Guns ‘n Roses were infamous for their offstage antics, antics which inspired some of their most famous songs. “Mr. Brownstone” is a song about heroin, a drug with which GnR was very familiar, and the lyrics nicely illustrate why the drug is so dangerous:
“I used to do a little, but a little wouldn’t do/so the little got more and more/I just keep trying to get a little better/said a little better than before…We’ve been dancing with/ Mr. Brownstone” etc.
Since the purity of the product varies, users inject heroin without knowing for certain the concentration of the stuff they’re injecting. (For me as an analytical chemist and biochemistry nerd, injecting a solution of unknown concentration is a frightening thought.) Almost anything becomes toxic at some dose; and the toxic dose for heroin isn’t that much bigger than the dose required to get high. Moreover, the addict is injecting the drug directly into their bloodstream, so the body can’t try to prevent more drug from entering by throwing up, like the way you start throwing up when you drink too much ethanol. It’s only too easy to miscalculate and overdose — a mistake that can easily end in death.
Given all this, it may seem bizarre that heroin was once sold as cough syrup, the kind of drug that parents gave their children. For the scientists who invented heroin didn’t mean to invent a highly addictive drug: in fact, they invented it by mistake. And the story of that mistake is one of the strangest in the history of drug discovery.
The seed pods of the opium poppy contain a milky sap; when dried, the sap is called opium. Although opium contains a variety of interesting compounds like codeine and thebaine, the main active ingredient is morphine. When you smoke opium you’re vaporizing some morphine, codeine etc. and inhaling it. The morphine is what makes opium both pleasurable and addictive.
If you compare the chemical structure of morphine with heroin, codeine and hydrocodone, you’ll notice something interesting. With the exception of a few tweaks, a group added here or removed there, they’re all extremely similar. Those few “tweaks” are what make the difference. (Again, all drawings borrowed from Wikipedia because I don’t feel like drawing my own right now.)
Notice that just like cocaine, morphine and its relatives contain an “amine” group, a nitrogen atom with a bunch of carbons attached to it, and just as in cocaine that amine acts as a base. (See part 1 for more about bases, acids, and why some things dissolve better in water than others.) So just as with cocaine, the salt I get by mixing morphine or heroin with an acid (e.g. hydrochloric acid, HCl) dissolves much better in water than the “freebase” form. If you want to smoke heroin, the freebase form would be better because it will vaporize more readily. Most users just want to dissolve the drug in water and inject it, though, so the hydrochloride salt is exactly what they’re looking for, and if you buy it on the street adulterated heroin HCl is probably what you’re getting.
To make heroin, you take the two OH groups on morphine and react them with acetic anhydride, which sticks two CH3-C=O groups on there. CH3-C=O is called an acetyl group. The verb acetylate just means “to add an acetyl group”, so heroin is just an acetylated form of morphine, and that’s why it’s sometimes called diacetylmorphine. The two OH groups in morphine can act as hydrogen-bond donors to form hydrogen bonds with water molecules. The oxygen in the acetyl groups, by contrast, can act as a hydrogen bond acceptor but not as a hydrogen bond donor (it doesn’t have a hydrogen attached to it). As we know from “like dissolves like”, the more hydrogen bonds it can form, the better it dissolves in water. Heroin can form fewer hydrogen bonds, and that’s why it’s less soluble in water.
Now here’s the interesting part. Morphine is better than heroin at binding to the opioid receptors in your brain; in other words, it binds to them more tightly. Based on this alone, you would expect that morphine would give users a better high than heroin, when clearly the reverse is true: heroin is more potent and more addictive.
And to make matters even more complicated, consider this. Heroin rapidly breaks down into morphine in your system. You can even think of heroin as a “prodrug”, a compound that gets converted into an active drug(s) inside your body.
So why does it give users a better high? The reason is water solubility.
What happens after you take a drug (any drug — aspirin, tylenol, ethanol, nicotine, caffeine, whatever)? First of all, if you take the drug orally, it has to get absorbed through the lining of your intestines. At that point, your bloodstream transports the drug throughout your body, and some of the drug enters your tissues. Meanwhile, your liver (and sometimes enzymes in your bloodstream) are working to break the drug down or metabolize it by altering it through chemical reactions. Finally, the drug is being removed from your system by your kidneys, which filter your bloodstream.
If we take samples of your blood at regular intervals after you take a pill and measure the concentration of the drug in your blood, we’ll get a so-called PK curve. The shape of this curve varies depending on the structure of the drug molecule, because that structure determines how well the drug gets absorbed, how quickly it gets distributed into your tissues and how rapidly it gets metabolized by the liver.
Most heroin users are injecting the drug, so absorption isn’t an issue — the whole dose hits their bloodstream right out the starting gate. Where metabolism is concerned, however, heroin gets broken down into morphine and related compounds like 6-monoacetylmorphine within mere minutes. Meanwhile, the liver gets busy chemically modifying the morphine by attaching a sugar called glucuronic acid. Most of the total heroin dose will eventually end up in your urine in the form of morphine attached to glucuronic acid. None of this in and of itself is terribly surprising. What makes heroin so much more potent than morphine is the difference in distribution.
Your brain is one of the most important organs of your body, and evolution has devised some safeguards to protect it from chance injury and misfortune. One of these is the blood-brain barrier. The cells that line blood capillaries in your brain are tightly linked to create a barrier that hinders many substances from crossing. The two acetyl groups on heroin make it less soluble in water and thus more soluble in fat than morphine, and since it dissolves much better in fat, heroin diffuses through the blood-brain barrier many many times faster than morphine. That’s why heroin gives you a better high: a much larger fraction of the injected dose actually ends up in your brain tissue. The higher drug concentration in your brain tissue means more of the opioid receptors are bound by the drug, so the effects are much more intense.
But if adding the acetyl groups makes morphine more fat-soluble and thus better at getting into your brain, why did the Bayer chemists do it? The simple answer is they did it by mistake.
Humans have used the bark of the willow tree to ease pain for thousands of years, but it wasn’t until the nineteenth century that chemists isolated the active ingredient, a molecule called salicylic acid. They started using this as a pain reliever, but unfortunately the pure stuff is a bitter-tasting irritant. Bayer Corporation wanted to find a form of aspirin that patients could take with fewer side effects. A Bayer employee named Felix Hoffmann came up with the solution. By reacting salicylic acid with acetic anhydride, he added an acetyl group, creating acetylsalicylic acid or aspirin.
Much to management’s delight, Hoffmann’s new drug was a huge improvement. Not only was it more tolerable, it was a better pain reliever. Neither Hoffman nor his management realized how lucky they’d been, however, because although aspirin and salicylic acid are both pain relievers, they work in different ways. By adding an acetyl group, Hoffmann had unwittingly taken a drug that worked in one way and converted it into a different drug that worked in another. But our knowledge of biology and biochemistry was more primitive back then, and Hoffmann had no idea how aspirin worked. He only knew that adding an acetyl group had transformed a poor drug into a more effective one.
And that’s why Hoffmann was adding acetyl groups to all kinds of other molecules too, in hopes that he could make them into better drugs. Another drug he worked on was morphine. Doctors had made widespread use of morphine as a pain reliever but had also come to realize it was highly highly addictive. Bayer was seeking modified forms of morphine that would relieve pain without getting patients hooked. So two weeks after he made aspirin, Hoffmann tried acetylating morphine too, hoping he could turn it into codeine and thus find a cheaper way to produce the latter. (Chemists in the audience may find this odd, but just remember the chemical structure of morphine and codeine was unknown at that time.) What he ended up with, however, was diacetylmorphine, a morphine with two acetyl groups.
Bayer’s management decided to name this new compound heroin as in “heroic”, because Bayer employees who tried the drug said that was how it made them feel, and because “heroic” sounded like a good marketing catchphrase. Unfortunately, Bayer couldn’t patent heroin, because as it turned out somebody else had tried acetylating morphine already. But they could mass-produce it and market it as an over-the-counter drug. And starting in 1898, that’s exactly what they did.
Heroin was very effective at relieving pain, suppressing coughs and inducing sleep. Many American cough syrup manufacturers started adding heroin to their products. And patients liked it. A lot. They liked it so much that many of them kept on taking heroin even after it was no longer prescribed. Doctors soon realized the new drug was no less addictive than the old, and more and more people were using the drug for recreational purposes.
It wasn’t long before diacetylmorphine’s legal status was changed in the US, and in the 1920s it was banned completely. Organized crime groups rapidly took control of production and supply. The rest, as they say, is history.
For more on the history of heroin, see http://opioids.com/heroin/heroinhistory.html
For more on the pharmacokinetics of heroin, see this PDF.
Elisabeth Rook, Alwin Huitema et al. (2006). Pharmacokinetics and Pharmacokinetic Variability of Heroin and Its Metabolites: A Review of the Literature Current Clinical Pharmacology DOI: 10.2174/157488406775268219
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Never get tired of reading these! Please keep on doing them!
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What makes meth so addictive?
Like other addictive drugs, it activates reward pathways in the brain so that you crave more of the same stimulant in future.
Probably wrong place for this comment, but I really enjoy this blog. Like many I assume, I stumbled upon your work in search of the particulars of methylamine and whether its truly used in methamphetamine production; as an avid breaking bad fan. So, I just wanted to thank you for these contributions. I’m not a chemist, though as a botanist I have endured a full 2 semesters of O-chem; just enough to grasp the concepts explained here. Thank again and keep up the solid work
Is Heroin as a syrup (e.g. Bayer formula) stronger than a tincture of Opium (I.e. Laudanum)? I’ve read that heroin is 3x stronger than morphine, but is Laudanum stronger because all the alkaloids of Opium are present in it? Or is Laudanaum stronger because heroin has a lower oral bioavailability then heroin? Also, is the Bayer Formula essentialy a tincture of heroin?
Would it be possible to do a posting on opium, its alkaloids, and all semi synthetic and sythetic opiates, describing which alkaloids they are synthesized from and a ranking of their strengths (e.g. All the way from Codeine to entorphine)?
Love the blog
Well, the laudanum definitely has a bunch of different alkaloids besides morphine. Heroin does have higher oral bioavailability and undergoes significant first-pass metabolism through deacetylation. I don’t honestly know what the concentration of the Bayer formula was or the concentration of the different alkaloids in laudanum though.
Usually when people say tincture they’re talking about when you use alcohol to extract compound(s) from plant tissue, e.g. from ground up leaves or whatever, so I don’t think you would call the Bayer syrup a tincture. Bayer was synthesizing heroin by first extracting morphine from the dried sap (the opium) then acetylating it. So generally folks buy heroin in solid form, usually as the hydrochloride salt, I think, although maybe some street dealers are selling the freebase form — not sure how common that is.
The opiates comprises a bunch of different compounds. I could do a post on it, but yikes! not sure I want to be THAT comprehensive :). But maybe I can post some more info here. Wanna talk about LSD and weed though.
Lastly, I am just wondering how does Heroin stack up (strength-wise or in layman’s terms which gets you more high?) as a syrup and in free-base form, against Laudanum?
As far as future posts maybe if you have time after LSD and Weed postings. Or if not maybe you could answer this; I’ve been doing some reading about Fetanyl, and alpha-fetanyl, which is quite confusing……what alkaloid is used to synthesize it? It it sythesized from Oxycodeine (thus making it a codeine or codienone derivative)? Or is it a fully synthetic product which isn’t derived from opium or any opiates?
Those were the days! Check out my collection of vintage pharmaceutical ads:
LOL, some of those are kinda funny. I like the one with the housewife and amphetamine.
excellent blog, the most clearly expressed explanation of the chemistry behind breaking bad I have read. Any chance you might do one on the chemistry of explosives?
When I was a child in the 1940’s, our neighborhood druggist, Mr. Murphy, kept some heroin under the counter for his older patients. I’m pretty sure I was given some for a cold when I was about five.
Can you do one on phenobarbital? I believe it was commonly prescribed to suburban housewives in the 50’s and 60’s. I don’t remember but it may have been what led to this woman’s insanity portrayed by Catherine keener in the following film:
I know it was definitely used as the poison in the heavens gate mass suicide. I’d b interested to understand the physiology behind why benzos and alcohol are so lethal.