Thursday, May 1, 2014

Cannabis, cannabinoids and cancer – the evidence so far


What are cannabinoids and how do they work?

Cannabinoids” is a blanket term covering a family of complex chemicals (both natural and man-made) that lock on to cannabinoid receptors – protein molecules on the surface of cells.
Humans have been using cannabis plants for medicinal and recreational purposes for thousands of years, but cannabinoids themselves were first purified from cannabis plants in the 1940s. The structure of the main active ingredient of cannabis plants – delta-9 tetrahydrocannabinol (THC) – was discovered in the 60s. It wasn’t until the late 1980s that researchers found the first cannabinoid receptor, followed shortly by the discovery that we create cannabinoid-like chemicals within our own bodies, known as endocannabinoids.
The CB1 and CB2 receptors
The CB1 and CB2 receptors. 

We have two different types of cannabinoid receptor, CB1 and CB2, which are found in different locations and do different things. CB1 is mostly found on cells in the nervous system, including certain areas of the brain and the ends of nerves throughout the body, while CB2 receptors are mostly found in cells from the immune system. Because of their location in the brain, it’s thought that CB1 receptors are responsible for the infamous ‘high’ (known as psychoactive effects) resulting from using cannabis.
Over the past couple of decades scientists have found that endocannabinoids and cannabinoid receptors are involved in a vast array of functions in our bodies, including helping to control brain and nerve activity (including memory and pain), energy metabolism, heart function, the immune system and even reproduction. Because of this molecular multitasking, they’re implicated in a huge range of illnesses, from cancer to neurodegenerative diseases.

Can cannabinoids treat cancer?

There is no doubt that cannabinoids – both natural and synthetic – are interesting biological molecules. Hundreds of scientists around the world are investigating their potential in cancer and other diseases – as well as the harms they can cause – brought together under the blanket organisation The International Cannabinoid Research Society.
Researchers first looked at the anticancer properties of cannabinoids back in the 1970s, and many hundreds of scientific papers looking at cannabinoids and cancer have been published since then. This Wellcome Witness seminar is also fascinating reading for aficionados of the history of medical cannabis, including the scientific, political and legal twists.
But claims that this body of preclinical research is solid “proof” that cannabis or cannabinoids can cure cancer is highly misleading to patients and their families, and builds a false picture of the state of progress in this area.
Let’s take a closer look at the evidence.

Lab research

Virtually all the scientific research investigating whether cannabinoids can treat cancer has been done using cancer cells grown in the lab or animal models. It’s important to be cautious when extrapolating these results up to real live patients, who tend to be a lot more complex than a Petri dish or a mouse.
A researcher with some cells in a Petri dish
Virtually all the research into cannabinoids and cancer so far has been done in the lab.
Through many detailed experiments, handily summarised in this recent article in the journal Nature Reviews Cancer, scientists have discovered that various cannabinoids (both natural and synthetic) have a wide range of effects in the lab, including:
  • Triggering cell death, through a mechanism called apoptosis
  • Stopping cells from dividing
  • Preventing new blood vessels from growing into tumours
  • Reducing the chances of cancer cells spreading through the body, by stopping cells from moving or invading neighbouring tissue
  • Speeding up the cell’s internal ‘waste disposal machine’ – a process known as autophagy – which can lead to cell death
All these effects are thought to be caused by cannabinoids locking onto the CB1 and CB2 cannabinoid receptors. It also looks like cannabinoids can exert effects on cancer cells that don’t involve cannabinoid receptors, although it isn’t yet clear exactly what’s going on there.
So far, the best results in the lab or animal models have come from using a combination of highly purified THC and cannabidiol (CBD), a cannabinoid found in cannabis plants that counteracts the psychoactive effects of THC. But researchers have also found positive results using synthetic cannabinoids, such as a molecule called JWH-133.
It’s not all good news though, as there’s also evidence that cannabinoids may also have undesirable effects on cancer.
For example, some researchers have found that although high doses of THC can kill cancer cells, they also harm crucial blood vessel cells, although this may help their anti-cancer effect by preventing blood vessels growing into a tumour. And under some circumstances, cannabinoids can actually encourage cancer cells to grow, or have different effects depending on the dosage and levels of cannabinoid receptors present on the cancer cells.

Others have discovered that activating CB2 receptors may actually interfere with the ability of the immune system to recognise and destroy tumour cells, although some scientists have found that certain synthetic cannabinoids may enhance immune defences against cancer.
Furthermore, cancer cells can develop resistance to cannabinoids and start growing again, although this can be got round by blocking a certain molecular pathway in the cells known as ALK.
And yet more research suggests that combining cannabinoids with other chemotherapy drugs may be a much more effective approach. This idea is supported by lab experiments combining cannabinoids with other drugs including gemcitabine and temozolomide.

Clinical research

But that’s the lab – what about clinical research involving people with cancer? Results have been published from only one clinical trial testing whether cannabinoids can treat cancer in patients, led by Dr Manuel Guzman and his team in Spain. Nine people with advanced, terminal glioblastoma multiforme – an aggressive brain tumour – were given highly purified THC through a tube directly into their brain.
Eight people’s cancers showed some kind of response to the treatment, and one didn’t respond at all. All the patients died within a year, as might be expected for people with cancer this advanced.
The results from this study show that THC given in this way is safe and doesn’t seem to cause significant side effects. But because this was an early stage trial, without a control group, it’s impossible to say whether THC helped to extend their lives. And while it’s certainly not a cure,  the trial results suggest that cannabinoids are worth pursuing in clinical trials.
There is also a published case report of a 14-year old girl from Canada who was treated with cannabis extracts (also referred to as “hemp oil”), but there is limited information that can be obtained from a single case treated with a varied mixture of cannabinoids. More published examples with detailed data are needed in order to draw a fuller picture of what’s going on. [Updated 26/03/14, KA]
A handful of other clinical trials of cannabinoids are currently being set up. We are helping to support the only two UK trials of cannabinoids for treating cancer, through our Experimental Cancer Medicine Centre (ECMC) Network funded by Cancer Research UK and the devolved Departments of Health. One early-stage trial is testing a synthetic cannabinoid called dexanabinol in patients with advanced cancer, and the other is an early-stage trial testing a cannabis extract called Sativex for treating people with glioblastoma multiforme brain tumours.

Unanswered questions

There are still a lot of unanswered questions around the potential for using cannabinoids to treat cancer.
Cannabis extract
An antique bottle of cannabis extract.

The biggest issue is that there isn’t enough evidence to show that they can treat cancer in people, although research is still ongoing around the world.
And it’s not clear which type of cannabinoid – either natural or synthetic – might be most effective, what kind of doses might be needed, or which types of cancer might respond best to them. So far there have been intriguing results from lab experiments with prostate, breast, lung cancer, skin, bone and pancreatic cancers, glioma brain tumours and lymphoma. But the take-home message is that different cannabinoids seem to have different effects on various cancer types, so they are far from being a ‘universal’ treatment.
Most research has been focused on THC, which occurs naturally in cannabis plants, but researchers have found that different cannabinoids seem to work better or worse different types of cancer cells. Lab experiments have shown promising results with THC on brain tumour and prostate cancer cells, while CBD seems to work well on breast cancer cells.
Then there’s the problem of the psychoactive effects of THC, particularly at high doses, although this can be counteracted by giving it together with CBD. Because of this problem, synthetic cannabinoids that don’t have these effects might be more useful in the long term.
There are also big questions around the best way to actually get the drugs into tumours. Because of their chemical makeup, cannabinoids don’t dissolve easily in water and don’t travel very far in our tissues. This makes it hard to get them deep into a tumour, or even just deliver them into the bloodstream in consistently high enough doses to have an effect.
The clinical trial led by Dr Guzman in Spain involved directly injecting cannabinoids into patients’ brains through a small tube. This isn’t an ideal method as it’s very invasive and carries a risk of infection, so researchers are investigating other delivery methods such as tablets, oil injections, mouth sprays or even microspheres.
We also don’t know whether cannabinoids will help to boost or counteract the effects of chemotherapy, nor which combinations of drugs might be good to try. And there are currently no biological markers to help doctors identify who might benefit from cannabinoids and who might not – remember that one patient on the brain tumour trial failed to respond to THC at all.
None of these issues are deal-breakers, but these questions need answering if there’s any hope of using cannabinoids to effectively and safely treat cancer patients.
It’s worth remembering that there are hundreds of exciting potential cancer drugs being developed and tested in university, charity and industry labs all over the world – cannabinoids are merely a small part of a much larger picture.
Most of these compounds will never make it into the clinic to treat patients for a huge range of reasons including toxicity, lack of effectiveness, unacceptable side effects, or difficulty of delivering the drug to tumours.
Without doing rigorous scientific research, we will never sift the ‘hits’ from the ‘misses’. If cannabinoids are ever to get into clinical use, they need to overcome these hurdles and prove they have benefits over existing cancer treatments.

Can cannabis prevent or cause cancer?

So that’s a brief look at cannabinoids to treat cancer. But can they stop the disease from developing? Or could they play a role in causing cancer?
Someone smoking a cannabis joint
There’s controversy around the health risks of cannabis. 

In experiments with mice, animals given very high doses of purified THC seemed to have a lower risk of developing cancer, and there has been some research suggesting that endocannabinoids (cannabinoids produced by the body) can suppress tumour growth. But there’s no solid scientific evidence at the moment to show that cannabinoids or cannabis can cut the risk of cancer in people.
When it comes to finding out whether cannabis can cause cancer, the evidence is a lot murkier. This is mainly because most people who use cannabis smoke it mixed with tobacco, a substance that definitely does cause cancer.
This complex issue recently hit the headlines when the British Lung Foundation released a study suggesting that the cancer risks of cannabis had been underestimated, although this has been questioned by some experts including Professor David Nutt.

What about controlling cancer symptoms such as pain or sickness?

Although there’s a lack of data showing that cannabinoids can effectively treat cancer, there is good evidence that these molecules may be beneficial in other ways.
As far back as the 1980s, cannabinoid-based drugs – including dronabinol (synthetic THC) and nabilone – were used to help reduce nausea and vomiting caused by chemotherapy. But there are now safer and more effective alternatives and cannabinoids tend to only be used where other approaches fail.
In some parts of the world – including the Netherlands – medical use of marijuana has been legalised for palliative use (relieving pain and symptoms), including cancer pain. For example, Dutch patients can obtain standardised, medicinal-grade cannabis from their doctor, and medicinal cannabis is available in many states in the US.
But one of the problems of using herbal cannabis is about dosage – smoking it or taking it in the form of tea often provides a variable dose, which may make it difficult for patients to monitor their intake. So researchers are turning to alternative dosing methods, such as mouth sprays, which deliver a reliable and regulated dose.
Large-scale clinical trials are currently running in the UK testing whether a mouth spray called Sativex (nabiximols) – a highly purified pharmaceutical-grade extract of cannabis containing THC and CDB – can help to control severe cancer pain that doesn’t respond to other drugs.
There may also be potential for the use of cannabinoids in combating the loss of appetite and wasting experienced by some people with cancer, although a clinical trial comparing appetite in groups of cancer patients given cannabis extract, THC and a placebo didn’t find a difference between the treatments.

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