Does Acetaminophen turn you into a sociopath?

mpathy is the ability to feel pain when someone else is in pain. There are two different types: cognitive empathy (deducing what others are feeling) and affective empathy (sympathetically feeling what others are feeling). They're mediated by different brain regions in the limbic system, which is the lower region of the brain. Cognitive empathy activates the dorsal medial cingulate cortex, while affective empathy activates the left anterior insula.

Pain regions in the brain. Adapted from J.H. Martin, Neuroanatomy Text and Atlas. 5th ed. , p. 103. The anterior insular cortex and cingulate cortex are depressed by acetaminophen. The amygdala is also important for pain, as it decides emotional valence, i.e. good or bad

For years, acetaminophen was thought to act the same way as aspirin, which inhibits cyclooxygenase, an enzyme that converts arachidonic acid to prostaglandin E2, a well known pain signaling molecule. This turned out not to be true. fMRI studies showed that acetaminophen depres­ses the anterior insular cortex (AIC) and the anterior parts of the cingulate cortex (ACC) (see figure at right). The pain signals are still there, but to the patient it feels as if the pain is more diffuse and easier to ignore.

Exactly how acetaminophen, or APAP (N-acetyl-para-aminophenol) as it's called in the scientific literature, does this is not yet clear, but because these are the same regions needed to experience empathy, a side effect of APAP is to block our ability to experience emotional empathy.

Mischkowski et al. ^[1] at Ohio University in Athens, Ohio found that when given normal doses, humans become more sociopathic and autistic. This discovery supports the ‘shared representations’ hypothesis, which says that empathizing with others uses some of the same neural pain pathways that we use to experience pain ourselves. They showed this by blasting the ears of college students with loud white noise up to 105 dB. Those given 1000 mg APAP beforehand reported the noise as less unpleasant for themselves and also expressed less concern and distress about the pain felt by others. They also showed less concern about the social distress of a fellow student who was socially excluded from an online game. However, they were still able to deduce the other student's distress, indicating that their ability to reason was unimpaired.^[2]

This is probably true for any pain-killer chemically related to acetaminophen, such as ibuprofen, that crosses the blood-brain barrier as APAP does.^[3] APAP is the active ingredient in Tylenol and is called paracetamol in the UK. Nearly one of every four Americans takes APAP at least once a week.

Different kinds of pain happen because there are different chemical signaling pathways.^[4,5] Aspirin covalently blocks COX-1 and COX-2, which is an enzyme that converts arachidonic acid into prostanoids like prostaglandin E2 (PGE2) and prostacyclin (PGI2). PGE2 signals to neurons by binding to proteins called EP receptors. Inflammatory mediators including IL-1β, TNFα, and bradykinin activate pain neurons called nociceptors ^[4]. These neurons send signals to the limbic region of the brain, where they are interpreted as pain, but only nociceptors that use PGE2 are blocked by aspirin, which doesn't cross the BBB efficiently.

APAP also reduces other types of empathy. It wipes out feelings of personal pleasure and other-directed empathic positive feelings^[1] but not the ability to deduce that a positive experience would result from a given scenario—only the empathic emotional response.

And don't ask me why they call it APAP, which confuses the heck out of patients because they're likely to take a Tylenol on top of it and whack their liver. Those guys need a kick in the pants. Oh, am I being un-empathetic again? Whoops.

Acetaminophen isn't a cancer risk, but it makes up for it by whacking your liver

APAP is the active metabolite of phenacetin, which was withdrawn due to phenacetin's ability to produce kidney toxicity, hemolytic anemia, and bladder cancer. Because of this, many cancer studies have been done on APAP. Unlike phenacetin, APAP produces only a small risk of bladder cancer ^[6]. One study ^[7] found that high doses produce a two-fold increase in hematologic malignancies such as myeloid neoplasms and non-Hodgkin's lymphomas, but not lymphocytic leukemia, total cancer risk, or non-hematologic cancers. ^[8]

In the USA, APAP causes 46% of acute liver failure cases. APAP is metabolized by CYP450, a liver enzyme to N-acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite, which reacts with and depletes glutathione. APAP toxicity is increased in patients who are anorexic, fasting or who chronically use alcohol. However, acute alcohol consumption protects by competing with CYP450. When glutathione is depleted, NAPQI starts binding to proteins in the mitochondria, causing mitochondrial dysfunction and oxidative stress, which causes hepatocyte necrosis and activation of the innate immune system (called sterile inflammation) by damage-associated molecular patterns or DAMPs including DNA fragments, ATP and cytokines such as HMGB-1. N-acetyl­cysteine, an antioxidant, is a standard treatment, but is only effective in the first eight hours.

APAP also interferes with some types of cancer treatment ^[10]. For reasons that are unclear, it produces a worse outcome in patients treated with immune checkpoint inhibitors or ICIs, possibly because it expands the growth of regulatory T cells (Tregs). This suggests that APAP also works directly on the immune system.

We want inflammation! Inflammation! You won't get it, you took an aspirin

Unlike aspirin and related compounds, acetaminophen is at best a weak anti-inflammatory agent. Prostanoids are only one of many classes of inflammatory signaling molecules. Other classes include bradykinin, leukotriene, and platelet-activating factor. So far antagonists of these pathways have been disappointing in clinical trials.

So, how does acetaminophen work? One clue may be that the analgesic effect of APAP is completely inhibited by tropisetron or granisetron, which are 5-hydroxytryptamine type 3 receptor antagonists that act as weak analgesics ^[11,12]. This suggests that APAP may activate the descending inhibitory serotonergic pathway, a neuronal circuit from the brain to the periphery that inhibits pain ^[14]. Adding to the mystery is that tropisetron also blocks oxidative stress induced by APAP, which is to say it prevents APAP from damaging your liver.^[13] The question is: what role, if any, does oxidative stress play in blocking the experience of pain? No one knows.

Like many other drugs, APAP also activates CAR, the constitutive androstane receptor. (Androstane is a generic term for a saturated steroid, and can be thought of as a metabolite of bile acids.) Activating CAR would make other drugs that act on the brain less effective. CAR is a sensor for fasting and caloric restriction (via PPARα). Under conditions of hypoxia (low tissue oxygenation), it gets translocated to the nucleus, where it dimerizes with RXR (retinoid X receptor) and transcribes its target genes. Although the CAR was originally found in detoxifying organs such as the liver and kidney, it's also in the brain, where its function is unclear^[15].

Ironically, a high dose of APAP also weakens the blood-brain barrier,^[16] letting more drugs and toxins enter the brain. Complicated things like this are the reason it's so important for your pharmacist to understand drug interactions.

Resolution of inflammation

Inflammation is a major cause of pain. It's now well understood that when inflammation resolves, the corresponding pain doesn't just go away passively. In many cases the pain continues for years. In a remarkable paper ^[17], it was recently discovered that to stop the pain, a type of immune cell called a CD206+ M2-like macrophage has to donate its mitochondria to sensory neurons via secreted vesicles. This happens when a protein called CD200R on the macrophage binds to a receptor called Isec1 on the neuron.^[17]

Mitochondria are important parts of every cell because they're responsible for providing energy. The idea seems to be that neurons are so active that they need immune cells to give them extra ones. The discovery that cells can transfer mitochondria to each other opens up powerful new ways of treating genetic mitochondrial disorders.

Sex differences in the brain

What these results show is that emotions—specifically our ability to feel pain—interact with the immune system. Sex differences in emotional empathy are well known, but until recently they were thought to be entirely socially conditioned. We now know that this is not so. The neuronal circuitry that determines pain is different for the two sexes. This may explain why women are more susceptible than men to autoimmune disorders.

One experiment that showed a dramatic sex difference in brain circuitry for pain was done using minocycline. Antibiotics such as minocycline inhibit microglia, the immune cells in the brain. It was found that minocycline eliminates pain hypersensitivity (called allodynia) in males but not females. Females, of course, still get allodynia, but they use T-cells instead of microglia.^[18]

The suppression of empathy by APAP doesn't mean it turns people into psychopaths. It tells us that painkillers that block our ability to feel pain come with a high price. Without empathy, we can't intuit the emotional feelings of others. We can only deduce them from behavioral cues, using the cues as a type of language. Empathizing is an important glue that holds society together. We need new painkillers that block the pain signals without interfering with the brain's function by blocking our ability to feel.

dec 29 2022, 8:11 am