The Dutch Transvaal Apotheek is a pharmacy with a history. The library contains books from 1889 and according to the website one of the clients has been coming here for more than seventy years. Under the leadership of Paul Lebbink and Arwin Ramcharan, in 2015 they made medicinal cannabis oil available in the Netherlands for the first time.

With this, the pharmacy from The Hague made headlines both in the Netherlands and abroad, much to the surprise of the Transvaal Apotheek staff. “The impact was larger than expected”, Arwin Ramcharan, chemist and QA at Transvaal Apotheek, remembers.

OMC

Since 2003 Dutch patients have access to medicinal cannabis flos. The cannabis programme is run by the Office for Medicinal Cannabis (OMC) on behalf of the Dutch government. Ramcharan about this time: “As pharmaceutical chemist we were already well acquainted with the dried product and many of the users. But once we had refined the production process and the oil was released onto the market, the demand proved to be much greater than expected.” The pharmacy currently serves patients throughout the Netherlands and sometimes even abroad. The oil, which is available in five different varieties, is used for a multitude of conditions, with pain, epilepsy, glaucoma, migraines, nausea, infections, restlessness and insomnia, spasms and decreased appetite being the most common.

Cystic fibrosis

The Dutch pharmacist made history again in 2017. The Transvaal Apotheek started to fight big pharma with their own cost-effective alternative to exorbitantly priced medication for cystic fibrosis.

Patients in the Netherlands can only get the oil on doctor’s prescription. They can obtain it at the counter or have it delivered to their home by ‘medical post’. The number of patients who come to The Hague from neighbouring countries to take home oil is gradually increasing. They need a doctor’s prescription and – of course – permission to bring the cannabis oil home. Ramcharan: “We mainly see patients who have tried all other types of medication and who have become more or less therapy resistant. They have heard of medicinal cannabis, but they also want a product with known contents and a traceable origin. And they often appreciate receiving guidance from their physician and the chemist. The price of the oil is sometimes the subject of a debate, but most patients understand that the production requires investing in equipment and knowledge and that this is a labour-intensive and strictly-controlled pharmaceutical production process.”

Magistral preparations

Cannabis oil is a commonly used form among patients who administer their medication themselves because it is easy to dose. Transvaal Apotheek is one of the last Dutch pharmacies that still make magistral preparations so it came as no surprise that Ramcharan and his colleagues were asked to produce cannabis oil. “The request for oil came from the BMC and was initially aimed at young patients”, Ramcharan says. “In approximately nine months time we, in collaboration with (then still) pharamcist-in-training Svenja Laarhuis and researcher Arno Hazekamp, created a standardised process for the preparation of oil with mainly CBD, based on the then new Bedrolite® brand. After a large number of trial runs and tests we were able to start supplying oil to our patients in 2015. We were lucky to have good active pharmaceutical ingredient.” Bedrocan products are being used for the production of the oils. Ramcharan: “The medicinal cannabis available through pharmacies in the Netherlands is standardised and extensively tested on contents and the absence of contamination. It is also produced in compliance with GMP which prevents unnecessary discussions. And… our oil is also extensively tested. Because if you supply a medicinal product while being unsure about its quality and safety, you are on the wrong track, to put it mildly. The responsibility is simply too great.”

Other pharmacies

Transvaal Apotheek is no longer the only pharmacist in the Netherlands that is allowed to produce cannabis oil. Three other chemists also received permission and have started production and deliveries in the last few years. Two of these received guidance from Ramcharan and his colleagues. “These pharmacies thought it was unnecessary to re-invent the wheel and wanted to start production of medicinal cannabis oil as quickly as possible, while also assuring top quality”, Ramcharan says, who thinks a standardised way of working is important. “We think it is important to work in a standardised way and to use the same ingredients. This way you produce the exact same product every time, which means you can make statements about the effects and possible side effects in the long run.”

In the meantime the pharmacists exchange information and thus collect clinically relevant information. Ramcharan says: “Especially in the case of medicinal cannabis, everyone is waiting for clinically relevant information. Collaborating with other dispensers can also reveal information about the application of medicinal cannabis for other conditions. We therefore have collected information about migraine patients.”

According to Ramcharan, more patients can be followed by the collaboration: “In collaboration with a specialist, our chemist is currently monitoring a group of approximately 20 epilepsy patients. We are seeing, for example, positive effects from the administration of CBD. But we can now also provide information about possible side effects. As soon as we are able to broaden and deepen the scope of this type of research, we will gain access to incredibly valuable data. Not just for patients and professional care providers, but also for researchers.”

Medicinal use of cannabis has been legal in Australia since 2016. There are currently an estimated one thousand patients who have been granted permission. That is a very small number in a population of 24 million. Indeed,  it is assumed that one hundred thousand patients still obtain their medicine from illegal sources. How is that possible? We talked about this with Professor Iain McGregor, Academic Director of the Lambert Initiative for Cannabinoid Therapeutics, an Australian research institute within the University of Sydney.

Since its establishment in 2015, McGregor and his team have been researching the effects of medicinal cannabis, among other things. This year they published the results of two surveys from both physicians and patients. This was the first time both target groups were surveyed about the medicinal use of cannabis. And it showed hidden populations.

High price

According to McGregor, the high price of medicinal cannabis is a major reason why Australian patients still depend on the black market: “Most of the people are extremely poor because they live on social welfare or pensions. People cannot afford pharmaceutical products that are on offer in the federal scheme. It would cost 60,000 Australian dollars a year to treat an epileptic child with 1,000 milligrams of CBD a day.”

Medicinal cannabis is not covered by health insurance or government pharmaceutical subsidies in Australia. Therefore, McGregor is not surprised that patients are looking for cheaper alternatives. “Our research even shows that a quarter of the patients sometimes don’t pay anything at all for their cannabis. They get it for free or grow it themselves.”

The same research shows that Australian patients do not want it to be this way. “The same as with other medications, patients want a standardised product of pharmaceutical quality that is available at the chemist. This wish does not comply with the current programme”, says McGregor.

General Practitioners

The Australian GP is not to blame. The majority of GPs think that medicinal cannabis should be available on prescription. The Lambert Initiative surveyed 640 General Practitioners (family physicians) last year and the results astounded even researcher McGregor: “We knew pain doctors and specialists are very negative about medicinal cannabis. But the majority of the GPs, the family doctors, are in fact in favour of medicinal cannabis. This was quite surprising.”

GPs also say they support the use of cannabis for conditions such as chronic pain, epilepsy (intractable epilepsy) and palliative care, but less for depression or anxiety disorders. According to McGregor, the problem with the Australian system is that GPs are not allowed to prescribe medicinal cannabis, although they would like to. This task is reserved for specialist physicians (neurologists, oncologists and palliative care physicians) only. McGregor: “In Australia it is very difficult to get access to specialised medical care, let alone to find a specialist who is interested in cannabis-based medication.”

Therapeutic Goods Administration

Over the past two years the Australian drug agency the Therapeutic Goods Administration (TGA) has approved 1,442 applications. The number of patients who actually use cannabis is lower than the number of applications because some physicians submit multiple applications for the same patient. McGregor and his team estimate there are about one thousand patients who actually make use of the programme legally. But he thinks there could be many more: “Our opinion is that people that are suffering should have the benefit of medicinal cannabis if it is going to have a favourable effect. It is very simple: if the doctor wants to prescribe it and the patient wants it then the politicians and regulations should probably get out of the way.”

Another obstacle is the complex application procedure for the Australian medicinal cannabis programme. The physician must first submit an application to the Federal Department of Health. This application must clearly show that alternative treatments are not effective and that an extensive literary study has been carried out.

Paperwork

Until recently the same application also had to be sent to the Department of Health in the state where the patient lives. McGregor: “The paperwork was just terrible. There were also a lot of refusals because both the state health and federal departments were really looking for evidence that cannabis products were better than existing medication.”

The procedure has been adapted so physicians only have to fill out one online form and most applications are now assessed within 48 hours. Still McGregor is not satisfied and advocates for expanding the number of permitted conditions: “Patients are using cannabis for quite different conditions to the ones that you can get an approval for from the government. Most of the conditions are not acknowledged by the Therapeutic Goods Administration. For example, fifty percent of the patients are using cannabis for controlling their back pain and back pain is not on the TGA list. There is no evidence or clinical study that shows back pain is a condition that cannabis treats. But people are doing it anyway.”

For more information about the studies mentioned in this article, see:

Nicotine gum is probably the most well-known medicinal application. But chewing gum containing medicinal cannabis is something new. So new that the first batch has not even been made yet. AXIM Biotechnologies developed the product and is waiting to start the first clinical trials in the Netherlands, Israel and Canada.

Earlier this month they uncorked the champagne bottles at both the American head office in New York and in the Netherlands. The company that is listed on the American stock market (AXIM U.S.: OTC) received a GMP certificate from the Dutch government to produce samples for clinical trials. This test medication may now be used worldwide as a research resource. This is a huge milestone for the company that has been trying to bring medicinal cannabis gum onto the market since 2007.

MedChew Rx

MedChew Rx, a type of gum produced by AXIM looks very promising. It contains 5 milligrams of CBD – a non-psychoactive component of cannabis – and 5 milligrams of THC – a psychoactive cannabinoid. The cannabis for this chewing gum is supplied by Bedrocan. The medication was developed to treat pain and spasms in Multiple Sclerosis (MS) patients. The Dutch VU University Medical Center in Amsterdam will carry out the clinical trials.

Motion sickness, pain, quitting smoking, dental decay and middle ear infections are all well-known or lesser-known medical conditions for which medicinal chewing gum is available. AXIM consciously chose chewing gum as a method of administration.

According to Lekhram Changoer, Chief Technology Officer, it is a socially accepted and user-friendly method. Much more so than smoking or inhaling cannabis. And does it work? Changoer: “Chewing has a considerable effect. Chewing activates your brain. Scientists at the Vrije Universiteit in Amsterdam have proven that the medication has a greater effect when chewed, especially for pain.”

Just like a pill

According to Changoer, physicians have responded positively to this administration method: “It is not entirely new. They are already familiar with nicotine gum. Physicians don’t want their patients to smoke cannabis because it is unhealthy. Some physicians are also weary of inhaling. Not all patients can or want to use a vaporizer. Chewing gum is easy to take with you, just like a pill.”

The goal is to have the gum officially registered as medication. This way a physician can prescribe it and determine the dose. But clinical trials must first show that the product works.

Changoer: ”Preliminary studies paint a positive picture of the implementation of CBD and THC. Research will provide us with more insight into dosage. The approach is that the patient will calmly chew on one piece of gum for about twenty minutes. The absorption of the active chemicals will then take place via the mucous membranes in the cheek.” Changoer expects it will take at least another three years before the chewing gum will be available on the market.

Friday the 20th of April 2018 was a momentous day in Israel – a number of pharmacies are now permitted to issue medicinal cannabis to patients. This also marked the start of a pilot programme, charting the course to a regulated and properly documented system for issuing medicinal cannabis in Israel once and for all. For Yuval Landschaft, head of the Israeli Medical Cannabis Unit (MCA), this is a dream come true. “We wanted a system where the entire chain – from research and cultivation to diagnosis and distribution – is carefully regulated. We call that the medicalisation of cannabis. That system is now in place.”

Since 2013, Yuval Landschaft has been on top of Israel’s cannabis programme. The programme intends to provide medicinal cannabis for patients in Israel, but over time it will also deal with the export of medicinal cannabis abroad. Compliant with quality and safety requirements, the starting point was ‘medicalisation’; the use of cannabis for medicinal purposes based on scientific knowledge. Landschaft recollects that “all the available knowledge of medicinal cannabis in Israel was brought together and was used to develop this programme. It makes medicalisation something quite different from decriminalisation or legalisation, because our programme is focused on patients.”

The Green Book

The Israeli programme – recorded as ‘The Green Book’ – covers medicalisation, the standardisation of cannabis products, the training of doctors and pharmacists and the organisation of agro-technical and medical research and development. That provides for a clear chain – from product development to the patient. It goes without saying that growers are selected carefully and that requirements are imposed on the distribution side (prescribers, pharmacists). The National Center for Cannabis, part of the Ministry of Agriculture and the Ministry of Health, maintains tight control.

Whilst in Israel the medicinal use of cannabis has been permitted for some time, a controlled programme for ‘medicalisation’ proved difficult to get off the ground. Setting up the MCA paved the way for a programme for medicinal cannabis. Yuval Landschaft was appointed to lead the unit. “There was a system where growers worked in a ‘traditional’ way and played a role in the distribution and information provision to patients”, remembers Landschaft. “But you can’t call that a medicinal programme, because it didn’t involve any healthcare professionals. In other countries, including the Netherlands, they were much further ahead. We obtained comprehensive information from the Dutch government and were impressed by the achievements; a clear programme focused on medicinal use and pharmaceutically responsible products. That was exactly what we had in mind.”

Cannacopia

The MCA – which has representatives from the Ministries of Agriculture, Health, Justice and National Security – summarised the chain for production and distribution into five chapters, which Yuval Landschaft refers to, in jest, as the ‘Cannacopia’ or ‘the Torah of cannabis’. “We have a clinical approach that is focused on collecting and distributing scientific knowledge, identifying indications, designing a treatment protocol, defining products and their potential, administration and risk of abuse and addiction. Furthermore the entire chain – from cultivation to distribution – is covered by quality protocols based on the familiar and recognised good practices at agricultural, clinical, delivery, manufacturing and security level. We are aiming high, but it is the only way to properly regulate the availability of medicinal cannabis for patients.”

Landschaft believes that Israel has now joined a small group of countries where the production and distribution of medicinal cannabis is organised by the book. “In Israel we have paved the way to a thorough system. The patient is always the starting point and the only route is that of safe, standardised products, prescribed and issued by healthcare professionals. They have the medical knowledge required to determine a diagnosis, to prescribe medication and to support patients. Without doctors and pharmacists cannabis is not medication.”

It took him seven years and tens of millions of dollars to transform a raw plant into a mainstream medical drug. Perry Davidson is the creator of the Syqe Inhaler – a new technology that allows doctors and patients to precisely dose pharmaceutical quality ‘cannabis flos’ by inhalation. After all these years of hard work, according to Davidson ‘it is still something worthwhile waking up each morning for’.

Is that still the case?

‘Yes. What’s really driving everyone at Syqe is the realisation that what we achieved with cannabis can and should be replicated with other medicinal plants. Plants that pharma has shied away from for so many years. A technology that from one end takes a raw plant, and from the other end produces a pharmaceutical grade product, will have a profound impact on health.’

You founded Syqe Medical seven years ago and you are running the business. How does a usual business day look like?

‘A usual business day in a medical start-up is relentless. Add to that the fact that the Syqe Inhaler is the first product of its kind, designed for an industry which is still in its infancy. This forces us to innovate in practically every frontier, be it technological, clinical, regulatory or legislative. Therefore a usual business day in Syqe is an interaction between the multiple dedicated teams – biology, chemistry, mechanics, electronics, software, design, product, engineering, operations, clinical, pharmacology, QA/RA, legal and of course the standard teams of HR, finance, business development, marketing and IP.’

What inspired you to start this company?

‘What drove me to start Syqe was sheer frustration. In 2006, I co-founded the first cannabis company in Israel and while I was the CEO I interacted with nearly 2,000 patients and of course the medical community at large. I experienced first-hand the hardships of introducing a plant into a western health system and offering patients a predictable and safe treatment. I did not accept the fact that cannabis had such a significant therapeutic role, but not a single pharmaceutical company was able to transform it into an acceptable and efficacious mainstream drug.’

What makes the Syqe Inhaler different from all other ‘vaporizers’ on the market?

‘For the cannabis industry, Syqe is the first and only metered dose cannabis inhaler meeting pharmaceutical standards, a strong emphasis on meeting pharmaceutical level drug delivery precision.

For the pharmaceutical industry, Syqe is the first and only drug delivery platform able to administer whole plants within pharmaceutical standards, and also the first that allows changing dose levels in real time – the first Selective Dose Inhaler.’

How did you manage to put the whole cannabis plant into a small cartridge that’s is not larger than a biscuit?

‘Syqe’s selective-dose inhaler consists of a cartridge that holds 75 VaporChips^TM. Each chip is loaded with an exact amount of fully-standardised whole-plant cannabis, ground in a unique process that preserves the medicinal properties of the plant in their entirety. Real-time thermal and airflow controls enable the inhalation of precise amounts of naturally-occurring molecules directly from the cannabis plant.’

You are using Bedrocan’s standardised raw plant material for the micro dosed cartridges. Why have you chosen for Bedrocan as a supplier?

‘Quite simply Bedrocan was able to provide us with pharmaceutical-grade GMP starting material. The standardisation levels Bedrocan has achieved is unparalleled, allowing us to guarantee the pharmaceutical precision levels which are so needed for this industry.’

Do you think this device can contribute to a better acceptance of cannabis as a medicine? 

‘Any technology that takes the cannabis plant as a whole and transforms it into a pharmaceutical product will immediately increase the acceptance of cannabis as medicine.’

Bedrocan recently funded the publication of a booklet explaining the effects of medicinal cannabis in clear language.

This booklet covers key information on the cannabis plant, cannabinoids, the biological pathway for their action, and the quality requirements of modern medicines. It also takes a forward step to consider the perspectives of experienced health professionals, and insights from patients.

The booklet is intended as an introductory text to the therapeutic use of cannabis. For now it is an English publication intended for the health sector, policymakers, and patient groups.

The booklets official release was at the International Cannabinoid Research Society 2018 conference; this coincided with its New Zealand release, by the author, at Medsafe, the Ministry of Health.

See link to download a copy.

There is perhaps no debate in the world of cannabis more contentious than that of species. The genus Cannabis sativa L. is the only official species, but the cannabis industry is using other terms as indica and hybrid to promote their varieties. Associate Professor Sean Myles from the Canadian Dalhousie University recommends avoiding the use of these terms as a recent study has demonstrated that current labelling of varieties as sativa and indica does not reflect any meaningful genetic identity.

Myles, who supervised the study on the genetic differences between the two cannabis types and their hybrids, will present his results on the International Cannabinoid Research Society (ICRS) conference in Leiden, Netherlands, from 1 – 4 July 2018. In the run-up to the conference, Bedrocan asked him a few questions.

Do you consider the results as ground-breaking?
‘No, I don’t. Any professional in breeding or genetics with even peripheral knowledge of the cannabis industry would have bet that the ‘sativa’ and ‘indica’ labelling in the current cannabis market was unlikely to reflect genetic reality. It just took some data to demonstrate the degree to which this is the case, which we have done and continue to do.’

How did you come up to study cannabis?
‘Our laboratory developed an interest in cannabis because we do similar research in genetic ancestry deconvolution in other species, like grapes and apples. It made a lot of sense to extend our expertise to cannabis since it is an economically valuable agricultural species, little was known about its genetic structure, and there was widespread use of a dichotomy (i.e. ‘sativa’ vs. ‘indica’) that was believed to reflect ancestry. For the study together with Bedrocan, we benefited from their expertise in chemical profiling and paired it with our expertise in genomics and bioinformatics. The result has been fruitful in terms of insights into the question of variety identity.’

What are the reactions to your research results so far?
‘Overall, the public has taken a strong interest in our results, which suggest that the manner in which the labels ‘sativa’ and ‘indica’ are currently being used do not reflect meaningful genetic identities. Many of those in the cannabis industry, both medical and recreational, have also headed our advice to avoid using these terms until there is a consensus about what they mean. In the end, I believe our results have contributed to a shift whereby varieties are being increasingly described by their measurable chemical content rather than by their purported ancestry.’

What were the responses from companies that sell cannabis?
‘There are those in the recreational cannabis market who are unlikely to abandon the terms ‘sativa’ and ‘indica’ because they are useful terms for marketing their products. This is especially the case for companies selling seeds online. Their discontent is acknowledged, but the evidence speaks for itself and I’m hopeful that, in the end, labelling of cannabis products will be based on empirical data rather than marketing tricks.’

Some people claim to be able to smell the difference between an indica or sativa type. What would you like to say to them?
‘Our results do in fact suggest that the labelling of strains as ‘sativa’ vs. ‘indica’ may have more to do with their aromas than their genetic ancestry. Thus, in this case, these people may in fact be partially correct – they can associate a smell with a label. However, this still does not mean that the labels are capturing meaningful genetic information.’

What would be your recommendation to medicinal cannabis producers? Whether or not to make the distinction?
‘Our recommendation is to avoid the use of ‘indica’ and ‘sativa’ as it’s likely to create confusion in the marketplace.  So far, there is no evidence to support this dichotomy as a useful tool for describing ancestry or chemical composition.  We advise producers to describe the content of their product empirically with regards to cannabinoid and terpenoid content.’

Cannabis has been on the worldwide list of banned substances since 1961 and according to the World Health Organization (WHO) has hardly any medical value. This view could very well be coming to an end. Last week the ECDD, a special WHO drug committee, met for the first time to discuss exclusively the pros and cons of cannabis for health. Various parties from the field – doctors, patients and experts – were invited to the hearing to give their advice to the committee.

At the ECDD meeting the International Association for Cannabinoid Medicines (IACM) showed a video message with the intention of giving doctors and patients more opportunities to prescribe medicinal cannabis. According to IACM director Franjo Grotenhermen, it is a good sign that his organisation was allowed to speak. The positions of the selected speakers say a lot about the possible outcome of the meeting. Grotenhermen: “For the first time in history speakers had the opportunity to say the current situation is no longer justified. The committee will probably use these statements in their own recommendations. Otherwise they would have invited parties which are more focused on the dangers of cannabis use.”

Michael Krawitz of the FAAAT, an international think-tank on drug addiction, calls the meeting of historical importance. Krawitz, an expert in the field of international drug policy for over twenty years, was in Geneva at the fortieth meeting of the ECDD to submit an advisory report. “It was a great meeting. Their recommendations are likely to change international law,” is the high expectation of Krawitz. “It is the very first time the medicinal use of cannabis is on the ECDD’s agenda. In 1961, cannabis ended up as a prohibited drug in the UN treaty without ever being officially reviewed by experts. A genuine formal scientific evaluation of cannabis as a medicine has never been done. That is now being put right.”

The Dutch Harm Hids was one of the individual speakers. “The meeting was very well set up. You would expect everyone to be against cannabis, but that was certainly not the case.“ Hids has a son with Crohn’s disease, a chronic inflammation of the intestine.

His son has successfully used CBD capsules and THC oil for years, which locally counteracts inflammation. Hids: “He is given a maximum of 12 mg of THC per day. He does not get high and can just go to school and study.”

During the meeting of the World Health Organization, it became clear that the committee is struggling with recreational cannabis use. In order not to blur the market, according to Hids, the medicinal cannabis industry must remain far away from recreational use. “As long as the product remains smokable, then you know for certain that people will also use it for recreational purposes. You prevent abuse by transforming cannabis to forms that are totally uninspiring for recreational use. That was my message to the committee.”

The final report and recommendations from the meeting will be available on the ECDD website by the end of July 2018.  After approval from the WHO the recommendations will then be put to a vote with the 53 member states of the Commission on Narcotic Drugs. This body must eventually reach agreement on whether the current UN treaties may be amended.

There is nothing Chelsea Leyland (30) would like more than for her older sister to have access to medicinal cannabis too to curb the daily epileptic seizures. But…her sister lives in the UK and medicinal cannabis is not permitted in that country. Leyland, an epilepsy patient herself, is currently working on a documentary about her own life and that of her sister, who has sustained irreparable brain damage as a result of the many seizures. The documentary Separating The Strains is aimed at providing more insight into the effects of medicinal cannabis and at fostering understanding and empathy amongst doctors and politicians in the UK.

The film, which is set to be released at the end of this year, will show a world of contradictions. Chelsea Leyland is a young successful DJ and model, lives in New York and travels around the world to attend the best parties. Her fascinating life is in stark contrast with that of her older sister Tamsin (35), who lives permanently in a full time care because of her illness.

Chelsea Leyland has access to medicinal cannabis, her sister does not. At the moment British-born Leyland lives in America, where medicinal cannabis has been legalised in 29 States. “People ask me why I don’t take my sister to New York, but she is too ill to fly. She has 20 to 30 seizures a day and needs 24/7 care.”

According to figures from the British epilepsy association, more than half a million Brits suffer from epilepsy. Since her early teens, Leyland has had a type known as juvenile myoclonic epilepsy. Two years ago, she stopped her regular medication and gradually moved over to CBD oil. Leyland had serious sleeping issues that were caused by her epilepsy medication. A nasty side effect, because a lack of sleep only increased the frequency of the epileptic seizures.

It was never Leyland’s intention to stop her epilepsy medication. She went to her neurologist for advice. He was very dismissive about her wish to learn more about medicinal cannabis. “I was so angry with my doctor. I felt totally unsupported. I expected supervision and involvement, but what I got was a narrow-minded response. The trust and confidence in my doctor was gone, and I decided to find out for myself.”

On the advice of an acquaintance, she started with CBD oil, which she bought from an online shop in England. As in most other countries, this oil is offered as a food supplement and consequently it is freely available. However, CBD is one of many substances in a cannabis plant and because cannabis is on the list of prohibited substances worldwide, CBD oil should really be illegal too. Yet most authorities turn a blind eye. Chelsea Leyland commented “The shops are everywhere. We have actually created an uncontrolled industry where patients use food supplements as medication without any real knowledge. They’ve read somewhere that CBD can cure cancer or can help treatment of MS or epilepsy and they buy a bottle of CBD from their local health store to be cured.”

Leyland argues for regulation and recognition of cannabis as official medication. ”You cannot stop patients. Look at me. I did the same and that’s a major issue. Patients buy cannabis on the internet, from the health store or on the black market. Those are not the right channels. They need support from a doctor. Patients are entitled to that.”

Her decision to reduce her medication herself was really dangerous – she realises that now – and she does not recommend it to anyone. Leyland said “I was stubborn and I was lucky. There is no guarantee that cannabis use will work well for everybody.” She is a strong ambassador for open and honest discussions between patients and their doctors. She also thinks that healthcare professionals should seek better information “More doctors should become involved with the subject of medicinal cannabis. There needs to be investment in education to ensure that medicinal cannabis can be used as normal medication and not as a food supplement.”

However, she does not regret her decision, because since she made the transition she no longer suffers from epileptic seizures. She recalls the first time she took the oil. “It was a real sensation. For the first time I hit the ground with both feet. As an epilepsy patient you feel like your head is full of individual pieces that you cannot connect. Your brain is out of kilter. Your memory does not work well and it is difficult to find the right words. It’s like a chest pain when you’ve got a cold, but in your head. After my first use I felt calm in my head for the first time. I was able to think clearly. I thought ‘Gosh, this is what it feels like for normal people, who don’t have epilepsy’.“

To the question what’s to happen to her sister, she answers with hope “The frontal lobe of her brain is completely damaged by the seizures and that damage will not repair, ever. But it is not too late to help her move to cannabis. It would be wonderful if we could improve the quality of her life by just a fraction and if we could half the number of seizures.”

Leyland firmly believes that the documentary, which is still in the making, will change the way in which doctors and politicians view cannabis. “I want to appeal to people’s empathy, including that of politicians and doctors. The power of my film is in the stories of the patients. Like that of a mother of a child that has 100 seizures a day. The viewer sees the health improve enormously when the child is administered medicinal cannabis. You don’t need any more proof.“

Chelsea Leyland also realises that success stories are not enough. “We need scientific evidence”, she continues her argument. “Cannabis is an extremely complexed medicine that contains many active components. We need more research and people need to receive the right information. We’re not talking about recreational use here, but about real medication. Let’s be clear about that.”

There are more and more cannabis-related conferences worldwide. Bedrocan chooses only meetings about the medicinal use of cannabis or where we can tell our story about GMP-quality medicinal cannabis. The ICRS symposiums is close to our heart.

This year it will be held in Leiden, the Netherlands (30 June to 5 July). ICRS, the peak International Cannabinoid Research Society, is an independent organisation promoting scientific research in cannabinoids, the most important components of cannabis.

ICRS provides impartial information about cannabis and cannabinoids. It is also provides a forum for research discourse, and a platform to share scientific the latest studies. This year the global scientific community meet in Leiden where Bedrocan is one of the principal sponsors.

During the year, you can catch up with Bedrocan, when we present at the following international conferences:

When a science student stepped into his office and explained about the medicinal use of cannabis, Dr Radovan Hřib developed a serious interest in cannabis as a medicine in the Sint Anna University Hospital, Brno city of Czech Republic. Prescribing since May 2015 under state registration, he currently treats around 80 patients experiencing pain of different origin. Dr Hřib has a message for reluctant doctors: “Do not be afraid about cannabis for medicinal use. It will surprise you pleasantly.”

According to Dr Hřib there are three types of patients in his hospital. The first already has some good experience with cannabis, and wants to the use it under his medical supervision. The second patient type is already taking a number of analgesics such as non-steroidals, paracetamol, anti-rheumatics and opioids. They only receive partial response. With the third type, current treatment using classical medications hardly work and cannabis is their last hope.

He prescribes fully standardised cannabis flos, the whole dried flower, as it is the only pharmaceutical-quality product available in the Czech Republic. His patients take their medicine either prepared by the hospital pharmacy, as capsules containing a single dose of cannabis flos and are taken by mouth, or are dispensed cannabis flos for inhalation by vaporization. Just recently the Sint Anna Hospital has set up a special area where pain and cancer patients learn how to operate a vaporizer.

Why do you prescribe medicinal cannabis to patients? Is there a personal motivation?

I prescribe medicinal cannabis to patients for one simple reason: because it is helping them. This is driven by my professional curiosity and the intention to provide the best outcomes for my patients. An overwhelming majority of patients are actively interested in possibility using it as a treatment for pain. However, there will always be a few patients with strong opinions against its use.

What are the key benefits of medicinal cannabis?

I still have many benefits to discover. However, the longer I prescribe it, the more I am fascinated. In the treatment of pain, cannabinoids act in several modalities, apart from a

good analgesic effect, it significantly improves sleep and its use is accompanied by a reduction in anxiety. In this way, the so called vicious circle of chronic pain can be broken in several places.

What are the risks of prescribing medicinal cannabis?

The very individual character of dosing poses a disadvantage for many physicians. In Czech Republic we prescribe cannabis as an individually prepared medical product. Therefore you need a collaborating pharmacist who understands what is needed. I am lucky that I can rely on the great support of our hospital pharmacist Monika Pecháčková. As a prescribing doctor I would like to point out that my work with medicinal cannabis would not be possible without the support and tolerance of my faculty superiors, my family, colleagues and co-workers at the workplace and in the hospital.

Why is that?

There is great stigma around medicinal use of cannabis and this is also present in the Czech medical community. It is still tightly regulated, it is risky because there are still unknowns. As opposed to other work places, the hospital I work at has been openly supporting me from the very beginning.

How do you decide the best dose for individual patients?

Mostly, this being specific for the Czech Republic, I use oral administration through capsules. Mainly for financial reasons as patients appreciate that this method does not significantly increase the price of already expensive plant material. The body is offered the whole herb, and we let the human organism to choose what to absorb from it.

At the moment, I am using two dosing schemes for capsules. First one is according to my own empirical experience. We start at a dose of 0.125 gram of cannabis decarboxylated by heat, presented in a gelatine capsule, per night (which makes up to 18 – 25 mg THC depending on variety). If the patient experiences difficulties, the patient can call me immediately, at any time of the day. Within 7 days I want to hear from the patient, also if they only benefit from the treatment. When there are significant side effects, usually it is dizziness, we reduce the dose or we try to encourage the patient to keep trying. The dose is increased at the earliest after one month from the beginning of the therapy.

I also started using the second scheme according to neurologist Ethan Russo. Starting with a dose of 2.5 mg THC per night. After about 5 days we gradually increase the dose by 2.5 mg THC.

When vaporizing, I teach the patient about gradual titration. In the near future, I would like to combine oral capsule administration with vaporization. Now that we have opened our user centre, we will try to introduce the gradual titration directly in the hospital, or during hospitalisation.

Do you encounter diversion for misuse or the abuse of medicinal cannabis?

So far, I was lucky to have disciplined patients, and I did not have to deal with this problem with regards to medicinal cannabis.

How do you identify this issue in your practice?

Given the fact that I have been prescribing highly addictive opioids to my patients for over 18 years, I have quite a lot of experience with diversion for misuse or the abuse. Fortunately, with patients experiencing chronic pain, this problem is minimal. Mostly, patients with this problem identify themselves. For example, they often “lose” medications, are not disciplined in treatment or check-ups, and so on. I believe that the best way to prevent and deal with abuse is to have an individual and personal approach to the patient.

If a doctor wants to know more about prescribing medicinal cannabis, what would be a good information source?

I recommend two basic resources to doctors.

• The publication An Introduction to Medicinal Cannabis by Arno Hazekamp. It is also translated in Czech and can be downloaded from Bedrocan’s Czech website.
• The retrospective analysis by the authors Zábranský, Hanuš, Rokyta: “An overview of the current knowledge about the healing effects of cannabis and its products and its perspectives“, published in the Czech language in the Bulletin of the Association of Practical Doctors 2016 and 2017.

Furthermore I recommend the following websites:

• IPVZ – the Institute of Post Gradual Education in Healthcare. They are holding already a third training seminar on cannabis.
• ICCI – International Cannabis and Cannabinoids Institute based in the Czech capital Prague. Our hospital is also now offering the opportunity to organize seminars in cooperation with ICCI.
• SAKL – State Institute of Cannabis for medicinal use
• KOPAC – Czech Patient Association

As the doctor’s experience grows, they can much more rely on their own experience, and only use the internet occasionally.

Do you have any advice for doctors starting out prescribing?

Do not be afraid of medicinal cannabis and try it in your therapeutic practice.

What would you like to say to doctors that are reluctant to prescribe cannabis because there is not enough clinical evidence that medicinal cannabis actually works?

I will only repeat myself. Do not be afraid about cannabis for medicinal use. It will surprise you pleasantly. On the contrary, you will be able to contribute to the creation of scientific evidence. And I mean this as criticism towards the almost exclusively strict use of evidence-based medicine, which is well described, and the tendency to adhere to prescribing only this, rather than being open to new methods and treatments. Trying out new treatments and creating your own opinion… only then you will discover yourself what the real art of medicine is.

The average daily dosage for prescribed medicinal cannabis among Dutch patients has remained remarkably stable over the past years. The average daily dose has risen slightly from 0.64 to 0.73 gram of cannabis per day during two study periods. This can be concluded from a recent study carried out by researcher Bas de Hoop. We asked him why is this important?

Where does the data for this study come from?

The Dutch Foundation for Pharmaceutical Statistics (SFK). SFK is an independent organisation who collects 90% of all prescription data from Dutch pharmacies. This includes the prescriptions for medicinal cannabis, but excludes pharmacies that are located in care homes or hospitals.

All manner of information can be collected from these prescription details. For example, the issue date, the amount of cannabis dispensed, the specialty of the prescribing doctor, and importantly the age and gender of the patient. On the basis of this raw data we produced calculations that provide an approximation, such as patients’ average daily dose and the total duration of use.

Is there an increase in the number of users in the Netherlands?

Certainly, you can observe a gigantic increase in users between the study periods 2003-2010 and 2011-2016. During the first eight years we identified 5,601 people. Six years later we identified 10,826. That is only for prescriptions of cannabis flos. In 2015, cannabis oil became available as a dosage form. In the year after Transvaal Apotheek in The Hague introduced cannabis oil, there are now 6.720 patient prescribed the oral dose form.

We also calculated how many patients there were in relation to the total Dutch population. Those figures are spectacular. In 2003, 6.4 patients per 100,000 inhabitants used a medicinal cannabis product. By 2010,this had moved up to 6.9, which is not exactly a gigantic leap in use. However, by 2016 we note that 24.6 patients per 100,000 inhabitants are prescribed medicinal cannabis, either as cannabis flos or oil.

The introduction of cannabis oil at the end of 2015 had a significant impact on the figures? 

The availability produced an enormous increase. In 2016 alone, the number of patients prescribed oil was much higher than for cannabis flos. Unfortunately, cannabis oil was introduced too recently to provide reliable data on the average daily use or other interesting aspects. However, those data demonstrate that patients prescribed oil were often older and more often female compared to patients who prescribed cannabis flos.

What do the figures say about the age structure and gender distribution of the average patient?

The largest group of patients is over 40 years of age. Eighty percent of the flos users are older than forty years, and this number is 88 percent for the patients who are prescribed cannabis oil. About the same number of men and women are prescribed cannabis flos. In relation to oil, women have a slight majority (60%). Most prescriptions are among patients aged between 41 and 60 years old (42.9%), followed by the category of 61-80 year olds (30.9%). So they are an older group, on average.

In this study we compared the current data with previously published material. The age distribution of patients remained virtually the same for the two study periods. However, there was a slight shift in the gender split – the percentage of female patients fell from 57.1%  to 51.4%.

Why should we care about these figures?

We have been gathering data about medicinal cannabis use in the Netherlands for more than 15 years. We can learn a lot about actual usage. As far as I know, there is nowhere else in the world where these figures are collected centrally. Not even in Canada, which was the first country in the world to start with a medicinal cannabis programme. In other words, these figures are fairly unique and, particularly when it concerns a daily dose of 0.7 gram. The Netherlands has a prescriber-pharmacy model, where guidance for using medicinal cannabis is actively provided. This is important because not every patient has the same course of treatment meaning a doctor and patient and pharmacy work together to find the correct dose and improve patient safety.

This data provides a framework for a doctor to take into account when considering prescribing for their patient.

Can you say something about the duration of use?

The figures demonstrate that as the patient gets older, the number of days they use medicinal cannabis reduces. While it is possible to calculate an average duration, but it is difficult to interpret, given the average duration of use is likely to be affected by deaths in the highest age category.

The daily dose in the Netherlands has been around 0.7 gram for more than 10 years. What does that tell us?

This shows clearly that there is no increase in the consumption of medicinal cannabis in the Netherlands. Policymakers may have fears that the introduction of medicinal cannabis will lead to an increased patient tolerance, physical addiction and dependency. In the Netherlands, policymakers fears are laid to rest with these figures; over a period of 10 years we cannot find an indication for unwarranted increased in medicinal cannabis use.

Can you say something about what conditions Bedrocan products are prescribed?

Unfortunately I cannot provide an accurate answer to this question. The reason is that we do not have the right information. The disease or complaint of the patient is not stated on the prescription, it just says who prescribed it. More than half of the prescribing doctors are GPs (59.2%), followed by specialists (27.1%). The data refer to specialisations, but when it says surgery, cardiology, or internal medicine you don’t know enough to identify the complaint.

Bedrocan has donated ten medical vaporizers to two Czech hospitals. They concern the Volcano Medic®, and they are used in the Sint Anna University Hospital and the Masaryk Cancer Institute in the Czech city of Brno. Under the guidance of trained personnel, pain and cancer patients learn how to operate and dose the device. The Sint Anna Hospital has set up a special area for this purpose, which was put into use officially on 17 April.

The Czech Republic has had a medical cannabis programme for many years. However, as in the Netherlands, cannabis and expensive vaporizers are no longer reimbursed by health insurance policies, causing a major problem for patients with low incomes in particular. Bedrocan hopes that by donating the vaporizers, patients are able to familiarize themselves with vaporization as a method of administration before they purchase the vaporizers. Vaporizing is generally regarded as the most efficient dosage form because the active substances are absorbed quickly into the body. It is also safer than smoking because there is no release of toxic substances, such as carbon monoxide, ammonia or polycyclic aromatic hydrocarbons (PAHs).

Capsules

Bedrocan has been working with one of the doctors of the St. Anna hospital, doctor Radovan Hřib, for many years. As a pain specialist, he prescribes medicinal cannabis for patients with chronic or acute pain. The special user space was his idea.

Doctor Hřib commented “Now patients often have to rely on capsules that are compounded by the pharmacy, but it is not the best dosage form in pain management. Vaporizing is preferable above all else, because the vapour is absorbed immediately into the bloodstream and the effect is felt immediately. ”

In addition to his work in the hospital, Dr Hřib is associated with the Czech patient organization KOPAC. In the Czech Republic he is regarded as the medical expert in the field of medicinal cannabis. He cooperates with government bodies to increase the availability of cannabis for medicinal use to the patients and to simplify administration for doctors.

He was also involved with the registration of medical vaporizers in the Czech Republic. The user area with the vaporizers is intended to teach patients to dose. Doctor Hřib said “Unfortunately there is no universal dosage. Every patient reacts differently to cannabis. Here they learn which dosage suits them best. Under expert guidance, they also discover any possible side effects occur and how to deal with those.”

Recently the Dutch Transvaal Apotheek in The Hague started marketing cannabis cream alongside cannabis oil. This cream is a new dosage form for patients. It is based on the cannabis variety Bediol and is intended for treating skin conditions.

According to Arwin Ramcharan, pharmacists QA of Transvaal Apotheek, the cream was developed at the request of a dermatologist in The Hague. “I won’t mention names, but it is a dermatologist with whom we have worked before. He was already familiar with the cannabis oil we have been preparing on the basis of the Bedrocan varieties since 2015 and which he prescribes from time to time. He wanted to try out a cream based on Bediol for group of approximately 40 patients. If the trial is positive, the group of patients will be expanded. For the time being, other patients can buy the cream from us on prescription.”

With the cream, for which a patient pays 60 Euro (per 20 gram), a new dosage form has been added to the range of cannabis products based on Bedrocan varieties. The Transvaal Apotheek will leave it at that for the time being. Ramcharan: “Occasionally we receive requests for capsules, but they are more difficult to make. Furthermore, it is a significantly different administration method as capsules go via the stomach where substances are broken down; it means you need to increase the dose.”

Apotheek SMA in Rosmalen, which prepares oil from Bedrocan varieties, also has a cream available for various skin conditions. However, this Cannabinoid Cream is made on the basis of CBD crystals.

Hospital staff or researchers are at low risk of exposure to patient’s exhaled cannabis vapour. An Australian study demonstrated staff who administer vaporized cannabinoid medication to patients in a clinical environment will not be exposed to THC. The active substance THC was not found in the blood after staff had been exposed to environmental vapours.

A vaporizer medical device is considered to be a safe administration method for patients. There is no exposure to harmful substances like from smoking. The medicinal effects occur sooner with vaporizing than with other administration forms, because the cannabinoids are absorbed into the blood almost immediately after inhalation. It is also a user-friendly method for patients who struggle with swallowing. However, until recently there was little or no knowledge of whether the exhaled vapour would be harmful to other people in the same environment. In other words, could someone else be exposed to THC?

The conclusion is therefore that vaporizing is safe for staff who administer medicinal cannabis to patients. However, a more comprehensive study of this subject is warranted. A study including more participants, room sizes, cannabis varieties, and types of vaporizers would be beneficial.

Since 1st January 2018, cannabis for medicinal use is permitted in Denmark. How did the first weeks work out? If we are to believe the stories in the media, Denmark will be cultivating cannabis on a major scale next year. Doctors on the other hand are sceptical, because there is insufficient scientific evidence. Meanwhile, a public pain clinic is unable to meet demand and patients are on a one-year waiting list.

Odense, the third largest city in Denmark, aims to become the European capital of cannabis cultivation. That was the heading of a newspaper article from early 2018 about the developments in what is known as the centre of Danish horticulture. At the end of last year, a local tomato grower and a hemp grower entered into cooperation with two major Canadian cannabis producers. The Canadians bring money and knowledge, whilst the growers supply the greenhouses and the land. Peppers and orchids are being exchanged for ‘green gold’ and thousands of square metres of old greenhouses are transformed into high-tech businesses.

Cannabis cultivation

According to the Danish medicines agency, which issues licences for cannabis cultivation, 12 Danish businesses have received permission to start cultivating. They may only do so within the context of a four-year pilot project. After two years there will be an interim evaluation and the Danish government will decide whether to continue the project or not. According to Henrik Uth of the company CannGros, currently the only importer of medicinal cannabis in Denmark, obtaining a growers licence does not mean you can start selling medicinal cannabis. “In principle, you just need to present a plan to the authorities. You don’t even need facilities. It will be interesting to see how the production, and the regulation on quality control on Danish grown medicinal cannabis, will come together. There is still little clarity on that point.”

Either way, government rules prescribe that the new growers must be able to produce standardised and consistent cannabis. The levels of active substances must be the same for every harvest. This has been Bedrocan’s speciality for years, and for doctors who wish to prescribe medicinal cannabis it is simply essential. Pain specialist Tina Horsted is familiar with the issue. She runs a pain clinic in Copenhagen where she treats 90 patients a day. Tina Horsted comments:  “Standardisation is essential. Patients must have the guarantee that with every inhalation, drop of cannabis oil or capsule they receive the same amount of THC or CBD. It is about safety and quality. That makes the difference between going to a doctor or obtaining cannabis on the black market.”

In Denmark, Tina Horsted is the only doctor who specialises in prescribing medicinal cannabis. Two years ago, she started the public pain clinic Min Smerte. A loophole in the law enabled her to prescribe cannabis to patients, because cannabis was considered to be a natural medicine. “It had to be a hand-written prescription and the end product had to be compounded by a pharmacist”, commented Horsted. She found one pharmacist who was prepared to produce oil and capsules with cannabis components. He lawfully obtained the CBD-containing cannabis from Austria and the THC was added separately.

At the moment, she treats 1,200 patients in her clinic who suffer from chronic pain, MS, RA and cancer. The change in legislation now enables her to prescribe Bedrocan products lawfully and everything is done electronically. In principle, a patient can take a valid prescription to any Danish pharmacy. At the moment, the Danish government has permitted two products – Bedrocan® and Bediol®, which are the most commonly prescribed cannabis products in the world.

Danish doctors

However, a majority of Danish doctors opposes the change in legislation. They argue there is insufficient scientific evidence to support the effect of cannabis. There is also little known about the correct dose, side effects and possible risks of combining cannabis with other medication. Danish patients are struggling to find a doctor who is prepared to write the prescription. Jens Thau is in charge of Clinic Horsted that is privately run and he is confronted with the doctors’ reluctance on a daily basis. “Each day we receive some 20 calls from patients all over the country who do not receive any assistance from their own doctor.” These patients, except for terminal cancer patients, end up on a one-year waiting list because of the high demand. “According to Danish rules we may only employ one doctor in our clinic and that is Tina.” The costs of treatment in the public clinic are reimbursed in full by the Danish government. Patients who do not want to wait, or who cannot wait, can attend the private clinic that has an open surgery every Friday. Patients pay for their treatment themselves or have it reimbursed by additional insurance. Thau comments: “Most pain patients do not have insurance, they are 65 or older and often did heavy labour. That is the saddest part of the story.”

Book

The couple Hosted and Thau are  convinced of the beneficial effect of cannabis and in their evenings they travel around the country to convince Danish doctors and parliamentarians. A book about their experiences with prescribing medicinal cannabis, which will be published this year, is also intended to contribute to more knowledge transfer. Until then doctors will have to make do with the guidelines of the Danish medicines agency, which are available online. Information about the two Bedrocan products that have been included in the trial, comes from importer Uth. “We are bound by rules and may not provide information that encourages the sales of the cannabis product. The only thing that is permitted is a general leaflet with advice about administration and doses. It is in high demand.” As in the Netherlands, the recommendation is vaporizing with a vaporizer or drinking tea. Smoking is not recommended due to the ‘risk of lung and airways infections’ according to Danish guidelines. It is also recommended to start with a low dose. According to the Danish government, it is ultimately the doctor who decides on the dose and the correct usage method.

Read more about this topic

• Odense aims to become the European capital of cannabis (Swedish)
• Pain doctor opens cannabis clinics in Denmark and abroad (Danish)
• The tomato king from Funen wants to grow cannabis in style (Danish)

Websites

• Private pain clinic Clinic Hosted
• Public pain clinic Min Smerte
• CannGros
• Danish medicines agency

Before the turn of the millennium ‘producing cannabis of pharmaceutical quality’ was a self-imposed task. Today it is nothing less than a tour de force for Bedrocan. Operating across the globe, Bedrocan is keeping abreast of the growing demand for the highest quality medicinal cannabis.

The will to move cannabis to the level of a licensed medicine came from Tjalling Erkelens, founder and chairman/CEO of Bedrocan. From the start he envisaged a specialised cultivation process. He made a three-fold promise to the Dutch government (in 2003 – ed.) – to be patient inspired, science driven, and regulatory compliant. Since then, Bedrocan has been the sole supplier to the Dutch prescriber-pharmacy medicinal cannabis programme.

“The cannabis varieties we supply now are based on years of knowledge and experience, and on patient need,” clarifies Erkelens. “In conjunction with our client, the Dutch government, we translated that into a number of standardised varieties of cannabis flos (the whole dried flower). These days there is more and more scientific research into the effect of the active substances in cannabis on the human body, to ensure the approach to medicinal cannabis moves from empirical and anecdotal to scientifically sound. We support this development wholeheartedly. Bedrocan continues to undertake and support scientific research. The same applies to studies of administration methods, such as our patient-friendly vaporizer. Input from patients continues to be essential, because they are the reason for our efforts. We have now come to a point where we initiate and support clinical trials. If your aim is to have cannabis registered as medicine, you can only achieve that on the basis of scientific evidence.”

Recreational use

In the area of compliance, Bedrocan has always taken a clear course. Erkelens continues: “From the start we have worked in accordance with applicable legislation and regulations. That is beyond dispute as far as we’re concerned.

Outside the Netherlands, we only wish to focus on countries where the production and use of medicinal cannabis is enshrined in law. We continue to focus on the medicinal application of cannabis; intended for patients.

We are never party to the global discussion about legalisation, we stay away from recreational use, and only seek to cooperate with partners that share our vision of compliance.”

This choice means that Bedrocan and its licensees are bound by increasingly stringent requirements in the area of quality and safety. Compliance, again. This time a commitment to pharmaceutical requirements. “Fair enough”, says Erkelens. “We are a pharmaceutical company. So you need to comply with strict requirements and be tested for those. That is why we were the first manufacturer to have the entire production process – including cultivation – good manufacturing practice (GMP) certified. It is why we invest in people, equipment and processes in that area.”

Cannabinoid therapeutic products

Globally there is increasing interest in the medicinal application of cannabis. Not only as pharmaceutical cannabis flos for vaporization, but also as an active ingredient for cannabinoid therapeutic products. Bedrocan keeps pace with those developments.

In 2016, we started with controlled cultivation, and that led to a larger, more streamlined organisation, where botany joins forces with pharmaceutical knowledge. In 2017, a new state of the art production site was commissioned. “This enables us to meet the growing demand in the Netherlands and abroad”, continues Erkelens, who realises that the interest in medicinal cannabis will increase across the world.

“The number of countries that are active in the area is increasing and that is all to the good. However, it is important that we express clearly who we are, what we do, and why we do it this way. Anyone can address us on that.”

A group of some 20 Dutch patients is about to test the new Bedrocan vaporizer. Recently, a call was made in the Dutch media and through patient associations. More than 70 patients have said they would like to participate. The purpose of the study is to collect feedback about, among other things, the user-friendliness of this medical device. The vaporizer will be marketed under the name Bedromedic®.

With a Bedromedic it is possible to inhale Bedrocan’s medicinal cannabis products safely. Heating cannabis releases vapours with active components. The vapour is inhaled by means of a mouthpiece and absorbed into the body via the lungs. It does not involve any tobacco. Temperatures are lower than during smoking, which prevents the release of harmful substances that are produced during burning.

The study is carried out by Bedrocan’s own research department, which screens patients in advance. Participants must have medicinal cannabis from Bedrocan prescribed by a doctor. It is also important that a participant has at least six months of experience with using cannabis as medication. Experience with using vaporizers is not necessary. Participants have the Bedromedic® vaporizer sent to their home and can try it out in their home environment. Afterwards, they complete a comprehensive online questionnaire.

Insights from experienced health professionals prescribing cannabinoids.

There is a place for cannabinoids in the therapeutic toolbox. So how should they be prescribed? Discourse with doctors is a series of interviews with experienced doctors prescribing cannabinoids. This article highlights prescribing realities and strategies to improve patient safety, dispels some myths, and aims to encourage self-driven inquiry.

Do you have any advice for doctors starting out prescribing?

My advice for clinicians who are starting to prescribe cannabinoids is to stick to specific indications where there is a solid foundation of evidence for its use, e.g. multiple sclerosis, patients experiencing central neuropathic pain, or cancer patients. This allows us to gain experience with the effects of this medication in a specific patient population.

Recreational cannabis users are, in my opinion, not a good patient category to start with. They may put considerable pressure on the clinician to prescribe for dubious indications.

Prescribing experience

How long have you prescribed cannabinoid therapeutics?

I have prescribed cannabinoids, mainly for patients with cancer, since I started working here in Holland ten years ago.

Can you describe a typical patient who you would prescribe products containing cannabinoids?

There are two typical types of patients where I would initiate cannabinoid therapeutics. These are in patients with:

• advanced cancer experiencing loss of appetite and possibly nausea and vomiting. Often many other medications have been tried before.
• central neuropathic pain (after unsuccessful trials of more common medications).

Prescribing cannabinoid therapeutics

How is prescribing cannabinoid therapeutics different to prescribing other medicines?

They are like any other medicine. However, many patients will have an opinion about cannabis [and cannabinoid products]. For some it has a rather negative connotation as being a substance of abuse.

What are the key benefits of cannabinoids as a therapeutic product?

There are three main advantages of cannabinoid therapeutics in general over other medicines used in my field of pain medicine, these include that:

• there are analgesic effects on neuropathic pain syndromes and, depending on the medicine type, anti-emetic and appetite stimulating effects. This is especially important for cancer patients with pain.
• there are no known organ damaging side effects in the adult patient. As compared to, for example, those linked with using NSAID’s.
• some cannabis flos variants have a soothing effect, which some patients greatly appreciate.

What do you think are prescribing practices that improve patient outcomes?

For patients with no experience using cannabinoid products, the possible psychological side effects can be distressing. In order to avoid this we advise patients’ to start with low dosage and use the medicine in a quiet and relaxing environment.

In our experience, it is advantageous to prescribe cannabis flos as an inhalational agent, administered by vaporization, as it creates more rapid analgesic effects and has a more reliable absorption profile.

Are there any special considerations you make when prescribing a ‘herbal’ medicine (cannabis flos)?

With cannabis flos, the prescribing clinician needs to be aware that in many countries the standards are different with respect to ‘regular’ medicines: concerning the quality control of the active ingredient, and toxicological contamination.

What is cannabinoid therapeutics?

Medicinal cannabis is a term used to describe the use of cannabis to treat or manage illness. It hails from a time when the products used where typically marijuana and patients smoked joints. Since that time, there have been major developments in cultivation techniques, product quality and controls. Today, the sympathetic regulatory environment favours standardised products (e.g., Bedrocan cannabis flos, Sativex) and safer modes of administration (sublingual, oral and vaporization). A prescriber-pharmacy model now offers patients better communication of risks and benefits, and the safety of health professional oversight. Standardised products and clinical research means plant-based products are closer to achieving full medicine registration. The use of the term ‘medicinal cannabis’ in these circumstances seems redundant.

In this article, we talk about the therapeutic use of cannabinoids. The class of medicines containing cannabinoids (e.g., THC and CBD) and other chemical compounds secreted by cannabis plant (e.g., terpenes) that are intended to be used in, or on human beings for a therapeutic purpose. This change in terminology from ‘medicinal cannabis’ to ‘cannabinoid therapeutics’ reflects our knowledge and understanding of the endocannabinoid system, the cannabinoid receptors, endogenous (human) cannabinoids, and exogenous (plant) cannabinoids.

For more information, please download the booklet An Introduction to Medicinal Cannabis by Dr Arno Hazekamp.

Using cannabis flos originating from controlled producers means patients are assured there is no biological or toxicological contamination.

In the Netherlands cannabis flos is produced under strict quality conditions by the government licenced company Bedrocan.

Administration by vaporization

Aside from eliminating the harms from smoking, what are the benefits of administration by vaporization?

With vaporization cannabis flos is heated to a specific temperature without burning it. Cannabinoids and terpenes are released in a vapour which is directly inhaled.

There are three main advantages of administration by vaporization is that it:

• allows for exact dosing,
• leads to a rapid effect, and
• avoids the disadvantages of smoking (i.e., no tar, ammonia, carbon monoxide).

What do patients say about the administration of cannabis flos by vaporization?

Using vaporized cannabis flos is the preferred means of use by most patients, especially when compared with an oral application. This is due to the more rapid effect by inhalation.

For some years the vaporizers where reimbursed by Dutch health insurance, thereby eliminating the threshold of a financial burden for the patient.

Patient considerations

Thinking about a first consultation with a patient, how do you start a conversation about cannabinoid therapeutics?

There are two types of discussion around the use of cannabinoids:

The elderly, cannabis naive patient:

An elderly cancer patient may be hesitant to use cannabis as a medication. This likely is related to prejudices about cannabis being a product for ‘recreational’ use. With these patients, I rarely discuss the use of these medicines during a first consult. If the patient is eligible and several other therapies did not provide sufficient pain relief, I then mention cannabinoid therapeutics as a possible option. This allows the patient and his/her family to contemplate that treatment option until the next appointment.

The experienced patient:

There may be patients who have extensive experience using cannabis recreationally. They may be actively looking into cannabinoid therapeutics as a potential adjunct to their pain therapy. These patients emphasise the ineffectiveness or side effects of other therapies, and may push clinicians towards prescribing a cannabis product. With these patients the topic must be discussed fully during a first consult. The main question during this consult is are they at all eligible to receive cannabinoid products.

Are you aware of patients experiencing interactions with cannabinoid therapeutics and other medicines?

Indeed, we do see patients who experience drug interactions using cannabinoids alongside other CNS depressant medications (e.g. opioids).

Sedative effects can be enhanced especially in the geriatric population. Severe drowsiness and hallucinations can also be provoked.

Aside from drug interactions, the smoking of cannabis is related to an increased risk of myocardial infarction and stroke. Cannabis as a trigger of myocardial infarction is plausible, given its cardio-stimulatory effects, which may cause ischemia in susceptible hearts. Carboxy-hemoglobinemia from the smoking of cannabis may also contribute to ischemia. Smoking is never recommended.

Do you encounter diversion for misuse or the abuse of cannabinoids? How do you identify this issue in your practice?

During the period when Dutch health insurers widely reimbursed medicinal cannabis, we had frequent discussions with patients, best described as ‘recreational users’, about their eligibility.

Patients of this group, who were already using large amounts of cannabis, were requesting access for rather dubious indications. Some patients were seeing it as a cheap way to get a ‘recreational drug’ which they were already abusing.

How do you deal with diversion for misuse or abuse in your practice?

This patient group can be quite challenging. They may put pressure on clinicians to prescribe cannabinoids as the only means to relieve their pain. Mentioning misuse and abuse can provoke abrupt reactions.

Clinicians should be coherent in prescribing cannabinoids only for indications with enough evidence for beneficial effects (e.g. analgesic for neuropathic pain, appetite stimulation etc). Misuse and abuse should be discussed openly if they become apparent.

Bedrocan has for decades been a household name as a brand and company when it comes to the development and production of standardised, medicinal cannabis of pharmaceutical quality. Based on the knowledge that a picture is worth a thousand words, a short film has been made showing the unique combination of growing, harvesting and production (in accordance with good manufacturing practice) and research & development. The film explains in just three minutes and thirty one seconds precisely what we mean by ‘beyond pioneering’.

As of November 2017, the new Dutch Bedrocan production facility officially manufactures in accordance with good manufacturing practice (GMP). This guarantees that Bedrocan meets international pharmaceutical quality and safety requirements.

It is the second time that a Bedrocan production site has been made compliant with the GMP requirements for an active pharmaceutical ingredient. Earlier this year, the manufacturer of standardised medicinal cannabis acquired a GMP certificate for the existing Dutch production site. This made Bedrocan the first manufacturer in the world where the entire production process – including cultivation – complies with the international requirements imposed on the production of pharmaceutical raw materials and end products.

On 15 September 2017, the new Bedrocan production site harvested the first batch of standardised medicinal cannabis and handed it over to the Office for Medicinal Cannabis. The new site, outfitted with state-of-the-art finishings and fittings, has a surface area of 10,000 m2, half of which is in use at the moment. With this significant increase in production capacity, Bedrocan meets the growing demand for standardised medicinal cannabis of pharmaceutical quality.

Cannabis labelled ‘Sativa’ and ‘Indica’ may not come from distinct ancestries, according to a study performed by the Canadian Dalhousie University in cooperation with Bedrocan on the genetic differences between the two types and their hybrids. In this study 149 Dutch cannabis samples were analysed, correlating the genotype and chemotype to their reported ancestries. Indica- and Sativa-labelled samples were not as distinct as sub species would be assumed to be, but the genetic differences between them do correlate to their terpene profile (resin fragrance), which could explain the variation between them. Results of this new study have been presented on the International Association for Cannabis as Medicine (IACM) congress in Cologne, Germany, September 2017.

There is perhaps no debate in the world of cannabis more contentious than that of species. The genus Cannabis sativa L. is the only official species, but the terms ‘Sativa’, ‘Indica’ and ‘Hybrid’ have been widely adopted by cannabis breeders and cultivators as a way of advertising their product’s effects, aromas or purported pedigree. The degree to which these labels correspond to their actual ancestry, however, is dubious, and how this informal classification scheme relates to genotype or phenotype has been largely unexplored.

In the study an analysis of 149 cannabis samples was performed, correlating the genotype and chemotype (based on terpene and cannabinoid content of the flowers) to their reported ‘ancestry’.  The researchers then compared the reported labels to new scales they generated by reclassifying the samples based on their genetic and chemical similarity.

The Indica/Sativa classification of Dutch cannabis does not correspond to distinct genetic lineages or to cannabinoid type, but there are genetic and chemical similarities that explain the variation between the groups. Deconvolution of the Indica-Sativa ancestry showed a strong relationship between the chemical and genetic profiles, suggesting that the distinct terpene contents of the types are heritable and important to the identity of these two groups. It is likely that strains are classified by their distinct aromas, and not their lineages, which has a direct impact on the genetics of this crop.

Bedrocan, worldwide producer of standardised medicinal cannabis, is already working on the terpene profiles that are associated with the current Bedrocan products. Hugo Maassen, head of the phyto engineering department at Bedrocan: “This study shows that the Indica/Sativa differences could be largely based on terpene content, which instead of the current Indica/Sativa labelling might require for more insight in the terpene profiles related to the Bedrocan products available for patient use.”

The terpene profiles of the Bedrocan products are expected to be announced in the near future.

Used by patients in the Netherlands since 2003, Bedrocan® standardised cannabis flos is now available for patients in Australia. This includes the same cannabis flos currently used in the NSW palliative care clinical trial.

Administered by vaporization, the consistent chemical profile of the flos better allows doctors to monitor dosage, condition progress, and reduce the risk of overdosing and unwanted side effects.

Being free of microbial contaminants (molds, fungi, and bacteria), pesticides, and heavy metals, Bedrocan cannabis flos is safe for vaporization and inhalation into the lungs. These qualities are especially important for people with weakened immune systems.

The recently published Prescribing Bedrocan provides information to assist health professionals on dosing, safety, and side effects. Our portal now allows doctors to report adverse events online.

Novachem, a specialist import and distribution agent, will supply flos and vaporization technology to licensed pharmacies in Australia.

The first of its kind in Australia, Bedrocan’s cannabis flos and placebo will be used in a cancer palliative care clinical trial. Led by Professor Meera Agar, the double-blind randomised controlled trial will explore whether vaporized medicinal cannabis flos can promote appetite and improve quality of life. For people with cancer, the pathways that promote appetite are disrupted. Their quality of life is reduced due to fatigue, low mood, nausea and insomnia – aspects critical to health and wellbeing.

Researchers are now recruiting patients. Approximately 30 adult patients with advanced cancer will be included in the trials undertaken at Sydney’s St Vincent’s Sacred Heart Health Service and Newcastle’s Calvary Mater Hospital. The results may lead to a further trial, enrolling up to 250 patients from metropolitan and regional hospitals across the state.

The New South Wales Minister for Medical Research, the Hon. Pru Goward, fully supports the trial as part of the state Government’s $21 million funding commitment to medicinal cannabis clinical trials and reforms. To learn about the NSW Government’s Centre for Medicinal Cannabis Research and Innovation and the trial see www.medicinalcannabis.nsw.gov.au.

For more on vaporization as a way of administering cannabis flos, read our article Not all vaporizers are the same.