Salicylic acid and its derivatives/metabolites have so many benefits, yet many people have been fearmongered of some “side effects” that aspirin is thought to cause.

In this article series I’m reviewing those side effects, look at the evidence and see if it’s real or not. I’ll be addressing:

• Intestinal bleeding and bleeding risk in general
• Mitochondrial dysfunction
• Metabolic alkalosis
• Reye’s syndrome

Here we go…

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In 1828, the active ingredient salicin (SA derivative) of the willow tree was isolated which is known to be converted to salicylic acid upon ingestion. Another natural salicylate, called methyl salicylate (MeSA), is found in wintergreen, birch tree, mango, meadowsweet, guelder-rose, and is used as analgesic medicine (for joint and muscular pain) and fragrance.

In 1897, Felix Hoffman, a German chemist working for the Bayer company, was able to modify salicylic acid to create acetylsalicylic acid, which was named aspirin. Before aspirin was made, sodium salicylate was used by arthritic patients to keep inflammation at bay. After aspirin was made, many switched to aspirin because they thought it had higher efficiency, which turned out to not be the case.

Before other NSAIDs were made, most people used aspirin in small and large doses for all kinds of ailments. After other NSAIDs were made, such as paracetamol, massive campaigns were launched to fearmonger aspirin to promote paracetamol sales.

Because of many unfound concerns about aspirin, I decided to create this article to put things straight.

Let’s dive right in.

Intestinal bleeding

One of the most common fears with aspirin is the risk of intestinal bleeding (or just too much blood thinning).

Aspirin is thought to cause intestinal bleeding through inhibition of COX as well as lowering glycine in the intestine (the last one is more of speculation). For the latter reason, many aspirin supplements in Russia for example combine aspirin with glycine in a 1:1 ratio.

Sodium salicylate, which isn’t a very strong COX inhibitor, doesn’t cause intestinal bleeding and actually has gastroprotective effects against other NSAIDs, ethanol or toxins (R). “In experimental animals, sodium salicylate not only lacks ulcerogenicity (Glenn et al., 1979; Whittle et al., 1980), but
can even prevent gastric mucosal damage induced by various stimuli such as indomethacin, aspirin, or ethanol” (R).

Although sodium salicylate is still slightly gut-irritating, it doesn’t cause bleeding or at least only in very few of the patients that take it. In fact, doses of 1.5-2g x2 daily of salicylate are safe on the gut and don’t cause bleeding (R).

Buffered, soluble forms of acetylsalicylates caused gastrointestinal bleeding in more than 50% of patients. However, enteric-coated and intravenous forms resulted in significantly less gastrointestinal bleeding (R).

But don’t envision vicious bleeding, rather think about temporary micro bleeding.

This temporary micro bleeding actually has benefits believe it or not. “…progressive iron loss from mucosal microbleeds, previously considered only as an undesirable side effect, could be a mechanism of cancer prevention from prolonged aspirin use, even in the relatively short term” (R).

And regardless of a little bleeding, it isn’t fatal. “With our study showing that there is no increased risk of death from stomach bleeding in people who take regular aspirin.” (R, R).

So all in all, intestinal bleeding goes as follows: aspirin ≥ buffered aspirin > enteric-coated aspirin > sodium salicylate

Although this study found that approximately 70% experience micro bleeding from aspirin (R), this study found that only 0.48–3.64 cases per 1000 experienced bleeding with low dose (75–325 mg/day) aspirin (R), which is far less than the first study.

The study continues with: “Neither aspirin dose nor duration of use had consistent effects on RRs (relative risks) for upper GI bleeding. … Aspirin was associated with increased bleeding risks when combined with non-steroidal anti-inflammatory drugs, clopidogrel and selective serotonin reuptake inhibitors compared with monotherapy.“

Lastly, this meta-analysis looking at aspirin and cancer prevention found that regular aspirin use (daily), didn’t contribute to bleeding. “On bleeding attributable to aspirin two reports stated that there had been no side effect or bleeding attributable to aspirin.” (R)

One of the main reasons why aspirin causes bleeding is related to gut bacteria. This study found that the presence of Helicobacter pylori may increase the risk of GI bleeding events in individuals taking aspirin (R). Furthermore, this study found that certain intestinal bacteria contribute to the development of NSAID-associated enteropathy and that rifaximin was effective at lowering the risk and/or preventing it completely (R).

Bleeding risk in general

Salsalate, which is converted to sodium salicylate upon ingestion, doesn’t cause the same blood thinning as aspirin, as it’s not nearly as powerful COX-1 inhibitor. “This study demonstrates that salsalate, which has anti-inflammatory activity and reduces prostaglandin synthesis, does not interfere with normal platelet function” (R).

Another major concern is that aspirin might cause intracranial bleeding. This study found that it initially increased the risk, but it went away with regular use. “The reduced risk of major vascular events on aspirin was initially offset by an increased risk of major bleeding, but effects on both outcomes diminished with increasing follow-up, leaving only the reduced risk of cancer. … Case-fatality from major extracranial bleeds was also lower on aspirin than on control” (R).

Furthermore, this study actually found that aspirin can actually reduce the risk of brain bleeding: “Hemorrhagic stroke events were reported in 13 of the 16 trials. In 11 of the 13 trials reporting hemorrhagic stroke, aspirin was associated with an increase in absolute risk of hemorrhagic stroke, but the increase was not statistically significant.” (R)

Also, “The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention.” (R)

But apart from the risk being very small, it’s actually protective:

“The findings “are reassuring for survivors of brain hemorrhage who need to take antiplatelet [anti-clotting] medicines to prevent heart attacks and strokes.” (R)

And…

“Aspirin has been found to be a safe in patients harboring cerebral aneurysms and clinical studies provide evidence that it may decrease the overall rate of rupture.” (R)

Summary

Aspirin can cause micro bleeding in a certain small group of individuals. Regardless, micro bleeding can be protective against the risk of cancer by lowering excess iron. Aspirin has been shown to reduce the risk of certain cancers, such as oesophageal, gastric, biliary, colorectal, bladder, etc. (R, R, R, R, R).

Switching to sodium salicylate should prevent micro bleeding completely if you’re concerned about that. Doses up to 4g daily is shown safe and even gut protective.

I should probably add that salicylate (in rats) actually positively modulates the gut bacteria, prevents leaky gut and reduces endotoxin translocation.

“ZDF and Zucker lean (ZL) rats were administered a high-fat diet with or without SAL intervention, and their relative rates of diabetes were compared. Our results showed that all rats in the placebo group developed diabetes, whereas only 10% of the SAL-treated rats presented with impaired glucose tolerance (IGT). None of the latter progressed to diabetes. Relative to the untreated rats, SAL lowered plasma glucagon and insulin while improving insulin sensitivity and β-cell function. SAL may protect against hyperglycemia by increasing the microbial diversity, ameliorating gut dysbiosis, restoring intestinal epithelial cell connections, inhibiting endotoxin influx into the blood, and attenuating inflammation. Together, these findings suggest that SAL may be a candidate prophylactic therapy against diabetes. The protective role of SAL may be attributed to its ability to reduce intestinal inflammation and improve gut dysbiosis.” (R)

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