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Medical cannabis: Riding the wave

pharmafile | October 16, 2019 | Feature | Business Services, Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing | Kanabo research, medical cannabis, pharma

Following on from our previous piece from Mewburn Ellis on the history of social attitudes towards cannabis, Israel-based Kanabo Research is one of many emerging firms leading the international surge of research and development into the potential of cannabis-based therapies. Founder & CEO Avihu Tamir discusses the company’s work within the context of the growing cultural shift in attitudes towards the substance around the world.

Where is Kanabo focusing its efforts when it comes to the treatment of patients?

Kanabo is focused on central nervous system (CNS) indications. Epilepsy is one of them, but we are more focused on the area of insomnia and sleep disorders. We had a very successful preclinical trial and we are now starting a clinical trial; in this indication we are focused on replacing addictive sleeping pills. We are also focused on neuropathic pain – another indication in which we hope to replace dangerous and addictive drugs such as opioids. The last indication that we are looking into is post-traumatic stress disorder, in the area of psychiatric illnesses. We are currently working with one of the leading doctors in Israel who has experience specifically with cannabis and post-traumatic stress. He has a lot of successful work in this area.

Medical cannabis has been authorised in the UK for severe forms of epilepsy. Why are cannabis-based therapies becoming the go-to treatments for these conditions?

Two companies have driven the use of cannabis as a treatment for epilepsy. The first company is Charlotte’s Web, which had a strain of cannabis that was unique in that it was very low in tetrahydrocannabinol (THC). That meant that children could use it without experiencing any psychoactive effects. That was around 2011-2012. We saw a lot of anecdotal evidence suggesting that the treatment was very successful. Based on that information, GW Pharma developed a cannabis-based pharmaceutical drug which was approved in the United States in June of this year: Epidiolex.

However, cannabis is showing to be a success in many other indications – some that have already been used on a widespread scale. Other evidence is very anecdotal – for example, in Israel, parents discovered the benefits of cannabis in children with autism after some of the children with autism were given cannabis for epilepsy. Children who had aggression became a lot more patient; they started being able to do tasks that they couldn’t do before. It increased focus. Coming from that, researchers in Israel are now running two clinical trials of cannabis in children with autism.

Cannabis is being explored in a range of conditions, including epilepsy, autism, multiple sclerosis and Parkinson’s. How does cannabis work as a medicine?

Cannabis affects the endocannabinoid system. The endocannabinoid system was discovered by a group of scientists at the Hebrew University in Jerusalem, with partners around the world. The leading doctor was Dr Rafael Mechoulam, who is well known as the godfather of cannabis. The endocannabinoid system operates through a naturally occurring molecule called anandamide. Anandamide is very similar to cannabinoids.

Within the endocannabinoid system there are two receptors that we are looking at from the scientific side – CB1 and CB2. CB1 affects the CNS. So any illnesses that affect the CNS have some kind of interaction with this receptor and cannabinoids also have an effect on this receptor. CB2 affects the immune system and the digestive system. Essentially, cannabinoids affect the way in which your receptors behave, so in relation to the CNS, cannabinoids boost the receptor’s ability to collect data or information between them. You could say it’s like turning on a light or turning up the dial.

Many of these illnesses are related to problems associated with the movement of information between receptors. Cannabinoids also have neuroprotective effects; for example, dementia, or Alzheimer’s or even brain trauma can all be protected against using cannabis. One of the reasons these illnesses occur is because the receptors lose their capacity to communicate – cannabis can act as a protective shield.

If we look ahead and understand that cannabis is going to become a neuroprotector there’s a lot of potential. In the future, most older people will take cannabis as a neuroprotector, on a daily basis, not in high doses but in micro doses – very small doses that do not affect your daily routine and have no psychoactive effects. It will be similar to a lot of supplements people take today such as iron supplements. To take it a step further, we are on the verge of the pharmaceutical industry being able to tell you that you have a cannabinoid deficiency. This is the real potential of the medicinal cannabis market.

What form do you see medicinal cannabis taking in the future?

The cannabis field is currently looking at three segments. First of all, you have synthetic cannabinoids, which are very interesting to pharma as it is presented in the sort of language that the pharma world understands. However, synthetic cannabinoid-based drugs and medicines have been a failure in the commercialisation side, while cannabis is a very successful product.

Then you have two other groups: the single molecule cannabinoid (for example THC or cannabidiol) and you also have the whole plant extract that includes many different cannabinoids and things that are other materials that come from the plant.

The single molecules are easier to work with. They are easier to make pharmaceutical grade, but it seems again and again in research that the combined effect of different cannabinoids together creates a synergy. In these cases, one plus one seems to equal more than two. The problem with plant extracts is reproducibility. That’s a big challenge because at the end of the day you are working with a botanical medicine that will always be changing; even if it’s the same exact strain, if you grow it in the summer or the winter, it’s different.

Which of these forms will become most common will depend more on regulation than anything else. If regulation permits any of these options, I believe we will see all of these things.

What role does Kanabo’s inhaler play in the market today?

First of all, we are focused on the natural compound. That means we believe in the full plant compound. At the same time, we want precision. So how do you take this plant – the raw material – and create a product that is very stable? We now know how to control the key cannabinoids and make sure that they will always be the same. So we are able to bring to the market a product that is natural, but we’ve enriched it and made it very stable.

The second focus is inhalation. There are two key reasons why: the first is that it’s immediate. Many of the indications that we are focused on require immediate release. If you consume cannabis orally, the relief can come after one or two hours. In some indications, such as seizure or pain, you don’t want to wait one or two hours.

The second thing is the bioavailability. You have between four and five times the bioavailability when inhaling cannabis than when consuming it orally. Consuming cannabis orally also changes the form of the cannabinoid and its effects. When you consume cannabis orally it’s like playing roulette. For some people it will have no effect at all, while others can have an overdose from the same dose. That’s one of the challenges of consuming cannabis. In bypassing the digestive system – through either inhalation or sublingual ingestion – you have much greater accuracy.

Kanabo hopes to use cannabis to treat psychiatric disorders. How would you respond to concerns regarding the link between cannabis and psychosis and mental health problems?

Any material that is psychoactive can have a negative effect on people who have a tendency to experience a psychiatric breakdown. Someone could have a breakdown from consuming alcohol; it is not unique to cannabis. The second point is that statistically this theory is not correct. The consumption of cannabis has increased by as much as 100 times in the last 30 years. However, the percentage of people suffering from psychosis is still 1% of the population. There hasn’t been a spike in the number of people with psychosis – even considering the amount of THC in cannabis is rising dramatically.

Having said that, today, we even know what is causing the side-effect of paranoia. This means we know how to prevent it. The main reason people experience side-effects on cannabis is consumption of high doses of THC when they have no tolerance for THC. That causes paranoia and anxiety. If someone is taking large amounts of cannabis over a long period that can obviously have a traumatic effect on anyone. How do you deal with it? Education and not buying cannabis on the street, when you don’t know the dosing and what is in it, but getting it from a pharmacy or a doctor.

To read the third article in our trio of in-depth pieces focusing on the growing medical cannabis phenomenon, click here.