Ensuring access to safe, effective, and affordable cannabis‐based medicines

1 INTRODUCTION

Over the past decade, patients, families, and medical cannabis advocates have campaigned in many countries to allow patients to use cannabis preparations to treat the symptoms of serious illnesses that have not responded to conventional treatment.1

Ideally, any medical use of a cannabinoid would involve practitioners prescribing an approved medicine produced to standards of Good Manufacturing Practice (GMP), the safety and effectiveness of which had been assessed in clinical trials. The prescriber would be fully acquainted with the patient’s medical history and well‐informed about the safety and efficacy of cannabinoid medicines and know the most appropriate formulations and dosages to use and how they should be used in combination with other medicines being used to treat the patient’s condition.2, 3 Current medical use of cannabinoids falls short of these expectations and regulations.

There is reasonable evidence that some cannabinoids are superior to placebo in reducing symptoms of some medical conditions.4, 5 Dronabinol, a synthetic form of tetrahydrocannabinol (THC), and nabilone, a synthetic drug with similar effects, for example, reduce nausea and vomiting in cancer patients.6, 7 Nabiximols, a standardised cannabis plant extract with equal doses of THC and cannabidiol (CBD), reduces muscle spasticity more than placebo in patients with multiple sclerosis.8 CBD has been shown in several clinical trials to reduce the frequency of seizures in children with intractable epilepsy of genetic origin.9

The challenge for regulators and researchers is that many patients want to use unapproved and non‐standardised cannabis products to treat conditions where there is either much weaker evidence, and in some cases, no evidence of safety and efficacy.1 Different regulatory responses to these patient demands (see Table 1) have often led to medical uses of cannabis‐based medicines that fall well short of the desiderata outlined above.1 This is because there is a combination of weak or limited evidence of safety and effectiveness, regulatory and cost obstacles to accessing GMP cannabis medicines, and an absence of unbiased clinical guidance on how to use medical cannabinoids. Our observations suggest that industry enthusiasm for the recreational cannabis market appears to be superseding interest in development of pharmaceutical grade medical cannabis products in view of the complexities associated with GMP.

2 SPECIAL ACCESS SCHEMES

Some Governments allow patients to use pharmaceutical “special access provisions” (e.g, Australia)10 or “Cannabis‐derived products” (e.g, Brazil)11 to access cannabinoids. These provisions (see Table 1) have primarily been used to allow seriously ill patients to use unapproved drugs, by permitting them to access drugs undergoing clinical trial or not available in the country. Special access schemes for access to medical cannabis face a number of major challenges.

First, patients often experience difficulties finding doctors who will prescribe or recommend the use of unapproved cannabis‐based medicines. Medical colleges and societies are reluctant to support the use of medicines in the absence of evidence of safety and efficacy. This is heightened as increasing scientific information including liver injury, drug interactions, and risks with concomitant psychoactive drugs comes to regulators about products.12

Prescribers also have reasonable concerns about being legally liable for any harms suffered by their patients. These ethical and legal problems make many medical practitioners understandably reluctant to recommend cannabis‐based medicines to their patients.

In some countries, these issues have prompted the establishment of “medical cannabis clinics” that enable patients to access cannabis products outside their normal medical care. Those who work in these clinics are registered medical practitioners, but speciality credentialing is not always required. The clinics appear to cater to patients with chronic pain and chronic neurological and gastroenterological conditions who often require daily dosing over substantial periods of time. These patterns of medical cannabis use raise significant issues in pharmacology and toxicology, and this fragmentation of care of patients with often complex medical conditions is not in line with ideal clinical care. In the short term, cannabis‐based medicines reduce pain and other symptoms for some patients modestly more than placebo, and they have comparatively few adverse effects.13 The risks and benefits of their longer‐term use for these chronic indications, many of which will be lifelong, are unclear, however. The medical profession is understandably concerned about the long‐term use of unapproved drugs given experiences with the opioids and drugs used to treat sleep problems and anxiety, such as the benzodiazepines.

Patients often complain about the burdensome regulatory requirements they must meet in order to access cannabis, even though the time required to approve access is often similar to that for other unapproved drugs, in Australia less than 48 hours. The high cost of pharmaceutical quality cannabinoids may lead patients to use “artisanal” cannabis products that they either produce themselves or purchase illicitly produced cannabis. Many patients fail to appreciate that artisanal cannabis does not deliver standardised cannabinoid doses or provide the doses claimed by their producers.14 They may also be contaminated by pesticides, heavy metals, and fungi.15

It is also noted that recreational legalisation of cannabis has influenced the cost of illegal cannabis. In Canada, in the years leading up to and in the year following legalisation, the cost of illegal cannabis has progressively fallen according to crowdsourced data analysed by Statistics Canada.16 Furthermore, in view of this price differential, patients are turning to this illegal market to access cannabis for medical purposes, leading to concerns about quality of product as well as contamination with microbes, pesticides, and heavy metals.

3 MEDICAL CANNABIS PROGRAMMES

Across Europe (the Netherlands, Italy, Germany, Czech Republic, Denmark, Austria, and Switzerland), a variety of medical cannabis programmes have been set up. The Netherlands followed temporally closely by Germany have documented such developments.17, 18

In some states in the United States, citizen‐initiated referenda and, in Brazil and Canada, Supreme Court decisions have forced governments to allow patients to use unapproved herbal cannabis preparations to treat a variety of medical conditions in the absence of evidence of safety and efficacy. In some US states, commercial retailers are allowed to sell cannabis products to patients who have a “medical recommendation,” a letter from a doctor indicating that the patients have a medical condition that qualifies them to use cannabis.

There are major concerns about the ethics and safety of medical practitioners being paid to recommend medical cannabis use to patients whom they may not know or have examined. For profit retail, cannabis dispensaries are staffed by sellers with no medical training who may inappropriately recommend medical use of cannabis products. For example, a recent US survey found that dispensary staff recommended cannabis use to treat nausea and vomiting in pregnancy.19This is of concern because the cannabinoids are very lipophilic, cross the placenta, and can affect the lipophilic embryonic brain.20

The pharmacodynamic and pharmacokinetic interactions among some cannabis molecules are well‐known and may be beneficial (e.g, nabiximols). However, there is a part of the cannabis business, some medical and regulatory authorities, consumers, the media, and sectors of the scientific community that portray the hypothesis of the “entourage effect” as a fact. The idea that the chemical compounds of cannabis act synergistically to modulate the overall effects of THC and to influence the pharmacological properties of the plant is yet to be proven and has no definitive scientific evidence.21

4 MEDICAL CANNABIS AFTER THE LEGALISATION OF RECREATIONAL CANNABIS USE

The legalisation of recreational cannabis use in Canada and the United States was arguably facilitated by liberal medical cannabis programmes.22 The legalisation of adult cannabis use allows any adult to use cannabis for any reason, including to treat the symptoms of medical illnesses. The increased adult access for nonmedical use has not unfortunately improved patients’ access to quality medical cannabis products. There has, for example, been a substantial drop in the number of patients enrolled in medical programmes in many US states after legalisation.23–25 Patients also report that after legalisation, it is harder to obtain the herbal cannabis products that they previously used because the retail cannabis market primarily caters to the daily recreational users who account for most of their sales.24, 25

Nor has cannabis legalisation led to more funding for research into the effectiveness of medical cannabinoids. Indeed, legalisation has arguably created a major disincentive for pharmaceutical companies to fund the expensive clinical trials required for drug registration when herbal cannabis is legally available to any adult. Legalisation has not increased researchers’ access to standardised pharmaceutical cannabis products for use in clinical trials. The continuation of federal cannabis prohibition in the United States still hinders access to cannabinoids in that country. In Canada, clinical investigators still have difficulty accessing cannabis for clinical trials. This is partly because licensed cannabis producers are unfamiliar with the requirements of GMP and partly because there are few incentives for producers to produce GMP quality cannabis products for use in clinical trials or to fund trials. It is more profitable for cannabis producers to develop products for the much larger recreational cannabis market.

5 CONCLUSION

There are no short cuts in making quality‐controlled cannabis‐based medicines available to patients in ways that ensure that they are used safely and effectively. In the absence of industry interest in funding clinical trials, governments need to fund large, well‐designed clinical and clinical pharmacological studies that will enable cannabinoids to play a more evidence‐based role in modern clinical practice. In the meantime, the clinical pharmacology field needs to share high‐quality data on the safety, efficacy, and pharmacology of medical cannabinoids as it becomes available. This should be presented in ways that permit the information to be regularly updated and provide clinically useful guidance on how these medicines should be used.2, 3, 10

COMPETING INTERESTS

J.A.C. is coinventor of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023,” Def. US number Reg. 62193296; July 29, 2015; INPI on August 19, 2015 (BR1120150164927). The University of Sao Paulo has licensed the patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1). The University of Sao Paulo has an agreement with PratiDonaduzzi Pharm to “develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders.” J.A.C. is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE – National Health and Medical Research Council, NHMRC). J.A.C. has received travel support from and was medical advisor of BSPG. JAC received a grant from the University Global Partnership Network (UGPN)—Global priorities in cannabinoid research excellence program. J.A.C. is a recipient of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) productivity fellowships. J.M. has a family member who is a shareholder in a cannabis start up company in Australia. This has been fully declared to the funding agency and is subject to a governance order from The University of Newcastle regarding management of this potential conflict.

CONTRIBUTORS

All authors contributed to the initial discussion. W.H. wrote the first draft; all contributed papers and guidance to initial submission. After review and request for more information, J.M. updated the document; all authors made final recommendations and edits. All approved the final version of the paper.