Zombie Cannabis Hits the Streets

Early in the morning of July 12th 2016 , the police in the Bedford-Stuyvesant area of Brooklyn, NY, were alerted to strange events occurring around the subway station at Myrtle Avenue and Broadway. According to the reports , numerous people, all men, were seen staggering around in a zombie like state making horrible groaning noises. Once the police arrived they found a scene that resembled something out of Shaun of the Dead. Movies posted on social media rapidly made their way round the world where a shocked audience could view the events in real time. Thirty-three men, ranging in age between 29 and 58 years old, were found to be completely incapacitated. Many of the men stared fixedly into space as they stumbled along aimlessly, moving their arms and legs very slowly like automatons. Emergency workers transported 18 of the men to the Woodhull medical center where they were reported to be suffering from “altered mental states”. It seemed obvious that the victims must have have taken some type of mind altering drug. Indeed, events like this were quite common in the area, although this particular case seemed to be worse than the others in terms of the number of people affected and the seriousness of their condition. The profound psychological symptoms displayed by this group of men differed somewhat from the victims of previous incidents who had also suffered symptoms such as psychosis, delirium, cardiotoxicity, seizures, acute kidney injury and hyperthermia.

But what was the drug they had taken, and how had it turned up in this particular area of Brooklyn at this particular time? A foil package was found on one of the victims labeled “AK-47 24 Karat Gold” and was sent to an expert laboratory at the University of California Medical Center in San Francisco to try and identify the drug responsible. The package contained some dried up looking plant material that resembled tobacco or cannabis (marijuana). The scientists extracted the samples and applied the latest chemical identification methods to the extract. The answer turned out to be a substance known as AMB-FUBINACA. It was a conclusion which made a lot of sense. Substances like this had been turning up all over the world resulting in incidents similar to the events in Brooklyn. It was a worldwide phenomenon that encapsulated all the problems associated with the confluence of designer drugs, underground illegal drug laboratories and the Internet. AMB-FUBINACA is what is commonly known as a synthetic cannabinoid, meaning that it was designed to mimic the effects of cannabis, which it does in many important respects. But clearly the drug was having effects on people that are not normally associated with smoking cannabis. It was much more dangerous. To understand where it came from, what it does and how it became part of a new designer drug problem, we will have to briefly look at the history of cannabis.

Just like opium, which I discussed in my previous post, cannabis is an extremely ancient drug. The source of the drug is the plant Cannabis Sativa (or a subspecies Cannabis Indica), more commonly known as the hemp or Indian hemp plant. The hemp plant has been used from time immemorial for numerous purposes. Hemp probably originated in the area around Northern India where it grows wild as a tall gangling weed. However, because it is such a useful plant, humans have cultivated it from early in their history. The stem of the plant is hollow and fibrous and its leaves have a characteristic serrate

Fig. 1 Cannabis Sativa

shape (Fig 1). Tiny glands found all over the plant secrete a sticky resinous material which is the richest source of the psychotropic drug with which it is associated. One of the most important uses for cannabis since ancient times has been the production of hemp cloth which is made from the fibrous stems. A useful oil can be made from the seeds of the plant. All parts of the plant can be used as a source of medical and psychotropic agents but these are most concentrated in the resinous material. Cannabis is referred to in ancient pharmacopeias from China, India and other parts of Asia, as well as in the texts of both Hinduism and Zoroastrianism. Preparations of cannabis were used historically throughout Asia for many different medical problems including pain, nausea, insomnia, inflammation and a host of other indications. The major pharmacopeia of the Zoroastrians listed cannabis as the most useful plant known to man.

Cannabis eventually made its way to Europe and America in the 19th century courtesy of Napoleon’s troops who had encountered it in Egypt. The drug became the darling of Parisian bohemians such as the Club des Hashischins, a group of writers who congregated around the poet Charles Baudelaire. In America, the effects of cannabis were widely disseminated particularly through the writings of Fitzhugh Ludlow in his 1857 book “The Hasheesh Eater”. Tinctures of cannabis were sold by American pharmaceutical companies like Eli Lilly and Parke Davis and were also used as ingredients in many patent medicines.

Of course, just as with crude opium, there was the question as to the nature of the chemical substances in cannabis that were responsible for its diverse medical and psychotropic effects. As I discussed previously, this question was solved for opium in 1805 with the isolation of morphine. Morphine was the first alkaloid molecule to be identified, so called because, from the chemical point of view, it has a basic or alkaline character owing to a nitrogen atom found within its structure. Following the isolation of morphine many other alkaloids were isolated from natural products during the 19th century, including substances like codeine, nicotine, caffeine and numerous others. But figuring out what was in cannabis proved to be a much more difficult problem. Potent concentrated extracts could be prepared from the plant but isolation of its major active

Fig 2. Phytocannabinoids

psychotropic molecule(s) proved elusive. The concentrated extracts that could be prepared from cannabis had the character of oils and it became clear that the active molecule probably wasn’t an alkaloid but rather something like a lipid, a substance more like a fat. In fact, is wasn’t until well into the 20th century that the main active psychotropic molecule from cannabis was finally purified and characterized by Dr Rafael Mechoulam at the Weizmann Institute in Israel in 1964. The name of this active substance is △9-terahydrocannabinol (THC). Crude cannabis also contains many other molecules with similar structures to THC, such as cannabidiol and cannabinol ,but these lack the psychotropic effects of THC. All of these plant derived substances are known as phytocannabinoids  (Fig 2).

THC has a complex chemical structure without a nitrogen atom. So, it is chemically very different from many other natural products like morphine and other alkaloids. At room temperature, pure THC is an oily liquid that is almost insoluble in water. The pure drug, which is also known as dronabinol, is sold under the name Marinol. It is a restricted Schedule III drug which means that you need a prescription to obtain it, but it can be prescribed by physicians for a number of indications, particularly as an antiemetic for cancer patients. Remarkably, crude cannabis itself is a schedule I drug and, under federal law at any rate, cannot be prescribed because it is viewed as having “no medical utility”. This situation is rapidly changing in the USA with many states going their own way and either allowing cannabis to be used for medical purposes or even for recreational purposes. Overall, the Federal laws in the USA make little sense either from the scientific or medical points of view, but have a long history which I will review in a later post. A related subject of great current interest is whether many of the non psychotropic substances found in cannabis, such as cannabidiol, might also have interesting medical effects. A great deal of current research is concerned with examining the possibility that substances such as cannabidiol can treat epilepsy in children. Some of these results are promising and I will post an article on them at a later date.

How exactly does THC work? How does it produce its numerous effects in humans and animals? In my previous post on the Opioid Epidemic, I introduced the concept of a drug receptor. This is a protein molecule that is expressed by a cell and binds the drug. If the drug is an agonist it will fit into the receptor and turn it on, triggering important molecular signals in the target cell. THC works exactly this way. It turns out that there are two different receptors for THC named cannabinoid receptors 1 and 2 (CB1 and CB2). These two receptors are found widely distributed in the nervous system and in other tissues throughout the body. The CB1 receptor is mostly found in the nervous system, whereas the CB2 receptor is mostly found on cells outside the nervous system, such as the white blood cells that play an important role in our immune defenses. But why should we have cannabinoid receptors anyway? It turns out that our bodies all make substances which act very much like THC and these are the normal activators of cannabinoid receptors. These are substances called endocannabinoids and they were also discovered by Dr Mechoulam in Israel. THC works by mimicking the actions of these substances. Interestingly, the endocannabinoids are derivatives of a substance called arachidonic acid which plays a major role in the synthesis of many important types of biological signaling molecules. Another interesting thing to note about THC and the endocannabinoids is that, although they fit into cannabinoid receptors and turn them on, they don’t do this to the maximal extent possible, so they are called partial agonists. As we shall see there are other molecules that can act as cannabinoid receptor full agonists; that is to say they turn the receptors on to their maximal extent. The wide distribution of the two cannabinoid receptors, both in in the nervous system and the rest of the body, reflects the many known effects of cannabis such as its psychotropic effects as well as effects on appetite, pain and inflammation. Indeed, some of these effects are what makes THC and its derivatives attractive as therapeutic agents.

The discovery of the chemical structure of THC raised numerous questions. In many respects these parallel the questions asked about morphine after its chemical structure was determined in the early19th century, as I described in my previous article on “The Opioid Epidemic”. In particular, scientists wondered how alterations in its chemical structure might change its effects and potentially produce novel therapeutic agents. The beneficial effects of cannabis are certainly of great interest and raise the possibility that derivatives of THC might be synthesized that were free of its psychotropic effects but still valuable in the treatment of pain, metabolic disorders, inflammation and many other things. So, it should be understood that scientists who began such investigations were not trying to get people high, they were carrying out basic scientific research on a most interesting scientific problem which had real promise in the area of therapeutics. However, as they say, “the path to hell is full of good intentions”.

There were really two ways of investigating the “Medicinal Chemistry” of THC. One way was to start by making molecules that looked like THC, but introduced small changes bit by bit into its chemical structure to see what would happen, just as molecules like hydrocodone, oxymorphone or heroin, which were made at the start of research on the chemistry of opioids, didn’t stray too far from the basic structure of morphine. Although attempts to make synthetic cannabinoids date back to the 1940s (i.e. prior to the identification of THC), some of the first substances to be made in recent times were synthesized by large drug companies such as Pfizer and Eli Lilly in the 1970s and 1980s. For example, the cannabinoids canbisol and nabilone were developed by Eli Lilly in the 1980s (Fig 3). These molecules share many structural features with THC and so replicate many of its pharmacological effects, including its antiemetic effects. Nabilone is still marketed for this indication today making it a useful treatment for cancer patients undergoing chemotherapy as well as patients with fibromyalgia and other painful conditions. A series of synthetic cannabinoids was also produced by Pfizer around 1980 in a search to produce non opioid analgesic drugs. This program culminated in drugs such as nantradol and CP-42,096 which had similar properties to nabilone (Fig 3). However, the program went a step further and synthesized a group of molecules which resembled the bicyclic molecule cannabidiol rather than THC itself. Somewhat surprisingly, many molecules from this series including CP (Charles Pfizer)-47497, CP-55244 and CP-55940 proved to have powerful THC like effects being considerably more potent than THC itself (Fig 4). Although such molecules never proceeded to clinical trials in humans they represented interesting advances in the molecular pharmacology of cannabinoids.

The second method for producing synthetic cannabinoids relied much more on serendipity. Some of the first inklings of this appeared in the late 1970s when the Sterling Winthrop drug company was investigating drugs that were based on the anti-inflammatory agent indomethacin (Tylenol). One of their derivatives was a drug called pravadoline (Fig 3) which proved to produce an unusual profile of effects including strong analgesic and anti-inflammatory properties with additional THC-like psychotropic effects. Indeed, it was ultimately shown to activate CB1 receptors and act as a strong synthetic cannabinoid. The Sterling Winthrop company developed their interesting finding further and came up with the compound WIN 22152-2, a further derivative of pravadoline, with potent THC like effects. What is interesting to note about compounds like WIN22152-2 and pravadoline is that, although they have THC like effects and are strong activators of CB1 receptors, they are chemically completely distinct from THC or the synthetic substances discussed above that were made to resemble THC. This means that chemists had a completely novel chemical route for making new, potentially useful, synthetic cannabinoids.

Fig. 3 Synthetic Cannabinoids

Most drug companies shied away from developing these new molecules because, although they possessed many interesting properties, they were still strongly psychotropic like THC, something that would certainly detract from their clinical utility. Nevertheless, academic researchers were still attracted to the problem of finding out more about how different chemical structures could activate, or perhaps block, CB1 and CB2 receptors. One of these researchers was Dr John Huffman who was on the faculty of Clemson university. Starting around 1995 with the structure of WIN22152-2, Huffman and his colleagues carried out an intensive exploration of how changes to the structure of such molecules affected their pharmacology. The series of substances he produced labeled JWH (for John W Huffman), such as JWH-018, proved to be of great interest (Fig 4). Many of

Fig. 4 John Huffman’s CB1/2 Agonists and the structure of some Pfizer (CP) agonists.

these substances were full agonists at the CB1 and/or CB2 receptors (remember THC is only a partial agonist) and had powerful THC like effects when tested on animals. These interesting results were published in the scientific literature. It should be understood that when a paper is published in the scientific literature it contains a Methods section so that, given the necessary expertise and equipment, anybody should be able to produce the same results. In other words, papers published by drug companies or by Dr. Huffman, are actually recipes so that anybody can theoretically make the same things. They are not trying to teach people how to get high, it is the way science has to be done. But of course unscrupulous people might take advantage of their work.

And that is exactly what happened. Somewhere in the early 21st century, somebody had a “good idea”. Cannabis was illegal at the time in most parts of Europe and the USA. However, the substances made by Huffman and others were not. It was pretty clear from what was already in the literature that taking these substances should get you high just like cannabis. Of course, doing so would also be profoundly stupid. Normally when a drug is released on to the market it has gone through tests to show that it does what it is supposed to do. Importantly, the tests also try to show that it doesn’t do what it isn’t supposed to do. In other words, that it doesn’t have unanticipated side effects that could be very dangerous or even fatal. We know that drugs like JWH-018, for example, have strong THC-like activity but they have never undergone full clinical trials in humans; so what else do they do? Remember many of these drugs are much better at activating CB receptors than THC itself and so might be expected to produce stronger or even different effects. They might also have effects on receptors other than CB1 and CB2. But, of course, if you are a drug dealer you aren’t going to worry about things like that. What you could do is something like this: take some dried plant material and shred it so that it looks kind of like tobacco. Then get a solution of JWH-018 or CP-47497 or some other synthetic cannabinoid and spray it onto the shredded plant material and let it dry. Now you can smoke this just like cannabis but, instead of inhaling THC, you would be inhaling a synthetic cannabinoid that might actually be much stronger than THC and had never been tested on humans.

Products like this started to appear around 2004, mostly sold on the Internet but also in “head shops”, gas stations, convenience stores and other outlets. They were normally packaged in small foil bags with attractive names like “Spice,” “Spice Gold,” “Spice Diamond,” “Arctic Spice,” “Silver,” “Aroma,” “K2,” “Genie,” “Scene” or “Dream” -but these are just a few of many. The substances were normally advertised as being “legal” forms of marijuana, allowing you to reach a “legal high”, or had New Age-like associations describing them as incense for use in participating in mind expanding exercises. These products caught on rapidly and they began to morph in all kinds of different ways. By 2008, Spice-like products were attracting the attention of law enforcement agencies all over the world. It was found that all of these products contained one or more synthetic cannabinoids. Initially, these would typically be things such as JWH-018, JWH-073, JWH-122, CP-47,497 and JWH-250. Law enforcement agencies moved to place restrictions on all of these substances. However, as soon as they did this, alternative synthetic cannabinoids started to turn up to replace them. Not only that, but it became clear that many people who were using Spice-like products were suffering from serious problems. These were things like psychoagitation, delirium, acute kidney injury, seizures, psychosis, hallucinations, cardiotoxic effects, coma and even death. The situation with respect to the use of synthetic cannabinoids in many respects parallels events associated with the Opioid Epidemic, which I discussed in my previous post. However, in some respects it is even more difficult to deal with. First of all, there is no precise toxidrome as yet associated with the inappropriate use of synthetic cannabinoids. That is to say, the symptoms reported by people taking synthetic cannabinoids are so variable that it is not clear which of them make up a core set of behaviors that can easily be associated with drugs of this type rather than some other type of psychotropic drug. Secondly, there is the chemical nature of the drugs themselves. It is very easy for illegal laboratories to come up with new versions of synthetic cannabinoids that have not previously been found on the streets or even in the normal scientific literature. If we go back to the original CP or JWH compounds you will see that in the middle of each of them there is a chemical group called an indole group (Fig 5). In some of the more recent manifestations of synthetic cannabinoids this has changed to and indazole or even a pyrazole group.

Fig. 5 Indole and indazole.Note the indazole in AMB-FUBINACA

The synthetic cannabinoids basically consist of one of these chemical groups with diverse other things attached to it. The chemistry involved here is not all that challenging. There are virtually an infinite number of variations on this theme that might result in a potent synthetic cannabinoid. As illegal labs copy what drug companies and others have already done and produce more and more of these substances, they are also learning how to make them stronger and stronger, just like the illegal labs making derivatives of fentanyl that are stronger and stronger are helping to fuel the Opioid Epidemic. Now some of these super potent synthetic cannabinoids like AMB-FUBINACA, a synthetic cannabinoid originally patented by Pfizer, are starting to appear in Spice like products on the streets and are responsible for incidents like the one described in Brooklyn last year. There is really no end in sight to all of this. It is very difficult for analytical laboratories to keep up with the new variations that keep appearing or for the law to adequately capture conceptually what should be considered illegal in an a priori manner. Moreover, in the Opioid Epidemic, an overdose can always be reversed by an antagonist drug like naloxone, but there is no widely accepted antagonist for reversing the effects of synthetic cannabinoids in humans, although such things do exist and may be useful in the future. As I mentioned above, the vast majority of synthetic cannabinoids have never been investigated in man. The effects they produce probably result from ultrastrong activation of CB1 and CB2 receptors –but quite possibly other things as well. This is because we are now starting to realize that synthetic cannabinoids can also target other receptors including many “orphan receptors”. The description “orphan receptor” is really just scientific jargon for saying “we know that this receptor exists but we have no idea what it does”. So, using street versions of synthetic cannabinoids is really playing Russian Roulette with your life. When you buy a packet of Spice or other “legal marijuana” you really have no idea what it has in it or what its effects are going to be. Caveat Emptor!

The Opioid Epidemic

On June 5th 2017 the New Yorker magazine published a long feature article entitled The Addicts Next Door. The article described the desperate situation in the state of West Virginia where an increasing number of people of all ages have succumbed to the syndrome of opioid addiction. Not only are the emergency services in much of the state stretched to the limit dealing with addicts and their problems, but a depressingly large number of these people are dying from inadvertent overdoses of the drugs on which they are dependent. As Nora Volkow, the director of the National Institute of Drug Abuse, recently wrote- “In 2015 two million people had a prescription opioid use disorder and 591,000 suffered from a heroin use disorder; prescription drug misuse alone cost the nation $78.5 billion in healthcare, law enforcement, and lost productivity.” Around 60,000 people died from opioid overdoses in 2016 and the numbers will probably increase this year.

The New Yorker article is one of many that describe different aspects of what is now commonly known as the “Opioid Epidemic”, a medical crisis which, in its severest forms, is unique to the United States. When reading such articles, or listening to commentators on different media, one is constantly bombarded with words such as heroin, fentanyl, morphine, Vicodin, OxyContin, naloxone and so on. However, it is doubtful whether a normal person who is not trained in medicine or some branch of medical research really knows what these things are, making it difficult to appreciate exactly what the crisis is all about. Heroin and fentanyl are opioid drugs- that is true enough. But what exactly are they? How do they differ from one another and what is the specific role of each of these substances in the current epidemic? In this post I will attempt to provide an answer to such questions for the lay reader.

In order to begin this discussion, we need to go back to the 19th century and the birth of a new type of science called “Organic Chemistry”. Prior to this time, it was thought that the materials that made up living things like animals and plants were endowed with a special life force, and were subject to unique physical laws that did not apply to nonliving objects such as rocks, ores, minerals and so on. However, certain key scientific results showed that this was not the case. These included the synthesis in the laboratory in 1828 of the substance known as urea (a chemical normally excreted in the urine). Results such as these demonstrated that the  substances that made up all living matter were certainly subject to the ordinary laws of chemistry. Organic chemistry concentrates on the chemistry of the carbon atom which is of particular importance for understanding the structure of all living things. Many of the important molecules in living organisms consist of large carbon based polymers and are studied by a special branch of organic chemistry called “Biochemistry”.

As the 19th century proceeded scientists became more and more familiar with organic chemistry and how it could be used to synthesize or modify natural products. A highlight of this occurred in 1859 when a young English scientist named William Perkin accidentally produced the first synthetic dyestuff from the organic molecule aniline. He named his new synthetic dye “mauve”. Prior to this time all dyes used for making clothing or other items were derived from plants or animals using very labor intensive processes. Now it became possible to produce these things synthetically. A new industry known as the “Chemical Industry” was created to deal with making such products. Indeed, the names of some of these companies today still reflect their origins e.g. the huge German chemical company BASF-“Badische  Analin und Sodafabrik (Baden aniline and soda maker)”.These companies were very successful and soon began to diversify. They found that some of the substances they made weren’t very good dyes but did have interesting therapeutic effects as synthetic drugs. So, some of them became drug companies and the pharmaceutical industry was born. One of the first of these new pharmaceutical companies was the Bayer company founded in Wuppertal, Germany in 1863 and, as we shall see, this was to have an enormous impact on the future of opioid drugs.

What exactly are opioid drugs? Even the earliest written records going back to Mesopotamia around 3000 BC refer to the remarkable properties of the poppy plant. It was known that extracts of the poppy had a number of important effects on mood, the sensation of pain, the control of diarrhea and so on. These properties were well known and described by the Greeks, Romans and other ancient peoples. In particular, the white gummy latex that encases the seeds of the poppy was found to be the most active part of the plant. It was possible to take this latex like material, boil it a little, and then dry it out in the sun to make a thick resin that could be shaped into balls or bricks. This is the material that we know as crude opium. Originally this would have been eaten either alone or frequently mixed with other ingredients. In the 16th century the alchemist Paracelsus discovered that you could extract opium with alcohol and drink it. He called this preparation “Laudanum”.

But what exactly is in the opium that is responsible for its drug like effects? Virtually all of the material in crude opium is irrelevant. However, somewhere in this sticky mess is a pure substance, an organic chemical with a specific molecular structure. This only makes up a few percent of the opium but it is responsible for most of the its effects. This substance was first isolated from opium in 1805 by a young German pharmacist named Friedrich Serturner. When he fed it to animals (or students) they fell asleep and so he called it “morphium” after Morpheus the god of sleep from Ovid’s Metamorphosis. The name changed to morphine when Serturner’s discoveries were translated into French (Fig 1). Some years later another pure substance was isolated from crude opium. This was the drug codeine whose chemical structure turned out to be very similar to that of morphine (Fig 1). However, a small alteration renders it much less potent. Nevertheless, codeine is still an extremely useful drug for treating pain, cough and diarrhea, three of the effects that are also produced by morphine. Soon after its discovery, people started to take advantage of “pure” morphine instead of crude opium and a German apothecary named Emanuel Merck began to prepare it in bulk and, in 1827, started to sell it from his shop. In 1853 the hypodermic syringe was invented allowing morphine to be injected intravenously. This increased the rate at which at which the drug worked as well as its effectiveness, but also accentuated its problems such as its tendency to produce addiction.

Fig. 1

The rise of organic chemistry in the 19th century allowed chemists to begin modifying naturally occurring substances like morphine in unique ways using newly invented chemical reactions. Perhaps,it was thought, it might be possible to modify morphine using a chemical reaction so that it retained its useful properties but lost its addictive potential? In 1874 CR Alder Wright, a

Fig. 2

researcher at St Mary’s hospital in London, took morphine and treated it with a chemical reaction known as “acetylation” producing diacetyl or diamorphine. Animal tests showed that, like morphine, this new substance was a potent opioid drug, but the research was never followed up and became a footnote in the scientific literature. However, 23 years later scientists at the Bayer drug company were also playing around with the same chemical reaction. They treated the substance salicylic acid, a natural product isolated from the bark of the willow tree, and produced acetylsalicylic acid which they found was very useful in reducing fever. They called their new product aspirin. The Bayer scientists wondered if something similarly useful might be obtained by treating morphine the same way-maybe one might produce something like codeine or even something better? Of course what they produced was diacetylmorphine. As was the custom at the time the Bayer scientists tested their new substance on mice and also on themselves. They were impressed. It made them feel “heroisch”, German for heroic and super strong. So, they called their new substance heroin. Remarkably, on the same day in 1898, Bayer began to market its two new discoveries, aspirin and heroin (Fig 2). The rest, as they say, is history.

Nevertheless, whatever the subsequent problems were with heroin, results like these made it clear that one could use chemical reactions to modify the structure of morphine and,if you were optimistic, this might lead to better morphine-like drugs or even the holy grail, a drug which retained all of the beneficial effects of morphine but was devoid of its problems such as its addictive potential. Over the years the morphine molecule has been modified by chemical reactions to produce tens of thousands of derivatives. Arguably none of these are much better than the original drug morphine which is still very widely used in medicine. Nevertheless, some small changes to the structure of morphine or codeine have produced useful drugs such as oxycodone and oxymorphone, hydrocodone and hydromorphone which are also widely used

Fig. 3

in medicine (Fig 3). These drugs were all first made in the early 20th century and all have very similar properties to morphine and codeine, representing very small chemical alterations to the original molecules. However, there is another reason for wanting to mess around with the chemical structure of morphine. It is very difficult to make morphine from scratch in a laboratory. A poppy has spent hundreds of thousands of years evolving a special set of biochemical reactions allowing it to make morphine, which has an intricate chemical structure, consisting of 5 interlocking ring systems. Really, the only way to obtain morphine or codeine efficiently is to isolate them from poppies. You can also isolate thebaine from poppies, an inactive molecule whose structure is related to that of morphine. Then it is relatively simple to make opioid derivatives like oxycodone or oxymorphone. But how can we free ourselves from the poppy and make drugs like morphine from scratch? Scientists began to ask  how much of the complicated morphine molecule was actually necessary for producing its effects in man? As discovered in the 1970s, opioid drugs work by activating a special protein expressed by some nerve cells called a μ-opioid receptor. Was the entire chemical structure of morphine necessary for activating this receptor or would just part of it do? Chemists began to deconstruct the structure of morphine first taking away one ring system from the structure, then another and then another. What they found was that the opioid activity of many of these synthetic molecules persisted. Perhaps the entire structure of morphine was necessary for some unknown function it had in the poppy plant ,but it clearly wasn’t necessary for producing molecules that could activate μ-opioid receptors in humans.

During World War II the Nazis organized all of the German pharmaceutical companies into one enormous cartel called IG Farben (Interessen Gemeinschaft Farbenindustrie or combined interests of the dye making companies). In 1939 one of their chemists was working on a project to

Fig. 4

make synthetic antispasmolytic drugs and invented a completely synthetic substance called pethidine (now also called meperidine or Demerol). By chance , pethidine was observed to have powerful opioid activity. Indeed, it was the first completely synthetic opioid drug. Pethidine is a much simpler chemical substance than morphine and only contains a single ring structure called a piperidine ring –a feature that it shares with morphine. No poppies are necessary for making pethidine ; you can make the entire thing from beginning to end in a laboratory. Around the same time, IG Farben developed another completely synthetic opioid called methadone which also has only a passing resemblance to morphine. Developments such as these clearly demonstrated that effective opioid drugs could be synthesized in a laboratory without recourse to poppies (Fig 4).

Soon after the war in 1953 Janssen Pharmaceutica, a relatively new company that was founded by Dr Paul Janssen in Belgium, began to develop  their own opioid drugs based on the structure of pethidine. Eventually, after considerable experimentation, they developed a new synthetic opioid named fentanyl. Not only was fentanyl completely synthetic but it proved to be around 50-100 times more potent than morphine. Within three years, fentanyl was being used clinically in Europe. As we shall see ,this is not the end of the story to which we will return later.

One other important development should be noted. As long ago as 1915 an industrial chemist synthesized a compound called N-allylnorcodeine, a derivative of codeine. What he surprisingly observed was that this substance didn’t mimic the actions of codeine but rather inhibited the effects of the latter drug or indeed of morphine or heroin. Nobody noticed this important  contribution to the scientific literature until the 1940s when N-allylnormorphine (nalorphine) was synthesized and was also found to produce the same inhibitory effects. These substances are what are known as opioid antagonists. Here is one way to think about it. We know that drugs like morphine and fentanyl work by activating  μ-opioid receptors. You might imagine that the receptor is a lock and that the opioid drug is a key that fits into it and unlocks it. These drugs are called opioid agonists. Some opioids (more “potent”) are better at fitting into the receptor and turning it on than others.  In contrast, an opioid antagonist fits into the receptor but cannot turn it on. However, by fitting securely into the receptor an antagonist prevents any opioid agonist drug doing the same thing and so inhibits its potential effects. Eventually very efficient opioid antagonists such as naloxone (Narcan) and naltrexone (Revia) were produced. These drugs are able to rapidly reverse any of the effects of drugs like morphine no matter whether they are “good” effects such as analgesia or “bad” effects such as depression of respiration. Because of this property they are widely used for treating people who have taken an overdose of any opioid agonist drug. They rapidly reverse these effects and therefore often have a life saving role in the treatment of addicts.

How did the opioid epidemic come about and what are the roles of these various drugs in its genesis? To understand this, we need to go back to the 1980s. At that time access to opioid drugs was fairly restricted particularly for patients with chronic pain problems.This was because of fear that they might become addicts. However, this attitude began to be questioned. It has recently been pointed out that a 150 word letter published in the New England Journal of Medicine in 1980 helped to foster the view that very few “patients” treated with opioids eventually became drug abusers. Attitudes began to change. It seemed that millions of Americans were suffering from chronic pain syndromes of various types and were being denied the use of opioid drugs that might make their lives more bearable. As a result, prescriptions for opioids became much more generally available. As the medical community encouraged the appropriate use of these drugs, pharmaceutical companies responded with new preparations of opioids.  Drugs like Vicodin and Percocet began to be widely prescribed. One should understand that these aren’t actually new drugs at all. The idea is to take the two major type of pain killing drugs, opioids and nonsteroidal antiinflammatory drugs (NSAIDs) like aspirin, and mix them together. Vicodin is just a common or garden mixture of hydrocodone and acetaminophen (Tylenol) and Percocet is just oxycodone mixed with acetaminophen. Another widely used opioid preparation is OxyContin which is nothing more than a controlled release form of oxycodone. All this means is that the drug is formulated in such a way that it is released slowly in the body over a period of 12 hours in an effort to keep the drug at a constant level over time. The idea here is that patients would only have to take two doses a day to maintain constant pain control which, on the face of it, seems like a good idea. When the drug was introduced it was backed by a huge advertising campaign aimed at doctors and patients.Why take something else when you only had to take OxyContin twice a day? The drug was a huge success and sales skyrocketed into the tens of billions. The problem was that things didn’t quite go according to plan. Lots of people did get hooked on opioids like OxyContin that they were initially taking for bona fide purposes.

Around 2010 it was realized that there was burgeoning problem with the way opioids were being prescribed and the consequences for promoting drug addiction. So ,the pendulum began to swing back the other way. Prescribing opioids became more restricted once again. But now there were a large number of people who were dependent on OxyContin and other prescription opioids who needed a source of drugs. Because access to opioids  was now more restricted, the price of drugs like OxyContin and other prescription opioids began to rise. The price of heroin on the street was much lower. This meant if you were an addict it became much more reasonable to cash in your dose of OxyContin and buy six doses of illegal heroin. And so many people who had begun by taking prescription opioids ended up as addicts buying heroin on the streets.

However, why are so many people dying from illegal opioid use? As we have seen a drug like fentanyl is much easier to make than heroin and is also much stronger. In principle, therefore, it is much easier for a drug dealer to make or obtain fentanyl than heroin and the same amount of illegal drug goes much further if you cut your heroin with it. But think about what might happen. Let us say you are used to taking a milligram of a white powder consisting of pure heroin to get high. Now you are presented with some white powder which is actually fentanyl or perhaps heroin cut with fentanyl. If you take the same amount of white powder you are actually taking an enormous opioid overdose. When an opioid drug enters your bloodstream it will be distributed to the various tissues of your body. If the cells in a tissue express  μ-opioid receptors, then the drug will produce an effect. We know that these receptors are widely distributed in the nervous system which is why morphine produces many different effects. Receptors exist in the spinal cord and the brain which mediate the effects of the drug on pain. Receptors in the gut mediate the constipating effects of the drug. Effects in the brain mediate the effects of the drug on mood and consciousness. Note, however, that there are also opioid receptors that regulate your breathing. Activation of these receptors suppresses breathing. If you take a large dose of an opioid, you will completely stop breathing and die. Taking an opioid drug therefore is always a balancing act so that the dose you take produces  effects that are therapeutically relevant and are not high enough to produce life threatening effects such as the suppression of breathing. The problem is that the use of fentanyl as a street drug has now lured many unfortunate addicts into situations where they inadvertently overdose and kill themselves.

Lately things have taken an even more ominous turn. The chemical structure of fentanyl is easily modified using a little organic chemistry. When this is done you can make drugs that are even more potent than fentanyl, which is already some 50-100 times stronger than morphine. Drugs like sufentanil or carfentanil are up to ten thousand time stronger than morphine. The current world champion is ohmefentanyl clocking in at some 30,000 times more potent than morphine! Imagine what this means. Even a tiny crystal of the drug that you cannot even see would be enough to kill you. Now underground chemical laboratories, especially in other countries like China, have figured out that by making drugs like this they can just ship a kilo or so to the USA, a quantity that is not that difficult to conceal, but is enough to incapacitate the whole of Chicago. Once heroin or other drugs are cut with even tiny amounts of drugs like this the results are devastating. The effects of such drugs on breathing can be reversed by continuous dosing with opioid antagonists like naloxone. But the supplies have to be available and medics have to be recruited in sufficient numbers so that they can rapidly respond to distress calls from addicts.

Because of the reasons discussed above the Opioid Epidemic represents a problem of the greatest complexity. However, the basis of the problem is rooted in the effects produced by opioid drugs themselves. Is there really some way of making drugs like morphine that are free of their addictive potential or fatal side effects? Over the last year papers have been published in the top scientific research journals Nature and Science suggesting that this might be possible. I will describe these results in a future post.



I want to welcome you to my blog “The Keys to all Mythologies: Science, Medicine and Magic.” I will be posting articles that concern scientific topics of current interest as well as historical accounts of scientific issues. Some of the articles will be relatively long and detailed, such as today’s article about the Opioid Epidemic. Other articles will be short and just designed to introduce a specific concept or a piece of information. I will try to post a new article at least once a month. Please feel free to contact me with your comments or questions!