Evidence Based Drug Policy?

OVERVIEW

This post is about the use and misuse of legal and illegal drugs. You should consider reading this if you'd like to know more about the relative risks and harms involved in using drugs. I will focus primarily on a research paper published in 2009 by Professor David Nutt on the relative harms associated with drugs. Professor Nutt is extremely knowledgeable in this area, and is passionate about evidence based drug policies, both in his native UK, and abroad. He and his colleagues are part of the Independent Scientific Committee on Drugs, ISCD in the UK. This independent body dispenses easily digestible information on many drugs of abuse, their website can be found here.

WHAT'S A DRUG?

You may not agree with this, but people love drugs! We ingest them willingly and knowingly, we use them socially and personally, for pleasure and stress relief. We take photos of them and show our friends, we recommend new places to try them, and we hand over our hard earned money for them. Like it or not, we use them, and it is unlikely we will want to stop using them. Attempting to define what is meant by the term drug is actually pretty difficult though. After thinking about it for a while I came up with the following definition,

• A small molecule capable of interacting in a targeted and predictable way with enzymes, receptors and structural proteins in the body to elucidate a known desired result, for example, relieving pain. 

However, as comprehensive as this may sound there's still a lot wrong with this definition. For example, are all drugs small? How small is small? Do they only interact with enzymes, receptors and structural proteins? Can they bind to sugars, or fats, or DNA? Are the results always predictable? If you look at the oxford dictionary definition you will see it says,

• "A medicine or other substance which has a physiological effect when ingested or otherwise introduced into the body"

This is an incredibly vague this definition. Medicine or other substance that has a physiological effect...isn't that everything! Well, not quite, noble gases such as helium, neon and argon, are chemically unreactive so we can remove these from the list of "drugs". However, what I hope you will take from this is that defining a drug is very difficult, and when you examine what is and what is not a drug you see some interesting results.

DRUGS ARE COMMONPLACE
For most members of society the term drug is synonymous with death, overdose, infection, poor health, poor education, and poor quality of life. People think of substances such as cocaine, ecstasy, and heroin. They are correct in the sense that these are drugs, but it is important to know  there are plenty of legal drugs that we ingest routinely. Caffeine (coffee, tea, cola), alcohol (beers, wines, spirts), nicotine (cigarettes), phenylethylamine (chocolate), paracetamol, ibuprofen, and codeine (painkillers) are all common place. Alcohol is a particularly dangerous drug, and its use is both legal and widespread.

PROFESSOR DAVID NUTT

David Nutt is a neuropsychopharmacologist by training, and currently chair of the Independent Scientific Committee on Drugs (ISCD). He has published over 400 research papers, a similar number of reviews and book chapters, 8 government reports on drugs, and 27 books. In short, if there's someone we should feel confident asking about drugs, their dangers, and drug policy, it's this guy! I first heard about Professor David Nutt from this guardian science podcast interview. He had just been fired from his position of Chief Adviser on the Advisory Committee on the Misuse of Drugs, the ACMD, in the UK for reason that will become more clear later.

His job at the time was to advise on the relative risks of illegal drug usage, and help determine the penalties for procession and supply of those drugs. The home office took exception to a paper he published in 2009, where he compared the risk of taking ecstasy to risky, but legal activity, more about this later. To give you some perspective on what's at stake for taking and supplying illegal drugs I need to introduce the misuse of drugs act. 

THE MISUSE OF DRUGS ACT (1971) UK

Currently, the UK MDAct separates drugs into three classes, A, B, and C, based on how harmful they are perceived to be. Every so often a drug is moved up/down the list as evidence is collected on their effects. The current classification is as follows. As you can see, the classifications really matter. It could be the difference between 14 years in prison, or a life sentence.

RANKINGS OF DRUG HARM

The classification of any given drug is a difficult process and it's unlikely that any system used will be perfect. However, like any government policy there should at least be an attempt to base it on evidence, because if you're making government policy on evidence what are you basing it on? The penalties for usage and supply of illegal drugs should reflect the harm likely to be inflicted. This arises in other aspects of law, murder incurs a worse sentence than manslaughter for example.

Arising from concerns that the media may be misrepresenting the relative risks of drugs, and therefore influencing public opinion and drug policy, Professor Nutt developed a means of classifying the relative risk of drugs. This system was based on, (a) the physical harms (to include acute, chronic, and intravenous), (b) drug dependence, (to include pleasure intensity, psychological dependence, and physical dependence), and (c) social harms, (intoxication, other social harms, and health care costs).

The scoring was performed by two expert groups, one consisting of psychiatrists, the other consisting of chemists, forensic toxicologists, police members of the legal profession, and epidemiologists. Each of the sub-categories was given a value of between 0-3, and the final result averaged for each of the three major categories. High scores were indicative of harm. When this was done they arrived with a ranking of drug harms as follows as shown below.

Table 1:Ranking of drug harms, 0 = not harmful, 3.0 is extremely harmful

If you look through this table you will see some familiar drugs, alcohol and tobacco among them. Some of these rankings are not surprising, drugs such heroin, and cocaine score very highly in the harm index, this is because they are physically harmful, they are very addictive, and intravenous administration is dangerous due to risk of infection from needle sharing etc. Treatment for those that do become addicted is both expensive, and difficult. As a result, the current classification for theses two compounds makes sense. The risks of using are high, the penalty for supply and possession are high. Others however are more surprising.

ECSTASY VS. EQUASY

One drug that does stand out on the above list is ecstasy. It gets a low score for each category of harm, although it does score highly in terms of pleasure, and psychological dependence. Professor Nutt compares the dangers of ecstasy to another known addiction, “Equasy”. In this 2009 paper professor Nutt says, 

• “The dangers of equasy were revealed to me as a result of a recent clinical referral of a woman in her early 30’s who had suffered permanent brain damage ...She had undergone severe personality change that made her more irritable and impulsive, with anxiety and loss of the ability to experience pleasure. There was also a degree of hypofrontality and behavioural disinhibition that had lead to many bad decisions in relationships with poor choice of partners and an unwanted pregnancy. She is unable to work and is unlikely ever to do so again, so the social costs of her brain damage are also very high”

EQUASY USAGE

Equasy is actually pretty widespread in the UK. There are 3.5 million users, that's ~5% of the population. Approximately 25% of these users are under the age of sixteen. In 2011, there were 225 traffic incidents resulting from equasy usage which resulted in 52 “serious injuries” and 8 deaths. The “Hospital Episode Statistics Online” website reported 3,935 incidences requiring hospital treatment as a direct result of equasy. Equasy usage is currently not accounted for in the misuse of drugs act and so professor Nutt poses the questions (i) how do we regulate for new drugs coming on the market? (ii) How do we know what the penalties should be? (iii) What are the the risks/dangers involved in taking them?

From above statistics alone you could make a strong argument that equasy should (a) come under the remit of the misuse of drugs act, and (b) classified as at least as a class C drug. Looking at the table below gives a direct comparison between ecstasy and equasy for example, using the same scoring criteria used for all other drugs, physical harm, socials costs etc.

Comparison of ecstasy and equasy, adapted from Nutt et al., 2009.

SO WHAT IS EQUASY?

Well, this is what professor what referring to! Horse riding. Admittedly, this was the most impressive photo of risky looking horse riding I could find, and may not be entirely representative of the sport. However, all of the above statistics mentioned for equasy really are true for horse riding. That brain damaged patient professor Nutt was referring to had become brain damaged as a result of a horse riding accident she had.

Safer than ....oh wait.

The point Professer Nutt is making in his 2009 paper is that risks and harms are present even in legal activities. In addition, he goes on to say a lot of the harms from illegal drugs come from the fact that they are illegal. A controlled and regulated legal supply would ensure that the strength of the drug was known, and that it was pure, just like paracetamol production for example. Nutt speculates that decriminalising may actually go some way to decreasing the harms associated with illegal drug usage, and that this is especially true in cases where the drug has a calming effect, such as cannabis.

As a quick example, I regularly take hay-fever medication called cetirizine, it's available over the counter without any verbal warnings from the pharmacists. If you read the information leaflet attached you will see there are 39 adverse effects associated with this medication. They range from tiredness to convulsions, and lapse of consciousness! Legal medications are capable of being dangerous too, and it's the reason there are measures put in place by the manufactures to document and investigate all instances of adverse events, even after the drug has gone to market. There is no such quality control with illegally manufactured drugs.

MEDICAL USES OF ECSTASY

Ecstasy (MDMA) does actually have legitimate therapeutic uses. For example, it has been used in the field of psychiatry for the treatment of post traumatic stress disorder. MDMA has the ability to enhance both positive and negative emotions simultaneously, and turns out to be an effective mix for patients attempting to relieve painful experiences in psychotherapy sessions. The patient is able to relive the painful event in the absence of anxiety or fear. They experience a mixture of introverted and extroverted sensations, so subjects report feeling confident as well as depersonalised, sensitive and contemplative.

This unique mix of confidence and depersonalisation allows the patient to relive a traumatic event, and talk about it in a psychotherapy session. It's worth noting however that acute administration of legally manufactured MDMA does come with side effects. Headache, increased heartbeat, muscle aches, dizziness, tics, tremors, restlessness, and agitation have all been reported. So, like many other aspects of life there is a trade-off to be made. Yes, you can stand a chance of treating your PTSD, and yes, you may also suffer some adverse effects, so it all depends on your quality of life. Some people may want to trade PTSD for tics and tremors, some, may not. And perhaps they should have that choice.

SO WHERE DOES ALL THIS LEAVE US?

Essentially, what all of this says is the UK government is not operating on evidence when it comes to its drug polices. Yes, there are dangerous illegal drugs out there, but there are dangerous legal drugs too. In the case of the illegal drug MDMA the risks are actually pretty low, lower than the usage of alcohol and tobacco, and as it turns out, about the same as horse riding. So we as a society we need to urge our government to make evidence based policies, because if it's not based off evidence, then what is it based on? Professor Nutt concludes his paper with the following statement, 

• "A debate on the wider issues of how harms are tolerated by society and policy makers can only help to generate a broad based and therefore more relevant harm assessment process that could cut through the current ill-informed debate about the drug harms. The use of rational evidence for the assessment of the harms of drugs will be one step forward to the development of a credible drugs strategy”.

SO HE WAS PROMOTED RIGHT ?
Wrong! As a direct result of the publication of his 2009 paper Professor Nutt was fired from his position as chief of the Advisory Council on the Misuse of Drugs (ACMD). A number of high ranking scientists within the ACMD resigned in protest, and together they established the ISCD mentioned above, which does not receive any government funding. Consequently, they are independent of government agenda and intervention, and there only remit is to provide the public with evidenced based drug polices. Regardless of what you think about drugs, I would urge you to think about what Professor Nutt is attempting to do here.  I for one find it admirable, and altruistic. He clearly cares about his work and is willing to stand beside his very educated and informed opinions on the matter.

LINKS OF INTEREST

• The ISCD Website 
• Radio Interview with David Nutt 
• Equasy- an overlooked addiction with implications for the current debate on drug harms.
• The Misuse of Drugs Act

How Do Painkillers Work?

BACKGROUND
If you have ever taken a painkiller and wondered, how does it know where to dull the pain then this article is for you. There are many over-the-counter pain medications such as Aspirin, Ibuprofen  and Naproxen, and these all produce their pain relieving effects in the same way. To discuss how painkillers work though it is important to appreciate how the body works on a molecular level, a topic known as molecular biology. A discussion of molecular biology often results in introducing some aspects of biochemistry, the study of chemical reactions that occur in the body, so some basic elements of both of these topics will be discussed.

TYPES OF PAINKILLER
There are three classes of painkiller, (i) Opiates, (ii) Opioids and (iii) Non-Steroidal Anti-Inflammatory Drugs. Opiates refer to a group of compounds which naturally occur in the poppy plant, they include Morphine, Codeine, and Thebaine. Opioids are man-made compounds that resemble Opiates. They are also effective at treating pain, and include compounds like Fentanyl, Oxycodone, and Methadone. The supply and sale of opiates and opioids is restricted since they are addictive. The final class of painkiller, NSAIDs, are available to buy over the counter.

Opiates and Opioids generate their painkilling effects in similar ways which will not be discussed here. Only the painkilling effects of NASIDs are discussed below.

COMMON NSAIDs

Aspirin, Ibuprofen, Naproxen are commonly used painkillers found in over the counter medication such as Advil, Nurofen, Disprin Aleve, and Brufen. These are all members of a family of drugs known as NSAIDs (Non-Steroidal Anti-Inflammatory Drugs). The molecular structure of both aspirin (left) and ibuprofen (right) is shown below.

For those of you unfamiliar with chemical structures the picture above won't make a lot of sense, but really all you need to know is that each and every chemical has its own unique structure associated with it. You can think of a chemical compound as being like a key. Just like a key each compound is unique, and interacts selectivity with it's environment. The locks in this analogy are actually large macromolecules called proteins.

CELL BIOLOGY - THE BASICS

Our bodies are composed of cells. Cells themselves are incredibly complicated, and in the same way we have organs cells have specialized substructures called organelles. It helps to think of a cell as an automated factory with different manufacturing compartments (organelles). Each compartment has its own set of sophisticated autonomous robots capable of gauging the supply and demand from the outside world, and ramping production up/down accordingly. For a cell, these sophisticated, autonomous robots are actually proteins, more specifically, proteins called enzymes.

SO - WHAT ARE ENZYMES ?

Sticking to our factory analogy, enzymes are the autonomous construction robots inside the cell. In the same way that robotic arms of a car manufacturing facility automatically cut, shape and paint car parts, enzymes work on a specific chemical compounds, biochemists called these substrates, and modify them by the addition or removal of individual atoms to make new compounds the body actually needs. In addition, in the same way a robotic arm only uses a small portion of its entire structure to perform its function, say, the delicate fingers of a larger robotic hand, the modification of substrates occurs only in a small region of the entire enzyme called the active site. The relevance of this becomes apparent later on.

Enzymes are extremely interesting molecules in their own right, with intricate moving parts, and complex structural features. It's difficult to envisage what they might look like, and in reality they have a myriad of different structures. The COX enzyme I refer to later actually looks like this in real life.

On the left is a 3D rendering of the entire enzyme molecule. It's worth pointing out that this is not an artist representation of what it might look like, but an accurate 3D model generated from X-ray images. It's similar to taking an X-ray of your arm to determine the structure of the bone underneath. This enzyme is a dimer, meaning it is composed of two identical subunits, therefore, the areas coloured red and blue represent different regions of the same enzyme molecule.  Both subunits have an active site capable of interacting with NSAID molecules.

The image on the right is simply a zoomed in version of the image on the left. Here you can see a yellow coloured molecule. This is where, and roughly the orientation in which an NSAID molecule would bind. You can see how it is located in only a very small region of the enzyme, this is the active site.

SO - HOW ARE ENZYMES AND PAIN RELATED?

When a person takes a painkiller they are introducing millions of painkiller molecules, say, Ibuprofen, into the body. These molecules circulate in the blood stream looking not doing very much. However, if one of the molecules should happen to encounter a molecule of COX-2, then there's a chance they will interact. If there is an interaction between Ibuprofen and COX-2 this results in a complete shutdown of COX-2, and ultimately and a reduction in pain, here's how.

COX-2, PROSTAGLANDINS & PAIN
Pain is often the result of inflammation. For example, you strain a ligament during exercise, the muscle becomes inflamed, and increases the pressure in the surrounding tissue. Increased pressure equates to pain. The inflammation that arises as the result of an injury is the result of the COX-2 enzyme. The COX-2 enzyme is responsible for producing a series of small molecules called prostaglandins from a precursor molecule called arachidonic acid. So, yeah, we have an enzyme that makes pain - thanks evolution!

One prostaglandin in particular, prostaglandin E2, or PGE2, is responsible for generating the pain response. Aspirin, Ibuprofen, and all other NSAIDs work by inhibiting the production of PGE2. Specifically, they bind to the COX-2 enzyme, and prevent it from making PGE2. Aspirin is able to bind selectivity to COX-2 because of its 3D arrangement of atoms. Simply put, it's one of a small number of compounds that fit into active site of the enzyme. There are many potential enzymes that Aspirin could bind to, and it may interact fleetingly with many other molecules, but it is particularly well suited to binding to COX-2. This makes the interaction between Aspirin and COX-2 a targeted one. So while a molecule of Aspirin doesn't "know" where it should go, it really can interact in one place in the entire body for any long period of time. Pretty cool eh?

COX ENZYMES
So, why do we even have the COX enzyme? Well, there are actually two COX enzymes, simply called COX-1, and COX-2. They both look and behave in similar ways, you can think of them as non-identical twins, performing in similar but distinct ways, and important, looking slightly different from one another. COX-1 is often referred to as performing essential house-keeping activities, for example, it is the enzyme responsible for maintaining our stomach lining. As a result of its importance our bodies make sure to maintain a constant level of COX-1 available, this is known as constitutive expression. COX-2 on the other hand is only required as a result of injury, and so its presence is said to be induced. Once the injury is repaired COX-2 is removed by the body so as not to cause unnecessary inflammation and pain. It is actually useful for us to have means of producing pain. It prevents us from further injury. Although it is annoying!

SUMMARY
So, there you have it. Aspirin and Ibuprofen both bind selectively to the COX-2 enzyme which in turn reduces the levels of PGE2, which in turn reduces inflammation and pain. The specificity of this interaction comes from the structure if Aspirin and Ibuprofen, they bind specifically to COX-2 which is present only in the areas of injury/pain. This is why when you take a painkiller it "knows" where to go to target the pain.

As always, feel free to leave any comments or questions below, I will do my best to answer them.

REFERENCES

• Prostaglandins and Inflammation
• Multifaceted Roles of PGE2 in Inflammation and Cancer
• Medicines.ie - lists the active ingredients of medications