What is the evidence for medical use of cannabis?

Posted on by Carolyn Brown

“Results reflect the … relative dearth of high-quality evidence related to cannabis for therapeutic purposes”

“The level of evidence for the use of medical marijuana among people with disabilities varies greatly and has a clear lack of methodologically sound studies”

“Evidence is gathering … but further research is required to declare cannabinoids a medicine”

“These studies suffered from multiple limitations, including selection bias, lack of standardized dose and route of administration, absence of blinding, recall bias and lack of a control population”

“The long-term safety profile of chronic cannabis use has not been well defined, mainly due to the heterogeneity of preparations, varying routes of administration, and the lack of controlled studies addressing safety”

“Evaluation of these low-quality trials … was challenged by methodological issues such as inadequate description of allocation concealment, blinding and underpowered sample size”

These are some of the things the experts are saying about the research into medical uses of cannabis to date. To prepare this article, I read 11 “review” articles — articles that pull together all of the research out there and reach conclusions.

The authors are unanimous in saying there is little research, and many of the studies that have been done are really small — less than two dozen patients. Some lack another treatment for comparison — either a placebo or another drug. Other studies can’t be blinded, because patients can tell whether they are getting cannabis, either because they are smoking it or they feel stoned. Others are “observational” studies (some patients are given cannabis and the researchers see what happens), considered the poorest type of evidence.

But there is some good research, and it shows that cannabis might be useful in a few health conditions:

  • Pain
  • Epilepsy
  • Inflammatory bowel disease (Crohn’s disease and ulcerative colitis)

These medical uses of cannabis are not just based on folklore (or, in this case, folk-singer lore). Science has shown that some of the chemicals in cannabis (cannabinoids) mimic natural chemicals in the human body that are important in the nervous system and the immune system. This is why its use is being taken seriously as a potential addition to the drugs we already have.

Pain

The toughest pain to control is cancer pain. A review of five randomized controlled trials looked at cannabis to treat this type of pain. Although one of the studies didn’t find any difference between cannabis preparations containing both THC and CBD (nabiximols) and placebo, there was definite effect in two larger studies with more than 150 patients each. Two earlier studies that had looked at short-term effects in small numbers of patients also found an effect. This review was funded by a Canadian medical cannabis company but was conducted with Sunnybrook Health Sciences Centre and the University of Toronto, so the oversight, ethics and evidence should be solid.

Epilepsy

I have known someone with very serious epilepsy who must cope with several seizures each day. This type of disability limits a person’s life and can even pose a danger. In some cases, the well-established drugs that control epilepsy in most people don’t work or cause serious side effects.

Four reviews of the research found evidence that cannabis preparations can reduce or even stop seizures in people with severe seizure disorders. But the effectiveness seems to vary from patient to patient.

A review that looked at cannabis research for many different disabilities found robust evidence only for epilepsy and pain. Another review that looked specifically at the non-intoxicating cannabinoid CBD for epilepsy showed that it was effective but also showed high rates of side effects, including sleepiness, loss of appetite and diarrhea. A third review found positive effects of CBD in the worst types of epilepsy: Dravet syndrome and Lennox-Gastaut syndrome.

Inflammatory bowel disease

There was a lot of hope that cannabis could help with IBD through its effects on the immune and gastrointestinal systems, but findings are mixed.

A review of five studies (only two of which were high-quality and all of which were small) found positive and remarkable effects on symptoms of IBD. However, two systematic reviews (one for Crohn’s disease and one for ulcerative colitis) by the Cochrane Collaboration — well known for its high-standard reviews — found that the effects were uncertain, the studies small, and conclusions unreachable. However, because of the positive findings of some studies, treatment of IBD needs to be tested in larger groups.

Why not more, better, larger studies?

That’s the question. When I attended a panel on medical cannabis earlier this year (2018), one of the panellists representing a cannabis company buttonholed me afterward about the difficulty in conducting studies. He pointed out that the best level of evidence is provided by randomized controlled trials involving hundreds or thousands of patients. But running those trials is incredibly expensive. He also argued that it is difficult to use placebos when testing cannabis, since those taking cannabis may be smoking it and it may be unethical to let patients go without some kind of treatment. This also means it might be impossible for the trials to be double-blinded — when neither patients nor researchers know who is getting the drug and who the placebo or comparison drug.

These are good points, but they sound like companies are throwing up barriers to running studies.

First, many randomized controlled trials compare the test drug with the standard treatment or best treatment (“gold standard”) rather than with a placebo. This is certainly the case for drugs for mental health problems, as it would be unethical to let a serious mental health problem go untreated. So, trials do not need to use a placebo.

Also, many trials are single-blinded rather than double-blinded. That is, the patients can figure out what they are getting, but the researchers don’t know who is getting what and aren’t influenced by that knowledge. In many trials, this is necessary, if not optimal.

The real issue is money. Running the kind of studies that you need to submit to Health Canada to have your drug recognized as a safe and effective treatment for a particular condition takes years and millions of dollars. Right now, cannabis companies are not that rich.

But in Canada the cannabis companies have formed a consortium that could fund trials. As well, disease foundations in Canada and other countries (like, the one to the south) are interested in the promise of cannabis, and they put money into research. With its open regime, Canada is a good place to carry out international studies of medical cannabis, which would not face the legal hurdles that exist in many other countries.

There are many conditions for which safe and effective drugs are needed. If cannabis can help, it should be prescribed and monitored by doctors to ensure it works for patients, and it should be covered by drug plans. It should not be bought at a dispensary for self-treatment, often by patients who can’t afford it.

As I mentioned to the cannabis company representative, doctors were burned on opioids. The manufacturers claimed opioids weren’t addictive, which wasn’t true. Studies would give doctors full information on cannabis’ effects and risks, so they could inform their patients. Doctors and patients deserve no less.

 

The cause of multiple sclerosis: we’re getting closer

Posted on by Carolyn Brown

My feature on the state of research into MS causes (published Dec. 1, 2016, in Nature Outlook) had a long and complex genesis, which is also true of the disease I wrote about.

I have long been interested in how diseases happen, from my days writing about research for my column in the Canadian Medical Association Journal (CMAJ). I covered a whole variety of health issues, of course, but the ones that were of most concern – the ones that could wipe out populations and cultures – were diseases.

A few years ago at the Canadian Science Writers Association conference, Dr. Brian Goldman presented a news clip on an experimental treatment for MS touted by Paolo Zamboni, which he (suspiciously) called “liberation therapy” based on a theory that MS is caused by chronic cerebrospinal venous insufficiency. Or let’s just say veins blocked by metal buildup. Goldman was critical of the glowing media descriptions of the treatment, as they were not evidence-based.

I was sitting at the same table with Dr. Goldman at lunch, and our gang of science writers debated the ethics of this type of coverage. I recall I said, “Of course, we don’t know what causes MS.” Because that was the understanding at the time.

That discussion stuck with me, especially as I met more people with MS over the past few years. Then, in reporting for CMAJ, I covered two research stories on discoveries relevant to the cause of MS. I starting following the references in one of the articles to other research, and I soon learned that the evidence was mounting for several causal factors. Some researchers were looking into whether these factors were linked. In fact, right now there’s a new article every month on these factors.

But I had seen nothing (and I looked) in the media about the good, solid, research that had been slowly amassing over years about Epstein-Barr virus and vitamin D, in particular.

I pitched an idea for a feature on this research at this year’s Canadian Science Writers Association conference as part of a “Dragon’s Den” pitch session to a panel of four editors. And – long story short – I was eventually asked to write it for Nature Outlook.

Why I included the Elmvale Acres Ottawa cluster

I was in the midst of my research on MS causes, and I was particularly interested in the paper from Winnipeg researchers showing clusters of incident cases of MS in that city. As the authors of this paper told me, clusters are an important clue into causation. They can indicate genetic differences, especially in a multicultural city like Winnipeg, or environmental factors. I was fascinated because the clustering in Winnipeg (unfortunately, for copyright reasons, I couldn’t reproduce the study’s maps, which are worth a thousand words) looked like maps of disease outbreaks. That doesn’t mean they are – it is just a possibility worth exploring.

I had wanted to get the human angle on this research, to show that this research is about real people, not just dots on a map. I was even thinking of calling the MS society in Winnipeg to contact patients in the affected neighbourhoods. At this point, several of my friends who knew I was working on the article called or emailed to say there was a CBC story on a cluster right in my city – Ottawa.

I contacted the man at the centre of the CBC story, Jacques Dutrisac. Now, I have some graduate courses in statistics and I’ve read plenty of biostatistics. I know that disease clusters often occur by chance alone. There’s also a well-known perceptual effect that once you have a problem you tend to see it all around you. Careful and complex statistical methods like those used in the Winnipeg paper are needed to determine “true” clustering.

So, to be honest, I called Dutrisac prepared for the possibility that the cluster in the Elmvale Acres neighbourhood of Ottawa might be by chance alone. Dutrisac is a wonderful raconteur and sleuth. Not only had he kept track of all of his former friends and neighbours with MS, he had their names, locations, schools, ages, and ethnic background. He was telling me about one after the other, and I was taking notes. After our chat, I made a table of all 14 people with MS (at that point – another neighbour with MS has come to light as a result of the publicity around the cluster). The prevalence of MS in Canada (where it is highest in the world) is 291 per 100,000 or a little under 3 per 1000. In an area of less than 1000 people, the rate was at least five times higher than the national average. When I looked at the fact that the people affected not only lived in a kilometre-radius area, but were all about the same age – in fact, most exactly the same age as Dutrisac –, went to the same schools and were two-thirds francophone… well… that can’t possibly be by chance.

So I feel that I’m being responsible as a journalist in covering a cluster that has not yet been studied, but should be.