not only make people uncomfortable, it can damage the joints permanently. And many women have pain in their abdomens during their periods, usually known as cramps, for no known useful reason. These processes appear to involve prostaglandins as well.

What Does Aspirin Do?

Aspirin helps these problems by stopping cells from making prostaglandins. Remember the enzyme, COX-2? It is a protein, made by your body’s cells, whose job is to take chemicals floating around in your tissues and turn them into prostaglandins.

COX-2 can be found in lots of normal tissues, but much more of it is made in tissue that has been damaged in some way. Aspirin, it turns out, sticks to COX-2 and won’t let it do its job; it’s like a lock you put on your bicycle. The bicycle won’t move with the lock on, and COX-2 can’t work with aspirin stuck in it. So by taking aspirin, you don’t stop the problem that’s causing the pain, like the tight muscles in your scalp, or the cramping in your abdomen, or the hammer-damaged finger. But it does “lower the volume” on the pain signals getting through your nerves to your brain.

One common question about aspirin and other medicines is, “How does it know how to get to where the pain is?” The answer is that it doesn’t! When you take aspirin, it dissolves in your stomach or the next part of the digestive tract, the small intestine, and your body absorbs it there. Then it goes into the bloodstream and it goes through your entire body. Although it is everywhere, it only works where there are prostaglandins being made, which includes the area where it hurts.

You may ask, “How come I have to keep taking aspirin if it works so well?” As with almost all chemicals, your body has ways of getting rid of aspirin. In this case, your liver, stomach, and other organs change aspirin to... surprise! Salicylic acid! This chemical then slowly gets changed a bit more by the liver, which sticks other chemicals onto the salicylic acid so that your kidneys can filter it out of your blood and send it out in your urine. This whole process takes about four to six hours, so you need to take another pill at that time to keep the effect going.

The problem with the fact that aspirin goes through your entire bloodstream is that your body needs prostaglandins for some reasons. One place they are useful is in the stomach; it turns out another enzyme called COX-1 makes a prostaglandin that seems to keep your stomach lining nice and thick. Aspirin also keeps COX-1 from working (it keeps most prostaglandins from being made equally well – it’s “nonselective”), so your stomach lining gets thin, allowing the digestive juice inside to irritate it. This is probably the biggest reason why aspirin and its relatives upset stomachs (not only because it’s an acid, as Hoffmann had thought).

COX-2 also works in some normal tissues like the brain and kidney. At normal amounts, one dose of aspirin probably doesn’t affect these areas much. And there are other places in the body where prostaglandins have a job in normal tissues, such as the blood.

Does it Have Side Effects?

Just like all medicines, aspirin isn’t all good. It has some effects on the body that you and your doctor don’t want (side effects). Some of them have already been mentioned; for example, if you hit your finger with a hammer and it’s bleeding, an aspirin may help the pain and swelling, but the wound may take longer to clot and stop bleeding (aspirin is a blood thinner). Also, it can be very upsetting to the stomach, especially at the high doses often used in arthritis.

Aspirin also isn’t used as much for fevers in children because research has suggested that aspirin given to kids with flu, chickenpox, or other viral sicknesses may cause a potentially deadly problem called Reye syndrome. (See, I told you doctors still think chickenpox is viral)

Aspirin also changes the way your kidneys make urine, can cause some people to have trouble breathing (rarely), and can be dangerous at very high doses.

For these reasons, chemists have found other chemicals closely related to aspirin that have some of its good effects and lack some of its bad effects. For example, ibuprofen and naproxen (e.g., Motrin and Naprosyn, respectively) also treat pain, swelling and fever, but they seem to have less of an effect on platelets than aspirin does. These medicines are called the non-steroidal anti-inflammatory drugs (NSAIDs) because they decrease swelling but they aren’t steroids, which are the most potent anti-inflammatory chemicals we have. Another family of medicines related to aspirin includes acetaminophen (e.g., Tylenol), which decreases fevers and pain, but it doesn’t affect either swelling or your stomach as much as the true NSAIDs do. (Check the side effects of ibuprofen, naproxen, and acetaminophen before jumping to the conclusion that they are truly better than aspirin.)

Felix Hoffmann was sure that aspirin would make a good drug for arthritis. But as he struggled to prove it to his cautious employer, how could he have known it would save lives, and in so many ways? So the next time you get out the hammer, think of Felix and set aside an aspirin or two. He deserves the tribute, and it’s best to be prepared for hitting the wrong nail.

Why Aspirin Works

from Infect Immun. 2005 Aug; 73(8): 4548-59

Department of Plant Pathology, University of Wisconsin-Madison, Madison, WI 53706, USA

Oxylipins comprise a family of oxygenated fatty acid-derived signaling molecules that initiate critical biological activities in animals, plants, and fungi. Mammalian oxylipins, including the prostaglandins (PGs), mediate many immune and inflammation responses in animals. PG production by pathogenic microbes is theorized to play a role in pathogenesis. We have genetically characterized three Aspergillus genes, ppoA, ppoB, and ppoC, encoding fatty acid oxygenases similar in sequence to specific mammalian prostaglandin synthases, the cyclooxygenases. Enzyme-linked immunosorbent assay analysis showed that production of PG species is decreased in both Aspergillus nidulans and A. fumigatus ppo mutants, implicating ppo activity in generating PGs. The A. fumigatus triple-ppo-silenced mutant was hypervirulent in the invasive pulmonary aspergillosis murine model system and showed increased tolerance to H2O2 stress relative to that of the wild type. We propose that ppo products, PG, and/or other oxylipins may serve as activators of mammalian immune responses contributing to enhanced resistance to opportunistic fungi and as factors that modulate fungal development contributing to resistance to host defenses.

That heavy paragraph merely says that fungi make the cyclooxygenase, (COX), which aspirin inhibits (being a COX-2 inhibitor as the first article stated), so basically the answer to the previous four pages is that aspirin kills fungi, which, in the case of arthritis, was the cause of the pain in the first place.

Tree Burls

Below is a picture of a burl cut off of a tree. To the woodworker, these things are pretty much in the same category as exotic woods. When cross-cut, they have beautiful grains with swirls and they are often as dense as hardwoods (e.g., Oak), even if they came from a softwood tree (e.g., Pine, Fir, Spruce).

Below is a picture of a spruce tree that has been cross-cut and it had five huge burls all at the same height. The actual tree trunk is that small circle in the middle of this picture, so you can see that the burls themselves grew outrageously in size compared to the main body of the tree itself.

So what, exactly, is a burl?

“They are basically tree tumors. They occur when a twig bud fails to grow normally, differentiating into the tissues needed for forming a limb, and instead just multiplies and multiplies and multiplies its bud cells. That’s how you get the round growth with an irregular grain structure.

“Many burls will sprout when placed into water, forming normal-looking shoots. Apparently the water saturation somehow helps them “remember” that they are, after all, limb buds.”

– Richard Barrans Jr., Ph.D.

There is enough similarity between the growth of burls on spruce trees and the occurrence of some cancer in humans that the two could be different manifestations of the same phenomenon.

Every spruce burl that I have seen cut shows highly ordered structure in the region of abnormal growth. These are not really cells gone wild; instead, they are just growing at a very fast rate under the same rules that govern the structuring in the normally growing tissue. This type of growth also is typical of some animal cancers.

When several burls grow on a single spruce tree, it is likely that they all began growing at the same time. Evidence for this simultaneity is seen when annual rings in the tree and its burls are counted to determine which year each burl began. So seems that whatever agent controls the abnormal growth is spread throughout that tree in a single year. And there has to be some mechanism that determines where on the tree burls will grow.

Trees that develop burls often tend to be undergoing environmental stress. Trees near the timberline (the altitude on a mountain above which trees cannot prosper) or on the north slopes, where living is tougher, are prone to burl growth. The analogy of smoking cigarettes in relation to lung cancer is extremely similar. (Remember, cigarette tobacco is full of mycotoxins.)

If this suggestion is correct, that there is similarity between the occurrence of burls and cancer, then research into what causes burls in northern spruce trees might advance human cancer research. The simpler structure of trees, compared to animals, might more quickly yield information on deviant growth processes that could then be applied to the understanding and control of human cancer.

Do you see where this is going? We already know quite a lot about what causes this “tree cancer.” It is that some microorganism got into the cells of the tree and broke the DNA, causing runaway growth. That is the same definition as cancer in humans. And we also notice that those trees that have cancerous growths, whether in the form of burls, bundled leaf overgrowth (rather like mistletoe sacs), or ridges next to scarred cuts on living trees (see picture below), also have a great deal of mold on them and near them. Is there a connection?

The fungus Leucostona kunzei (Cytospora kunzei variety picea) causes Cytospora canker, a stem disease.

There are more than 1,200 species in the genera Cercospora and these fungi attack a wide range of plants. Cercospora sequoiae juniperi attacks juniper trees and juniper shrubs. Most selections of Eastern Red Cedar and Chinese Juniper have good resistance to this disease. However, Rocky Mountain Juniper is known to be one of the most susceptible juniper species. This disease can also attack the Oriental Arborvitae.

It is, without question, caused by these fungi. And we also know that some forms of fungi also break into human cells and alter the DNA. How long will doctors continue to deny that there is a serious connection between fungi and human diseases? Yeah, you and I both know the answer to that one, don’t we? As long as the money points in another direction, so will the research. Sigh…

Quotes and Commentary

“Mycotoxins cause oxidative damage.” – Toxicol Appl Pharmacol 2003 Sep 15 191(3) 255-63

Hmm… any wonder that antifungal plants or medicines are also antioxidants?

What exactly is oxidative damage? Oxidative damage in our bodies is the result of oxidation, which is the reaction of oxygen (and products of oxygen) with other molecules. Two of the most familiar examples of oxidation are the rusting of untreated metals (the paint gets scratched on your car and suddenly there is rust there) and the browning of an apple when exposed to air (sitting out on your countertop for a couple weeks).

“Increased production of reactive oxygen species is a feature of most, if not all, human disease, including cardiovascular disease and cancer. Dietary antioxidants may be especially important in protecting against human diseases associated with free radical damage to cellular DNA, lipids, and proteins. - Jacob RA; Burri BJ American Journal of Clinical Nutrition, 1996 Jun, 63(6):985S-990S

So, mycotoxins are again scratching our cells and oxygen started breaking down those cells.

“Fungi produce oxalic acid.” – Natural Toxicants in Feed, Forages and Poisonous Plants, 1998

Oxalic acid is nasty stuff. It is a poison to your bodily systems, in spite of what some stupid people are saying in advertisements trying to sell you mushroom tea as a cure-all. Those teas, while tolerable in doses of less than eight fluid ounces per day, can be deadly in larger doses. This is rather like eating a small amount of arsenic every day in hopes that you will build up a tolerance or resistance to it. Why eat such poison at all? Of course, a flu vaccine is also a small dose of the flu, yet doctors love giving those shots to people…

Oxalic acid (AKA ethanedioic acid), HO2CCO2H, is a colorless, crystalline organic carboxylic acid that melts at 189°C with sublimation. Oxalic acid and oxalate salts are poisonous. Oxalic acid is found in many plants (e.g., sorrel and rhubarb), usually as calcium or potassium salts. Oxalic acid is the only possible compound in which two carboxyl groups are joined directly. For this reason, oxalic acid is one of the strongest organic acids. Unlike other carboxylic acids (except formic acid), it is readily oxidized, which makes it useful as a reducing agent for photography, bleaching, and ink removal. In other words, we use this as an industrial cleaner.

Your body hates oxalic acid so much that when it detects it, usually in one of the filtering organs (kidneys or liver), your body will throw all the calcium it can at the acid in an attempt to bind it so it can be flushed rather than continue circulating through your system. Let’s see… what was it Lannie said in her article about kidney stones? Yes, calcium and oxalic acid make stones. I am sure your body intended to flush these stones, but sometimes they get too big to flush and are stuck in the kidneys or the ureter (exit from kidney) or the gall bladder (exit from liver).

And we get this oxalic acid from where again? Oh yeah, fungi… Are you sure you want to eat those whole grain breads, pastas, potatoes, cereal, and popcorn? Or the corn syrup sweetener in your soda pop?

Please stop poisoning yourself. I’d like all of you to stay around for a few more years.