The Paracetamol Papers

I have secretly obtained a large cache of files from Johnson & Johnson, makers of TYLENOL®, the ubiquitous pain relief medication (generic name: acetaminophen in North America, paracetamol elsewhere). The damaging information contained in these documents has been suppressed by the pharmaceutical giant, for reasons that will become obvious in a moment.¹

After a massive upload of materials to Wikileaks, it can now be revealed that Tylenol not only...

• eases social rejection
• mends a broken heart
• lessens mortality salience (i.e., fear of death)
• reduces antisocial behavior
• treats chronic anxiety disorder

...but along with the good comes the bad. Acetaminophen (paracetamol) also has ghastly negative effects that tear at the very fabric of society. These OTC tablets...

• change how people process information
• blunt positive emotions ²
• kill empathy for other people’s physical and emotional pain
• kill empathy for other people’s joy
• cause rude behavior on Twitter ³

In a 2018 review of the literature, Ratner and colleagues warned:

“In many ways, the reviewed findings are alarming. Consumers assume that when they take an over-the-counter pain medication, it will relieve their physical symptoms, but they do not anticipate broader psychological effects.”

In the latest installment of this alarmist saga, we learn that acetaminophen blunts positive empathy, i.e. the capacity to appreciate and identify with the positive emotions of others (Mischkowski et al., 2019). I'll discuss those findings another time.

But now, let's evaluate the entire TYLENOL® oeuvre by taking a step back and examining the plausibility of the published claims. To summarize, one of the most common over-the-counter, non-narcotic, non-NSAID pain-relieving medications in existence supposedly alleviates the personal experience of hurt feelings and social pain and heartache (positive outcomes). At the same time, TYLENOL® blunts the phenomenological experiences of positive emotion and diminishes empathy for others' people's experiences, both good and bad (negative outcomes). Published articles have reported that many of these effects can be observed after ONE REGULAR DOSE of paracetamol. These findings are based on how undergraduates judge a series of hypothetical stories. One major problem (which is not specific to The Paracetamol Papers) concerns the ecological validity of laboratory tasks as measures of the cognitive and emotional constructs of interest. This issue is critical, but outside the main scope of our discussion today. More to the point, an experimental manipulation may cause a statistically significant shift in a variable of interest, but ultimately we have to decide whether a circumscribed finding in the lab has broader implications for society at large.


Why TYLENOL® ?

Another puzzling element is, why choose acetaminophen as the exclusive pain medication of interest? Its mechanisms of action for relieving fever, headache, and other pains are unclear. Thus, the authors don't have a specific, principled reason for choosing TYLENOL® over Advil (ibuprofen) or aspirin. Presumably, the effects should generalize, but that doesn't seem to be the case. For instance, ibuprofen actually Increases Social Pain in men.

The analgesic effects of acetaminophen are mediated by a complex series of cellular mechanisms (Mallet et al., 2017). One proposed mechanism involves descending serotonergic bulbospinal pathways from the brainstem to the spinal cord. This isn't exactly Prozac territory, so the analogy between Tylenol and SSRI antidepressants isn't apt. The capsaicin receptor TRPV1 and the Cav3.2 calcium channel might also be part of the action (Mallet et al., 2017). A recently recognized player is the CB₁ cannabinoid receptor. AM404, a metabolite of acetaminophen, indirectly activates CB₁ by inhibiting the breakdown and reuptake of anandamide, a naturally occurring cannabinoid in the brain (Mallet et al., 2017).

Speaking of cannabinoids, cannabidiol (CBD) — the non-intoxicating cousin of THC — has a high profile now because of its soaring popularity for many ailments. Ironically, CBD has a very low affinity for CB₁ and CB₂ receptors and may act instead via serotonergic 5-HT1A receptors {PDF}, as a modulator of μ- and δ-opioid receptors, and as an antagonist and inverse agonist at several G protein-coupled receptors. Most CBD use seems to be in the non-therapeutic (placebo) range, because the effective dose for, let's say, anxiety is 10-20 times higher than the average commercial product. You'd have to eat 3-6 bags of cranberry gummies for 285-570 mg of CBD (close to the 300-600 mg recommended dose). Unfortunately, you would also ingest 15-30 mg of THC, which would be quite intoxicating.

"the typical cup of CBD-infused coffee that you buy in your local trendy coffee shop will have, on average, 5-10 mg of CBD, which is nowhere near the therapeutic dosage [at least 300 mg] required for it to have any kind of anxiolytic effect" https://t.co/trytic2nf2

— sarcastic_f (@sarcastic_f) April 26, 2019

Words Have Meanings

If acetaminophen were so effective in “mending broken hearts”, “easing heartaches”, and providing a “cure for a broken heart”, we would be a society of perpetually happy automatons, wiping away the suffering of breakup and divorce with a mere OTC tablet. We'd have Tylenol epidemics and Advil epidemics to rival the scourge of the present Opioid Epidemic.

Meanwhile, social and political discourse in the US has reached a new low. Ironically, the paracetamol “blissed-out” population is enraged because they can't identify with the feelings or opinions of the masses who are 'different' than they are. Somehow, I don't think it's from taking too much Tylenol. A large-scale global survey could put that thought to rest for good.

Nope, it’s not just you: The world around you really is getting angrier

Footnotes

¹ This is not true, of course, I was only kidding. All of the information presented here is publicly available in peer-reviewed journal articles and published press reports.

² except for when it doesn’t – “In contrast, effects on perceived positivity of the described experiences or perceived pleasure in scenario protagonists were not significant” (Mischkowski et al., 2019).

³ Yes, I made this up too. It is entirely fictitious; no one has ever claimed this, to the best of my knowledge.


References

Mallet C, Eschalier A, Daulhac L. Paracetamol: update on its analgesic mechanism of action (2017). Pain relief–From analgesics to alternative therapies.

Mischkowski D, Crocker J, Way BM. (2019). A Social Analgesic? Acetaminophen(Paracetamol) Reduces Positive Empathy. Front Psychol. 10:538.