Introduction

The use and cultivation of hemp in Asia dates back 10,000 years. Cannabis oil and seeds were used for food in China 6,000 years BCE and the first recorded use of cannabis as a medicine comes from 2737 BCE. Since then cannabis use has spread across the world, being used for the production of clothes and paper, as incense, for rituals and recreation, as well as an analgesic, an antiemetic, an antibiotic, an aphrodisiac, and to treat depression.

Only in the 1830s did cannabis first start to be considered as an intoxicating and dangerous substance; it was withdrawn from medical use and its use penalized in many countries. In the intervening years, governments have sought to punish cannabis use and distribution; so far a hundred thousand people have been imprisoned and arrested in the US alone, costing billions of dollars without a visible reduction of use and users, in fact, quite the reverse.

Did you know...

Amount spent annually in the U.S. on the war on drugs:
$58+ billion
Number of arrests in 2017 in the U.S. for drug law violations:
1,632,921
Number of drug arrests that were for possession only:
1,394,514 (85.4%)
Number of people arrested for a marijuana law violation in 2017:
659,700
Number of those charged with marijuana law violations who were arrested for possession only:
599,282 (90.8%)

By the 1990s the creeping liberalization of marijuana laws began. Simultaneously, the medical use of cannabis was resumed, with the ultimate aim of registering the drug and its derivatives as marketed products, undergoing the development and registration process required for any other medicinal product.


How easy will it be to improve the reputation of cannabis and its users today?
This article provides:
  • Some insight into the current science
  • Pharma industry landscape involved in the development of cannabis products
  • Regulatory environments for usage and clinical research
  • Challenges related to clinical trials conducted with controlled substances, including cannabis

Therapeutic effects of cannabis and recent recommendations from Canada

Marihuana (Marijuana) is the common name for Cannabis sativa (cannabis), a hemp plant that grows throughout temperate and tropical climates. The leaves and flowering tops of cannabis plants contain at least 489 distinct compounds distributed among 18 different chemical classes, and harbor more than 70 different phytocannabinoids(2). The principal cannabinoids are delta-9-tetrahydrocannabinol (i.e. Δ9-THC, THC), cannabinol (CBN), and cannabidiol (CBD)(3),(4),(5). Despite growing in popularity in the last decade, prescription of medical cannabinoids can be challenging. Doctors may be hesitant due to bias, both for and against medical cannabinoids, or because of the limited research and lack of clinical data. The therapeutic effect of cannabinoids can be lower than expected, and the approved use of marijuana is currently limited to only a handful of indications.

What Medical Conditions Are Eligible for Treatment with Medical Cannabinoids?
A Prescribing Guideline Committee (PGC) was assembled to direct the Evidence Review Group (ERG) to develop clinical practice guidelines for a simplified approach to prescribing medical cannabinoids in primary care (6). Most of the authors of the publication highlight a small number of clinical studies that prove the effectiveness of cannabinoids. The ERG performed a detailed systematic review of four clinical areas informed by the best available evidence around cannabinoids and concluded that there are currently three conditions that have an adequate volume of evidence to inform prescribing recommendations: pain, nausea and vomiting and spasticity.

The pharmacological effects of cannabinoids are presented below (7):

Body System/Effect Detail of Effects
Body System/Effect
Psychological Euphoria ("high"), dysphoria, anxiety, depersonalization, precipitation or aggravation of psychosis
Perception Heightened sensory perception, distortion of space and time sense, hallucinations, misperceptions
Sedative Generalised CNS depression, drowsiness, somnolence; additive with other CNS depressants (opioids/alcohol)
Cognition, psychomotor performance Fragmentation of thoughts, mental clouding, memory impairment, global impairment of performance especially in complex and demanding tasks
Motor function Incoordination, ataxia, dysarthria, weakness
Analgesic Modest effect for chronic non-cancer pain
Anti-nausea/anti-emetic; hyper-emetic Observed with acute doses.Tolerance may occur with chronic use. Hyperemesis may be observed with larger doses or chronic use
Appetite Increased in normal, healthy subjects, but also in patients suffering from HIV/AIDS-associated anorexia/cachexia
Tolerance To most behavioural and somatic effects, including the "high" (with chronic use)
Dependence, withdrawal syndrome Dependence has been produced experimentally, and observed clinically, following prolonged intoxication. Abstinence leads to withdrawal symptoms which can include anger, anxiety, restlessness, irritability, depressed mood, disturbed sleep, strange dreams, decreased appetite, and weight loss.
Cardiovascular and Cerebrovascular System
Heart rate/rhythm Tachycardia with acute dosage; tolerance developing with chronic exposure, Premature ventricular contractions, atrial fibrillation, ventricular arrhythmia also seen with acute doses
Peripheral circulation Vasodilatation, conjunctival redness, supine hypertension, postural hypotension
Cardiac output Increased cardiac output and myocardial oxygen demand
Gastrointestinal System
Liver Increased risk of hepatic steatosis/fibrosis, especially in patients with Hepatitis C. Increased Hepatitis C treatment adherence resulting in a potential sustained absence of detectable levels of Hepatitis C virus
Pancreas Acute risk of pancreatitis with chronic, heavy, daily use
Gastrointestinal System
Males With chronic administration: anti-androgenic, decreased sperm count and sperm motility, waltered sperm morphology in animals (and possibly in humans). Tolerance to these effects may develop. Possible inhibitory effects on sexual behaviour in men
Females Effects inconclusive in women (possibly due to tolerance) but changes in menstrual cycle, suppression of ovulation, and complex effects on prolactin secretion observed in female animals. Dose-dependent stimulatory or inhibitory effects on sexual behaviour in women

Indications for use of medical Cannabinoids are shown below (6):

Pain
a. Neuropathic Pain: The PGC believes that clinicians should only consider cannabinoids after patients have had three reasonable therapeutic trials with more established agents for neuropathic pain and that, if they are used, it should be as adjuncts to other analgesics.
b. Cancer and Palliative Pain: PGC did identify the potential for concurrent small benefits for pain as well as nausea, vomiting, and appetite stimulation. The PGC cautions that clinicians should only consider cannabinoids after patients have already had at least two therapeutic trials with established agents for cancer or palliative pain (April 2018 Simplified Prescribing Guidelines for Medical Cannabinoids)
Nausea and Vomiting
Chemotherapy-Induced Nausea and Vomiting (CINV) - medical cannabinoids should only be considered for cases of CINV that are resistant to current therapies for preventing vomiting and nausea. Contemporary recommended treatments for CINV often include: ondansetron, dexamethasone, and aprepitant, with metoclopramide prescribed as needed.
Spasticity
Spasticity in Multiple Sclerosis and Spinal Cord Injury. The PGC asserts that medical cannabinoids should only be considered in cases of MS or SCI that are resistant to current established therapies.

Clinical Trials with Cannabis

As of September 5, 2018, a search in the U.S. National Institute of Health Database reveals 700+ clinical trial studies for cannabis. A current list, which is actively maintained, is available on CannabisClinicalTrials.us. A search of clinicaltrials.gov shows 721 studies investigating cannabis in one way or another. Of the 721 studies listed, 108 were interventional, actively recruiting and in subjects aged 18 – 64 years. Of those 108 studies, 47 were in Phases I, II or III. There are a number of websites dedicated to clinical trials with cannabis, including; cannabisclinicaltrials.org, medicalcannabis.com, citiva.com, cannatrials.com.

Clinical trials with cannabis are underway in several indications, including; advanced cancer pain, chronic pain, neuropathic pain, multiple sclerosis (MS), autism, attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, dementia, post-traumatic stress disorder (PTSD) and bipolar disorders.

GW Pharmaceuticals’ Epidiolex (oral solution of pure plant-derived cannabidiol, or CBD) was the first cannabinoid prescription medicine to be approved in the US, gaining approval to treat two rare forms of treatment-resistant epilepsy (Dravet syndrome and Lennox-Gastaut syndrome (LGS)). In Europe, Sativex® (an oromucosal spray derived from two strains of cannabis leaf and flower), has received marketing authorization in 21 countries for the treatment of spasticity (muscle stiffness/spasm) due to multiple sclerosis. In a study of Sativex, run by EastHORN Clinical Services on behalf of Almirall, the data were used successfully to qualify the product for reimbursement by the German healthcare system., (ref; GW Pharmaceuticals webpage, 10 September 2018).

Pharma Company Market for Cannabis products

As the population grows older due to improved healthcare, there is a greater incidence of chronic diseases. Biotechnology companies are looking to take advantage of the growth of the cannabis-derived pharmaceutical market. By obtaining further data on the therapeutic effects of cannabis, putting their products through rigorous testing for quality, safety and efficacy they intend to reach a broader market, including patients in those countries in which medical marijuana has not yet been legalized.

Andrew Kessner
Research Analyst
www.williamoneil.com

Cannabis Market Opportunity:

By the Numbers

$40B+
Projected size of the North American
cannabis market in 2025

$25B
Total market cap of the 10 largest
Canadian cannabis producers

$7.8B
Legal U.S. cannabis sales in 2017

33%
Portion of U.S. population living in states allowing recreational cannabis sales

25
Number of countries that have passed
medical marijuana laws since 2013
Source: William O’Neil +Co; Aug 20, 2018

North America Cannabis Market Opportunity ($bn)



Americans’ Support for Legalizing Recreational Marijuana (% in favor)



Bloomberg North America Cannabis Index

Source: William O’Neil + Co.

The cannabis biotech market has been growing rapidly in this decade and is largely classified as part of the specialty pharmaceutical market, the fastest growing segment of the overall pharmaceutical industry targeting multiple therapeutic indications. According to The Growth of Specialty Pharmacy, an April 2014 issue brief by the United Health Center for Health Reform & Modernization, spending on specialty drugs in 2012 in the U.S. was about $87 billion and is estimated to grow to $3-400 billion by 2020.

The most successful country in large-scale commercial production of cannabis is Canada. Medical use of cannabis was legalised in 2001 but their national program for medical marihuana access wasn’t rolled out until 2013. The country introduced the system by which authorized patients purchase cannabis directly from government-licensed commercial growers named as Licensed Producers (LPs). Since that time licenses have been awarded to 112 operators, many of whom have raised money through the public markets These producers now serve a population of more than 300,000 patients to whom they sold an estimated CAD 300M of cannabis and cannabis-derived products in 2017.


Medical Cannabis Patients Registred with Health Canada (shown in 000s)

Source: Health Canada

It is a reasonable estimate that the revenues in the cannabis biotech/pharmaceutical sector could represent 10% of the overall specialty pharmaceutical market over the next five years, suggesting a market size of at least $20 billion, and exceeding $50 billion by 2029 with leading biotech companies such as InMed Pharmaceuticals, Inc., GW Pharmaceuticals plc, Zynerba Pharmaceuticals, Inc., AXIM® Biotechnologies, Inc. and OWC Pharmaceutical Research Corp.

2018 was a particularly successful year for Global Cannabinoid Biotech and other legal medical marijuana operations such as: Therapix Biosciences, Medical Marijuana Inc., Corbus Pharmaceutical Holdings, Inc., Cannabics Pharmaceuticals Inc., INSYS Therapeutics, Inc. and Canpoy Growth.

Regulatory Environment for Cannabis Medical Use and Clinical Research

The regulatory environment to conduct clinical trials with controlled substances is complex and sponsors initiating trials with these substances should be aware of various clinical and logistical challenges ranging from protocol design and site selection to management of the drug supply chain and clinical supplies across difference countries. Ensuring the adequate availability of controlled substances for medical and scientific purposes is one of the objectives of the international drug control treaties that have yet to be universally achieved (WHO Report 2011).

The relevant European legislation is reflected in the Single Convention on Narcotic Drugs of 1961, the Psychotropic Convention of 1971 and the Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances of 1988, which contain provisions relating to controlled substance precursors. Several European Union (EU) member states designated responsible agencies and enacted laws or regulations to implement the requirements of these conventions. However, this has resulted in different classifications of controlled substances among EU Member States, and sponsors must be aware of the prevailing legislation in each country. The International Narcotics Control Board (INCB) classified cannabis and its derivatives as schedule I (substances with addictive properties, presenting a serious risk of abuse) and therefore the degree of controlis extremely strict. As classification of controlled substances varies among different EU member states, sponsors must be aware of the prevailing legislation in each country where a clinical trial may be conducted. As clinical trials mainly involve new and innovative substances which have not yet been formally classified, an IMP should be considered a controlled substance when the IMP has the same potential for abuse as the already classified controlled substance.

It is important for sponsors to recognize the abuse potential of a study drug as a risk early in the development process, as abuse potential comprises a dimension of the safety profile and needs to be assessed in pre-clinical testing and Phase 1 first-in-human studies.

Furthermore, the classification as a controlled substance means that researchers (both preclinical and clinical) require a special licence to hold the drug. In the UK only four (out of many hundred) hospitals have such a licence. Interestingly, all can hold heroin, a much more harmful and sought-after drug because heroin is in Schedule 2. Moreover, what little research has taken place—such as the development of the cannabis oral spray Sativex—has been delayed by the question of what licence it should be given (in the UK, it is Schedule 4 despite being identical in pharmaceutical content to plant cannabis, which is still held in Schedule 1] (Nutt, PLoS Biol. 2015 Jan; 13(1): e1002047).

Additionally, there is often considerable extra bureaucracy with the requirement for and associated cost of import licences, since most suppliers are overseas. In some countries, an import license is given to a limited number of active substances and needs to be renewed every 8 weeks, even for the placebo. Several member states will not initiate the import/export process for controlled substances until the proper regulatory and ethical approvals are in place. Furthermore, in the EU, licenses are also required for individuals who wish to produce, dispense, import or export controlled substances, but requirements vary from country to country.

Exporting nations must obtain advance permission for each transnational shipment, typically in the form of an import permit or authorization from the competent government authority, from each country to which they wish to ship the drug. This import authorization must be received by the exporting nation’s authorities prior to obtaining export authorization or shipping the drug.

As WHO states in their report, all countries have a dual obligation with regard to these medicines based on legal, political, public health and moral grounds. The dual obligation is to ensure that these substances are available for medical purposes and to protect populations against abuse and dependence. Countries should aim at a policy that ultimately achieves both objectives; in other words, a “balanced policy”. There is still a long way to go.

Challenges in clinical study conduct - cultural, legal & logistic

Although the medical effects of cannabis have already been proven in some instances, the fear of addiction, illegal trading, the crime associated with it and its social impact are limiting the potential for patients to benefit from this therapy. This state of affairs has been brought about by cultural and historical influences as well as the difficulties involved in the regulation and control of the cannabis market. There is also a correlation between lower levels of democracy in a particular country and more restrictive laws for these substances. In some instancesthe country’s political/business establishment benefits enormously from the existence of the black market.

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For example in Russia the approach to marijuana is still quite proscriptive and clinical investigations of cannabis are not allowed. Promotion of the therapeutic benefits of marijuana is not widespread. While Cannabis is used in many other countries for medical purposes, top Russian medical officials strongly reject even the slightest possibility of legalization. However, cultivation, sale and possession of cannabis for personal recreational purposes (up to 6 grams) is largely decriminalized in Russia and will only be punished with a fine, which may be dependent on the discretion of the policeman who catches you.

As a result, patients who suffer from cancer and other illnesses that may provide a legal ground for prescribing marijuana abroad are deprived of such an opportunity in Russia. Farmers who grow hemp for industrial purposes are a more organized lobby for legalization. Their hemp is too weak to smoke (less than 0.1% THC), but is perfectly suited to produce anything from smoothie drinks to pesto sauces to clothes. Nonetheless, possible legalization in Russia is an unlikely scenario because decriminalization has too many powerful opponents.

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Georgia, the country with the fastest start up process for clinical trials in the world, has a neighbour notorious for the production of various drugs. Earlier in 2018, the Constitutional Court of Georgia (the highest court in the country) decided to decriminalize the use of cannabis and it has been a hot topic ever since. Other governmental institutions like the Parliament opposed this move and are creating barriers to prevent the implementation of the decision of the Court. As a response, the Ministry of Internal Affairs put forward potential legislation to the Parliament regarding the cultivation of cannabis for medical use. The new regulation could be implemented after the parliament’s approval which is expected by summer 2019. It is however doubtful whether this proposed legislation will achieve the necessary majority of the members of parliament; there is huge opposition from the conservative part of the political parties as well as from the Georgian Orthodox Church which remains a very influential institution. Therefore, the current climate for the conduct of cannabis clinical studies is not very encouraging and any approval by the MoH to investigators participating in clinical trials may attract some unhealthy and unnecessary attention from those keen to maintain aconservative approach towards this issue.

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By contrast, in Spain there are around 20.000 hectares dedicated to legal marijuana cultivation.. In Spain there are cannabis social clubs (more than 1400). In these clubs cannabis can be obtained legally from other members. These clubs only allow entry to adults of legal age, upon referral of another member of the club.

The consumption of Cannabis is not punished in Spain, and therefore buying marijuana is not illegal. It is not punished via a criminal trial either, but with an administrative fine between 601 € and 30,000 € for consumption and/or possession of cannabis on the street, without the possibility of exchanging fines for detoxification treatments. Cultivating marijuana outdoors can incur a fine between 601€ and 300,000 €. Cultivating marijuana indoors for self-use or shared consumption (low quantity) is allowed. This law was implemented in 2015.
So far, the only authorized medicine in Spain based on cannabis is Sativex. Since 2010 this treatment can be purchased in the pharmacies with a medical prescription but is not reimbursed by the national health system.

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Other European Union countries have well-established regulations for controlled substance use in clinical trials although logistic management is the most challenging aspect. For example, Romania has a dedicated officer at the Ministry of Health for controlled substance import and its use for clinical trials and this person may influence the overall duration of the clinical trial application period. Special transportation conditions should be taken into consideration as the products should have unfalsifiable labelling indicating instructions for use (precautions and warnings that are required for user safety and allow an audit trail).

Sites should be authorized to perform clinical trials with controlled substances and investigators should present current and clean criminal record to the MoH application. Without careful management, all this may prolong the start-up process. Special consideration should be taken regarding drug security (only authorized personnel to have controlled access and it will vary from site to site if it comes to drug dispensing procedures). There is an authorized depot in Romania – UNIFARM which has all required logistics and approvals for import in place and can distribute this kind of medication. There is no restriction with regard to the depot used, but it is better to use this one as it will make the entire process shorter and much easier.
Patient compliance might be a big challenge as the patients enrolled in one of the trials with inhaled IMP used more puffs than indicated. While the study had double blinds, the smell of cannabis easily broke the blind.

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Hungary is quite well regulated if it comes to the cannabis substance. It is permitted to grow cannabis with a THC content of less than 0,2% and there are some companies which have plantations. They produce CBD but they cannot market it, as the Hungarian Regulatory Authority does not approve dietary supplements containing CBD.

Officially registered Sativex can be prescribed by physicians and the patient needs to get an import license from the Regulatory Authority. The process is similar to the clinical trial approval process. Additionally, the patient needs to find a pharmacy willing to import the drug and supply the patient. Only a few patients are using Sativex as it is very expensive, and it is easier to get illegal marijuana. There is a society which supports the use of medical cannabis and they provide information to physicians and patients. www.orvosikannabisz.com

From the study point of view the biggest challenge is to get a contract with an authorized importer prior to submission to the RA

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Serbia follows quite strict internal regulations concerning clinical trials related to psychoactive substances and the main issue to be dealt with is the import licence. A good calculation of the quantity of the active substance for the entire duration of the study is needed and might be a challenge in some study designs. Import licences are valid for three months only and take a long time to obtain and this has to be taken into consideration for the entire management of the drug logistics. A potential solution is to import the entire quantity of the medicinal product planned for the study and store it in a warehouse, then deliver as needed or deliver the full quantities to sites. However, this creates a new problem as unused medicinal products must be returned to the sender. This requires obtaining an export licence from the Serbian MoH and the recipient of the unused medication must have a valid import licence, which takes time and relates to the coordination challenge. The Serbian MoH does not allow the destruction of narcotic drugs through an importer of the clinic participating in the clinical trial. The pharmaceutical form of the medicinal product also needs to be checked, as the packaging of used drugs is also considered pharmaceutical waste with a regulated destruction process.

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A similar situation exists in Bulgaria, where the import of controlled substances are regulated very rigorously.

The Legislation states:
» Pursuant to Article 2, paragraph 2, point 3 of Ordinance No. 7 / 26.01.2001 on the conditions and procedure for issuing licenses for import and export of narcotic substances, a license for import and / or export of narcotic substances and their preparations is not required in the case of a clinical trial. However, according to Article 2, paragraph 3 of the same Regulation, in this case, the appointment of a person responsible for import / export as well as for the accountability is required.

» In this context, it shall be provided:
A contract designating a person responsible for the import and / or export and accountability of imported drug-containing investigational medicinal products.

“Person responsible for the import and / or export and accountability of imported drug-containing investigational medicinal products” could be:
Import, export, transportation, processing, storage, incorporation and use in the production process of mixtures under Art. 5a may be carried out by a natural or legal person registered as a trader under the Bulgarian legislation or under the legislation of another member state of the European Union.
(2) The persons may import and export mixtures within the meaning of this Act and / or the incorporation and use in the production process of mixtures after filing a notification to the Ministry of Economy. The order for submission and the form of the notification shall be determined by the Minister of Economy in the Ordinance.

The quantity of imported product the process requires periodic reporting. Each year, by 30 April, producers and wholesalers licensed, as well as persons importing and exporting narcotic substances for the purposes of the authorization of a medicinal product or for a clinical trial, declare to the Ministry of Health the quantities of narcotic substances on the official lists and their preparations necessary for their activity in the following calendar year, according to an order determined by the respective ordinance. Conditions for storage of the narcotic substances, imported drugs for the purposes of clinical testing are also regulated and a product shall be kept by the importer in a metal frame, fixed and connected to the signal- security system. In this context it is necessary to have a separate contract (or an annex to the contract between the sponsor and the healthcare facility) according to which the relevant hospital pharmacy is committed to providing the necessary conditions for the storage and release of narcotic substances for the purposes of the clinical trial.
Storage conditions and the availability of dispensing procedures have an impact on the site selection. The local legislation stipulates that the drugs for clinical trials are stored at hospital pharmacies. However, the pharmacies should possess an additional license for storage of narcotics and special access and storage facilities (lockable metal cabinets, security systems etc.). In addition, regardless of the purpose of usage of narcotic/controlled substances, pharmacies must provide an accountability report to regional health center on monthly basis. It is very important during the site selection to ensure that the hospital pharmacy complies with these requirements.

Destruction of the unused drug is possible only on the territory of Bulgaria, i.e. the export of unused/expired controlled drugs is not possible. The destruction protocol is issued, and a copy provided to the Bulgarian Drug Agency (BDA) and the presence of the agency inspector is needed which might be an additional challenge to coordinate the availability of all representatives from the authorities and the capability of the drug destruction facility to execute the destruction. This process might take even years.

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In Poland Sativex was approved on the 1st November 2017, although it is not widely used due to the cost. For this reason, Polish patients often look for illegal marijuana on the internet or abroad, e.g. in the Czech Republic. In a recent case, compassionate use of cannabis for a child with protracted epilepsy resulted in a disciplinary action taken by the hospital against the prescribing physician.

Individual countries may have their own idiosyncrasies and a full spectrum of legality and illegality exists across the globe, however, there can be no doubting the significant and meaningful progress that has taken place in the last decade. This progress is fully expected to continue at a near exponential pace. The therapeutic benefits and availability of product will be down to the foresight of the individual regulatory agencies and the commercial nous of the biotech industry. It’s up to all of us to get it right.
To discuss further please contact Iain Gordon, Chief Business Officer, EastHORN Clinical Services.
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