The importance of standardisation

Unlike other medication, cannabis does not have a fixed chemical/molecular composition. A cannabis plant contains hundreds of different substances and each individual plant is different in terms of its composition. THC and CBD are the best-known substances, but there are dozens to hundreds of other known and unknown substances in the plant that may have an effect. No two cannabis plants are the same. Even if the levels of THC and CBD are the same, the substances around them can produce a different effect for the patient; this known as the ‘entourage effect’. There have been various studies of this entourage effect. Ultimately, the complete ‘fingerprint’ of the plant determines its effect.

In the Netherlands, there are now five medicinal cannabis varieties available. Each variety has a unique, fully standardised genetic composition that is and remains the same each time, for every batch, year in, year out, because of the unique production process. The result is that the CBD and THC levels are always the same, but the other substances are also always present in the same ratio. The reproducible chemical profile enables doctors to monitor the dose and the effect on the disorder in the same way as for other certified medication. Furthermore, it makes these varieties suitable for carrying out scientific medical research.

Constant availability of a standardised product is extremely important to the patient

Just like ‘normal’ medication, all patients are ‘set’ on a certain variety. Sometimes it can take a long time to get patients on the right variety with exactly the right dose on the basis of the existing five varieties. The same applies to the use of cannabis oil. Changing the dose or administering medication with a different genetic composition can have adverse consequences for individual patients. In some cases medicinal cannabis oil is used for children and adults with serious epilepsy. The Dutch Epilepsy Fund and doctors recommend changing brands as little as possible for epilepsy medication, because somebody can end up with a seizure after changing medication.

Constant availability of a standardised product is extremely important to the doctor

Quite rightly, doctors want to know exactly what they give to their patients and what its effects are. It takes a lot of time and effort for doctors to become used to prescribing cannabis. The reproducible chemical profile of standardised medicinal cannabis enables doctors to monitor the dose and the effectiveness in the same way as for other certified medication. As this medicinal cannabis is also produced in accordance with pharmaceutical standards (GMP), quality and safety are guaranteed as much as possible. As doctors have prescribed the same products from the Office of Medicinal Cannabis for years, they know what it does and they feel comfortable with it. The same applies to the pharmacists who ultimately hand over the product.

Constant availability of a standardised product is extremely important to researchers and clinical research

For the first time, there is now larger scale serious clinical research into the effect of medicinal cannabis. In December 2018, the first results were published of a placebo-controlled, comparative study of 3 of the 5 varieties available in the Netherlands, carried out by the University Medical Centre Leiden. Different doctors, pharmacists, and study groups are now preparing further clinical research. They prefer to work with standardised medicinal cannabis that has a guaranteed quality, safety and availability.

In order to obtain permission for medical scientific research with humans, you need a detailed statement of the product that is studied. At the end of the study, the outcomes only say something about the specific plant, and its unique genetic composition, that was used in the study. Clinical research that is carried out with the existing Bediol variety, can only be carried out with that plant. Changing variety in the meantime is not possible from a substantive point of view, it is legally impossible, and certainly not desirable. If there were to be a change to a plant with only comparable THC and CBD levels, permission for the research would have to be applied for again. THC and CBD may well be comparable, but the chemical and genetic composition of the plant and the presence of other substances changes. So therefore, in essence the product used for the research changes too. It means the outcomes that were gathered up to that point are no longer usable, because they do not apply to this new, different plant.

Constant availability of a standardised product is extremely important to developers of medication and medical devices

At the moment, medicinal cannabis only applies as a medical raw material, i.e. an API or Active Pharmaceutical Ingredient. Various companies around the world are working on developing medication or medical devices on the basis of this active pharmaceutical ingredient. One example is an extremely advanced inhaler, which was developed by using standardised products from the Netherlands from the beginning. This inhaler is so advanced that it detects even the slightest change in the form and composition of the product to be administered. For the device to work correctly, the same percentage of THC and CBD and exactly the same genetic and chemical composition of the product are important. Any change in plant will produce high modification costs and months, if not years, of delay in its further development.

Scientific research with standardised products; an overview

The importance of standardising the complete chemical composition of the plant is supported by various scientific studies. Below is a list of a number of studies into other substances in the cannabis plant and the entourage effect they cause:

  1. From Cultivar to Chemovar II—A Metabolomics Approach to Cannabis Classification

The study considered the ‘cultural’ designation of cannabis varieties, how to distinguish them in terms of effect and how they can be separated chemically and scientifically. The chemical difference is expressed in THC and CDB values, but also in other cannabinoids and terpenoids. This means that clinical research and anecdotal evidence could be used to study the various therapeutic effects of cannabis and/or certain varieties of cannabis could be prescribed to patients on the basis of the complete chemical profile.

More information>

  1. Taming THC: Potential Cannabis Synergy and Phytocannabinoid-Terpenoid Entourage Effects

This study introduces the ‘entourage effect’, which assumes interaction between cannabinoids and terpenes. This interaction may lead to positive effects regarding treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections. Unique therapeutic properties are ascribed to terpenes, the odour and flavour substances in cannabis.

More information>

  1. Terpenes and Derivatives as a New Perspective for Pain Treatment: A Patent Review

This study deals with the role of terpenes in pain relief and is particularly focused on the role those terpenes could play in developing new analgesics.

More information>

  1. Synergy Between Cannabidiol, Cannabidiolic Acid, and Δ⁹-Tetrahydrocannabinol in the Regulation of Emesis in the Suncus Murinus (House Musk Shrew)

This study demonstrated that a combination of THC, CBD, and CBDA (cannabidiolic acid) produced better control of vomiting and fewer side effects. This combination was administered to shrews. These effects are also expected to occur in humans.

More information>

  1. Beyond Cannabis: Plants and The Endocannabinoid System

Not just the substances in cannabis have an effect on the endocannabidoid system. This article deals with a number of other plants that could produce similar effects. It also deals more in-depth with the ‘entourage effect’.

More information>

  1. Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads

This article aims to answer the question as to the synergy between cannabinoids and terpenes in the therapeutic treatment of pain, psychiatric complaints, cancer and various other disorders. It also considers the therapeutic effects of substances in cannabis roots, leaves and seeds.

More information>

  1. Cannabis Constituent Synergy in a Mouse Neuropathic Pain Model

This animal study demonstrated that CBD strengthens the pain-killing power of THC during the treatment of neuropathic pain. The results suggest that a combined low dose of THC and CBD is the best option for dealing with neuropathic pain.

More information>

  1. Single and Combined Effects of Δ⁹-Tetrahydrocannabinol and Cannabidiol in a Mouse Model of Chemotherapy-Induced Neuropathic Pain

This study in mice demonstrated that really small doses of CBD or THC – administered separately – do not have an effect on reducing neuropathic pain caused by chemotherapy. However, when THC and CBD are administered in combination, these two substances have a synergetic effect and can be effective in dealing with pain.

More information>

  1. Appraising the “Entourage Effect”: Antitumor Action of a Pure Cannabinoid Versus a Botanical Drug Preparation in Preclinical Models of Breast Cancer

This animal study demonstrated that a full extract of cannabis has a better effect on treating tumours (breast cancer) than pure THC.

More information>

  1. The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No “Strain,” No Gain

This article proposes to stop categorising cannabis varieties by strains and to categorise them by chemical properties (‘chemovars’) instead. Furthermore, according to this article it is assumed that the combination of substances has a better therapeutic effect than the active substances alone – the ‘entourage effect’.

More information>

  1. An Experimental Randomized Study on the Analgesic Effects of Pharmaceutical-Grade Cannabis in Chronic Pain Patients With Fibromyalgia

This clinical study demonstrated that administering a combination of THC and CBD demonstrated a synergetic effect in patients, whereby the CBD increased the amount of THC in the bloodstream.

More information>

THC level in blood increases in combination with CBD

CBD can have a strengthening effect on the THC level in the blood. This was observed in data from a clinical study with fibromyalgia patients. A poster presentation about this matter gathered a large and engaged group of researchers and regulators at the ICRS congress last June. The ICRS congress is a leading scientific conference where international scientists present their findings in the field of cannabinoid research.

ICRS Poster

Previous research has shown that administering THC together with CBD can help reducing the undesirable side effects of THC, especially those related to increased anxiety. However, recent clinical and psychopharmacological research shows that co-administration of THC and CBD can lead to additional, unexpected effects.

Specifically, a recently published clinical study conducted at the Leiden University Medical Center, with the support of Bedrocan, compared the blood levels of THC in chronic pain patients after the administration of three cannabis chemovars (varieties): Bedrocan® (THC 22% | CBD <1.0%), Bediol® (THC 6.3% | CBD 8%), and Bedrolite® (THC <1.0% | CBD 9%).

Bedrocan’s research coordinator Mikael Kowal presented the results at the ICRS congress and there was great interest in his analyses. “The findings from our clinical study regarding the complex interactions between THC and CBD in the body are novel and were surprising to many.”

Knowledge

“Apparently, the effect of CBD increasing THC concentrations in the blood was discovered by one researcher in the early days of creating the formulation of Sativex. However, at that time this finding was difficult to explain, due to lack of sufficient knowledge on the workings of CBD. Currently, we seem to be the first to have this data published and similar results are being found in animal research.”

Mikael Kowal PhD

In the case of Bediol, the mixed THC/CBD cannabis chemovar, the blood levels of THC were about 50% higher than expected from the administered THC dose. Moreover, a similar effect was observed in a psychopharmacological study conducted with healthy cannabis users at the University of Sydney, in which higher THC levels were found in the blood of subjects who received cannabis containing equal amounts of THC and CBD, than in the case of cannabis containing an equal dose of THC, but without CBD.

The exact mechanism by which this effect occurs is still not clear. Possible explanations include an increased absorption of THC in the lungs or the inhibition of THC metabolism, both induced by CBD, or the conversion of CBD into THC. In any case, knowledge of these pharmacokinetic THC-CBD interactions can help physicians and patients in establishing a proper therapeutic dose of cannabis to treat their symptoms. Further research is needed to confirm this, however it is possible that lower doses of THC are required when co-administering it with CBD, in order to achieve symptom control of a particular disease.

Three misconceptions about medicinal cannabis

What are we talking about when we talk about medicinal cannabis?

The term ‘medicinal cannabis’ leads often to faulty assumptions and misconceptions. That’s why we think it’s important to make clear what medicinal cannabis actually is. In a series of short articles we present the most common misconceptions about medicinal cannabis, in order to speak the same language in discussions, news articles and so on.

All cannabis is suitable for medicinal use

There is a great difference between ‘medicinal cannabis’ and ‘cannabis for medicinal use’. That difference is all about the manner in which and the purpose for which the cannabis is produced. Medicinal cannabis is intended solely for patients and the production process is fully attuned to that purpose.

Production takes place in a fully standardised manner, in a pharmaceutical environment, and is subject to those stringent quality and safety standards. The production processes are designed so that the cannabis is genetically consistent, the proportion of active ingredients is consistent, and there is minimum risk of contamination (microorganisms, heavy metals, and no pesticides). The cannabis quality is tested by an independent laboratory. This way quality is guaranteed. Both the patient and doctor clearly know what is being prescribed.

Industrial hemp is medicinal too

Hemp belongs to the family of Cannabis sativa L. It contains cannabinoids and is sometimes used for ‘recreational’ or ‘medicinal’ purposes, although it is never produced under pharmaceutical conditions. When referring to hemp, this typically concerns ‘industrial hemp’; a sturdy agricultural crop with long, strong fibres.

It differs genetically from the medicinal cannabis species. Mainly used in clothing, paper, (animal) feed, and automobile industries, industrial hemp contains negligible or zero levels of THC (the psychoactive component of cannabis). This is why it may be legally grown in many countries under more relaxed regulations. Industrial hemp does however contain CBD. As a result it is sometimes also used for the production of CBD rich oils which are not for medical use.

Medicinal cannabis is expensive

The production of medicinal cannabis requires considerable investment. The production process must continuously comply with the applicable quality and safety requirements of medicines. Nonetheless, in the Netherlands – a programme designed to provide patients with acceptably priced pharmaceutical quality medicines was initiated in 2003 – it has proven possible to gradually reduce the price.

Indeed, the price for one gram of medicinal cannabis has remained below the average price for recreational cannabis in the Netherlands for some time. This was made possible due to industrial efficiencies, scalable production process, and – in more recent years – income from exports.

In 2018, the Minister for Public Health, Welfare and Sport – who is ultimately responsible for the Dutch medicinal cannabis programme – further reduced the price per gram. A patient today pays € 5.80 (net) at the pharmacy.

Dr Timna Naftali: ‘IBD patients feel a lot better after being treated with cannabis’

Dr. Timna Naftali, Gastroenterologist at the University of Tel Aviv, was the first person to research the effect of medicinal cannabis on inflammatory bowel disease (IBD). While she received great criticism, one patient always inspired her not to give up. Scientific evidence is crucial for Naftali, and she is therefore devoted to the cause. She is determined to supply proof that medicinal cannabis works for IBD sufferers.

Ten years ago, a young patient walked into Dr Naftali’s surgery for her initial consultation. She had not been back for a check-up for a year. Naftali was surprised to see her again and wondered why she had never made a follow-up appointment.

“She had something to confess,” says Naftali. “The patient explained she had been using cannabis for the last year. All pain had disappeared, and had therefore felt no need to come back. In the meantime the patient had married, was trying to get pregnant, and had therefore stopped using cannabis. Her situation had once again deteriorated.”

The positive effect of cannabis on this young woman triggered many questions for Naftali. Would it not be fantastic to help more patients suffering from Crohn’s disease and colitis ulcerosa?

Dr Timna Naftali
Dr Timna Naftali

Lecture

In the end, it was a lecture by Dr. Yehuda Baruch, former head of the Israeli medicinal cannabis programme that was the deciding factor to look for answers. “To my amazement, he informed me that medicinal cannabis could be prescribed for patients in Israel suffering from Crohn’s disease. I was surprised that as a doctor, I was unaware of this.”

With total dedication, Naftali searched for clinical studies that supported the policy of the Israeli government. Finally, she concluded there was nothing to be found. “Nothing at all. Not a scrap of scientific evidence.” In the end, it was Naftali herself who took up the challenge to produce the much-needed scientific evidence. But where to start the research?

Dispensaries

Israel has special cannabis dispensaries where patients with a government permit may source their medicinal cannabis. “I approached a local cannabis producer and supplier and they put me in contact with thirty Crohn’s disease patients. Their experience with medicinal cannabis was impressive.

Patients required less (typical prescription) medication, suffered less pain, retained a healthy weight. Some patient no longer needed hospitalisation. Their quality of life had visibly improved because of their medical use of cannabis.”

That research was published in the Israel Medical Association Journal (2011) and promptly received criticism. The small retrospective observational study asked patients about their experience. It did not include patients who experienced little or no improvement. However, the positive consequences made Naftali more convinced of the necessity of continuing her research. She was determined to undertake a randomised, double-blind study. “A proper study”, as she herself refers to it, complete with a placebo, so that patients would not know what they were taking.

The research took around two years and the results were nothing less than spectacular. “Nearly half of the patients (45%) felt completely healthy after using medicinal cannabis. As if their disease had disappeared. In the placebo group on the other hand, a mere 10% experienced a complete remission. Once again, Naftali research was criticised within her professional field. Apparently, the study was not objective enough and there was insufficient clarity on the effect in the bowel after the use of cannabis. A justifiable observation, Naftali believes with hindsight: “We all know that cannabis can give a sense of euphoria. Was that why these patients felt better or was it the condition of their digestive tract and an actual solution for the disease?” She had also deployed an unhealthy method of application, namely smoking. A new study therefore proved to be essential. The latest study used a different administration method (cannabis oil for oral use). Patients received endoscopic intestinal examinations before and after the use of medicinal cannabis, in order to detect any improvement in inflammation levels.

Latest study

The results, published in October 2018 at the annual United European Gastroenterology congress, received positive reactions. Naftali herself was not satisfied. “Although patients felt much better after consuming the cannabis, no improvement was visible in the digestive tracts during the endoscopy. What does that mean? Either cannabis has no influence or there was not enough time between administration and the intestinal examination. It was only an eight-week period after all. Perhaps an interval of three months would have been more useful.”

Naftali also encountered another problem: “There are many types of cannabis, and as a researcher you have no idea which will work best. I still genuinely wonder what type of cannabis to administer, for how long and in what form.” In other words, her work is not finished yet.

Naftali is in the early stages of a new study designed to show the effects of purely synthetic CBD. CBD is known to have few side effects and is therefore considered safe. “It could serve as a supplement to further medication. But we first need to know whether it actually works.”

Crohn’s disease and Ulcerative Colitis

Crohn’s disease is a chronic inflammatory disease of the bowel. Like Ulcerative Colitis, it is therefore generally referred to as inflammatory bowel disease (IBD). In Ulcerative Colitis, there is usually chronic, recurrent inflammation of the large intestine. In most Crohn’s disease patients, there is inflammation of the small intestine, large intestine and/or rectum. Although there may also be inflammation in the rest of the digestive tract.

Naftali would appreciate being able to cooperate with researchers outside of Israel. Although the Meir Medical Centre in the Israeli city of Kefar Sava, where Naftali works, treats a thousand IBD patients, she believes this population to be too limited. The main obstacle to international cooperation however is that all researchers must be able to use the same cannabis. “The product I use here in Israel is not the same as that available in the Netherlands. We would therefore need to export the product, which has not exactly proved simple so far.”

By now, the patient who revisited Dr. Naftali ten years ago, has married and moved away to a different region of Israel. Naftali no longer has contact with her, but it is thanks to this patient that she remains convinced of the usefulness of medicinal cannabis for a majority of patients.

If you are interested in further research by Dr Timna Naftali, check out PubMed.

Podcast organiser Cannabis Economy launches first digital workshop

Bedrocan’s CEO Tjalling Erkelens has been featured on the Cannabis Economy podcast a significant number of times over the past few years. For the first time, Cannabis Economy’s Digital Workshop will take place on July 30th and 31st, bringing together leaders in policy, science and business. American events moderator Seth Adler is the driving force behind these podcasts. We discussed his background and the reasoning behind the podcast.

Who are you?

I’m a host, moderator, producer and unlicensed anthropologist. I’ve spent over 20 years producing international events, podcasts, video, and the written word. I am responsible for bringing “The greatest show on earth Ringling Bros and Barnum & Bailey”, the former American traveling circus, to town. I have also produced music showcases at the historic – now closed – New York City music club CBGB. I’m currently focused on the societally significant industries of legal cannabis and artificial intelligence through the production and hosting of Cannabis Economy and the AI & Intelligent Automation Network.

Seth Adler

I procured a network of leaders in the space, including Catherine Sandvos of the Netherlands’ Office of Medicinal Cannabis’, and began running events. A six month gap between events is too long, and so I launched the Cannabis Economy podcast. The podcast has now reached the 850K downloads milestone and over 400 episodes have aired.

Cannabis Economy Digital Workshop
Date: July 30 & 31
Location: Online
Cost: It is free

What is the digital workshop about?

The Digital Workshop brings global leaders from across the cannabis space together on one platform. Experts include elected officials, regulators, scientists, business leaders, advocates and activists discussing cannabis as a medicine, wellness and economic opportunity.

Why do you organise it? And why digital?

While the global cannabis economy has experienced dynamic growth, 2019 is specifically a year of sea-change with the World Health Organization setting guidelines, Israel exporting, EU members taking action, Asia-Pacific diving in, the first full year of legal cannabis in Canada and actual federal legislation receiving votes in the United States.

With a huge variety of cannabis events specialising in global policy, science and business, the Cannabis Economy Digital Workshop supplements this extensive calendar and provides parties the opportunity to learn from leading experts without blocking up schedules.

What do you want to achieve?

The goal of the Cannabis Economy Digital Workshop is to connect best-in-class thought-leadership and information-sharing in order to identify standard sensible regulations, safe patient access and industry advancement within the cannabis space.

How, where and when can people join?

While the content is designed for leaders in business, policy and science, attendance is free thanks to our sponsor’s support. Please register at the Cannabis Economy website.

Bedrocan presents at Cannabis Europa

Cannabis Europa has grown to become the foremost arena to share knowledge and shape the future of medicinal cannabis in Europe. The 2019 event hosts more than eighty expert speakers – ranging from politicians, policy-makers, scientists,  health care professionals, patients and industry. Bedrocan will be there.

Tjalling Erkelens, founder and CEO of Bedrocan, has been invited to speak about business leadership and global business development. It is indeed an interesting subject. Working within highly fragmented regulatory environments and often immature markets, the challenges facing industry leaders are numerous.

 

Cannabis Europa
Date: 24 & 25 June 2019
Location: Southbank Centre
London, United Kingdom

Programme Highlights

Monday 24 June – 15.30 – 16.30

Strong and Stable | Business Leadership
Nicholas Vita – Columbia Care
Tjalling Erkelens – Bedrocan
Nick Davis – Memery Crystal
Sabah Meddings – Sunday Times (Chair)

Tuesday 25 June – 10:00 – 11:00

Seizing the Initiative | Political Opportunity
Dr Ricardo Baptista Leite MP – Assembly of the Republic of Portugal
Delano Seiveright – Cannabis Licensing Authority Jamaica
Dr Marco van de Velde – Office for Medicinal Cannabis of the Netherlands
Andrea Paine – Aurora (Chair)

New research into use of opiates and medicinal cannabis

Can medicinal cannabis reduce the use of opiates? In order to answer that question, Leiden University Medical Centre (LUMC) is starting a study into the use of medicinal cannabis as an opiate-saving product among chronic pain patients. The product Bediol®, which contains both the cannabinoids THC and CBD, is used for this purpose. The study is carried out by the Anaesthesiology Department and is partly supported by Bedrocan, the world’s most experienced producer of legal medicinal cannabis.

The principal investigator, Prof. Albert Dahan, previously did research into the effect of medicinal cannabis in the treatment of chronic pain caused by fibromyalgia. An article about this was published in the journal PAIN at the end of 2018. Results of that research were positive and Dahan will now start a follow-up study. The main purpose of the study is to assess whether comedication with Bediol (6.3% THC and 8% CBD) will reduce the side effects of opioids among chronic pain patients.

Opiates are painkillers based on the natural substance opium. Examples of opiates are morphine, oxycodone and fentanyl. Prof Dahan said “Long-term use of these painkillers is addictive and causes unpleasant side effects like drowsiness, nausea and constipation. We believe that you can reduce the amount of oxycodone prescribed if you give people the option to use medicinal cannabis.”

The research team is currently working on the study’s preparatory phase. It is expected that the first patients will participate this year. From then on the study will take about two years to complete.

Bedrocan market leader in Europe

Facts and myths – the MJBizDaily factbook ‘Medical Cannabis in Europe: The Markets & Opportunities’ provides a clear picture of the European medicinal cannabis for the first time. What does the European market for medicinal cannabis look like? Which regulations apply to which country, who produces, who imports and which producers make the largest contribution?

Those questions and many more are answered factually and in detail for the first time by a special edition of Marijuana Business Daily, an American news outlet on the global cannabis industry. What transpires? Bedrocan is the clear market leader in Europe. More than 61% of the medicinal cannabis that is used by patients in Europe comes from our sites in Emmeloord and Veendam.

A special team of journalists and researchers analysed the European market for medicinal cannabis. It produced a diverse picture, both in terms of regulation and figures. Just three countries – the Netherlands, Germany and Italy – have a significant domestic market, whilst all other countries together account for just 3% of the market. Furthermore, the Netherlands is the only country that is able to meet the needs of patients internally, as all other countries depend on import. In contrast to a popular argument, this import does not come from Canada.

Besides the general European figures, the report also provides a good overview of the market and the regulations in more than 20 individual countries. If you are interested, you can download the MJBizDaily factbook free of charge.

Canfusion – No, this title is not an error

Developing new medication is a long and expensive process, marred by uncertainty. On average it takes 10 years before medication is registered officially, but in the world of cannabis it works the other way around. Cannabis and cannabis products are on the market already, be that legal or illegal. “It’s time for governments to get into gear”, argued Bedrocan’s CEO Tjalling Erkelens in a guest article he wrote for the German Hanf Magazine. Politicians and policy makers need to come up with universal regulations that are meaningful to the cannabis industry, the healthcare professional and the patient.

By: Tjalling Erkelens – CEO Bedrocan
Published in Hanf Magazin

No, this title is not an error. However, it certainly has to do with “confusion” and more in particular about confusion surrounding cannabis these days. Aside of all ‘big money’, ‘big pot’ and ‘big pharma’ discussions I do see an immense amount of confusion among doctors, patients, pharmacists, but also scientists, regulators and politicians.

Since cannabis has become ‘hot’ everybody is trying to jump on the bandwagon and be part of the current ride that cannabis is taking in the world. Even worse, everybody nowadays also has an opinion on cannabis. At the numerous conferences and meetings that are now being held on this subject we see so much information either lacking, being false or at least incorrect and certainly not patient-focused.

I am working in the world of cannabis since 1992. So that started only 16 years after fellow Dutchman Harm Dost, was arrested in Kleve (as a tourist). Harm Dost was known for his sales of cannabis in Arnhem, also to German people who he, at that time, treated as patients, calling himself a caregiver. In 1977, after having spent 18 months in a German prison, he was extradited to The Netherlands. In 1986 he was again sentenced in Germany, now to 10 years in prison. In 1987, on appeal the sentence was diminished such way that he was released from prison immediately. Twenty-two years later (2008) Germany imported its’ first medicinal cannabis from The Netherlands and sales through pharmacies, on prescription of a medical doctor started.

So, I have seen the world of cannabis change from a full illicit/grey product and industry, basically without any surrounding scientific knowledge, into one in which science, industry and regulators / politicians have started to see the added (medical) value of cannabis. That doesn’t mean that everything now is perfectly right and ok. As said in the intro, there is still a lot of confusion among many stakeholders. Even today, a lot of politicians and regulators don’t see the difference between cannabis for medical use or recreational use. At the least they are struggling with it. Although the amount of positive scientific evidence is more and more piling up these days, the acceptance of cannabis as a medicine is still highly driven by emotions and (contra-)activism. Lack of consensus among scientists, lack of coherence and harmonization of regulations and an un-unified industry are frustrating development of proper cannabis-based medications, let alone proper access for patients globally.

To unravel this relative complex problem, we have to start with a very basic question: ‘What is cannabis?’ Even till 5 years ago, the general answer was: ‘A plant, well-known for its’ healing, though psychotropic effects due to its’ main constituent THC.’ If you will ask today, a majority will tell you: ‘A plant, well-known for its’ healing and non-psychotropic effect due to its’ main constituent CBD.’ In between you will find people talking about terpenes, minor-cannabinoids, flavonoids, entourage-effect. But in the end, nobody is able to provide all the right answers. The only thing we do know is that cannabis works well for a lot of people in all kinds of suffering and diseases. However, from that point on, we all got stuck in a swamp of so-called expert-opinions, testimonies, n=1 studies and even hearsay.

Solving this problem is not an effort that can be put on the shoulders of industry, research institutions or NGO’s only. The consequences of more than 60 years of global prohibition will have to be borne by the politicians who made that decisions back in the early sixties of last century. So actually, that means all of us, represented by our politicians. If we want proper research, proper products and proper access for patients and that way allow cannabis to become the medicine we all think it is, this is a bigger task than making industry responsible in the traditional pharmaceutical way. Such would have worked 60 years ago, just like it did with other controlled substances producing plants (poppies and coca mainly). Some then would say legalize all cannabis use and thus have the recreational user contribute to the development of cannabis medicines. That is what I call: mixing apples and pears. The 60 years of prohibition were not caused by recreational users or activists and patients neither of course…

Now a number of governments is telling the newly arising cannabis industry to follow the well-known track of pharmaceutical drug development. That would mean in very broad strokes: develop your product, perform your (clinical) research, register your product, get market authorization and have your product into the patient’s hand hopefully reimbursed partially or in full. Following that track will mean another 10 – 20 years of waiting because that is what this ‘royal route’ brings with it. However, that time is not really available. Cannabis and cannabis derive products already are in the market (licit or illicit); efficacy is shown by means of the numbers and experiences. If you can show a 100.000 times or more positive N=1 (research on 1 person) results, is a result that cannot be ignored.

In the end it means that the ‘royal route’ is not available, simply because we’re already far beyond that point. The combination of allowing cannabis to the market but having no proper or sometimes very ‘creative’ regulations in place is not good for patients, nor their caregivers. It has become time now for regulators on a global, or at least multi-national level, to come together and unify regulations on the basis of safety and efficacy on one hand and immediate, proper and responsible access on the other. Germany (although still struggling as we all know) is a good example of allowing and regulating at least that combination of factors to happen. Maybe instead of all those business conferences, the industry should focus on more regulator conferences. Let’s make 2019 “Year Of The Regulator”.

Medicinal cannabis. Lawful, but still difficult to obtain in the UK

At the end of last year, the rules for using medicinal cannabis in United Kingdom were relaxed substantially, but many patients are still looking for ways to obtain medicinal cannabis or derived products in a lawful, affordable and responsible way. Healthcare professionals are extremely cautious with prescriptions, because of the attached ‘clear published evidence of benefit’ condition. According to Hannah Deacon, mother of epilepsy patient Alfie Dingley, time is of the essence. “There is much more awareness in the UK and important steps have been taken, but the procedures are too bureaucratic and time consuming. Patients can’t wait for those.”

In 2018, the UK government took significant steps in terms of the use of medicinal cannabis. Since the 1st of November 2018, medical specialists have been permitted to prescribe medicinal cannabis in specific situations. For a while, it seemed like the icing on the cake for a large group of patients and supporters in the UK who worked tirelessly to put medicinal cannabis on the political agenda and for the rules to be amended. Young patients Alfie Dingley (7) and Billy Caldwell (13) became the figureheads. Both boys suffer from a serious type of epilepsy, but it had become evident that medicinal cannabis could make an enormous difference to them. After Charlotte Caldwell, mother of Billy, was arrested at Heathrow Airport in June 2018 after purchasing medicinal cannabis oil in Canada, they were given an emergency license so Billy could continue taking his oil. Hannah Deacon, Alfie’s mother, also made the news on a regular basis. She started a campaign, personally met PM Theresa May and asked her to change the rules and allow a license to be issued to Alfie to use the oil he had used so succesfully in Holland. Among other things, they also managed to win actor Patrick Stewart for Alfie’s case. Alfie’s doctors recieved the first medicical cannabis license which was issued on 19th of June 2018 and then they could import and use medicinal cannabis from Holland. Hannah was the first person in the UK to bring in THC oil legally through customs in July 2018.

‘Sensible’ approach

In addition, in June 2018, Home Secretary Sajid Javid announced that the use of medicinal cannabis would be reviewed. He made it clear from the start that this review would not lead to a full legalisation of cannabis, ensuring a clear distinction between recreational use and medicinal applications. The outcome was a strict set of rules that became effective as of the 1st of November. Medicinal cannabis was also moved to a category of drugs (Schedule 2) that is still controlled, but that may be prescribed in certain situations. For example, only specialists in a hospital may issue prescriptions for a limited number of disorders. This concerns children with rare and serious types of epilepsy, adults who are undergoing chemotherapy and adult MS patients. Furthermore, treatment with medicinal cannabis may only start when all the other options have been exhausted, whilst the NHS argues that the treatment method needs to be proven to be effective too. Dr Michael Bloomfield, a leading research fellow in psychiatry at University College London was able to accept this ‘sensible’ approach as, like many other healthcare professionals, he is waiting for scientific evidence. “When we don’t have very strong evidence for any medicine, then it should be hard to prescribe something because we should be prescribing medicines when there’s a very strong evidence base for them”, he told BBC News.

New phenomenon

Hannah Deacon understands that perfectly well, but also sees the practical issues for the nearly 25,000 young patients in the UK with refractory epilepsy who, like Alfie and Billy,  could benefit from medicinal cannabis. “We are of course extremely grateful that the responsible bodies acted and that we received permission to import the oil for Alfie. We also understand that healthcare professionals have responsibilities and want scientific evidence, but in practice the new rules mean that many patients still don’t have access to medicinal cannabis. Medicinal cannabis is a new phenomenon for doctors and everyone is waiting for the outcome of clinical trials. Patients simply don’t have that amount of time to spare. More to the point, the rules are limited and complicated and manu clinicians do not understand them. Or they do not understand medicinal cannabis and how to prescribe it.”

Availability

Yet it cannot be denied that the UK is taking steps in line with other countries in Europe. Up to the 1st of November 2018, Billy, Alfie and many other English patients did not have access to medicinal cannabis at all without a special license. Nearly all medicinal products based on cannabis were Schedule One drugs, that were assigned no medicinal or therapeutic value and the use of which was prohibited. MS patients were allowed to use Sativex®, whilst Nabilone® was given to cancer patients. However, the use of these registered products was subject to conditions. Availability was a general problem for patients for whom regular treatment methods no longer worked, as was the case with Alfie Dingley. So in September 2017, Hannah and Alfie crossed the Channel to the Netherlands to find out whether medicinal cannabis provided relief; in the Netherlands medicinal cannabis has been available on prescription since 2001. Time was of the essence for Alfie.

Hannah, Drew, Alfie, Patrick Stewart and supporters.

Responsible product

Alfie suffers from PCDH19 epilepsy, which is caused by a mutation in the PCDH19 gene that disturbs the production of the protein protocadherin and disrupts the communication between brain cells. This is a serious form of epilepsy that produced clusters of seizures in Alfie; sometimes as many as 30 seizures a day or 150 per cluster. “Initially, the cluster attacks occurred every eight months, but when Alfie was five years old he was in hospital every week”, remembered Ms Deacon. “In the meantime we tried all sorts of different medication, but nothing worked. The situation became more serious as Alfie grew older, so something had to be done.”

Hannah and her husband Drew Dingley explored the possibilities of medicinal cannabis. “There is a lot of anecdotal evidence. In consultation with our GP we went to the Hague, where a specialist was prepared to treat Alfie and where the Transvaal Apotheek produced oil from medicinal cannabis in a responsible manner”, said Ms Deacon who is familiar with stories about illegal and often contaminated cannabis products. “When it comes to health, a little scepticism is a good thing. We were convinced that we needed to look for a legal, standardised and pharmaceutically responsible product. In the Netherlands that is available on prescription.”

After five weeks of treatment in the Netherlands, Alfie started to respond positively to an oil with a low THC content. After adding another oil (with more THC), Alfie’s situation improved enormously. Ms Deacon said: “After five months we were fairly certain that we had found good medication for Alfie. We returned to the UK and started the campaign that enabled Alfie to be given the license after a fair number of setbacks and other patients taking action. In the end, that license led to a prescription from the National Health Service (NHS), ensuring that Alfie can have lawful access to medicinal cannabis. The only problem is that we need to travel to the Netherlands on a regular basis, because the oil used by Alfie is not yet available in the UK.”

Savior

“All things concerned, Alfie is doing well”, continued Hannah Deacon. “The number of attacks has been reduced to just a handful. When they come, they are also far easier to deal with and Alfie recovers far quicker. He goes to school, rides a bike, rides a horse and is developing like any other child. Previous medication worked less well and made him aggressive too. We can truly say that medicinal cannabis has been a savior for us all. Alfie and the people around him have their life back.”

Unfortunately, this is still not true for all patients in the UK. It is with good reason that Hannah Deacon is concerned. “We did not campaign for Alfie alone. There are so many other patients – with different disorders – who could benefit from medicinal cannabis. Now the government has given consent, the availability of medicinal cannabis should be improved rapidly.”

First batch of medicinal cannabis arrived in the UK

On Thursday the 14th of February, the first bulk batch (800 gram) of medicinal cannabis from the Netherlands reached the UK. The English company Grow Biotech had been given permission to import the batch. This is not cannabis oil, but standardised medicinal cannabis of pharmaceutical quality that is produced under the responsibility of the Dutch government. That first batch of cannabis appears to have opened up a new, official route and possibly puts an end to a system where import is permitted for a select number of patients who then need to organise the import process themselves. The risk is that the import procedure takes longer than the validity of a prescription (28 days), making the bulk import essential according to many of those concerned.
The cost of medicinal cannabis is another threshold for many patients. Some patients spend approximately 700 GBP per month and there is still no set procedure for reimbursement. At the end of 2019,  the National Institute for Health and Care Excellence is due to publish guidelines for medicinal cannabis. The NHS will use those as the basis for possible reimbursement.

‘CBD does not mitigate the impairing effects of THC’

It is often reported that cannabis strains which are high in CBD are less impairing than those with equivalent THC but low levels of CBD. However, a recent study carried out by the Lambert Initiative at the University of Sydney and led by Australian researcher Thomas Arkell suggests that CBD might actually exacerbate some of the impairing effects of THC on driving and cognition.

It has already been established that cannabis can negatively impact the ability to safely drive a car. The effects can vary substantially between individuals; however, cannabis is generally thought to have a mild to moderate effect on driving. This is a point of concern for patients who often use medicinal cannabis as a last resort in dealing with their illness.

Looking for participants

The research team of Maastricht University is looking for healthy volunteers between the age of 18 – 50, ideally a fifty-fifty mix of male and female. They are looking for occasional cannabis users, who use no more than twice a week.

If you are interested in participation please send an email to:

fpn-cannabisanddriving@maastrichtuniversity.nl

Driving performance

Driving is a complex activity that requires many cognitive skills – looking, changing gear, assessing, planning, judging etc. PhD student Thomas Arkell recently ran a randomised, double-blind and placebo-controlled crossover study to investigate the effects of vaporized THC and CBD on driving with the support of the Australian research institute the Lambert Initiative. He was surprised by their findings: “We found that cannabis containing both THC and CBD had a worse effect on driving performance than cannabis with only THC”. Further, when participants received both THC and CBD, they had slightly higher levels of THC in their blood compared with when they had just received THC.

“These results therefore suggest that CBD does not mitigate or reduce the effects of THC, and that it may in fact exacerbate these effects.”

Patients

According to Mr Arkell, patients in particular will benefit from this new information. “Cannabis patients who are using high CBD products which also contain THC (such as Bediol or Sativex) need to be made aware CBD could potentially elevate the amount of THC in your blood and may under some circumstances actually increase the effects of THC.”

Thomas Arkell

Generalised advice

So should patients not be allowed to drive after they take their medication? It continues to be difficult to issue general advice to patients who use medicinal cannabis. The effect of cannabis differs from patient to patient. Mr Arkell continued: “Cannabis is not as straightforward as alcohol. Each person metabolises the drug and responds to its effects in a different way which makes it hard to say whether a certain amount of THC in your blood or saliva will have a particular effect”.

In the study, participants were still impaired 3.5 – 4 hours even though they felt much less ‘high’ at this time. According to Mr Arkell these results suggest that patients should probably avoid driving for at least 3-4 hours after taking their medication.

Arkell: “With more research, we can hopefully provide better guidelines for patients who may be unsure how long they need to wait before driving.”  A follow-up study led by Dutch Professor Johannes Ramaekers of Maastricht University is currently being developed and will begin this year. The follow-up study will use the Bedrocan and Bedrolite products as well as a placebo and will incorporate an on-road driving test.

Test vehicle

Maastricht University has carried out studies into the effects of cannabis on driving performance before. They use a unique test vehicle with dual-controls and roof-mounted equipment to measure various aspects of driving ability. The driving test runs for approximately 1 hour and is done on a 100 km stretch of highway near Maastricht with an instructor present in the car at all times.

The on-road driving test has a significant advantage over a simulated driving test as it better approximates real world driving conditions.

What is considered to be impaired driving?

Thomas Arkell said: “To measure impairment we look at something called standard deviation of lateral position. This is a measure of lane weaving, or how much people are moving around on the road. Normally, people are pretty good at maintaining a steady position in their lane. When people are impaired due to alcohol or other drugs, however, they are unable to control this as well and so their standard deviation of lateral position goes up. We can use this same measure to detect the effects of cannabis on driving.”

SDLP – Standard Deviation of Lateral Position

Placebo
(e.g. SDLP = 16 cm)

Sedating drug
(SDLP = increases)

Bedrocan is returning to Canada and South America early

An arbitration tribunal rules that the Dutch medicinal cannabis producer Bedrocan International (“Bedrocan”) is allowed to resume commercial activities in Canada as of September 11, 2019, and allowed to engage the same in South America (retroactively) as of March 14, 2019.

A legal settlement agreement containing a moratorium on commercial activities between Canopy Growth Corporation and Bedrocan, prohibited Bedrocan from operating in Canada until 1 January 2020, with the same prohibition applying to South America until 7 June 2019. This moratorium was enforced by Canopy in June 2018 after both parties agreed to terminate their joint licensing agreement.

The arbitrator has now reduced the duration of this moratorium due to Canopy not meeting all the conditions set out for the termination in the license agreement. The arbitrator concluded that the mere fact that Canopy was seriously prejudiced by a reduction of the moratorium is for the account of Canopy and Canopy only. He concluded as well that Canopy could have prevented any damage (i.e. reduction of moratorium) themselves had they simply adhered to the terms of settlement in a timely fashion. Following this ruling Bedrocan will be announcing its next steps within these markets some time later this year.

Bedrocan CEO, Tjalling Erkelens believes that “lifting of the moratorium not only results in an important milestone for Bedrocan as a company, but is also very good news for Canadian and South American patients who rely on the use of medicinal cannabis and who already used medicinal cannabis from Bedrocan before the moratorium commenced.”

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