The hidden potential of MDMA and psilocybin

Earlier this week I went to a talk by Professor David Nutt entitled ‘Time to Grow Up?’ where he spoke about the damage caused by the UK government’s approach towards drugs. David Nutt has become quite well known in the UK after he was fired in 2009 by the Home Secretary as the chairman of the Advisory Council on the Misuse of Drugs for clashing with government policy. Most notably, he published an editorial in the Journal of Psychopharmacology in which he said that the dangers from ecstasy were comparable to that of horse-riding.

I was already well aware of his views on the relative risks of drugs (alcohol causes far more damage overall than anything else) and his views on the government’s approach to banning new drugs (such as mephedrone, which potentially saved more lives than it took). He laid out the evidence very clearly and presented it in a very engaging manner – I would recommend checking out his blog if you’re interested.

When adding together harm to self and harm to others, alcohol tops the list of most harmful drugs. Image credit: The Economist

When adding together harm to self and harm to others, alcohol tops the list of most harmful drugs. Image credit: The Economist

However, one aspect really caught my attention – the study of illegal drugs as therapeutics or medicine. The case for cannabis is well-known: its potency as a pain reliever has led to it now being prescribed by doctors in some countries. But what about MDMA (ecstasy) used to treat post-traumatic stress disorder, or psilocybin (the hallucinogen found in magic mushrooms) used to treat depression or obsessive-compulsive disorder? These drugs have been suggested as potential treatments but there are so few studies conducted that we can’t be sure.

Science on drugs

Cannabis, MDMA and psilocybin are all considered have no therapeutic value by the UK government and so are listed as Schedule 1 drugs. This means that not only are researchers required to get a licence from the Home Office, but they also have to find a supplier who also has the correct licence. These licences cost thousands of pounds, take about a year to be approved and then result in police inspections on a regular basis. Not only that, many research funding bodies are reluctant to sponsor studies on illegal drugs or refuse to fund it altogether.

It is easy to see why there hasn’t been much research done.

Nonetheless, David Nutt made a big splash two months ago when he televised a study on the neurological effects of MDMA. In Drugs Live: The Ecstasy Trial, 25 volunteers were studied by fMRI after taking either the drug or a placebo in a double-blind trial – making it the largest ever brain-imaging study of MDMA conducted. In time, the full results will be published in peer-reviewed journals and they are actually expecting to publish 5-6 papers from this single study.

The researchers used pure MDMA, avoiding the contaminants usually found in ecstasy

The researchers used pure MDMA, avoiding the contaminants usually found in ecstasy pills

This research was not just to look at the effects of taking an illegal drug – understanding the neurological mechanism of MDMA could potentially help millions. Back in 2010, a US study of patients with post-traumatic stress disorder showed that MDMA, combined with psychotherapy, cured 10 out of the 12 people given the drug in a randomized-control trial. These were people who had not responded to government-approved drugs or psychotherapy alone, and two months after the study they were free of symptoms. MDMA appears to dampen negative emotions, which allows a patient to revisit their traumatic memories without the associated emotional pain. This can be the starting point for the patient to come to terms with their trauma and deal it with through therapy. These results, although from a very small sample size, are near miraculous and yet it took over ten years for the researchers to get approval.

The magic of mushrooms

David Nutt has also previously studied the effects of psilocybin on the brain and the results were surprising. Psilocybin is a hallucinogen, causing colours, sounds and memories to appear much more vivid than usual. With this kind of effect it was expected that psilocybin would activate certain areas of brain, which would be seen as bright patches on an fMRI scan. However, they actually saw dark blue patches of decreased brain activity, but only in a specific area of the brain that acts as a central hub for connections.

Psilocybin is the hallucinogen in magic mushrooms. Like MDMA is a class A drug in the UK

Psilocybin is the hallucinogen in magic mushrooms. Like MDMA, it is a class A drug in the UK but could it used to treat depression?

Decreasing brain activity doesn’t sound like a good thing, but one of these connector hubs, known as the posterior cingulate cortex, is over-active in people with depression. This area is responsible for several roles but can cause anxiety, particularly when it is over-active. When David Nutt and his colleagues asked people on psilocybin to think of a happy memory, they found that the volunteers could remember happy memories more vividly – almost as if they were reliving them. These test subjects were also much happier after recalling positive memories. Dampening the activity in the connector hubs and getting a boost from recalling happier times could be enough to get people out of the vicious circle of depression. Fortunately, the Medical Research Council has since funded David Nutt to conduct further studies into the use of psilocybin as a treatment for depression.

Post-traumatic stress disorder and depression are two of the biggest mental health issues that we face and current treatments are plainly inadequate. It seems ridiculous that the government’s policies on drugs prevent scientific studies aiming to reap benefits from them. These treatments show good potential and yet little is being done to take advantage of them. This situation is nothing new – after being fêted as a treatment for alcoholism in the 1960s, LSD has largely been ignored ever since it was declared illegal. Even though, according to David Nutt, it is probably as good at treating alcoholism as anything we’ve got now, researchers are limited to reanalysing studies completed 50 years ago.

What treatments are out there, undiscovered because of governments’ heavy-handed approaches towards recreational drugs? I’m just glad that there are researchers like David Nutt who are willing to make the effort, and take the flak, in order to find out.

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Red Alert: How red hair can cause skin cancer without sun exposure

I’m not usually that interested in research completely based on mouse studies, but any paper that starts with ‘People with pale skin, red hair, freckles and an inability to tan…‘ is always going to get my attention.

People like me, with the ‘red hair/fair skin’ phenotype, are pretty bad at dealing with the sun. Not only do we get sunburnt much more easily, but we have the highest risk of developing melanoma, the deadliest form of skin cancer. It is (hopefully) very well known that exposure to UV light increases the risk of melanoma. However, unlike other other skin cancers, melanoma also appears to develop independently of UV light, although this has been poorly studied to date.

The sun can be your worst enemy when you’re ginger. (Photo credit: coltera)

In a letter published in Nature this week, researchers wanted to see if hair-colour pigments affect this UV-independent pathway for melanoma. To do this, they engineered mice to mimic human complexions by mutating a gene known as MC1R. This is responsible for producing the pigment eumelanin which is dark coloured and results in dark hair. Most people with red hair have an inactive form of MC1R, which instead leads to the red-coloured pheomelanin being produced.

The researchers compared mice with black hair (active MC1R), red hair (inactivated MC1R) and albinism (produces neither pigment). In addition, all the mice had a specific mutation that causes benign moles, but leaves them predisposed to developing melanoma. The mice were kept away from sources of UV light and their health was charted over time.

The differences are startling. In under a year 50% of the red-haired mice had died compared to only 20% of the black-haired or albino mice. This, and further tests, seem to suggest that producing pheomelanin is actually harmful, increasing the rate of melanoma when there is no UV light.

Pheomelanin is responsible for the colour of red hair, but could also cause cancer

It was also apparent that the DNA of the red-haired mice had suffered twice as much oxidative damage as the albino mice. It is known that UV light causes oxidative DNA damage and that this increases the chances of mutations occurring. In previous studies looking at UV radiation, it was thought that eumelanin protects against this damage. However, the mice in this study show that pheomelanin is actually harmful and eumelanin has little effect under these conditions. It’s still not clear how this damage was created in the absence of UV light or why production of pheomelanin made it worse.

The authors of the paper make it very clear that UV radiation is still an important factor in the development of skin cancer, but suggest that this UV-independent pathway should be considered in the future for strategies to prevent melanoma, especially for gingers.

Redheads have long understood that we lack the natural sun protection that others enjoy, but it is still quite a shock to think that our distinctive colouring is actively causing us damage. However, this study was done under very artificial conditions, and the rates that the researchers saw are far higher than we can plainly observe. After all, we don’t see half of redheads dying every year. But whatever your hair colour, melanoma is still very deadly – one American dies from melanoma every hour. So make sure you don’t forget your sunscreen.

Keeping up with the Red Queen: Co-evolution of hosts and pathogens

While most micro-organisms are harmless to humans, and in some cases even beneficial, there are those that are not welcome. These are known as pathogens, from the Greek for ‘producer of suffering’. For us, pathogens can be very damaging and even deadly, and so we have evolved ways to resist their attacks. For the pathogen, infecting a human might be the only chance to survive and reproduce. The potential reward is so great that pathogens will develop ways around our defences. This becomes an ongoing battle and means that neither side can stop evolving in case the opponent becomes too dominant; in the words of the Red Queen from Lewis Carroll’s Through the Looking-Glass: “It takes all the running you can do, to keep in the same place.” This interplay between host and pathogen is known as co-evolution and can lead to very different strategies being used on both sides.

The Red Queen (not to be confused with the Queen of Hearts) and Alice

All-out war

Aggressive strategies, like that used by the malarial parasite Plasmodium falciparum, can drive co-evolution rapidly. Once it has infected a person, the pathogen replicates as quickly as possible. This is risky because it seriously affects the infected human and can even cause death, and if the host dies, the pathogen die with it. This strategy works because P. falciparum spreads between humans via mosquitoes. High concentration of the parasite in the bloodstream is the best way to ensure that they are taken up by a mosquito and passed on to a new host. However, the severity of malaria and the high likelihood of death means there is a strong evolutionary pressure for humans to develop resistance, even if that comes at a price.

Indeed resistance has developed, via a specific mutation in the gene coding for the blood protein haemoglobin. Everyone has two copies of the haemoglobin gene – one from each parent. A mutation in both copies of the gene provides malarial resistance but causes sickle cell anaemia. This causes blood flow to be restricted and eventually leads to premature death, which obviously outweigh any benefits. Fortunately, having just one copy of the mutation maintains some resistance and avoids sickle cell anaemia. However it can never be guaranteed that a child will inherit exactly one copy of the mutated gene, so there is always a risk of children being born with sickle cell anaemia. This means that the level of the mutation present in the population is determined by the balance between the risk of malaria and the risk of sickle cell anaemia. There is little risk of malaria in the UK and so the mutation is rare. In sub-Saharan Africa, where malaria causes a quarter of all deaths in children under five, the balance shifts. The mutated gene is present in up to 40% of the population, meaning that approximately 2% of children are born with sickle cell anaemia.

When a specific glutamic acid residue (highlighted in magenta on the far right) is mutated to a valine it causes haemoglobin molecules to aggregate, which distorts the shape of red blood cells

Under the radar

Evolving against every new infectious disease that we encounter is not possible. Humans, with our relatively slow reproductive rate, take a long time to develop new, beneficial mutations. This is why many infections, such as the common cold caused by the rhinovirus, have evolved to avoid affecting humans severely. Catching a cold will not affect the ability to reproduce, which is the main driving force behind evolution. Without this evolutionary pressure, humans do not appear to have developed mutations to specifically deal with the rhinovirus. Keeping the host able and mobile also has the benefit of boosting the spread of the disease. If the host feels well enough to leave bed and go to work, then the rhinovirus is presented with a wide range of potential hosts with every sneeze.

The immune system provides a flexible defence against a huge variety of diseases, lessening the need to evolve in response to new infections. The system learns to recognise a part of the pathogen known as the antigen, which allows the pathogen to be targeted. This means that a strain of rhinovirus, or any pathogen, that has mutated its antigen can evade detection by the immune system for longer. Unfortunately for us, this happens very often as the rhinovirus mutates very easily and reproduces incredibly quickly, allowing a huge number of mutations to accumulate within a population rapidly.

Gaining ground

Today the risk of dying from an infectious disease is lower than at any point in human history. After thousands of years locked in an impasse with diseases, we have finally developed an advantage through modern medicine. Although it seemed that we have surpassed the power of evolution, pathogens are still working towards breaking through our defences. Whether it is a new strain of flu or an antibiotic-resistant superbug, if we want to maintain our advantage it will take all the running we can do.

Note: this post was updated 16:53 GMT 21/10/2012 to remove any suggestions that Plasmodium falciparum is a bacterium

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2012 Nobel prize in chemistry: G protein-coupled receptors

I couldn’t let today pass without writing something about the Nobel prize. Before long I’ll write a full piece about G protein-coupled receptors (GPCRs) but that’s quite a big story. For now, I just want to stress their importance and their place in current research.

A cell requires isolation from the outside world; maintaining different concentrations of ions inside and outside the cell is a vital part of how it functions. GPCRs play a hugely important role in detecting signals sent from outside the cell and relaying them to the inside. They are known as trans-membrane proteins because they extend from outside the cell, through the membrane and into the inner region. This means that when they bind a ligand on the outside of the cell (e.g. a hormone), the resulting structural rearrangement can trigger a chain of signals through to the inner machinery of the cell.

Beta-2 adrenergic receptor

Beta-2 adrenoceptor, the first structure of a human GPCR. It was solved by Brian Kobilka’s lab in 2007. The red portion indicates the membrane-bound section and the green indicates the intra-cellular section [the extra-cellular region was not observed].

Trans-membrane proteins are poorly studied, largely because it is so difficult to keep them stable when studying them in the lab. The parts of the protein that are outside the membrane will have positive and negative charges pointed outwards, interacting with water molecules. However, the membrane is made from fatty chains that repel water and so the region of the protein that stays in the membrane will be structured in a way that avoids water by having its hydrophobic amino acids pointing outwards. Keeping both of these regions stable in the same solution is tricky, but manageable. Detergents can mimic the membrane and are widely used.

Detergents can make it difficult to study the structure of GPCRs. Most protein structures are solved using X-ray crystallography or nuclear magnetic resonance (NMR). However, crystallography requires all the protein molecules to be very uniform which is difficult with the added complexity of a detergent that may form different shapes and sizes. NMR begins to lose its sensitivity as the size of the protein increases. In this case, the detergent counts towards the protein’s size which makes it difficult to get data.

This has meant that despite the huge importance of GPCRs in biochemistry and medicine (over a third of all drugs act via GPCRs), our understanding of them is still relatively poor. However we would be a lot further behind if it wasn’t for Lefkowitz and Kobilka – they are very deserving Nobel laureates.

Magnetic trigger for cancer death

A team of researchers from Seoul have developed a magnetically-controlled nanoparticle that can kill cancer cells.

One of the key challenges in the fight against cancer is that potential treatments can often be worse than the disease. These treatments are so destructive that it takes a lot of effort to find one that will kill the cancer before it kills the patient. This means that treatments need to be as selective and controllable as possible.

The nanoparticle can be controlled by simply turning a magnetic field on and off. This means that its effects can be aimed at a specific area (if you have a focused magnetic field) and for a specific length of time. This level of targeting would reduce the severity of side-effects, allowing patients to receive stronger doses.

The zinc-doped iron oxide nanoparticle is attached to an antibody which binds tightly to death receptor 4, DR4. There are many copies of DR4 on the surface of the cancer cell and the nanoparticles can bind to them all, without any effect. When a magnetic field is applied, the nanoparticles move towards one another across the cell surface. This causes the DR4s to come together to form a complex. This is known as death-inducing signalling complex and it starts the chain reaction of events leading to apoptosis (programmed cell death).

Antibodies bind very specifically to their target protein, making them very useful in medicine

This mechanism is actually a mimic of the one used by the TNF-related apoptosis inducing ligand (TRAIL). TRAIL has been investigated as a cancer treatment, however it degrades easily, a problem that is unlikely to affect the nanoparticles.

The paper, published in Nature Materials, looks at the effect on cancer cells in vitro and the effects on zebrafish. This research is still very much in the early stages and it will be quite some time before its effects on cancer in humans can be tested. However, it is a fine example of the novel ways that scientists are trying to fight cancer. It is the trickiest disease there is, and it will take a lot of ingenuity to tackle it.