This Podcast Will Kill You - Ep 120 Acetaminophen/Paracetamol: Pain. Killer.

Episode Date: July 11, 2023

It’s safe to assume that the vast majority of you have a bottle or blister pack of acetaminophen/paracetamol/Tylenol/Panadol in your home medicine cabinet, and an even vaster majority of you have taken the medicine at some point in your life. After all, acetaminophen/paracetamol is one of the most, if not the most, widely used medications worldwide. Despite its near ubiquity, many unanswered questions remain. How does it actually work? Should safe dosage guidelines be revisited? Why on earth does it have multiple names? And finally, who was responsible for the Tylenol murders in 1982? In this jam-packed episode, we do our best to make sense of the mysteries surrounding this drug, weaving our way from the pharmaceutical nitty gritty of acetaminophen/paracetamol to the bizarre story of its discovery, from the horrific crimes that shocked a nation and revolutionized consumer safety standards to the ongoing discussions of whether we’re under- or overestimating how safe this medication actually is. See omnystudio.com/listener for privacy information.

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Val, bad fun. Outdo it with Intuit QuickBooks. Feature availability varies by product. On that September day, the postal worker picked his daughter up, as he often did, from preschool at Our Lady of the Wayside in the Chicago suburb of Arlington Heights, Illinois. They stopped at a nearby grocery store on the way home. Cassia always loved running errands with her dad. she wanted to go everywhere he did.

She remembers walking with him down the aisles of Jules Osko that day. He picked out a bouquet of gladiolis for her mother. Kasia paused to point out a travel-sized bottle of mouthwash. She loved how it fit in her hand so easily. That's when her dad picked up the bottle of extra strength Tylenol. They headed home together. She didn't know then it would be the last time. That's awful.

It is, it is. So that is from a CNN article titled Transformed by Tragedy by Catherine E. Shoichet published September 24th, 2020. And that is about the Tylenol murders, which we will chat about later in the episode. It is horrible. Yeah. Yeah. Hi, I'm Aaron Welsh. And I'm Aaron Olman Updike.

And this is, this podcast will kill you. And today, we're talking about Tylenol. We are. Well, acetymothin, paracetamol, the whatever. Trying not to use the trade name. Right. Well, it's also really difficult because I feel like there are, like, why are there two generic names for it? There are two official, like chemical, like short names for it. But why?

Why? Because two different people decided they wanted to name it. No joke. But like, couldn't we come to a consensus? Like, flip a coin. Let's just go with. I think mostly I use paracetamol in this. And I usually use acetaminopin because that's what we call it in the U.S. I don't know why I use paracetamol. I think it was the papers I read. It must have been UK-based or something.

You're at least. It's good to know that paracetamol is the same thing because it's definitely worldwide, the more common term. Okay. That must be why it was in the papers too. Yeah. Yeah. Yeah. Yeah.

So acetaminopin paracetamol. Yeah. Today. Yeah. It's going to be a really interesting one and I can't wait to get to it. But first, it's quarantine time. It certainly is. What are we drinking this week?

We're drinking the chills pills. Nice. Get it? Nice. Yeah. Pretty good. Because when you have chills often, acetaminopin, paracetamol is one of the drugs that you reach for. Yeah.

And as we'll talk about, there might be other mechanisms by which it chills you out. But I'm... Interesting. We'll get there. And the chills pills is based on a very classic cocktail called The Pain Killer, which we also could have gone with. But like, I don't know. We wanted to put our own little spin on it, I suppose. As we do.

But it is a delicious set of ingredients. It has rum, pineapple juice, orange juice, cream of coconut. Pretty sure we haven't done this, but we've probably done something very similar. It's inevitable after six seasons. Yes. We'll post the full recipe for that quarantini as well as our non-alcoholic placebo-rida on our website, this podcast with kill you.com, and all of our social media channels. We certainly will. On our website, you can find all sorts of cool things like the sources for each and every one of our episodes, transcripts, our bookshop.org affiliate account, our goodreads list, merch, music by Bloodmobile, Patreon. Just check it out.

Are you reading you post it? I'm on our website, actually. So I'm just scrolling over the top menu. I could see your eyes like flicking back and forth. That was nice. Well done. I was like, wow, finally I don't have to just like somehow bring this to the surface of my brain. It's right here.

Anyway, check it out. It's great stuff. It's really great stuff. Well, with that, shall we get into paracetamol acetaminopin? Let's do it right after this break. Dinner shows up every night, whether you're prepared for it or not. And with Blue Apron, you won't need to panic order takeout again. Blue Apron meals are designed by chefs and arrive with pre-portioned ingredients,

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names are just literal shorthand for that chemical name, an acetyl paraamino phenol. Acetaminopin or paracetamol, also in the literature often called APAP, aka brand name Tylenol in the U.S. I'll probably call it acetaminopin for most of this section, and it sounds like Aaron, you'll call it paracetamol, and both are entirely correct. In pretty much every single paper I read, acetaminopin is cited as the most popular and widely used over-the-counter medication, possibly of any class, but certainly of analgesic anti-piratic medications, that is, pain relievers and fever reducers.

And this is like worldwide. Worldwide is true. It's a very common medication on its own, but it's also very common in combination medications, like all of those cough and cold mixes that you buy, almost all of those have acetaminopin in them. Some studies suggest that nearly 80% of, for example, the U.S. general population use acetaminopin at some point in their lives, if not on the regular. And because of this, acetaminopin is also, in many countries, the most commonly used drug in in in in its, intentional overdoses, as well as responsible for the most unintentional medication overdoses in a lot of countries. And we'll talk about why that's so important in terms of the dangers

of acetaminopin. But first, like, what does it actually do? Like, what does acetaminephine do? What does it do to you? No one knows. That's the answer. As always, on this podcast. So, like I mentioned, it's bought and sold as an antipyretic, meaning a fever lowering, and an analgesic meaning pain reducing medication. So it reduces pain and it reduces our fever. And like you said, as it turns out, we don't fully know how it actually does this. And that fact alone still blows my mind. Like, I knew that we didn't fully know the mechanisms of acetyaminephine. But it was astounding to read so many papers about the potential theoretical mechanisms of this drug and have them all be like, so just what we hypothesize on other people hypothesize this. So, well, who knows?

It's wild. I feel like it's really interesting. And I think that when I tell you the origin, story of acetymenifin, it might make a bit more sense why we don't know. Oh, okay. I can't wait. It's going to be fun. I know nothing except like, well, yeah, I know essentially nothing. So let's get into what we do know and what is hypothesized in the literature, shall we? The thing about pain that I will grant everyone trying to figure out the mechanisms of acetaminopin

and the thing about fever is that they're both a bit complicated, to say the least, meaning it's not all just one mechanism to begin with. The other drug that we've talked about in detail on this podcast that has similar effects is aspirin. Aspirin is also a medicine that reduces pain and can be used as an antipyretic reduces temperature. In that episode, which was all the way back in season two. Yeah, right? Yeah. Wow.

I talked in detail about inflammation, the process of inflammation, the indicators of inflammation, like redness, swelling, pain, and heat. And I talked in more detail than I realized about one of the main pathways that mediates inflammation. And this is something called the arachidonic acid pathway. I promise it's not going to be too heavy biochemistry in this episode, so please don't tune out. But I talked specifically about these enzymes called cyclooxygenase or Cox enzymes. So to review that, because none of us remember, arachanonic acid is this substance that's present in all of our cells. It's in our cell membranes.

And it is released when we have damage to our cells and then metabolized by Cox enzymes into a whole bunch of different molecules, like, prostaglandins and leukotrienes and thromboxanes. These are different kinds of signaling molecules that induce inflammation, which again, you'll have swelling and pain and heat, things like that, right, when we have inflammation. Enseds like aspirin and ibuprofen are what are called cox blockers. And in blocking these cox enzymes, They act as anti-inflammatory medicines. And that is how they reduce pain and swelling and temperature.

But pain is not just from inflammation. And neither is fever or rather our temperature regulation. Pain is incredibly complex and probably worthy of its entire own episode someday if we can figure out how to do that. But inflammation is just one potential cause of pain. There are a lot of other kinds of noosiceptive pain, which is when we have pain from like an actual or a threatened, like an almost damage to our tissue. That's called no susceptible pain. But you can also have neuropathic pain if you have damage to the nerves or what's called nociplastic pain. And this is from alterations in the way that we perceive pain, the way that pain signals are sent without any actual damage.

And then we can also have mixed pain, like pain that comes from a lot of different sources. And our temperature regulation process is mostly mediated in our brain, but there are a lot of messengers and receptors that are involved in this process. So back to what we're actually talking about. Acetaminophen is not an N-Set. It's not like aspirin, like a cox blocker. It doesn't work directly by this Cox pathway, but it kind of works by that pathway. And the reason that I brought it all up is because we thought for a really long time that that is the way that it worked. So there is still confusion out there as to what the effects of Tylenol are on inflammation.

But as it turns out, Tylenol doesn't affect our inflammatory pathways at all. And yet, it still mediates both pain and fever. But by a different mechanism than things like ibuprofen and aspirin, which is really cool. Are there other drugs that are similar to acetaminophen in that they also either reduce pain or fever but also don't act as NSAIDs act? Yes. Yes. There are a lot of other medicines, especially for pain, that are going to act on entirely different parts of the system. than things like ibuprofen or aspirin. When it comes to fever,

I think there are at least a couple, but I'm not super familiar with them. Okay. Yeah. So let's get into how Tylenol actually does work. Mm-hmm. And then we'll learn a lot about some of these other ways that pain is kind of mediated besides inflammation.

There are three main pathways by which acetaminopin probably, we think, exerts its effects. And one of them does, in fact, involve cox, cyclooxygenase. So it was worth me telling you that whole story. So it turns out that we thought for a long time acetaminophen worked very similarly to ibuprofen, just blocked this enzyme. It turns out it does do some cox blocking, but it's neither direct nor is it universal in our body. So rather than binding to this enzyme and blocking its activity, it seems more likely that acinaminophen, what it does is reduce the active form of this enzyme. Not like reduce the amount of it, but like oxidation reduction reaction, donate some electrons and renders it inactive in that way.

But, and here's where it gets really fun and interesting, acetaminopin seems to only do this in our central nervous system. not in all the cells in our body like most cox inhibitors. What? How? I knew you'd ask. Again, we hypothesize that it has to do with the levels of peroxide. Because this is like an oxidation reduction reaction, it only works under certain conditions that are present in the brain,

but not in our peripheral tissues. Okay, so because it's not straight up blocking, it's just sort of interfering with this enzyme that the conditions have to be right. Okay, that's interesting and weird. And why aren't the conditions the same? Why are they different? What makes them different? What purpose does that different serve?

Those are two deep of biochemistry questions for me. But what I can tell you is that in doing this in our brain, the end result is that acetaminopin inhibits the production. of prostaglandins, which are some of these molecules whose normal action is to increase our temperature and increase our sensitivity of pain receptors to various stimuli in our brain. So by blocking the production of prostaglandins, acetaminopin in our brain is reducing our temperature and reducing our sensation of pain. Fascinating, number one.

I love it. Number two, is it too early to ask about compare and contrast with nsets and how, like, does acetaminifin work better than at these targeting prosa glandins in your brain, stuff like that? I love it. You know, I don't think that it's too early. We've got several more mechanisms to get through. We can just put a pin in it and come back if we need to. Okay. Let's do that. We'll go through these and then ask me. that again because it's it is a really interesting question okay okay okay but but there's more so another big mechanism by which acetaminophen seems to have an effect and this one's really fun also involves arachidonic acid that molecule that's released from our cell membranes turns out that a metabolite of

acetaminophen conjugates so binds up with arachidonic acid and is then converted into something called AM404, N-iracidinoil phenolamine. Am-404, it's easier. This molecule happens to be a weak but present agonist of our cannabinoid receptors in our brain. So this ends up leading to an increase in cannabinoids and has an effect on this other receptor that's related. Okay, what does that actually mean? Uh-huh.

I'm lost. Yeah. Canabinoids, does that word sound familiar? Yeah. Sounds like cannabis. Yeah. Yeah. So cannabinoids are a group of substances, some of which are found in marijuana, cannabis, among other things. We have in our bodies and brains an entire system called the endocannabinoid system.

We don't fully understand it or how it works. It's involved in a lot of different things. but some of the things that it has been shown to be involved in, especially via a couple of specific receptors, is the perception of pain and our temperature regulation. Turns out that this molecule that acetaminophen can turn into in our brain, AM 404, acts on these receptors indirectly and increases the production of cannabinoids that interact with these systems. and then mediates both pain and temperature in our brain through these receptors. Are these different hypotheses mutually exclusive? Absolutely not, which is the most fascinating thing about them. Okay.

So it could be through interfering with the production of prostaglandins, or it could be by upregulating these cannabinoid receptor things? Yeah, but they're not mutually exclusive. So it's likely, like, all of this is happening at the same time. At the same time. Yeah. It's interacting with like a number of different receptors and enzymes in a number of different ways, which is probably why it's been so hard for us to pinpoint the exact mechanism if it's multifactorial.

Mm-hmm. Because there's one more. Okay. There has to be three, you know? Always. Acetaminopin seems to additionally activate, again, in our brain, our descending inhibitory serotonergic pathway. So many words. So much complication. But okay, let me simplify. When we have an injury or tissue damage or whatever and pain is a result, that information of pain

is transmitted from our skin or wherever that injury is through our spinal cord and through what's called the dorsal horn of our spinal cord and then up to our brain via these ascending pathways, right, like skin, spinal cord, brain. The pathway goes up. Then our brain has these other pathways that go back down through our spinal cord and then out to the periphery. These are called descending pathways. One of these descending pathways involves serotonin, which most people have probably heard of because of things like serotonin reuptake inhibitors or antidepressant medications. Serotonin is like a happy hormone, right?

serotonin via this pathway helps to mediate, decrease the perception of pain, right? So it's like our brain gets a signal, ah, we have pain. And it has these pathways to go, it's cool, man, we can deal with it. We don't have to feel the hurt. That's this very simplified way of looking at it. Okay. But by activating these inhibitory pathways, these serotonin pathways, a Cetaminopin likely has at least some small effect on the sensation of pain via these serotonergic pathways as well.

So it like says reassure this person even more that they're okay and they can handle this pain? Exactly. Okay. Interesting. Yeah. Yeah. Right? Interesting. I know. That's why I said the chills pills thing works on so many different levels. Yeah. Right?

Hmm. It doesn't mean that Tylenol is making everyone just feel really happy. anything. That's not how it's more complicated than that. But it's so many different little mechanisms that all of which are in our central nervous system, which I think is fascinating. So again, acetaminopin seems to pretty specifically affect pain via our central nervous system rather than peripherally or like directly at the site of wherever that pain is coming from. And it's likely these multiple little mechanisms that all together produce the overall. all effect.

Now can I ask my question again? Please. Compare and contrast, please, with the following drugs. Ibuprofen, aspirin. Those are the only two I can think of. You could even say opioids. Opioids. There we go.

Yeah. So in general, acetaminopin is considered a very mild analgesic and a mild antipyretic. And mild really does seem to be the keyword. Most studies have shown it results in about. like a 0.2 to 0.4 degree, and I believe that's Fahrenheit, decrease in human body temperature, which is even less than I would have thought based on my personal usage of it. Yeah, that seems really low. It's really minor, yeah. It's a minor decrease in an overall temperature. But it might be

enough to make you feel a lot better. I don't know. Yeah. Yeah. Pain is something that's obviously very difficult to quantify and measure, but one thing that's interesting, at least, about the pain relieving effects of acetaminopin in comparison to n-sense, is that it's not having any anti-inflammatory activity. So if the pain is primarily and directly from the process of inflammation, it's generally not well treated with Tylenol. And that's been shown in, In some studies, things like rheumatoid conditions and things are not very well treated with something like acetaminophen. In some things like osteoarthritis, which is more of a direct pain rather than an inflammatory pain, some studies have shown it's about equivalent or maybe a little less effective than something like Ns for that kind of purpose.

So in general, it's considered pretty similar in terms of pain reduction to something like an ibuprofen. Okay. Some studies show that it does fairly well at things like cancer pain, at least mild cancer pain, not severe cancer pain, and migraine headaches, though I feel like a lot of people with migraines would disagree with that, and is less good for things like tension headaches. So it's like very specific types of pain that it seems to be more effective versus less effective. Well, I would imagine that just person to person variation is probably pretty big. 1,000 percent, yes. Yeah, interesting. The other interesting thing is that because of Cidaminopin as a mild analgesic and a mild antipyretic is considered very similar to something like ibuprofen, which is another over-the-counter medication, again, is working via a different anti-inflammatory pathway. Ibrofen is an N-Sed, a non-steroidal anti-inflammatory. they're very similar in terms of used to treat mild pain, mild fevers.

The difference often is cited as the risk of these two medicines. And depending on what paper you read and who you talk to, you might think that one is very risky and the other is not, but which one might be up in the air. Mm-hmm. Mm-hmm. For a long time, by a lot of people, acetaminopin was considered very, very, very safe and safer compared to nseds. The reason for this is because nseds do have a significantly increased risk of GI side effects, specifically bleeding from the gastrointestinal tract.

And that is because of their effects on cocks, peripherally and in our stomach. That's a whole episode on its own, but it greatly does increase the risk of gastrointestinal bleeding. More so than acetaminopin. However, that's not to say that acetaminopin is without risk. And so I think in recent years, as we've learned more and more about acetaminephine, the risk-benefit calculus for some people, and in some of the studies that I read, has perhaps shifted. And so especially if you're talking about short-term versus long-term use

and degree of severity of the possible side effects, one could argue that acetaminopin might be more dangerous than ibuprofen. And some people do argue that in the literature. So let's talk about the adverse effects of acetaminophen. Yeah. It's also, it's interesting that I feel like sometimes the mechanism of a drug is figured out, at least in part, by looking at adverse effects. Yeah, that's a good point. And so it's, it's interesting that that doesn't seem to be the case with acetaminopin.

Yeah, not at all. Okay. Yeah, I don't know. It's a good question. So, let's talk about it, shall we? Yeah. Despite being so widely used, cannot overstate just how widely used acetyaminephine, paracetamol is worldwide. And despite it being considered, in general, a very safe medication that's used over the counter so frequently,

it is incredibly toxic to the liver if too much is ingested. So how does this toxicity occur if this medicine is super safe? And if all of the effects that I talked about with acetyamine are in the brain, why is the liver involved all of a sudden? Well, our liver metabolizes acetaminopin, unsurprising. Our liver does that for most things. And the majority of acetaminopin is metabolized in a way that produces the various substances that we talked about that cross into our blood brain barrier and exert their effects and help us feel better, right? Most of the way that our liver metabolizes acetaminopin is all great, but our liver is complicated, and it actually has multiple pathways by which it metabolizes acetaminopin. It's not just one.

And one of these pathways, which most papers I read, say, accounts for about 5 to 15 percent of the total metabolism of acetaminopin, uses one of our systems in our liver called the P-450 system. And this results in an incredibly toxic metabolite called NAPQI. I'm not going to try and say the real name. And it turns out that this specific metabolite is really toxic to our liver cells. So when that is produced, it can then just kill off the liver cells right around where it's produced. Now, most of the time, we have enough of another molecule hanging out. in our liver called glutathione that neutralizes this toxic metabolite. So no problem. We make a little bit of it, but we can neutralize it. But if this metabolite is produced in excess, say from too much

acetaminophen that we take too much at one time, we run out of this glutathione. So then we can't neutralize this toxic NAPQI. And then this molecule literally starts killing our liver cells and resulting in liver necrosis. Very bad. Is this why there are warning labels on acetaminopin products that are like, do not take with alcohol, or if you consume more than this number of alcoholic drinks today? Yes, because not only can chronic or high amounts of alcohol damage your liver, which can just affect the way that your liver metabolizes things to begin with, alcohol also interacts with our cytochrome P450 system in a way that can directly alter the metabolism of acetaminopin specifically as well. So do a number of other drugs.

And so there's other drugs that have potential interactions with acetaminopin. But yes, that is the reason for those warnings. Okay. So when you have acetaminopin toxicity, there's kind of four stages of disdemeanors. disease that you can have. First, probably unsurprisingly, since this is a medicine you're ingesting, you can have nausea, vomiting, maybe some stomach pain. A lot of times, though, in the early stages, people might be entirely asymptomatic. But then what we start to see in terms of lab numbers is that liver enzymes start to increase. These are a marker of liver damage.

and this starts to show usually within 24 hours, sometimes within 12 hours of ingestion, and then continue to increase over the next three to five days. And this can become so severe, depending on how much acetaminophen was ingested, that it can progress to fulminant liver failure, complete liver failure, which can result in things like hepatic encephalopathy, which is when your brain begins to swell and not function because of all of the other things that are building up in your body because your liver has stopped working. We can see hyper bilirubinemia. This is an elevation in the breakdown products of our red blood cells that our liver is supposed to take care of.

We can see lactic acidosis, so our blood becomes acidic. We can have profound hypoglycemia because our liver can't produce more glucose. You can have thrombocytopinia, so we're not able to make platelets. which can lead to bleeding, and then this can progress to shock and eventually death or the need for a liver transplant. And so the damage can happen or keep happening or increase even after you stop taking acetaminopin. Yeah, we can see this kind of lag in maybe when those toxic metabolites had started to build up and then when the liver is being the most affected, if that makes sense. Mm-hmm. On top of that, once our liver starts to fail and have severe liver damage, this can then

cause additional damage to the kidneys, what's called renal tubular necrosis. So we have now death of the cells lining the tubules of our kidneys because that's where acetaminopin and its metabolites are excreted. We pee out the metabolites of acetaminophen. So if these toxins build up, then it can end up affecting our kidneys as well. So this is obviously very severe and can and often is fatal if it's untreated. There is kind of an antidote, a treatment available. It's called n acetyl cysteine or knack.

And it can prevent fulminant liver failure if it's given early enough. Early enough usually means within eight hours of ingestion, but it can also help prevent like complete liver failure, even if it's given later than that. depending on how severe the damage has been to begin with. So the question really is how much does it take to do this, right? Like how much does it take to have these severe side effects? And the answer to that question is why in more recent years, I think there has been a larger push, I guess,

or maybe chorus of papers that I found online, saying maybe we should rethink how safe we, we consider acetaminifin. Most countries and most manufacturers list a maximum daily dose of acetaminifin for adults, not talking about children, as four grams. So as an example, extra strength Tylenol that you can buy in the U.S. is 500 milligrams. So that's like taking two of those four times a day or every six hours in a 24-hour period. And a lot of the older literature used to cite, based on data from intentional acute overdoses, that we don't see toxicity to the liver until we get to doses like 10 or 12 grams.

So you'd have to take quite a lot to overdose. But more recent data, especially data from people who perhaps weren't intentionally overdosed. dosing, but were unintentionally taking slightly more than was recommended over the course of several days or a week, like maybe the time period in which you've got the flu, we have seen evidence of very severe hepatotoxicity or liver toxicity, including leading to death at much lower daily doses, like six or eight grams in 24 hours, which is only a couple pills more than the maximum recommended dose. So I'm going to talk a little bit more about this in the current event section because I think it's one of the main stories with how we think about acetaminopin today.

But this potentially small margin of error between the maximum daily recommended dose and a potentially incredibly toxic dose has become pretty controversial, especially because of how many other medicines acetaminopin can be found in, that you may not know that acinamininifin is there. Right, right. So, yeah. And that's all kind of just the acute toxicity. In terms of chronic use, it also used to be thought that acinaminephin overall was much safer

than other things like ibuprofen or ensigns, aspirin. et cetera, because we know those definitely increase the risk of GI bleeding. Turns out it's a little more complicated because acetaminophen definitely has a significantly lower risk of GI bleed than Ns, but it's not non-existent because there might be some peripheral Cox activity going on. Who knows? But there also is some mounting evidence that there's potential for other long-term risks of large amounts of acetyaminephine use over the long-term, even if it's below that 4-gram threshold. And that is things like cardiovascular side effects, maybe a little increase in blood pressure.

But in general, these data are not very well fleshed out at this point, which is really interesting considering how long acetaminopin has been around, which I know you'll talk about. Yeah. Interesting. It's very interesting in general. It is. So, yeah, that sounds very scary when it comes to acute, especially, overdose of acetaminopin. I don't want to fearmonger because this is a medication that we have a ton of data to show that when it's used as directed, which is below.

that 4 gram threshold for adults, or some countries have further reduced it to 3 grams just to like increase that margin of error, it does remain a very safe medication without this liver toxicity, right? Yeah. So even though those numbers are not that much higher than what's recommended, they are higher than what is recommended. So yeah. Anyways, that's acetaminopin paracetamol.

and how it works. It's mysterious and interesting. It remains so, doesn't it? Yeah. So tell me, Erin, how did we find it? How do we come up with it? Okay. How did we get here, like, where we still don't know very much?

Mm. And, you know, tell me all the depressing things. Yeah, there is some of that. And I'll get to it all right after this break. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands hand cream is such a relief.

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And I'm Janice Torres. Join us for Season 4 of Mind the Business, Small Business Success Stories from Ruby Studio and Intuit QuickBooks. We're back and talking to more inspiring small business owners about everything from the changing business landscape to the rise of artificial intelligence and how QuickBooks on the Intuit platform helps you outdo what you're capable of. So outdo it with Intuit QuickBooks. Working in QuickBooks just makes it easier to run the business, right? There's so much that you need to do when it comes to running a business, building

products, setting up marketing campaigns. And to run a business, you have to make sure that your finances are in order. So it removes my anxiety from one side of it so that I can focus on everything else. Listen to new episodes of Mind the Business, Small Business Success Story. every other Thursday on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. This is Bethany Frankel from Just Be with Bethany Frankel. Listen, I have a bone to pick with these dog food brands calling themselves fresh, natural, healthy. Sounds great, but a lot of these, quote-unquote, fresh dog foods in your fridge are not even 100% human grade,

which is why feed your babies, just food for dogs. It's good enough for big and smalls, my precious babies, so it's good enough for your babies. 100% human grade, real ingredients, beef, sweet potatoes, green beans, delicious. These are foods that you would want to eat. Not that the babies would ever share. Just Food for Dogs is the number one vet recommended fresh dog food back by over a decade of research. No marketing fluff. My dogs lose their minds at dinner.

They run to the bowl, tags wagging, paws tapping, full Broadway performance every single night. So I do care about the food I feed Biggie and Smalls. So go to just food for dogs.com for 50% off your first box, no code, no gimmicks, just real fresh food. The history of paracetamol slash acetaminopin slash Tylenol slash panadol is a fascinating one. I'm sure there are more brand names out there I'm missing. And it's one that I want to tell in two main parts. Okay. The first is, of course, a history of discovery of happy accidents and nisphemy.

necessity acting as the mother of invention and all that jazz. The second is a tale of murder, of the shocking revelation that the public wasn't as safe as they thought and the fallout from this horrific crime. Let's get started. Let's do it. To help set the stage for the discovery of paracetamol, I'm going to ask you to cast your mind back to two very old episodes. malaria all the way back from our first season and aspirin from our second, which I know you revisited, so you're good to go. I'm there.

And malaria because I want to talk about cinchona bark, which is where quionine is derived, and which is used to treat malaria and other fevers. And aspirin, because I want to talk about aspirin, derived from willow bark and other plants and also used to treat fevers and pain. Full disclosure, I don't remember exactly how much I covered in either episode about this, but I'm going to talk for just a second about the enormous role that these two substances played in the development of the chemical and pharmaceutical industry in the 19th century. So the plant sources of both quinine and aspirin had been used for hundreds of years to treat fevers and pain,

But it wasn't until the first decades of the 1800s that the active compounds, quinine and the glycoside of salicylic acid, were isolated. And that was thanks to huge advancements in the field of chemistry. And what this meant, what this isolation of these chemicals meant, was that the effects of these two compounds could be studied individually and in association with different dosages. and that they could be administered more accurately because you were giving a known amount of its pure form rather than accrued preparation. Right. Because like the amount of quionine varies in different parts of the bark and from tree to tree and so on and so forth. So you're like taking a medicine rather than just like chewing on the bark. Exactly.

Yeah. And that's great news, right? Like having these extracts is awesome. Except for the fact that getting enough of the source material, a.k.a.a. the plants to meet demand was a huge problem. Oh, yeah, I bet. And the British Empire especially wanted a ton of quinine to protect their officers and administrators of tropical colonies from malaria. Quineine has been called one of the major tools of imperialism of the British Empire. I feel like I do remember you talking about that in the malaria episode. Yeah, I feel like there's so

much more to that history of Sinchona Bark and Quineineineine that, like, I didn't cover. but anyway, look into it. It's really interesting. But this is just to show you that by the mid-19th century, the need for alternative pain killers or fever reducers was enormous. Like people just couldn't get enough of what would later be known as aspirin and quinine. Fortunately, improvements in technology and major intellectual advancements in all fields of science, basically, meant that the field of chemistry was up to this task. In this quest to find alternative pain killers or fever reducers, chemists first directed their focus towards extracting compounds from natural sources, figuring that there had to be more plant parts like willow bark or cinchona bark that harbored

potential drugs. But then, with the birth and rise of industrial chemistry, chemists began to work on the synthetic production of drugs, mass-producing. compounds that they previously had to extract or just creating new ones entirely. What an interesting time. I know. I, you know, I feel like I have never really talked very much about or thought very much about the history of chemistry, but we should try to do more of that. I feel like you've alluded to it on several of our episodes and it has always blown my mind every time. And so, yeah, how do we do that? We'll brainstorm. We'll brainstorm. Yeah. Yeah. And because I have to mention germ theory, as I always do, even in an episode on paracetamol.

Contractually required. Just kidding. Just kidding. When germ theory was introduced in the mid-second half of the 19th century, and malaria was shown to be caused by a parasitic organism and that quinine worked in part to actually attack the parasites, people began looking more towards chemical compounds to treat diseases and not just the symptoms of those diseases. Right, right, right, right, right. So that does become relevant in a second here. Oh, okay. But here's where the history, I think, gets a little bit chemical.

So I'm just going to do the best that I can in taking us through it without getting to bog down in the ides or ines or. or whatever. And for those of you who want that more extensive thorough history, I'll post some great sources where you can get it. Okay. So in the 1880s, a couple of young physicians, Khan and Hep at the University of Strasbourg,

had a patient come in with intestinal worms. They weren't sure how to get rid of the worms. So they went to their professor, who was the famous physician Adolf Kusmall, to ask his advice. As in Coosmal breathing? Wow. Mm-hmm. He suggested that they used something called naphthalene, which had been prescribed before as a quote-unquote internal antiseptic.

And so this is, again, trying to treat the worms. This is where the germ theory thing becomes relevant. They're like, we're going to try to eliminate these worms. Okay. They went to the pharmacy to get some of this naphthalene stuff, gave it to the patient, and were surprised to see their fever plummeted. which was not one of naphthalene's known effects. So they were like, uh, what just happened? First of all, this is really weird.

Why hasn't anyone described this before? This would be really great if we could use this as a fever reducer. Yeah. So then they were like, all right, let's dig around. Let's see like what's going on here. And they found out that the pharmacist had not, in fact, given them naphthalene. Oh, dear. But rather, something else entirely.

A compound called acid anilide that had not been used in medicine before, ever, but was actually a byproduct of the organic dye industry. I don't know how. What? Yeah. What? Apparently, that is where, that's what acid analyde came from. But, like, why was it at the pharmacy? I don't know.

They were handing this out. They're like, it's cool, bro. What? So maybe the pharmacist was more like a chemist in that sense. Like it wasn't just someone who only worked on medications, but also just on chemicals more broadly speaking. Oh, so maybe they just like had that and by accident got it mixed up? Yeah. I think that that is my understanding.

Oh, my gosh. Wow. Okay. Yeah. Yeah. Wow. But I mean, like, this story could have ended in so many other. Very differently. Very, very bad ways. Yeah. Yeah. But once the two physicians realized that not only did this acid analyde not poison people, but it was actually a super effective fever reducer, they were like, boom, we're marketing it and we're naming it anti-febrin. Okay. So then they started selling it. Okay. And this, the success of this kicked off a ton of research into these types of compounds as potential fever and pain reducers, especially the search for ones that didn't cause some of the bad side effects that acid analyte had. So once it started to become more widely sold, people were finding that it interfered with hemoglobin's ability to carry oxygen in the blood.

And so they were like, we kind of need something that doesn't do this. We kind of need to be able to carry oxygen. It's like a little important. It's kind of important. See our altitude sickness episode. But this boom and research also revealed that a metabolite of acid analyte. So a metabolite basically means something produced by the body after breaking down acid anilide, that this metabolite might hold some promise. It was called.

Paracetamol. Story over, right? The end, yeah. The end. Yeah. Never is. No. In 1893, a world-renowned clinical pharmacologist named Joseph von Mering

ran some trials on this metabolite paracetamol, comparing its efficacy and safety with existing fever reducers or painkillers. And he was like, hey, this is great. Paracetamol reduces fever and pain, but it's actually just as dangerous as acid analyde. It also interferes with oxygen transport by hemoglobin. No one should sell it. It's not going to be a good replacement. Kind of weird, right?

Mm-hmm. Because we know that it doesn't do this. Right. And while, yes, you talked about that it can be toxic in large amounts if not taken as instructed, Von Mering wasn't working with enormous doses, but like standard ones. So researchers today think that the paracetamol that he was using in these tests had been contaminated in some way, possibly with like acid analyde or one of the previous steps. Interesting.

But von Mering had such a strong reputation that no one questioned his results. for 50 years. 50 years. What had he done to be so well-renowned, man? You know, I don't know. I also don't know if it was one of those things where they were like, oh, you know, this whole thing is toxic. Like how much interest was there in acid anilide and paracetamol and so on?

Yeah, that's so interesting. Yeah. People were like, oh, there must be other things that we could. put our attention to. So I don't know. But yeah, 50 years. And I don't know what happened in the 1940s that prompted this, but around that time, two researchers named Brody and Axelrod began a systematic study into paracetamol. Wow. And in 1948, they published a paper that outlined how paracetamol was actually the compound responsible for the fever-reducing or pain-reducing ability of acid analyde.

And importantly, it did not have the hemoglobin oxygen interfering effects that acid anilide had and that von Mering was mistaken. Yeah. Paracetamol also had some advantages over popular painkillers of the day. It could be given to kids as well as people with stomach ulcers, both for whom aspirin was a big no-no. And Brody and Axelrod's paper. on paracetamol were enough to convince the medical and scientific community that it was worth

another shot and that it could and should be marketed. And so in the 1950s, it began to be sold, first generically in 1953 and then as Tylenol in the U.S. in 1955 and as Panadol in Britain in 1956. So hopefully that wasn't too confusing of an origin story. But I just, I feel like it is so amazing that we have this thing at all. Yeah. And I wonder whether this kind of bizarre, accidental, so many things had to happen, origin story may play a role in like why we still don't know. Because like this thing was just, here's this random chemical that somebody is getting. And well, and then for it to be known, used a little, had someone say, no, no, stop using it. 50 years later, no, no, it's the safe version.

Like, that's a lot of like whiplash back and forth to then just be like, okay, cool, we're just, we're using it. Yeah. Let's not question it too hard or something. I don't know. Right, right. Yeah. And after this long and bizarre and kind of unexpected journey, once it was on the market, especially in the early years, it seemed like a really safe alternative to Nseds. Right.

like I mentioned, were increasingly becoming associated with GI ulceration and hemorrhage. But it wouldn't keep that super 100% safe reputation for very long. In the 1960s is when reports of severe liver damage began to spring up in association primarily with intentional overdose. But the publicity of these reports did hurt the popularity of paracetamol for a while, which, like you talked about, Aaron, is actually like, quite a safe medication when taken properly. However, these reports were nothing compared to the infamous and heartbreaking tragedy surrounding Tylenol in the early 1980s. Yep.

Introducing the Tylenol murders. Before I get started, I want to give everyone a content warning here that I will be talking about the deaths of several individuals and you can skip ahead. I don't really know, but like maybe 25, 30 minutes to be on the safe side, if you like. You can always backtrack if you need. Yeah, yeah. I also want to shout out the sources for this section right at the top here. I primarily used the online articles and podcasts produced by the Chicago Tribune in September and October of 2022.

Investigative reporters Christy Gatowski and St. Clair did an amazing in-depth review and investigation. of this case and where we are today with it, and you should check it out for much more detail and much better storytelling than I'm about to do. The Tylenol murders began on September 29, 1982, a regular Wednesday morning for most of the residents of the suburbs around Chicago. Early that morning, at around 6.15 a.m.,

a 12-year-old named Mary Kellerman, woke up with a bad head cold. She convinced her dad to let her stay home from school that day and went into the bathroom to take a couple of extra strength Tylenol that her mom had bought from the store the night before. Not more than a few seconds passed when Mary's dad heard her coughing and then collapsing to the floor. He rushed in and found her on the ground,

breathing shallowly and with her eyes fixed and dilated. He called the paramedics, but they weren't able to revive her. Mary's mom arrived home in time to see her only child being placed in an ambulance and was held back from getting any closer to her. Mary was in full cardiac arrest even before reaching the hospital, and this happy-go-lucky, inquisitive, kind, and so very loved 12-year-old was pronounced dead at 9.56 a.m. This was a nightmare, and it was only the beginning. That same morning, around 11 a.m., 27-year-old Adam Janice, resident of nearby Arlington Heights, was outrunning errands with his wife, Teresa, and their young kids. This is the firsthand account I mentioned. One of his stops was at a grocery store where he picked up, among other things, a bottle of extra strength Tylenol.

When he got home and put the groceries away, he opened the bottle of Tylenol and swallowed a couple. Within moments, he came out of the bathroom, clutching his chest. breathing shallowly, and his wife saw that his eyes were fixed and dilated. Again, paramedics were called, and again, they couldn't do anything to save Adam. He was pronounced dead at the hospital at 3.15 p.m. No one knew what had killed him or Mary, but a massive heart attack was suspected in Adam's case, and the two deaths had yet to be linked. At 3.40 p.m., a resident of nearby Chicagoland suburb Winfield, named

Mary Lynn Reiner was home with her six-day-old son. Before feeding him, she took a couple of Tylenol that she had bought earlier in the day to ease her headache. She began to feel dizzy and collapsed almost immediately, experiencing seizure after seizure. She was also taken to a nearby hospital where she was put on life support. She died the next day. Going back to the Janice family, who had gathered at the hospital where they were informed of Adam's death, Adam's wife, parents, sister, brothers, and their wives decided to gather back at Adam and Teresa's house to start planning his funeral.

Adam's brother, Stanley, wanted to head back to his own house with his wife, Terry. They had just married three months ago. They hadn't even gotten the wedding pictures back yet because his back pain had started to flare up, but his mom convinced him to stay. When he and Terry got to Adam and Teresa's house,

he said he was going to take a couple of times, Tylenol for his back pain and headache and asked if anyone else wanted some. Everyone else said no except for his wife Terry, who also had a headache. He grabbed the bottle that he found in Adam and Teresa's bathroom, took two for himself, and gave two to Terry. Within moments, both Stanley and Terry began complaining of chest pain and collapsed. Again, the paramedics were called, and they were shocked when the call came in. because it was the exact same address as just a few hours before.

And when they got there, it was like the most horrible deja vu. They found a frantic family huddled around Stanley and Terry who were on the floor breathing shallowly and with fixed and dilated eyes. What was happening? Remember, they thought that Adam might have had a massive heart attack, but it was next to impossible for two other young and healthy members of his family, 125 and 120 to also have died of heart attacks within a few hours. Something was terrifyingly wrong. Oh. Yeah. Sorry. I know that was a lot. There is more. Yeah. I have, I mean, I have heard of this,

but I don't think I've ever actually heard it all laid out side by side. And it's just, it's really horrific. It is really horrific. And that's one thing that I kept. feeling when I was when I was reading these articles or checking out the podcast was just like this sensation of like terror like to to to have this unfold throughout the course of a day and not know what was going on and be like where is this how is this going to stop is this ever going to stop and just like the absolute tragedy for the families and it's just it's just it's just often full. Yeah. Yeah, I feel like in public health, we often learn about it from like this change, the way we package drugs. And I'm like, well, there's also like the lived experience of it too. That's, I feel, I don't know. Yeah. Which and it's all of that is important. Yeah. Yeah. Yeah. Yeah. But yeah. And so at this point, it was obvious that something was really terrifyingly wrong, right? was it a deadly airborne pathogen or an environmental poison that somehow people were exposed to?

Because at this point right now, you know, only the Janus family is showing the link, right? This is where the cluster is that's like what is happening here. Right. The other cases have yet to be linked. Linked. Yeah. Yeah. Because it's all, you mentioned like different suburbs every place.

Different suburbs. Yeah. Isolated cases. Right. But and so because this was happening, within one family, the family, the Janice family, was rushed to the hospital to be put in an isolation room. Oh my gosh. Yeah, can you imagine how terrifying that would be like not knowing? And while the family was in isolation and while Stanley and Terry were fighting for their lives,

in a town 20 miles away, a woman named Mary McFarland, who was single mother of two young boys, was at work with a headache. She grabbed a freshly purchased bottle of Tylenol from her purse and took a couple of pills, you can guess what happened next. Moments later, she came back into the break room saying she didn't feel good and she collapsed. The paramedics, when they got there, attempted to revive her and her friend mentioned the Tylenol, but the doctors told Mary's family that they suspected a massive stroke. One more death would round out this horrifying day. Paula Prince, flight attendant for United, stopped at a store after a long day of work and picked up a bottle of Tylenol.

When she got home, she took a single capsule from her new bottle while getting ready for bed. And her sister and friend found her body two days later. Oh, no. Over the course of less than 24 hours, seven people, Mary Kellerman, Adam Janice, Lynn Reiner, Stanley Janice, Terry Janice, Mary McFarland, and Paul. Paula Prince unsuspectingly swallowed Tylenol pills that would kill them. When did people start to connect the dots? Turns out pretty quickly. After the paramedics were called to the Janice's house for the second time for Stanley and Terry,

the fire department was also called because the situation was so unusual. Fire lieutenant Chuck Kramer was one of the firefighters on the scene, and he suspected right away that something wasn't right, that these were not heart attacks, and that someone in public health should probably get involved as soon as possible. So he called his friend, the only public health official in the area, nurse Helen Jensen. She rushed to the hospital and started asking the Janice family about their day, what they had eaten, where they went, and she learned that all three of the people who had gotten sick had taken Tylenol just moments before. So she then went to their house to see if she could spot anything. She looked around,

found the bottle of Tylenol, counted them all out, and found that six were missing, two for each person who had gotten sick. Of course, no one believed her when she went back to the hospital and told a rep from the Cook County Medical Examiner's Office that she thought the cases were linked to Tylenol. She repeated herself several times, was met with skepticism each and was like, you know what? Okay, I'm going home. But her friend, Fire Lieutenant Chuck Kramer, who had called her initially, he had learned of her suspicions, and he told a friend of his, another fire lieutenant, Phil Capitelli, who mentioned that Mary Kellerman, the 12-year-old who died, had also taken Tylenol moments before collapsing. That seemed like too much of a coincidence to Kramer, who called the hospital. where the Januses were and told their doctor, Thomas Kim, what he had found out. Dr. Kim was interested and had already suspected that the Januses had ingested some sort of poison, but this didn't seem like the other cases of paracetamol poisoning that he had treated in the past.

For one, the symptoms were wildly different, and for two, paracetamol poisoning took much longer to show. There was only one poison he could think of that caused deaths. so quickly after ingestion. Cyanide. Yeah. He ordered cyanide tests to be done on blood from Stanley and Terry. And meanwhile, a police officer picked up the bottle of Tylenol from the Janus House and brought it to the hospital. The deputy chief medical examiner told his investigator, who was at the hospital, to take a whiff inside the bottle.

Like just smell it, which not a good idea necessarily. But what he smelled was bitter almonds, which is the signature scent of cyanide. But also apparently I read that only 60% of the population can even smell it. So like, pretty amazing. Yeah, yeah. And the blood test from Stanley and Terry came back at 1.30 in the morning, and they showed an incredible amount of cyanide, certainly the cause of death. Later analysis would show that each pill in the Janice's bottle had an amount of cyanide three times what would take to kill someone.

What? Each pill. Each pill? Yeah. The news of the cyanide-laced Tylenol pills didn't break in time to be included in the next morning's newspapers. But it was broadcast on local TV and police and public health officials went around door to door. posting flyers, warning about the pills, ordering stores to pull it from shelves, and driving around using bullhorns to announce like, hey, if you bought Tylenol, throw it away.

Whoa. Yeah. And amazingly, probably due to what seems like in an incredible speed with which this medical mystery was solved, no other deaths occurred from the tainted bottles. And at least three other bottles were found, but it's, likely there were more because so many people just simply threw them away. That was going to be my question is, did they find any other bottles? They did. Yeah, they found a handful more, only three, but like, yeah. Wow. Likely there were more out there. And these tainted bottles

had been sold from grocery stores all around the Chicagoland area. That is so, I think that's one of the weirdest parts. Yeah. Like the wide distribution of them and how it all has. happened like so fast. And like all at the same time. Yeah. Like what? That's what? Yeah. Yeah. It's yeah. And also I think that that is sort of what helped contribute in some way to both confusion initially, but also figuring out what was actually going on. Because it wasn't immediately clear whether these bottles had been tampered with or contaminated sometime during the manufacturing process, in which case, like, whoa, we may have a nationwide problem, or did someone slip the cyanide tainted bottles onto the shelves in these stores later on? Right. And just in case it was

the former that it was a manufacturing contamination, Johnson and Johnson, who produced Tylenol, halted production, issued recalls, stopped advertising, and sent out, like, tons and tons of warnings. but when it was found that the bottles were from different lots entirely, it seemed much more likely that it was like an individual or a couple individuals that did this. Right. How? How do they do this? How? Simple.

Like disturbingly simple. Today, when you buy a new bottle of Tylenol or any other over-the-counter medication or anything, really, it comes in tamper-proof packaging in a sealed paper. paper box, plastic wrapped lid, foil seal over the top, several things that would make it apparent if someone else had opened the bottle before you. Back in 1982, that type of packaging did not exist yet. You could say, buy a couple of bottles of extra strength Tylenol, bring them home, take them out of the non-glued box, unscrew the cap, replace the acetaminopin inside the capsules with cyanide, put them back in the bottles, screw the cap back on, put the bottles back in those

boxes, and then just walk into the store and put them back on the shelf without anyone realizing. Oh, wow, the 80s. It's, yeah. Wow. It's kind of, like, I think from our perspective today, with literally everything that is, Tampa proof packaging, hard to imagine. Like mustard. Yeah.

Everything. Yeah. It's kind of like a loss of innocence in a way. Like it's like, oh, wow. Yeah, I don't know. It's just, it seems very shocking. Yeah. That that was not something that you did immediately.

But then when you think about it, it's like, oh, it's so sad that all of our, everything we buy has to be. like that because because people will people will murder people yeah yeah for example as an example not just like

take a few pills you know like then you're getting less than you paid for or something it's like oh no we replaced all the pills with cyanide what right right yeah so so what the heck yeah great question investigators

knew pretty soon after the murders happened, what had killed these people and how they had gotten exposed, which honestly, like, it still, I think is so amazing how fast that was solved. And I think in large part, it's because the Janus family and how it was like, okay, what is the commonality among these three individuals? And then, but also like this fire lieutenant talking to this fire lieutenant calling this particular nurse who just like had that like detective work. down. It's just amazing. I think that's my favorite part is that not only did the fire lieutenant call his buddy,

but that person also had heard about the Tylenol with the other person. And so then how many other fire chiefs did they call or like whoever it was that they called from the other suburbs and places like, I mean, because all of these would have been very like dramatic at whatever hospital these people presented. to. Right. But it's still very amazing that that information got passed around so rapidly to be able to identify all of these and then really pinpoint it so that you could get the word out everywhere and not just in the one neighborhood. Right. And, you know, different hospitals were involved in this. Yeah. And then you have the doctor going, oh, I think it's cyanide. Like, right. It's so amazing.

And then all within 24 hours. And so the number of lives. And so the number of lives. I feel like that were saved. I mean, I think it's absolutely horrible that seven people lost their lives. But it's also like you can imagine how if it hadn't been solved so quickly, there could have been so many more. Ugh, it's just, yeah. But yeah, so even though they figured this out so quickly, there were two big questions that remained, who and why. Yeah. The short answer is like the mechanism of.

Acetaminopin paracetamol, we don't know. Oh no. To this day, no one has been charged for these murders. There are a few notable suspects, one in particular, and the Chicago Tribune series is excellent if you want to get all the details about who investigators suspected and why. There's like a whole, it's really good. And I'll just briefly tell you about one of them that seems like the, prime suspect and some of the reasons why he is. So a week after the murders, Johnson and Johnson

headquarters received a letter saying, if you want to stop the killing, wire $1 million to this bank account. Huh. The letter was traced to a 36-year-old man named Jim Lewis, who had ties to the Chicago land area. At first, investigators thought that he was probably just an opportunist trying to profit off of these deaths. But they dug a little deeper and found that he had been charged in but not convicted of a murder in Kansas City four years prior, showing that he was potentially capable of violence. And he was currently under investigation for a credit card scam. He was tried for extortion. And while he awaited sentencing, he reached out, Jim Lewis reached out to an FBI agent on the case and offered his expertise, drawing detailed sketch after detailed sketch of the

logistics of poisoning, the capsules, like how you would go into this store versus this door and how you would empty out the acetaminophen with cyanide and replace it with cyanide and all of these things and like troubleshooting. What would happen if something went wrong? What would you do in this case versus this case? He wanted to read all the case files, like get really involved. A little bit suspect, right? Circumstantial. But anyway, ultimately, Lewis was sentenced to 10 years in prison for the extortion letter plus time for the credit card scam. And when he was released in 1995, the FBI still had him in mind for the murders, continuing to monitor him and even running an undercover sting in 2007, where an agent posed as someone writing a book

about the murders and offering to clear his name. They collected lots of strong circumstantial evidence against Lewis for one motive. So he had a young daughter named Tony who died after a heart surgery, her second, and an autopsy revealed that the sutures that had been used in her first heart surgery were made by Johnson & Johnson, possibly faulty, possibly contributing to her death, during the second heart surgery. Oh. So maybe investigators thought that he wanted to take revenge on the company in this way.

Mm-hmm. Number two is that he allegedly wanted to start a pill-press business, so like making pills. Hmm. Number three, his timeline for being out of town and writing the letter kind of changed. So, like, he definitely wrote the letter, but he, like, when was it sent? Was it sent before the pills were placed on the shelves? or before the news broke, like, how did that all sort of come into play? And that sort of is in question, but how much of that is like just incorrect recall?

And, you know, 40 years have passed. I don't know. But there's been a lot of DNA testing in recent years of the bottles that are still, you know, in evidence or whatever. And none of them have linked him physically to the pills. And the investigation is still ongoing. currently. Wow. Wow. Yeah. There's there's so much more to that case. Like really most, I feel like most of why I talk about is like the first article and then like snippets of like each of the later ones. Wow. But yeah. But the Tylenol murders prompted huge changes both in the

way pharmaceuticals and other products are packaged as well as it disrupted the sense of of safety or trust that the public had in these products. Two months after the murders, tamper-proof packaging was introduced, and in 1983, it became a federal offense to tamper with consumer products. By 1989, the FDA introduced guidelines for all consumer products to have tamper-proof packaging. Still, it took a long time for the public to trust Tylenol and other medications again. And one of the sort of the sort of of like searing things, I think, about the story about these cases is the horror of it all, right? Like these people's lives were just ripped away from them, like within moments who were just

completely out of the blue doing nothing and then one day attacked for no reason whatsoever. And then just like, that was it. It's done. And it just feels like such a senseless and horror. horrible thing. And I think the horror of it all and how scary and how how this was able to happen is really, you can see that in just how rapidly things changed and how much things changed in terms of like it is really, I mean, there was a before and after, very starkly different in terms of like tamper-proof packaging, how we approach that, how we view safety in stores.

protections for consumers. And it is horrible that these deaths had to spur that on. And it's also horrible that their family members and their friends and their loved ones still don't have the resolution and closure in the form of justice. Yeah. It is remarkable how this one incident in being so terrifying and horrific literally changed not just an entire industry, but like how all consumer goods are packaged and how we view consumer safety in that way.

That's, it's massive. It really is. And I think there was at least something I read that suggested that the Tylenol murders actually sort of inspired or fueled the fear surrounding Halloween candy in the early 1980s, particularly that year where they were like, oh, Halloween candy is poisoned, it's tainted, blah, blah, blah, which it's like, well, you just, yeah. So, yeah. Anyway.

Oh, wow. Yeah. Okay. Well, with that, Erin, true crime podcast over and back to science podcast. I'll turn it over to you to fill us in on where we are with time and all today. Okay. We'll take a quick break and I'll do my best. So like I said at the top, acedaminopin, paracetamol, remain.

one of, if not the most, widely used over-the-counter medications worldwide, especially of analgesic antipyretics like pain reliever, fever-reducer medication. It also, in many countries, is one of the most common causes of both intentional and unintentional overdose admissions to hospitals. And in the U.S. and the U.K. and Europe, one of the most common causes of acute liver failure, as well. I could not get solid data on the exact number of overdoses or deaths or even liver transplants that are due to acetaminopin toxicity worldwide. Most sources that I read for the U.S. data cited about 56,000 overdoses that result in emergency department visits and up to 500 deaths

annually in the U.S. But from what I can tell, that's data from like 2005 that's just still cited everywhere. So I don't know if there's more up-to-date data. And it seems like that might not be the most accurate because some of the numbers that I saw from the U.K. are quite significantly higher in terms of overdoses, like 80 to 90,000 hospitalizations, but between 150 and 200 deaths. And obviously our population sizes are very different. So it's really hard to say how many people this is affecting worldwide, but certainly it's not an insignificant number of people that are becoming very sick or potentially dying from liver toxicity associated with the Cedaminopin.

However, there's also tens of millions of doses that are taken every single day across the globe. This is an incredibly ubiquitous medication. So again, this is something that when taken in the dosages that are recommended or below the maximum recommended doses is quite safe. But I think that this idea of how do we determine what is safe and what a maximum dose should be, and how do we label medications and package medications? to let people know what is safe and what is potentially dangerous about them is kind of where the story of acetaminopin or paracetamol is going and is likely to continue to go in the future. There was a really comprehensive, very, very, very long article published by ProPublica from 2013,

so it's fairly old now. But I found it really interesting because it really focused on the pushback from manufacturers on changing anything about the way that we label acetaminopin to let people know that it is potentially toxic and specifically what that toxicity might look like because acetaminopin toxicity, because it can build up over several days, you might not know that it's happening while it's happening. So it could be asymptomatic, right? And there's been a lot of pushback or laxity from like the FDA in terms of implementing stricter safety measures, which we've seen implemented in other countries like the UK, which has much stricter requirements on how many pills can be in a package and things like that with mixed results on whether that's actually decreased overdoses overall. But at least there's like public health attempts, if that makes sense.

So I think that that's kind of an important part of the acetaminifin story is really not only understanding the mechanisms, how is this really working in our bodies. Are there other like chronic effects that we might not be aware of that are happening or are they only happening at very high doses? How do we label this medicine that's so ubiquitous, right? It's in so many of our other like mixed formulation drugs that are available over the counter. And in some cases, in relatively high quantities that you might not realize altogether add up to more than four grams. Right. Are there other public health measures that could be implemented that would reduce the risk of unintentional overdoses, especially, as well as intentional overdoses? So I think that that's kind of where the future of acetaminopin research.

and like public health is likely going to go. And I think for me, what it really highlights is something that that we've talked about actually kind of a lot on this podcast. And that is that the dose makes the poison, right? Yes. Literally nothing. No medication. Antibiotics.

Anti-fever. Pain medication. Gas medication. Constipation medication. Any medicine, any drug, any thing that you. consume or put into your body has pros and cons. It has the potential to help us and has the potential to have undesirable side effects. And so all of medicine is balancing these and making sure that the benefits outweigh the real or potential harms. And so I think that maybe for

acetaminophen, there's been a long period of just focusing on all of the benefits. and the fact that it is safer than Ns in certain respects. It is safer than Ns in terms of risk of GI side effects or even kidney side effects. But that doesn't mean that it's without its potential for very serious harm. And so how do we then balance that both on an individual level and also on a population level from a public health perspective? Yeah. Yeah. So that's paracetamol?

Acetaminophant. Sources? Sources. Okay. I have several for like the history of acetamin paracetamol. I'll shout out one in particular by Bruna at all from 2014 called Acetaminin paracetamol, a history of errors, failures, and false decisions. Oh, I read that one.

And then again, I'll shout out just the amazing series by Chicago Tribune on the Tylenol murders. The podcast I will shout out specifically is called Unsealed, the Tylenol murders. I had quite a number of papers for this episode, most of which focus on the various mechanisms. So there's a lot more detail there if you want to know all about it. one of my favorites for just a very good overview was a paper from 2020 in Frontiers and Pharmacology titled The Analgesic Effect of Acetaminopin, a Review of Known and Novel Mechanisms of Action. I thought that was a great overview. But there's a ton more.

And I will link to that ProPublica article if you want to dig deep on all of that business. So we'll post all of our sources from this episode and all of our previous episodes and future episodes on our website. This podcast will kill you.com. We certainly will. Thank you to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to Leanna Squillachi for the amazing audio mixing. And thank you too, exactly right? And thank you to you, listeners. Hopefully you enjoyed this episode. You learned something. It was interesting. Yeah. And a special thank you, as always, to our wonderful, generous patrons. Seriously, thank you, thank you. Thank you. We can't.

We can't do it enough. It's true. The thanking of the you. Yeah. Well, until next time, wash your hands. You filthy animals. This is Bethany Frankel from Just Be with Bethany Frankel. Listen, I have a bone to pick with these dog food brands calling themselves fresh, natural, healthy.

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