Saturday, April 27, 2019

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...
...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...

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.


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 CBand 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.

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.


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.


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.

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Saturday, April 13, 2019

Does ketamine restore lost synapses? It may, but that doesn't explain its rapid clinical effects

Bravado SPRAVATO™ (esketamine)
© Janssen Pharmaceuticals, Inc. 2019.

Ketamine is the miracle drug that cures depression:
“Recent studies report what is arguably the most important discovery in half a century: the therapeutic agent ketamine that produces rapid (within hours) antidepressant actions in treatment-resistant depressed patients (4, 5). Notably, the rapid antidepressant actions of ketamine are associated with fast induction of synaptogenesis in rodents and reversal of the atrophy caused by chronic stress (6, 7).”

– Duman & Aghajanian (2012). Synaptic Dysfunction in Depression: Potential Therapeutic Targets. Science 338: 68-72.

Beware the risks of ketamine:
“While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.”

– Sanacora et al. (2017). A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry 74: 399-405.

Ketamine, dark and light:
Is ketamine a destructive club drug that damages the brain and bladder? With psychosis-like effects widely used as a model of schizophrenia? Or is ketamine an exciting new antidepressant, the “most important discovery in half a century”?

For years, I've been utterly fascinated by these separate strands of research that rarely (if ever) intersect. Why is that? Because there's no such thing as “one receptor, one behavior.” And because like most scientific endeavors, neuro-pharmacology/psychiatry research is highly specialized, with experts in one microfield ignoring the literature produced by another...

– The Neurocritic (2015). On the Long Way Down: The Neurophenomenology of Ketamine

Confused?? You're not alone.

FDA Approval

The animal tranquilizer and club drug ketamine now known as a “miraculous” cure for treatment resistant depression has been approved by the FDA in a nasal spray formulation. No more messy IV infusions at shady clinics.

Here's a key Twitter thread that marks the occasion:

How does it work?

A new paper in Science (Moda-Sava et al., 2019) touts the importance of spine formation and synaptogenesis basically, the remodeling of synapses in microcircuits  in prefrontal cortex, a region important for the top-down control of behavior. Specifically, ketamine and its downstream actions are involved in the creation of new spines on dendrites, and in the formation of new synapses. But it turns out this is NOT linked to the rapid improvement in 'depressive' symptoms observed in a mouse model.

So I think we're still in the dark about why some humans can show immediate (albeit short-lived) relief from their unrelenting depression symptoms after ketamine infusion. Moda-Sava et al. say:
Ketamine’s acute effects on depression-related behavior and circuit function occur rapidly and precede the onset of spine formation, which in turn suggests that spine remodeling may be an activity-dependent adaptation to changes in circuit function (83, 88) and is consistent with theoretical models implicating synaptic homeostasis mechanisms in depression and the stress response (89, 90). Although not required for inducing ketamine’s effects acutely, these newly formed spines are critical for sustaining the antidepressant effect over time.

But the problem is, depressed humans require constant treatment with ketamine to maintain any semblance of an effective clinical response, because the beneficial effect is fleeting. If we accept the possibility that ketamine acts through the mTOR signalling pathway, in the long run detrimental effects on the brain (and non-brain systems) may occur (e.g., bladder damage, various cancers, psychosis, etc).

But let's stay isolated in our silos, with our heads in the sand.

Thanks to @o_ceifero for alerting me to this study.

Further Reading

Ketamine for Depression: Yay or Neigh?

Warning about Ketamine in the American Journal of Psychiatry

Chronic Ketamine for Depression: An Unethical Case Study?

still more on ketamine for depression

Update on Ketamine in Palliative Care Settings

Ketamine - Magic Antidepressant, or Expensive Illusion? - by Neuroskeptic

Fighting Depression with Special K - by Scicurious

On the Long Way Down: The Neurophenomenology of Ketamine


Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, Witztum J, Shaver DC, Rosenthal DL, Alway EJ, Lopez K, Meng Y, Nellissen L, Grosenick L, Milner TA, Deisseroth K, Bito H, Kasai H, Liston C. (2019). Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science 364(6436). pii: eaat8078.

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