The Dangers of Acetaminophen

Each week, around 23 percent of U.S. adults, or 52 million Americans, use a medication containing acetaminophen, according to the Consumer Healthcare Products Association (1). The ubiquitous use of acetaminophen, both by itself and as a component of over-the-counter and prescribed medications, is a major public health issue. Acetaminophen is generally considered safe when taken as recommended, but the margin between a safe dose and a potentially lethal one is incredibly small.

Even when taken as recommended, acetaminophen use can have major side effects. In this article, I’ll discuss the many reasons we should avoid acetaminophen whenever possible and share several safer alternatives for pain relief.

Liver Toxicity

Taken over several days, as little as 25 percent above the maximum dose, or just two additional pills a day, has been reported to cause liver damage. This staggered overdosing may be more dangerous than a single large overdose (3).

Think twice before you reach for Tylenol.

Current guidelines recommend taking no more than 4,000 milligrams of acetaminophen daily (4). Yet according to a 2006 study published in the Journal of the American Medical Association, even this dose, taken for four or more days, frequently causes elevated serum alanine aminotransferase (ALT), a marker of liver injury. Moreover, the elevations in ALT often persisted for several days after the acetaminophen was discontinued (5).

Concerns about liver toxicity were raised as early as 1977, when an FDA advisory panel said it was “obligatory” to add warning labels about liver damage. The FDA dragged its feet until 2011, when it finally issued a statement urging drug manufacturers to limit the strength of each capsule to 325 milligrams of acetaminophen and mandated warning labels about liver toxicity (4).

Acetaminophen toxicity is increased when combined with narcotics like codeine or hydrocodone, when more than the prescribed dose was taken in a 24-hour period, when more than one acetaminophen-containing product is taken at the same time, or when alcohol is consumed while taking acetaminophen (6, 7).

How does it cause liver damage? Acetaminophen depletes levels of glutathione, the body’s master antioxidant. Glutathione helps protect cells from damage by free radicals. Interestingly, prompt administration of N-acetylcysteine (NAC), the precursor to glutathione, can prevent mortality from acetaminophen toxicity (8).

Gut Health and Microbial Drug Metabolism

Chronic use of acetaminophen doses greater than 2,000 milligrams has been associated with a 3.7 times increased risk of bleeding in the upper gastrointestinal tract (9). Acetaminophen can also cause intestinal permeability. Overdose with acetaminophen causes massive necrosis of the liver tissue, which releases a protein that results in leakage of bacteria from the gut into the bloodstream (10).

I’ve written before on the Kresser Institute blog about the role of the gut microbiota in drug metabolism. Interestingly, those with higher levels of certain gut bacterial metabolites may be more susceptible to acetaminophen toxicity (11).

Cardiovascular Health, Kidney Disease, and Cancer

Several recent studies have also shed light on acetaminophen’s relation to cardiometabolic health. One study, published just this month, found that those taking opiates (some of which contain acetaminophen) were 95 percent more likely to be obese and 63 percent more likely to have hypertension (12). Of course, we can’t separate out the effects of acetaminophen in these combination drugs.

This is especially true when combined with alcohol consumption. One study found that concomitant use of acetaminophen and alcohol resulted in a 2.23 times increased risk for kidney dysfunction (13).

Researchers have also found associations with cancer. A 2013 meta-analysis of epidemiological studies found that acetaminophen was associated with a significantly increased risk of kidney cancer (14). A 2011 study of more than 64,000 older men and women found that acetaminophen use was also associated with several different types of blood cancers, including myeloid neoplasms, non-Hodgkin lymphomas, and plasma cell disorders like multiple myeloma (15).

Blunted Emotions and Empathy

Researchers at Ohio State University wanted to determine if acetaminophen affected emotional processing. They found that participants who took acetaminophen “evaluated unpleasant stimuli less negatively and pleasant stimuli less positively, compared with participants who took a placebo.” In other words, both negative and positive stimuli were less “emotionally arousing” to people who had taken acetaminophen (16).

In another double-blind, placebo-controlled experiment led by a different research group, participants rated their perceived pain, personal distress, and empathic concern after reading scenarios about another person’s physical or social pain. Participants who had received acetaminophen beforehand showed less empathy towards others’ pain (17).

Together, these studies raise concerns about the broader social side effects of acetaminophen. If a quarter of Americans use this every week, what impact is this having on us as a society?

Autism, ADHD, and Brain Health

Acetaminophen is currently marketed as safe during pregnancy. However, acetaminophen use may have neurodevelopmental consequences for the fetus. A 2016 study followed more than 2,000 mother–child pairs from the first trimester of pregnancy and performed several tests of behavior when the children were about five years old (18).

Forty percent of the children were exposed to acetaminophen in utero. Exposure to acetaminophen was associated with lower attention function and a greater risk for ADHD-like hyperactivity and impulsivity symptoms. In boys, acetaminophen exposure was also related to a greater number of autism spectrum symptoms, and mothers who used acetaminophen more frequently had an even greater chance of having children with autistic-like behavior. The authors even ran the data again, excluding mothers that had chronic illness, urinary tract infections, or fevers during pregnancy, and found the same results, suggesting that it was not illness itself that contributed to the association.

A study in rats found that acetaminophen causes toxicity to neurons even at concentrations too low to cause liver failure (20). It caused the neurons to undergo apoptosis, or programmed cell death.

Severe Skin Reactions and Asthma

Acetaminophen has also been linked to rare but very serious skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. These reactions can be fatal. Between 1969 and 2012, there were 107 such cases, of which 67 required hospitalization, and 12 people died. In 2013, the FDA issued a warning and mandated that skin reactions be listed on acetaminophen-containing drug labels as a potential adverse effect (21). Exactly how acetaminophen causes these potentially fatal skin reactions is unknown, but particularly alarming is that they can occur even if you’ve taken acetaminophen in the past without any problems.

Researchers have also found an association between acetaminophen and asthma. A 2009 systematic review and meta-analysis found that in both adults and children, the risk of asthma increased with prior acetaminophen use. Moreover, prenatal exposure to acetaminophen also increased the risk of asthma in child, possibly by increasing oxidative stress during prepregnancy. (22)

Of course, these are only associations, and they don’t prove that acetaminophen is the cause of these problems. Some of these children may have received acetaminophen due to viral respiratory infections that may have also contributed to the development of asthma. Still, the evidence is strong enough that several experts have recommended that acetaminophen use should be avoided in children with asthma or at risk for asthma (23, 24).

Altered Reproductive Function

Acetaminophen is also an endocrine disruptor. In a 2016 study, rats given acetaminophen had female offspring with fewer eggs, smaller ovaries, and smaller litters when they reached reproductive age. Male offspring had fewer numbers of sperm progenitor cells early in life, but these returned to normal by adulthood. Particularly concerning was the effect it had on the next generation. Granddaughters of the rats given acetaminophen were also found to have smaller ovaries and stunted reproductive function (25).

How did this happen? The researchers speculate that it has to do with acetaminophen’s effect on prostaglandins, hormones that are involved in pain and inflammation but are also important in regulating female menstrual cycles and reproduction.

In humans, acetaminophen use during pregnancy, especially for durations of more than four weeks, is associated with an increased risk of having male children with an undescended testicle at birth (26). Prolonged exposure to acetaminophen also decreases the amount of testosterone produced by human fetal testes (27), which could have major effects on male development.

Alternatives to Acetaminophen

Hopefully, I’ve convinced you to think twice about taking acetaminophen.

For acute relief, there are some alternative painkillers that are far less toxic and, in many cases, just as effective as acetaminophen. Here are a few that I always keep in my “medicine” cabinet:

1. Curcumin: a potent anti-inflammatory, curcumin is one of the natural compounds found in turmeric. I recommend 1,500 mg up to three times a day of the Meriva-SR form, which is much more bioavailable than other forms of curcumin. (Note: curcumin is contraindicated if you are taking blood thinners.)
2. Magnesium: three of the most common reasons for taking acetaminophen over the counter are headaches, muscle pain, and menstrual cramps. For many people, magnesium can provide significant relief from these symptoms, often equivalent to or better than Tylenol. I recommend 400 to 600 mg of the magnesium glycinate form.
3. Boswellia: another anti-inflammatory, the resin of the Boswellia tree has been used medicinally for centuries. It works via a different mechanism than curcumin, so they are complementary when taken together. I recommend 100 mg up to three times a day in the AKBA form.
4. Clove oil: works like a charm for toothaches. Mix a few drops of therapeutic-grade clove oil with a spoonful of coconut oil and swish it around the mouth.
5. CBD oil: also known as cannabidiol, this is the non-psychoactive oil of the cannabis plant that has pain-relieving and anti-inflammatory properties. It does not produce the “high” that THC does, and as of now, it is currently sold legally over the counter. After extensive research on CBD products available today, Ojai Energetics Hemp Elixir is my top choice. It’s what I use myself and with my family, and what I recommend to most of my patients, because it’s effective, safe, and made from 100% organic ingredients.
6. Acupuncture: can be quite effective at modulating local and systemic pain and reducing inflammation.
7. Mind-body interventions: emotional-freedom techniques, yoga, and meditation can all provide short-term pain relief.

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